The FG Syndromes (Online Mendelian Inheritance in Man 305450): Perspective in 2008

Advances in Pediatrics 55 (2008) 123–170

ADVANCES IN PEDIATRICS The FG Syndromes (Online Mendelian Inheritance in Man 305450): Perspective in 2008 John M. Opitz, MDa,b,c,d,*, James F. Smith, MDe,f, Lucia Santoro, MDg a

Pediatrics (Medical Genetics), University of Utah, Salt Lake City, UT 84132, USA Human Genetics, University of Utah, Salt Lake City, UT 84132, USA c Pathology, University of Utah, Salt Lake City, UT 84132, USA d Obstetrics and Gynecology, University of Utah, UT 84132, USA e Surgery (Division of Pediatric Urology), University of Utah Center for Health Sciences, Salt Lake City, UT 84132, USA f Urology, University of California, San Francisco, CA, USA g Pediatrics, Universita` Politecnica delle Marche, Ancona, Italy b

S

yndrome delineation refers to the study and analysis of phenotypes. Syndrome definition refers to the determination of causes (genotypes). Over the last 100 years these processes have become enormously refined and allow some generalizations. None of the manifestations in a given syndrome is causally specific (ie, pathognomonic) and none is obligatory (ie, must be present for a diagnosis). Multiple manifestations in a segregating syndrome represent pleiotropy, which must have its root in a single cause affecting development and function of several embryonic primordia, potentially reproducible in mouse experiments. Structural and functional complexity of a given syndrome does not rule out heterogeneity. Frequently, syndromes that are strikingly different phenotypically turn out to be based on mutations of the same gene. Spectacular examples of this are the L1CAM, ATRX, FLNA (Box 1) and PTEN entities. In the last century, the identification of syndromes in institutions for the mentally retarded led to the conclusion that such syndromes could not exist in the absence of mental retardation. One of the axioms of syndrome delineation from the early 20th century is increasingly being ignored. According to this axiom, it is best to establish the phenotypic spectrum on the basis of the secondarily ascertained relatives after

*Corresponding author. 2C412SOM, University of Utah, 50N Mario Capecchi Drive, Salt Lake City, UT 84132, USA. E-mail address: [email protected] (J.M. Opitz). 0065-3101/08/$ – see front matter doi:10.1016/j.yapd.2008.07.014

ª 2008 Elsevier Inc. All rights reserved.

124

OPITZ, SMITH, & SANTORO

Box 1: The filaminopathies at Xq28, FLNA (Online Mendelian Inheritance in Man 300017) 

The periventricular nodular heterotopias, X-linked dominant, male lethal, with patent ductus arteriosus and coagulopathy (loss of FLNA function mutations).



Otopalatodigital syndrome type Ia



Otopalatodigital syndrome type IIa



Frontometaphyseal dysplasiaa



Melnick-Needles syndromea



Ehlers-Danlos variant of periventricular nodular heterotopia



FGS2 [1,2]



Chronic idiopathic intestinal pseudo-obstruction



Periventricular nodular heterotopias with frontometaphyseal dysplasia

a

Localized mutations preserving the reading frame of FLNA. From Robertson SP, Jenkins ZA, Morgan T, et al. Frontometaphyseal dysplasia: mutations in FLNA and phenotypic diversity. Am J Med Genet A 2006;140(16):1726–36.

exclusion of propositi, who would tend to bias our understanding of the condition toward the severe end of the spectrum. All of these considerations apply to the FG syndrome (FGS). The FGS [3] was ascertained in the 1960s in a propositus in an institution for the mentally retarded in Madison, Wisconsin, in collaborative studies with the University of Wisconsin. The name of the condition derives from the initials of the surnames of two sisters who had had a total of five affected sons. Subsequently, the third sister in that sibship also had two affected sons. Our studies of the prototypic family were not published until 1974. However, in that first kindred, X-linked inheritance of the FGS was established unequivocally. The maternal grandfather of these three sisters was 47 years old when their mother was born, strongly suggesting a paternal age effect in the first occurrence of the FGS mutation in that family, like that leading to the carrier state for hemophilia in Queen Victoria, whose father was 52 years old when she was conceived. We studied eight affected males in the FG family [4,5]. With respect to that pedigree of 1982 (Fig. 1), note that the normal boy V-6 was adopted, and that V-8 had sufficient manifestations of the FGS so that presently we would have designated him as mildly affected. Also, IV-14, the younger sister of Mrs. F. (IV-12) and Mrs. G. (IV-13) had a third pregnancy and delivered an apparently normal girl in 1974. Thus, all boys born to these three carrier sisters were affected. The phenotype of the original FG propositus can be summarized as follow. Relatively small size at birth with catch-up growth to about the 40th centile, growth of head circumference (occipitofrontal circumference [OFC]) from ‘‘normal’’ to 98th centile, estimated IQ of 50, congenital hypotonia, abnormal electroencephalogram without seizures, a striking personality and speech

FG SYNDROMES

125

Fig. 1. Most recent drawing of the FG family pedigree based on prior publications and information from Mr. F, husband/widower of IV-12. Older clinical data led us to suspect that V-8 may be mildly affected [3–8]. Recently, V-10 was shown to carry the FGS1 MED12 mutation R961W. III-5, married, no children. V-12, stillborn. (Bull’s eye) evident carriers. (Solid square) affected male. (Diagonal slash) deceased. (Horizontal line above symbol) personally examined.

pattern, dolichocephalic skull, frontal prominence and upsweep of the anterior hairline, hypertelorism, short and abnormally modeled auricles, hypotonic mouth-breathing facial changes with prominent lower lip, imperforate anus with severe constipation in infancy, partial cutaneous syndactyly of fingers 3 and 4 and toes 2 and 3 bilaterally, and several minor skeletal anomalies. He also had bilateral alternating esotropia with large-appearing corneae, abnormal sternum, short fingers, deep sacral dimple, with ‘‘spatulate,’’ broad, and flat thumbs. Like many FG boys, he had a habit of ‘‘bolting’’ his food and choked to death (asphyxiated) on a piece of meat at 18 years. At autopsy, no visceral anomalies were found. Brain was larger than normal (1750 versus 1500 g) and showed pachygyria in several areas, irregularity in thickness of the cortical gray matter, focal areas of disorientation of neuronal layers with increased numbers of neurons, midline fusion of the mammillary bodies, heterotopias and neuroglial tissue in the seventh and eighth cranial nerves, focal areas of ependymal cell loss associated with increased neuroglial tissue, and heterotopias of neurons in the white matter of the centrum ovale. Most of these anomalies can be considered a developmental defect of neuronal migration. The corpus callosum was apparently normal in this case.

126

OPITZ, SMITH, & SANTORO

This boy’s condition epitomizes the severity so characteristic of many prototype reports of new syndromes. Subsequent evaluation of all sibs of a propositus or proposita in many families have taught us that these prototype ‘‘cases’’ were the tip of an iceberg leading to the identification of several hundred of less severely affected FGS children and some adults with a subtle but complex phenotype and the promise of holding important basic biological implications. Opitz and colleagues [6] documented the phenotype of three brothers who in their own way characterized the by far more common, milder, more typical form of the FGS seen commonly in the pediatric genetics clinic. Their pattern of psychomotor development was distinctly unusual, but cognition was normal. The following clinical reports are but a minute sample of the more than 700 propositi/families we have studied to date. CLINICAL REPORTS Patients 1 and 2 (Family 1) Proposita 1 was seen at age 7 years to address the diagnosis of FGS made by her family. This was the sixth child/pregnancy of this healthy, normal, nonconsanguineous couple (IV-8 in Fig. 2). During this pregnancy, maternal age was 39 years and paternal age was 40 years. Delivery occurred at 38 weeks of gestation and was vacuum-assisted because of fetal distress. The cord was around the neck and the infant had thrombocytopenia. Neonatal jaundice was treated with phototherapy. Laryngotracheomalacia improved gradually. For profound sensorineural hearing impairment, the girl had a cochlear implant. An MRI before the transplant showed apparently normal brain structure. Patent ductus arteriosus and atrial septal defect led to heart failure necessitating ductus ligation. Severe gastroesophageal reflux initially required nasogastric tube feedings and later a gastrostomy. Constipation was treated with MiraLax. Because of lower-limb spasticity, nightly leg pains, sacral dimple, short perineal body, and constipation, she had a tethered cord operation. Since her tethered cord surgery 2 years ago, she has been successfully toilet trained. Her prior chronic constipation is almost nonexistent. The child has had recurrent middle ear and sinus infections and was diagnosed as having an immune deficiency. She receives intravenous immunoglobulin every 4 weeks and this seems to have virtually eliminated her chronic sinus and ear infections. She also has reactive airway disease. The tone of the upper part of the body is reduced. Delay in motor development was mild, but speech development severely delayed. Nevertheless, she knows over 500 signs and impresses as a cognitively very perceptive child. Abnormalities of sensory integration affect primarily oral tactile aversion. She is a basically good-natured and humorous, and at times a somewhat mischievous attention-seeking child. Growth has been normal (25th centile), but her head circumference is above the 98th centile.

FG SYNDROMES

127

Fig. 2. Pedigree of patients 1 and 2, family 1. Proposita 1 is IV-8 (arrow pointing up). Proposita 2 is V-4 (arrow pointing down). (Bull’s eyes) Known or presumed carriers. (Small open triangles) Spontaneous miscarriage/fetal loss. (Solid symbols) Affected persons. IV-2 (crosshatched) mildly affected but has bipolar disorder. V-5 (square with double lines) was a male fetus with total dorsal rachischisis. IV-2 is mildly affected but has had bipolar disorder from a young age together with obsessive-compulsive disorder. III-9, IV-3, and IV-5 are highly gifted (G) individuals. IV-7 has Crohn disease (C). The carrier status of II-1 is uncertain because no diagnosis was ever made in her severely mentally retarded son, III-1 (square with dots). Obsessive-compulsive disorder in I-1, II-2, and IV-6. Tourettelike tics (T) with social adjustment disorder in III-6. IV-3 and V-2 have ADHD.

The patient is a most attractive youngster with indication of hypertelorism; large corneae; gray iris color; short tip of nose with short, thick philtrum and columella; prominent lower lip; broad thumbs and halluces; short fifth fingers; sacral dimple; short perineal body; spastic legs; and hypotonia/lymphedema sequence. She has a tendency to pull and to eat her hair and prefers highly structured, self-absorbed play with mechanical fascinations. Her older niece, proposita 2 (see V-4 in Fig. 2), was referred for a similar pattern of anomalies. She has a congenital hypotonia/lymphedema sequence, a defect of sensory integration, constipation treated with MiraLax, and developmental delay with independent walking at 19 months. She uses ankle-foot orthoses, experiences sleep disturbances, and has a basically sweet and mellow temperament, but tends toward tantrums. Growth in height and weight was in

OPITZ, SMITH, & SANTORO

128

the range of the 25th centile, with head circumference at the 50th centile. She has broad thumbs and halluces; fluid in her ears; a high, broad forehead; telecanthus or hypertelorism with epicanthic folds; a prominent lower lip; a short perineal body; and normal cardiac status on echocardiography. Her older sister (see V-2 in Fig. 2), born in 2000, is only mildly affected but has an obsessivecompulsive and oppositional defiant disorder, attention-deficit/hyperactivity disorder (ADHD), bipolar disease, ear infections, mild constipation with ‘‘potty problems,’’ height and weight between the 10th and 25th centiles, and head circumference at the 50th centile. The family history of these children (see Fig. 2) is highly instructive and by no means atypical for FGS kindreds for its presence of: 

 

Psychologic difficulties, such as obsessive-compulsive disorder (I-1, II-2, IV-6, V-2), Tourettelike tics (III-6), bipolar disorder in IV-2, IV-6, V-2, the latter at a young age; social adjustment difficulties (III-6); ADHD (IV-3 and V-2), difficulties with short-term memory and auditory processing problems (IV-7), ‘‘perfectionism’’ (V-4) (On the other hand, this family also includes a number of very gifted individuals, including IV-3, IV-5, and III-9.) Presumed autoimmune disorders: neonatal thrombocytic purpura in IV-8, and Crohn disease in IV-7 Constipation in V-2, V-4, and IV-8.

Other signs and symptoms of FGS in this family: repeated ear infections, prenatal deaths in V-1, V-3, and V-5, and gestational hypertension in IV-1. The occurrence of total dorsal central nervous system rachischisis or anencephaly in the male fetus of IV-3 and IV-4 may be coincidence. However, an FGS gene segregating in this family may have caused either or both rachischisis and anencephaly. The high preponderance of manifesting persons in this family is suggestive of a process of segregation distortion or transmission ratio distortion. The mother’s family is of Danish ancestry. The progenitor, ancestor I-1, who must have been a remarkable lady, was always counting. She is recorded as saying that she counted everything from how many times she stirred the cake batter to the steps she took to the post office. Thus, she must have had a form of obsessive-compulsive disorder. Her daughter II-2 was a concert pianist and continues, at age 88, to play the organ at church, but is an obsessive worrier. Patient 3 (Family 2) Patient 3, the propositus (Fig. 3A) was the fourth of his mother’s pregnancies. He has an older half sister, who is mentioned below, and an older brother. The birth of propositus was preceded by a spontaneous pregnancy, lost at 6 weeks. During the pregnancy with the propositus, the mother had hypertension with a blood pressure as high as 170/115 mm Hg, which progressed to severe preeclampsia. She also had hyperemesis gravidarum and was on bed rest as of 22 weeks’ gestation. Premature onset of labor was treated with nifedipine. Labor was induced between 36 and 37 weeks of gestation. The infant had

FG SYNDROMES

129

Fig. 3. (A) Patient 3 (family 2) at age 4 years, 2 months (Also illustrated at an earlier age in Smith JF, Wayment RO, Cartwright PC, et al. Genitourinary anomalies in pediatric FG syndrome. J Urol 2007;178:656–9.) with the charming, sweet-natured personality of a (presumed) non-FGS1 boy. Born with hypospadias, stridor, obstructive sleep apnea, reflux (Nissen, G-tube), Chiari I malformation (operated), atrial septal defect with persistent left superior vena cava. He has reactive airway disease and constipation. His height is in the 3rd centile, OFC between the 25th and 50th centiles. (B) Patient 3’s grade 1 laryngeal cleft remains unrepaired.

mild intrauterine growth retardation with a birth weight of 2890 g and length of 45 cm. Neonatally, it was noted that the boy had glandular hypospadias and megameatus without scrotal rhaphe´. This was repaired at 8 months, but since then the boy has required Furadantin prophylaxis for urinary tract infections. From birth, the patient had severe gastroesophageal reflux. At 8 months, a Nissen fundoplication was performed and a G-tube was inserted. He has been treated with Zantac, Reglan, and Prevacid, which has not, however, completely prevented aspiration. Otorhinolaryngological evaluations, because of severe stridor, showed a grade 1 laryngeal cleft (see Fig. 3B) with rather posteriorly placed epiglottis and tightness along the epiglottic folds and rather large cuneiform cartilages. However, the cleft did not extend into the cricoids. Subsequently, a supraglottoplasty was performed with removal of the cuneiform cartilages. The MRI study of the brain showed a Chiari I malformation with tonsillar ectopia, which progressed from 6.6 mm to 15 mm (operated). There also was dysgenesis of the corpus callosum, especially of the posterior portion, with hypomyelination of white matter. Severe constipation has been treated with MiraLax. For repeated attacks of otitis media, he had pressure equalization tubes inserted at 8 months. A murmur was evaluated cardiologically. Echocardiography showed a 3-mm secundum atrial septal defect with subaortic ridge stenosis and left superior vena cava entering the coronary sinus. The atrial septal defect closed spontaneously.

130

OPITZ, SMITH, & SANTORO

The propositus has also had blocked tear ducts. These have not been probed yet. He has retraction of the upper lids with mild ptosis on the left, and an epiblepharon. He appears not to have any Bell’s reflex and the eyes do not close at night, with subsequent drying of corneae. Ultrasonography of the abdomen showed polysplenia, without further evidence of heterotaxy. This boy has had rather pronounced reactive airway disease with wheezing, noisy respiration, aspiration, and several attacks of bronchiolitis due to respiratory syncytial virus. These were accompanied by central apnea and were treated with Flovent, Albuterol, Singulair, and an occasional dose of prednisone, to which he appears to be resistant. The patient’s growth was retarded. His initial weight was at the 10th centile and length at the 3rd centile, but head circumference stayed between the 25th and 50th centile. Severe speech delay notwithstanding, he is cognitively exceptionally bright and perceptive. Perhaps it is his inability to communicate that causes severe temper tantrums and head banging. He also has a rather severe oral tactile aversion and sometimes carries food inside his cheeks for hours so that his perceptive mother, a registered nurse, makes sure to wipe them at night before sleep. On our initial physical examination, the boy had a large round head, a Cshaped hair whorl at the vertex, a flat bridge of nose, hypertelorism, epicanthic folds, mild ptosis on the left, increased anteroposterior diameter of the chest, mild hypotonia/lymphedema sequence with broad thumbs and halluces, and down-curved second toenails. He also had a Y-shaped shallow sacral dimple, without capillary hemangioma, exactly at the same site as his mother’s sacral dimple. On pediatric follow-up examination, he was found to have hypertension. Ultrasonography showed normal retroperitoneal anatomic structures, and the pathogenesis of this disorder has not been elucidated. With respect to diagnosis, this is one of the several patients in whom it was initially difficult to differentiate between G/BBB syndrome and FGS. Because of his laryngeal cleft, rather unusual degree of reflux, and hypospadias, the G/BBB syndrome was suggested. However, in view of family history, the rest of his physical findings, and subsequent medical history, a diagnosis of FGS seems more likely. This child’s older half sister, now 6.5 years old, also has reflux, is a hypotonic mouth breather with broad thumbs and a prominent forehead, and appears to be a carrier of FGS. The older brother, now 5 years old, has had many attacks of otitis requiring pressure equalization tubes. He is constipated. He has an anal (sacral) dimple, which may indicate that he has a tethered cord; prominent eyes; broad thumbs; a recently increased frequency of urinary accidents; and slow speech development. An earlier reactive airway disease has now improved. The mother of these children is an exceptionally intelligent woman with a high broad forehead as her only indication of a potential carrier state. Subsequently, it has become evident that one of the unusual, but nevertheless not incompatible, anomalies in FGS is the laryngeal defect so far never more

FG SYNDROMES

131

pronounced than a grade 1 cleft. Thus, the presence of a small laryngeal cleft does not rule out FGS, particularly if the medical and family history and other physical findings are compatible with the diagnosis. Some surgeons repair such clefts. Patient 4 (Family 3) This patient, patient 4, was born in Illinois 32 years ago after a normal term gestation, spontaneous rupture of membranes, and onset of labor, but delivery by cesarean section at 40 weeks’ gestation, at a maternal age of 26. This was the mother’s second pregnancy. The first child, a girl, was apparently normal. Birth weight for patient 4 was 3473 g, Apgar scores were 8 and 10, and the infant was jaundiced for a few days. He was born with congenital hypotonia and subsequently was noted to be developmentally delayed. In infancy, he had rather pronounced stridor and tracheomalacia, subsequently developing a hoarse voice. Laryngoscopy at 5 years did not demonstrate any gross malformations. Imperforate anus and perineal fistula were repaired neonatally, with additional surgery at age 6. He was diagnosed with a ventricular septal defect with anomalies of the right ventricular muscle bundle requiring repair and resection at the age of 3 years. Subsequent cardiac catheterization at age 5 showed relatively normal morphologic findings. However, electrocardiography evidenced a complete right bundle branch block. He is also known to have mild infundibular pulmonic stenosis. Because the boy was born with strikingly broad thumbs, the late Hans Zellweger was inclined to make the diagnosis of the Rubinstein-Taybi syndrome. When the patient’s mother pointed out that she had had at least one and probably two uncles with the same condition, Dr. Zellweger concluded that this was an unknown X-linked syndrome. At 10 days, the boy’s head circumference was 37.5 cm; at 11 months it was 43.5 cm with large anterior fontanelle. Since then, the patient has had consistent megalencephaly. Examination of his eyes showed a retinal and optic coloboma on the right with virtual absence of central vision, and a squint. MRI demonstrated agenesis of corpus callosum. Intermittent impaction during infancy and childhood improved at 6 years after surgery for a right-angle curve in his rectum. Thereafter, he was treated in an encopresis clinic. He remains constipated to this day. On physical examination (Fig. 4), the patient has a high, broad forehead; low nasal bridge; hypertelorism; downward slant of palpebral fissures; abnormally small ears but with normal hearing; and a highly arched palate. He also has had body and facial tics diagnosed as Tourette syndrome. During childhood, he had behavior problems with tantrums, occasional aggression, and rather volatile emotions, the unknown seeming to frighten him unduly. To this day he worries excessively. A pediatric psychiatry evaluation at 10 years stated that he had ‘‘head jerking, shoulder and arm throwing, making guttural sounds and sucking noises, swearing, licking his hands, rubbing his stomach, putting fingers into his ears, and being relatively hyperactive.’’ At that time, the diagnosis was made

132

OPITZ, SMITH, & SANTORO

Fig. 4. Patient 4 (family 3) at age 32 with confirmed R961W mutation in MED12.

of Tourette tics, ADHD, mental retardation (with a presumed verbal IQ of 55, performance IQ of 51, full-scale IQ of 49), with ‘‘Rubinstein-Taybi’’ syndrome, to be treated with Haldol. Subsequently, it was noted that the patient had patellar subluxation. When the boy reached the age of 16, Dr. James Hansen at the University of Iowa finally made a diagnosis of FGS. It was stated that up until age 6 he still had impactions and required repeat rectal surgery at age 6. In his first three years, the boy was hospitalized 11 times for pulmonary infections. When we first examined the patient in 1998 at the age of 22, his height was 163.7 cm, weight 81 kg, and head circumference 63 cm (far above the 98th centile for age and sex). Inner canthal distance was 4.2 cm, with downward slant of palpebral fissures, bilateral alternating esotropia, and corneal diameter greater on the right than on the left with large coloboma of optic nerve and retina of right eye. He had small ears, micrognathia, a hypotonic mouthbreathing facial appearance, high broad forehead, striae from recent weight gain, a sternum-splitting scar, and a scar over the patellae from orthopaedic repairs. He had puffy hands and feet with 3þ lymphedema, very broad and long thumbs with extra flexion crease, and broad halluces. His dermatoglyphics were relatively unremarkable. Neurologically, he was hypotonic, with normal deep tendon reflexes. His receptive language was much better than his expressive language. Thus, we confirmed Dr. Hansen’s diagnosis of FGS and our pediatric psychiatry staff confirmed the diagnosis of Tourette syndrome. This patient’s mother has constipation and an anal dimple. Her oldest child, a daughter, has three boys. The middle son appears to be affected, requiring tethered cord surgery. The sister of the patient’s mother had an older daughter (who has since developed multiple sclerosis) and a younger son. The woman

FG SYNDROMES

133

with multiple sclerosis has two girls. The oldest, who was evaluated at the Children’s Hospital of Denver and by us, appears to be a strongly manifesting carrier of FGS. Her younger sister appears to be unaffected. The sister of patient 4 has rheumatoid arthritis. The patient is a part of a large family of Welsh immigrants to Iowa. At the moment, this kindred numbers at a minimum 143 relatives in the mother’s family. MED12 mutation testing confirms the presence of FGS1, however, with normal results in the nephew with tethered cord. The MED12 mutation is also present in the patient’s mother and maternal grandmother. This is one of the more conspicuously affected patients with FGS, with somewhat uneven performance, gifted in several respects, and able to manage remarkably well on his own, living in close proximity to his mother and sister. Patient 5 (Family 4) Patient 5, an 8-year-old boy, was born to a severely dysfunctional mother who has had three known children, each with a different partner. The oldest child is the propositus. The younger half sister was evaluated by Dr. Gerald F. Cox of Harvard University. This woman’s sister is said to have ‘‘two affected boys.’’ The boy’s parents had drug- and alcohol-related problems, ADHD, and mental health and cognitive difficulties. The father was diagnosed as schizophrenic. The mother, whom we have not examined, has pronounced speech and language delays. Early history has been difficult to document (after adoption). At birth, the infant had congenital hypotonia with lax joints; genua valga/recurvata, developmental (especially speech) delay; severe defects of sensory integration, necessitating tagless shirts; pronounced oral tactile aversion (eg, aversion to toothbrushes); and a tendency to bolt his food. The boy has twice required the Heimlich maneuver (once for aspiration of a marshmallow and another time for a piece of ham). He has had multiple middle ear infections, requiring pressure equalization tubes with subsequent adenoidectomy and tonsillectomy. Reactive airway disease/asthma, worse in fall and spring, has been treated with Flovent, Albuterol, and Singulair. The boy has obstructive sleep apnea; constipation, which improved when treated with MiraLax; and a ‘‘lazy eye,’’ for which he was fitted with a series of glasses, finally requiring surgery with subsequent conjugate gaze and apparent 20/20 vision (Fig. 5). This patient is extraordinarily charming and sweet-natured. However, he has ADHD and has obsessive-compulsive behaviors. He is also moody, impulsive, anxious, and prone to tantrums. He flaps his hands with sensory overload, but is able to refocus when he has something to chew on. His cognitive development was very uneven, performing at age 8 on the ‘‘average’’ at a 4- to 5-year-old level, most delayed in expressive speech, but learning sign language. He is clearly gifted in other respects, especially in regards to numbers, and has a number of mechanical fascinations. He has an individualized educational program in place in his local school system and functions well in

134

OPITZ, SMITH, & SANTORO

Fig. 5. Patient 5 (family 4) at age 6 years, 4 months, with (A) and without (B) glasses to demonstrate squint (now operated). Note also abnormal scalp hair pattern.

a special education setting, but experienced disastrous deterioration in behavior following attempts at ‘‘mainstreaming.’’ In his special educational school, he finds himself in such an advantageous position that he has begun to care for a Down syndrome boy in his class, who frequently comes home with him after school. His sleep disorder was treated successfully with melatonin. Neonatally, the patient had a bilateral inguinal hernia operation. He also has the ‘‘banana’’ sign (as the FG parents call it) referring to a torsion of the penis when erect to right or left without chordee. Neurologically, the patient has hypotonia, learning disabilities, sleep difficulties with restless legs, obstructive sleep apnea, leg pain at night (which may make him scream), and normal cerebral MRI, but a fatty filum on cine-MRI of his lower spinal cord. This finding, together with progressive bladder unreliability, spasticity of lower limbs, and constipation caused him recently to be operated on for tethered spinal cord in spite of apparently normal urodynamic study results. Since his tethered cord operation, he has done exceptionally well. On physical examination (see Fig. 5), height continues between the 5th and 10th centile (weight slightly higher) and head circumference between the 75th and 90th centile. His scalp hair whorl pattern is ‘‘a barber’s worst nightmare,’’ such that he is frequently just ‘‘butched,’’ demonstrating his bilateral cowlicks and abnormal hair whorls. He is a relatively hirsute lad with prominent forehead and anterior sagittal suture, telecanthus, squint (preoperatively), short thick nasal septum and columella, prominent lower lip, downward slant of palpebral fissures, inguinal herniorrhaphy scars, genua valga/recurvata, flat feet, and prominent hypotonia/lymphedema sequence. The latter appears to have

FG SYNDROMES

135

greatly aided the spread of his warts in spite of several attempts at eradication. The warts recur rapidly and become 1 to 2 cm in diameter with a flat, soft, verrucous surface. His wonderful adoptive mother’s comments mirror those of many mothers of FGS children: In so many ways Calvin [pseudonym] is wise beyond his years, but as time passes, I find it just a little hard to watch other kids his age. When he asks. . .his 4-year-old brother to tie his shoes or help him with a puzzle, I get a bit sad. I wonder what life has in store for him; there is so much he may not get to experience. Then again, what are we missing by not being like him? Calvin is a wonderful, amazing tornado and the life he has spun through will never be the same.

In his home county and several adjacent ones, his ‘‘Calvinism’’ has initiated a new school of thought: Sometimes you just got to let a cat go. It’s a good to be alive if you are not dead. You better run for your death. It was an ass-ka-dent. Why can we not have some meats? Let us to move, shake our bodies.

Results of all laboratory tests, including chromosome analysis, were normal. This boy’s 23-month-old half sister was evaluated in 2005 by Dr. Gerald Cox in Boston for mild developmental delay (walking at 16 months); temper tantrums, during which she bites herself; short attention span; talkativeness; and oral tactile aversion requiring oromotor therapy. Her biological mother has hypertelorism, cognitive deficits with inability to read or write, shortness of stature with a ‘‘big’’ head, a thin body habitus, and maternal family history of mental retardation. By history, the child has unilateral hearing loss, constipation treated with MiraLax, some dental decay and lack of three teeth, and a heart murmur. On examination at the FG clinic, height and weight were respectively at the 25th and 40th centile, with OFC at the 60th centile. She had a prominent forehead, hypertelorism, relatively low-set small ears with overfolded helices, short upper lip, thin vermilion of the upper lip, prominent vermilion of the lower lip, inverted nipples, decreased muscle tone, large toenails, and U-shaped posterior border of the hard palate with a nasal voice. Results of all tests (chromosome and subtelomeric regions, fragile X, 22q11.2 deletion, cardiological and otorhinolaryngological evaluations) were normal. Results of X chromosome inactivation studies are pending. Patients 6, 7, and 8 (Family 5) Patients 6, 7, and 8, who are full brothers (Fig. 6), were ascertained almost 12 years ago and reported by their gifted and highly insightful mother [6]. Given that mildly affected brothers had been noted previously in sibships of FGS boys with mental retardation, it should not have been surprising to finally break through the stereotypic barrier of mental retardation as an obligatory anomaly

136

OPITZ, SMITH, & SANTORO

Fig. 6. Patients 6, 7, and 8 (family 5) at ages 12, 10, and 7 years. (From Opitz JM, Rauch AM, Poss A, et al. The FG syndrome: Perspective from 2001. Ital J Pediatr 2001;27:715–29, with permission.)

in FGS. If these three brothers had been mentally retarded, no one would have questioned the diagnosis of FGS. However, in view of normal intelligence, albeit with unusual developmental pattern, it took some years for these parents to persuade the medical profession of the specific syndromic nature of their sons’ condition. Having struggled for many years with the numerous medical, surgical, and psychologic needs of their children, these admirable parents went to China to adopt a special needs child, specifically a boy with prior history of hypospadias repair, who, upon arrival in his new home, also was found to have FGS with von Willebrand/factor VIII deficiency, more a comment on prevalence than on chance or ‘‘bud luck.’’ The oldest brother (patient 6) in this sibship was born at a gestational age of 32 weeks with a birth weight of 1465 g, length of 42 cm, OFC of 29 cm, with size appropriate for gestational age. Prenatally, it was noted that he had absent diastolic cord blood flow, asymmetric intrauterine growth retardation, and a single umbilical artery. Prenatally, fetal movements decelerated and the fetus experienced severe bradycardic episodes. He was born by cesarean section with respiratory distress syndrome requiring resuscitation, but resolving naturally. He had severe hypospadias, chordee, hydroceles, multiple congenital anomalies, and a right simian crease. Neonatally, he experienced hypoglycemia, metabolic acidosis, and jaundice treated with phototherapy. He required 6 weeks of care in the neonatal intensive care unit. Neonatally, he was also noted to have persistent neutropenia requiring three white blood cell

FG SYNDROMES

137

transfusions, and anemia requiring red cell transfusions. He had respiratory apneas. A murmur, initially considered due to peripheral pulmonic stenosis, on later evaluation turned out to be an innocent murmur. The boy was finally able to go home at 6 weeks with oxygen for 1 month, an apnea monitor, and antibiotic therapy for otitis media. His motor development was normal. Subsequently, he had many attacks of otitis media, constipation, delayed eruption of teeth, and, at 15 months, the first of many procedures for hypospadias. At 5 years, he had a bilateral inguinal hernia repair and bilateral orchidopexy. During early childhood, this boy had exceptional tantrums, but only a mild disturbance of sensory integration. He also experienced reactive airway disease/asthma and was noted to have mild left exotropia. A striking historical finding was his severe leg pain, with only a mild hypotonia/ lymphedema sequence. When we first examined him, his height was between the 3rd and the 5th centile, OFC at the 50th centile. He had no cowlick, but upward slant of the palpebral fissures, flat philtrum, diastema of the upper central incisors, depressed sternum, broad thumbs and halluces, somewhat short fingers, and a right single palmar crease. Subsequently, he was noted to have mild splenomegaly and an increased size of the left kidney, a unilateral sternocleidomastoid (branchial arch) cyst, and flat feet. Hematologically, he has mild von Willebrand disease, as evaluated by the University of Utah, with persistent neutropenia and recurrent vesicular skin eruptions of unknown cause. He has an excessive response to insect bites and to heat, sometimes requiring emergency room treatment. He has also been treated for ADHD and depression. This boy is exceptionally gifted and able to read a 700-page book in 3 or 4 hours. Recently, we learned that he taught himself Latin in one semester. He was included in the Ozonoff and colleagues [9] study and was found to function at the 98th centile without any evidence of autistic-like behavior. Results of a detailed chromosome examination were normal. The second brother (patient 7) in this sibship was also born prematurely at 34 weeks after spontaneous rupture of membranes, weighing 2140 g, with a length of 44.5 cm and OFC of 32 cm. He also had asymmetrical intrauterine growth restriction. Prenatal ultrasonography demonstrated fetal anomalies and oligohydramnios. He was born by repeat cesarean section after mild heart-rate decelerations, with Apgar scores of 8 and 8. He also had severe hypospadias, hydroceles, and chordee operated at 15 months. Neonatally, he experienced mild respiratory distress, jaundice, and feeding difficulties, and subsequent postnatal growth deceleration. He has also been operated for bilateral hernia with hydrocelectomy and orchidopexy. Motor and speech development were delayed. He had striking congenital hypotonia and language skills were absent until 4 years. He walked at 19 months. For persistent foramina parietalia permagna and choroid plexus cyst and a few mild early seizures, an MRI was performed with normal results. The electroencephalogram was normal. The patient also had severe tantrums, frustration, and agitation until speech development at 4 years. With respect to environmental stimuli, he was

138

OPITZ, SMITH, & SANTORO

hyposensitized and, in fact, sought painful stimuli. He enjoyed spicy food and upside-down positioning. When we first examined him with his older brother, it was clear that he also had FGS with shortness of stature, head circumference proportionately greater than length or height, moderately severe constipation, rectal stricture, and broad thumbs and halluces. He had odd behaviors, such as bolting food, compulsive eating of string, and unraveling rugs and sweaters. His IQ was at least normal. He was also found to have von Willebrand disease with factor VIII deficiency. MRI showed that his conus was low, with markedly spastic legs. His hands shook severely, making writing difficult, and he had leg pains. He also has neutropenia with recurrent vesicular skin lesions. He is a gifted learner. He was home-schooled and has a nearly photographic memory and particular aptitude for mathematics and science. Until recently, he had urinary incontinence at night. The third brother in this sibship (patient 8) was born at gestational age of 36 weeks, with premature onset of labor starting at 28 weeks treated with tocolysis. Ultrasonographic examination of the fetus showed apparently normal findings. There was no intrauterine growth retardation and amniocentesis at a gestational age of 35 weeks showed mature lungs. After repeat cesarean section at 36 weeks, this boy weighed 2870 g, was 48.3 cm long, and had OFC of 34.5 cm, with Apgar scores of 8 and 9. Examination at 37 weeks appeared to show no gross defects, but a flat occiput. A cystic lesion above his left upper eyelid turned out to be a deep dermoid cyst. At 10 months, he needed supplementation to breast-feeding to improve weight gain. At that time, he also had mild anemia. At 10 months, he changed from his prior happy and easy-going status to temperamental behavior, with fitful outbursts and high-pitched crying. He had frequent sinus infections with high fever and serum sickness in response to antibiotics. Speech development was slow and, if scared, he preferred isolation, hiding in tight spaces. He was self-injurious and bit others. He showed few signs of affection and outside evaluation seemed to suggest that he had ‘‘autism.’’ He also complained of frequent headaches. When examined at 2 years, 3 months, his length was at the 10th centile, OFC at the 50th centile, with hypotonia/lymphedema sequence, prominent forehead, two C-shaped vertex hair whorls, mild micrognathia, broad thumbs and halluces, anterior cowlick, increased anteroposterior diameter of chest, inattentiveness, and hyperactivity. Thus, he was also diagnosed with FGS. An MRI study showed a Chiari I malformation, a short-segment syrinx in the cervical cord at C2, and a prominent cavum septi pellucidi and cavum vergae, with inflammation of sinuses. After an operation on his Chiari malformation, full language acquisition considerably improved. However, a few months later, his behavior deteriorated again, the syrinx was growing, and he was reoperated with a dural graft to enlarge space for the displaced cerebellum. Two weeks later, he developed a postoperative pseudomeningocele, which was operated with temporal alleviation of recurrent leg pains. Within 5 months of this

FG SYNDROMES

139

procedure, a syringosubarachnoid shunt had to be placed. For his continuing severe pains, primarily in limbs, he has been treated with a large regimen of analgesics, which, however, caused liver toxicity. Hematologically, he was also found to have von Willebrand disease with persistent neutropenia and anemia and recurrent skin lesions. Finally, another spinal cord operation had to be performed to remove scarring, which had tethered the cord at the cervical level. Now, he appears to have a neurogenic bladder. During a bilateral orchidopexy and unilateral herniorrhaphy, a fatty tumor was removed unilaterally. Presently the boy has chronic severe pain, overwhelming fatigue, hypotonia, dysesthesias of hands and feet. When not in pain, he is a wonderfully friendly, charming boy with normal IQ. The family history suggests that one of mother’s brothers may also be affected. Mother has identified the following possible carrier manifestations in herself: diastema of the upper central incisors (treated with orthodontia), absence of the lower bicuspid teeth, a sacral dimple, broad thumbs and halluces, clinodactyly of fifth fingers, constipation, recurrent throat/sinus infections, urinary tract infections, retroflexion of the uterus (noted also by many other FGS carriers), and an apparent autoimmune disorder designated fibromyalgia/ chronic fatigue syndrome, with Raynaud phenomenon and chronically increased erythrocyte sedimentation rate. In view of the family history, it is possible to conclude that the maternal grandmother is a carrier. Patient 9 (Family 6) Patient 9, a 7.5-year-old girl, was born at a maternal and paternal age of 28. During this pregnancy, the mother had kidney stones at 36 weeks. Preterm labor was stopped twice with medication. The girl was delivered normally at 37 weeks, weighing 3880 g and with Apgar scores of 9 and 10. She has a history of frequent ear infections, essentially normal motor development, bilateral vesicoureteral reflux with neonatal pyelonephritis and severe Escherichia coli sepsis, which was almost lethal at 8 weeks. Subsequently she was treated with prophylactic antibiotics for several months. She has seasonal allergies, sleeps and eats well, but recently has developed nightmares. She has auditory processing difficulties, a rather severe defect of sensory integration involving shoes, socks, and tags in her shirts, and a past history of constipation. She fatigues easily and has had several attacks of ‘‘strep throat.’’ Her growth is normal between the 80th and 90th centile with a body mass index equal to or over the 95th centile. Mother has noted that the girl is a clumsy child and that she walks ‘‘poorly’’ and stumbles. She clearly has decreased muscle tone and complains of joint pains in legs and arms. She has had many attacks of otitis. Her speech development has been borderline normal. With respect to toilet training, she has occasional accidents. She toe-walks on the left with increased deep tendon reflexes in that leg. Her behavior difficulties have been diagnosed as bipolar and oppositional defiant disorders with school problems. She has a triangular tuft of hair in the lumbosacral area and soon will be evaluated for tethered cord.

140

OPITZ, SMITH, & SANTORO

She is in kindergarten. In our clinic, her height was at the 90th centile, weight at the 95th centile, and OFC at the 90th centile. She has a prominent forehead; right frontal transverse hairline; short, thick nasal septum; short sternum with hypotonia/lymphedema sequence; increased deep tendon reflex; and toe walking on the left. Her younger sister, 3 years old, was delivered at a gestational age of 38 weeks weighing 3160 g, measuring 50 cm in length, with OFC of 34.5 cm. Neonatally, she experienced hypoglycemia, hypocalcemia, hypothermia, dehydration, hypotonia, and hydronephrosis. She was born with a cleft palate. Since birth she has experienced severe gastroesophageal reflux requiring a Nissen fundoplication with residual velopharyngeal incompetence. For severe feeding problems she required a G-button. On MRI, she was found to have a decreased amount of cerebral white matter, hypogenesis of the corpus callosum, and metopic/anterior sagittal suture ridging. She has a longstanding history of constipation, and was severely ‘‘tongue-tied’’ with a short, thick upper labiogingival frenulum requiring operations for both of these conditions. For multiple attacks of otitis, pressure equalization tubes were inserted. She has a sacral dimple and an anteriorly displaced anus with a long history of developmental and speech delay. Her squint has been repaired. She has remarkable mechanical fascinations, especially for the nuts and bolts in the bottom of her toy cars, and she is a sorter, placing items from basket, to basket, to basket. When she is sitting, she will, when excited, whirl her dangling feet rapidly in a counterclockwise pattern. Results of chromosome studies were normal, including evaluations for 22q11.3 deletion and 15q abnormalities. A test of her X inactivation ratio was performed with a result of 60:40, leading to the erroneous conclusion that therefore she does not have FG syndrome, when in fact, she clearly has FGS, a diagnosis made by her parents. Patient 10 (Family 7) Patient 10 was previously evaluated in our region and was diagnosed either with GBBB or FGS. The severely dysfunctional mother is diagnosed as having bipolar disease, for which she is being treated with Zoloft. She is also a heavy smoker. From a first union, she had a boy who, while clearly not as severely affected as the propositus, has required at least one operation for hypospadias. In a second union, this mother had a loss of twins, then the propositus, and finally a girl, who is now 4 years old. The mother of these children is in ‘‘rehabilitation’’ and the father is in jail. The maternal grandmother had two additional children, both boys, one of them mentally retarded. The propositus, now 7 years old, was referred with severe pseudovaginal perineoscrotal hypospadias, having required several operations, severely complicated by the child’s tearing out of catheters and removing bandages. His other diagnoses are bilateral cryptorchidism, severe ADHD, insomnia, and pronounced aggression, which required emergency admission to a regional university hospital. The past history, as far as we were able to ascertain, suggested

FG SYNDROMES

141

that the boy was born at 31 weeks weighing 1019 g or 1106 g, that he was hospitalized for 1 month, and probably had been delivered by cesarean section for fetal distress and transverse lie. Neonatally, he had feeding difficulties and hyperbilirubinemia. His weight is now over the 98th centile, head circumference at the 50th centile, and height at the 50th centile. The maternal grandmother, who is his guardian, states that he appears to have no control over his bowel movements. He has had multiple attacks of otitis and mastoiditis. Initially he had developmental delay and speech delay and a severe defect of sensory integration. In school, he is considered to have average IQ, but his behavior is at times unmanageable. He has explosive mood swings between mania and affection, severe aggression, and depression. He has been diagnosed as having ADHD with oppositional-defiant disorder and ‘‘autistic-like’’ signs and symptoms. He had striking mechanical fascinations. He coughs and chokes while eating and sleeping; he also has a deep sacral dimple. Recently, he had a chromosome evaluation (SignatureChip) at Pullman, Washington, with normal results. Patient 11 (Family 8) Patient 11, a 3-year-old girl, was the middle of three sibs, all girls, the oldest having attracted attention prenatally on the basis of a choroid plexus cyst. The youngest is known to have a metatarsus adductus, a plagiocephalic skull, and small palpebral fissures. Patient 11 was delivered after a normal gestation and normal spontaneous vertex vaginal delivery without intrauterine growth retardation, but with congenital hypotonia. She had bilateral pes cavus, metatarsus adductus, and is presently wearing braces. She had her first seizure with fever at 3 months and thereafter some seizures without fever treated with Trileptal. She has had bilateral ptosis requiring a levator resection, also repeated attacks of otitis with developmental delay, speech delay, and gastroesophageal reflux treated with Zantac. She has rather severe defect of sensory integration and oral tactile aversion. Her growth has been between the 50th and 75th centile and her OFC is between the 75th and 90th centile. She has rather striking ADHD. An MRI showed the conus of the spinal cord at L1 and abnormally wide gyri in her brain. Patient 12 (Family 9) Patient 12, a boy, was referred at 2.5 years. He was born at term after a normal gestation without intrauterine growth retardation, but with a congenital hypotonia/lymphedema sequence, and plagiocephaly. He has had constipation, treated with GlycoLax and flaxseed oil, and developmental delay. He also had neonatal seizures, congenital nystagmus with myopia. His seizures were treated with Trileptal. The electroencephalogram is normal. Because of his unresponsiveness to sound, he was tested and found to have severe bilateral sensorineural deafness, for which he had a cochlear implant. Following the implant, mother noticed that he smelled strikingly of maple syrup and, when evaluated in a regional university hospital, it was initially thought he might have the vitamin B responsive variety of maple syrup urine disease. However,

142

OPITZ, SMITH, & SANTORO

further detailed metabolic evaluation showed that he did not have maple syrup disease. He is described as ‘‘somewhat autistic.’’ His growth is normal with OFC at the 90th centile. He also has a sacral dimple and has had attacks of otitis. Two older brothers have a striking family resemblance; in addition, their mother has had four spontaneous fetal losses. The results of all laboratory investigations, including cytogenetic tests, were normal. Patient 13 (Family 10) Patient 13 was seen at 18 months. This mother describes herself as having shortness of stature, ADHD, a high broad forehead, and constipation. During this pregnancy, she noted strikingly decreased fetal movements. The infant was delivered at term with intrauterine growth retardation and developed seizures on the third day on account of ‘‘meningitis.’’ She had an atrial septal defect requiring an operation and valvar and supravalvar pulmonic stenosis requiring two balloon valvuloplasties. She has speech delay. The MRI showed hypoplastic corpus callosum. Neurologically, she has congenital hypotonia. On genetic testing, she has had chromosome evaluation, subtelomeric comparative genomic hybridization and biochemical studies, all with normal results. She has a very unusual pattern of dental eruption and presently has a retarded bone age. Her craniosynostosis involves the inferior aspect of the left coronal and superior aspect of the sagittal suture. Thus, she had primordial shortness of stature with speech delay, congenital heart defects, and craniosynostosis with all of the minor anomalies of FGS. Patient 14 (Family 11) Patient 14, a now 4-year-old boy, was rather severely affected. He was the first child of this mother, who also had one spontaneous pregnancy loss after artificial insemination by donor. The mother considers herself ‘‘a carrier’’ on the basis of ADHD, constipation, shortness of stature, a high broad forehead, cowlicks, and clinodactyly of the fifth toes. Because she was adopted, her family history is unknown. This child has been evaluated in detail on several occasions and is known to have a congenital hypotonia/lymphedema sequence, nystagmus, squint, constipation, severe gastroesophageal reflux requiring a Nissen fundoplication, failure to thrive requiring a G-button, otitis, and sinusitis with insertion of pressure equalization tubes. He has a severe defect of sensory integration and oral tactile aversion and apparent rumination with abdominal distention. The height of this moderately retarded boy is less than the 3rd centile, but his head circumference is at the 50th centile. He has not yet had an MRI or evaluation for a tethered cord. Patient 15 (Family 12) Patient 15 is Kim Peek, the man whose condition is the basis for the Dustin Hoffman character in the movie Rain Man [7,8]. Patient 15 was born on November 11, 1951, in Salt Lake City after an apparently normal pregnancy, but difficult 12- to 13-hour labor, presumably

FG SYNDROMES

143

due to his big head. His birth was followed by that of two sibs, one in 1953 and one in 1954. The patient’s brother has two daughters, one of whom has a girl, the other having had two normal boys and a girl. Patient 15’s birth weight was 3000 g. His length was 49.5 cm. His head circumference was ‘‘30% larger than normal.’’ He appeared to have a large right occipital meningocele, which did not disappear until age 3. Except for some minor anomalies, the boy had no gross malformations, but rather a pronounced hypotonia/lymphedema sequence, torticollis to the right, with some facial asymmetry persisting to this day. Vomiting, spitting up, and colicky crying through infancy may have represented reflux. From the very beginning, his family knew that the boy was different. He was described as ‘‘sluggish’’ and he cried a lot. There was no playing, no normal responses to stimuli, no solid stages of development; ‘‘each of his eyes moved independently. . .’’ [7]. To judge from the present-day MRIs, it is difficult to reconstruct the condition of his cerebellum at birth. In any event, he seems to have had an apparent right occipital meningocele (soft, baseball-sized blister. . .’’), which gradually retracted by age 3. At 9 months, the boy was considered ‘‘mentally retarded’’; institutionalization was recommended. Instead, he was raised at home, the parents reading to him ‘‘hour after hour, [Kim] tracing the rows of words with his tiny fingers as he went.’’ Soon, the lad began to show some remarkable abilities with ‘‘. . .an early interest in books.’’ At 18 months, he became a ‘‘creature of habit,’’ always turning his books upside down on the shelf to separate them from those he had not yet read. Kim did not walk until ‘‘past 4,’’ but his parents always sensed that he possessed ‘‘some special gift, some mental powers beyond our ability to explain.’’ At age 3, he was ‘‘browsing’’ through the newspapers and asked his father about the meaning of ‘‘con-fi-den-ti-al.’’ As his father records in his loving biography of Kim: ‘‘. . .without thinking, I jokingly told him to look it up in the family dictionary. He did. About 30 seconds after putting his head down, crawling like a snowplow to the dictionary, he found the word and read out the definition. Thereafter he never stopped reading and memorizing everything he could get his hands on including phone directories, atlases, biographies, and histories.’’

By 1996, at age 45, he had read an estimated 7600 books and by now over 12,000 books. With perfect photographic memory, he can recite ‘‘whole paragraphs’’ from a book at the mere mention of a page number. By age 6, ‘‘he had memorized the entire index of a set of encyclopedias.’’ Medically, Kim did fairly well in childhood, initially bolting his food, but now eating normally. Gradually, he gained motor skills, but with the most unusual speech pattern, hyperactivity, introversion, and motor disability such that he could not bathe, dress himself, or brush his teeth. His public school career lasted ‘‘a grand total of 7 minutes. . .’’ because of hyperactivity.

144

OPITZ, SMITH, & SANTORO

A recommendation was made for Kim to have a ‘‘prefrontal’’ lobectomy. He had many middle ear infections. His constipation has improved so that he has a bowel movement every 3 days. Kim’s prodigious gifts are well documented in his father’s wonderful biography [7], in an article by Treffert and Christensen [8], and in several documentaries produced in North America and the United Kingdom. Walking into my office, then still in the Primary Children’s Medical Center in Salt Lake City, he asked my former secretary the date of her birthday and within a second or less told her the date, year, and day of the week she would retire (at 65). At a prior meeting on the ‘‘Opitz’’ syndromes in Salt Lake City, Kim came to my ‘‘banquet’’ table humming that marvelous eight bar theme from the finale of Brahms’ Fourth Symphony. When I said, ‘‘Why Kim, you are a music lover,’’ I was promptly corrected. Kim only wanting to point out that Brahms and I were born only a few blocks and a century apart in Hamburg, a town he had never visited, but knew better than I ever will. Now, at the age of 56, Kim has a large head and brain (OFC 61.6 cm); is a light sleeper, but has no sleep apnea (has had three sleep studies); is 175 cm tall, and weighs 93.3 kg. He has persistent torticollis to the right, hypertelorism, downward slant of palpebral fissures, a high broad forehead, right anterior cowlick, a (congenitally) hypotonic mouth-breathing face, striking hypotonia/lymphedema sequence, broad halluces and thumbs, and a prominent lower lip with mild micrognathia and malocclusion (Fig. 7A). Except for the apparent right posterior/cerebellar exencephalocele, Kim has no gross malformations. In recent years, Kim has developed gout, diabetes, and hyperlipidemia, for which he is receiving Lipitor. In 2001, he spent 6 days in the intensive care unit for congestive heart failure, but with appropriate treatment has regained his normal health. Kim’s tested IQ is 87 [8]. However, his prodigious gifts in a dozen intellectual areas have made him an international celebrity and honorary alumnus of Oxford University. He has been referred to as ‘‘autistic.’’ However, that would impress us as clearly incorrect since he makes excellent eye, social, and personal contact and, within limits, can carry on a normal conversation. Neurologically, Kim remains hypotonic, considerably incoordinated so that his devoted father has to help him still with many daily living skills. His deep tendon reflexes are hypoactive and his eyes function independently. He is able to read both pages of a paperback book simultaneously, the right page with his right eye, the left page with his left eye. After the movie Rain Man, Kim developed extraordinary social skills. At one time he would seclude himself in his bedroom to avoid seeing visitors. Now he has presented himself to at least 4.25 million persons at national and international meetings. His MRI (see Fig. 7B, C), obtained by Dr. Daniel D. Christensen at the University of Utah in 1988, shows complete absence of the corpus callosum; normal gyral pattern and cerebral cortex; dilated third ventricle with an elevated roof; enlarged posterior bodies and horns of the lateral ventricles, which were laterally displaced; normal brainstem; enlarged fourth ventricle communicating with a retrocerebellar cyst (Blake’s pouch cyst); moderate

FG SYNDROMES

145

Fig. 7. (A). Patient 15, Kim Peek (left), at age 54 years, with his father, Fran Peek. (Kim’s condition was basis for the movie Rain Man [7,8].) (B and C) MRI of patient 15 shows absence of corpus callosum; normal cerebral cortex and gyral pattern; dilated third ventricle with an elevated roof; enlarged posterior bodies and horns of lateral ventricles, which were laterally displaced; normal brainstem (B); enlarged fourth ventricle communicating with a retrocerebellar cyst (Blake’s pouch cyst); moderate hypoplasia and upward rotation of the cerebellar vermis; and hypoplasia of the cerebellar hemispheres, more severe on the right than on the left (C) (Courtesy of W.B. Dobyns, University of Chicago and G.L. Hedlund, University of Utah).

hypoplasia and upward rotation of the cerebellar vermis; and hypoplasia of the cerebellar hemispheres, more severe on the right than on the left (readings by WB Dobyns, University of Chicago and Gary L. Hedlund, Primary Children’s Medical Center Department of Medical Imaging, University of Utah). Like many savants, Kim possesses absolute pitch, an enormous knowledge of classical music, and has been remarkably successful in learning to play the piano; and, because he is no Caruso, his skills at the piano have made it possible for Kim to communicate very effectively his love and knowledge of classical music. Abstract notions of theology and philosophy are beyond him; however, Kim is

146

OPITZ, SMITH, & SANTORO

able to articulate a spirituality to the effect that he does not want to be a member of a particular ‘‘church,’’ but rather wants to ‘‘meet people of all faiths and be a part of their lives too’’ and being ‘‘a missionary just for God. . .to do whatever he thinks I ought to do for everyone’’ [7]. We conclude that Kim Peek probably has FGS. His DNA is stored in a California research institution, and will be available as soon as all the FGS genes are accessible for clinical diagnostic testing. CLINICAL SUMMARY FGS is a group of common conditions presenting frequently in the office of every pediatrician and of every pediatric subspecialist. Prenatal FGS may present before birth with asymmetric growth retardation, decreased fetal movements, ultrasound detection of congenital anomalies, and oligohydramnios or, more commonly, polyhydramnios. Fetal death and increased spontaneous prenatal loss has been recorded, and there is frequent perinatal fetal distress, requiring emergency cesarean section, and abnormal presentation, either breech or transverse lie. The condition may also affect mothers before birth, with an increased frequency of high blood pressure and preeclampsia, which may end in hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. This may occur not just in the first pregnancy, but in all pregnancies of a carrier mother and not just at the end, but at the beginning and throughout pregnancy. Thus, any FGS carrier mother who has had an affected child with these manifestations automatically is a high-risk mother and should be followed as such in subsequent pregnancies (Fig. 8A). Mothers may also develop pruritic eruption of pregnancy or pruritic urticaria of pregnancy (PUP/PEP), an intensely itchy red rash, usually toward the end of pregnancy, which gradually fades after delivery. There is frequently premature onset of labor, sometimes as early as 22 weeks, requiring tocolytic treatment. However, if signs of fetal distress become overwhelming, premature delivery or induction of labor may be necessary at 34 weeks or earlier. Decelerations, bradycardias, and other signs of fetal distress are common prenatally and intrapartum, leading to a high rate of cesarean sections in FGS carrier mothers. FGS may affect the placenta, which in a few cases has been described as abnormal, small, fragmented, and sometimes infarcted. Some babies may have a single umbilical artery. Neonatally Many FGS babies experience complications of congenital hypotonia and respiratory distress syndrome, in part correlated with the degree of prematurity, hypoglycemia, hypocalcemia, hypothermia, and commonly hyperbilirubinemia, which may require phototherapy. Commonly, FGS infants have feeding difficulties, which may progress to failure to thrive, requiring a G-button.

FG SYNDROMES

147

Fig. 8. (A) Pedigree of an FGS family with 8 affected males (solid squares) born in generations 4 and 5. Note also occurrence of toxemia (T) in 12 pregnancies, at least one with HELLP syndrome leading to the death of one of the twin sisters’ boys. (B) Pedigree with the occurrence of bipolar disorder (Bp) in this family. (Bull’s eyes) evident carriers. (Solid squares) affected male. (Diagonal slashes) deceased. (Horizontal line above symbols) personally examined.

Some FGS babies have such severe gastroesophageal reflux as to necessitate a Nissen fundoplication. Infancy The failure to thrive of FGS infants frequently leads to nasogastric tube placement with high-calorie feedings. Neocate is contraindicated because of its risk for constipation. FGS infants may have hematologic abnormalities, such as thrombocytopenia, less commonly thrombocytosis, anemia, and leucopenia/ neutropenia, in some cases requiring transfusion of red blood cells, white blood cells, or platelets. Many FGS infants have stridor/laryngomalacia, and at that point should be seen by an otorhinolaryngologist to be sure that they do not have a laryngeal cleft or subglottic stenosis. Many FGS infants develop constipation, sometimes alternating with diarrhea. Otitis with or without mastoiditis or sinusitis is virtually universal in FGS children. Sinusitis or opacification of mastoids are frequently noted coincidentally on brain MRI studies. Many FGS children have a history of respiratory syncytial virus infection and other viral infections with at times life-threatening bronchiolitis requiring hospitalization. Almost all children with FGS have reactive airway disease/asthma, which many require years of treatment, even in adulthood.

148

OPITZ, SMITH, & SANTORO

Virtually every child with the FGS has a defect of sensory integration, most commonly oral tactile aversion. It is frequently recounted that such children resist having their head washed, their hair cut, or their teeth brushed; they will not touch anything sticky, cold, or hot; will overreact to sound, light, crowds, social pressure; do not want to walk on sand or grass, but most commonly have difficulties with oral food textures and tags in shirts. Children with pronounced oral tactile aversion may develop ‘‘bolting’’ with prolonged chewing of food and delayed swallowing; a sudden attempt at swallowing risks choking and aspiration. Hence, all caretakers in the child’s home must know the Heimlich maneuver. To the best of our knowledge, three FGS boys, including the prototypic boy in the FG family, have died from choking and aspiration after sudden swallowing. Affected men and carriers may still choke as adults. Sometimes aspiration will lead to aspiration pneumonia. Almost all children with FGS, with the exception of some carrier girls, have developmental delays, particularly speech delay. The motor delay is primarily due to congenital hypotonia, which improves with time; but, as motor development improves, delayed speech development, sometimes as late as 4 to 6 years or older, becomes a more serious concern because of inability to communicate. Thus, every effort must be made to teach speech-delayed children sign language and other effective means of communication to reduce their frustration levels and tendency toward tantrums. FGS children frequently are described as extraordinarily charming, sweetnatured, and affable boys and girls. However, they may develop behavior difficulties, particularly as their frustration levels increase with inability to communicate. Many of these children, particularly the boys, have striking mechanical fascinations and tend to play in a rigid and compulsive manner, preferring solitary play. This prototypic report about such a 6-year-old boy is from a child psychiatrist: The child has self-injurious behavior and does unsafe things, such as getting out of the car and running into traffic, climbing out of windows. The patient may bang head daily, even when happy; patient has done this on several occasions so hard as to knock himself out, hence the scars on his forehead.

Some FGS boys may be aggressive, and this particular patient is described as having ‘‘thrown the aunt’s 4-month-old infant in a car seat across the room’’ and having made threats toward family members, saying ‘‘I’m going to kill you, you, and you.’’ With respect to obsessive-compulsive disorder, this particular patient ‘‘lines cars up perfectly; lines up underwear by color; lines up socks by size and color; when the room is cleaned, everything is in its place; foods cannot touch each other.’’ Other children are mesmerized by patterns, ceiling fans, and repeated patterns on the television. With respect to conduct problems, the above-mentioned particular patient showed ‘‘aggression, was assaultive, had an explosive temper, was destructive,

FG SYNDROMES

149

and cruel to animals; he was oppositional, defiant, lacked empathy, disobeyed rules, was argumentative, threatened others, and lacked remorse.’’ Also, he had ‘‘motor recklessness, was disruptive, impulsive, hyperactive, and fidgety,’’ and was therefore diagnosed as having ADHD. With respect to delusions, this particular patient believed that he had ‘‘powers like superheroes and tended to act on these powers, even in dangerous situations.’’ Many FGS children overreact to sensory input by either ‘‘checking out and crawling into bed, completely covered by their blanket,’’ or by ‘‘losing it’’ and having a temper tantrum, which may sometimes last for hours. Some eat unusual things, such as strings and dirt. Others are ultimately diagnosed as having oppositional-defiant or obsessive-compulsive behavior, distractibility, ADHD, or ‘‘autism.’’ The latter is sometimes designated Asperger syndrome or pervasive developmental disorder not otherwise specified (PDD-NOS). All children are attention-seeking. Many have a strikingly selective memory, involving, for example, places, smells, music, and numbers. MRI may be normal or show any number of anomalies as illustrated in Fig. 7B and C and Fig. 9. School age School can be overwhelmingly difficult for FGS children, particularly boys, because of fatigue, distractibility, and behavior. Some teachers have tried to solve these problems by using earphones, either on themselves with a microphone on the child’s desk, or with earphones on the child and a teacher microphone so

Fig. 9. MRI of a patient at age of 4 years with absence of corpus callosum and of septum pellucidum, colpocephaly, periventricular nodular heterotopia, cortical ‘‘dysplasia’’ of the posterior frontoparietal regions more pronounced on right than on left, abnormal course of sinus rectus, and single (azygous) anterior cerebral artery, possible indication of an FGS2 (FLNA mutation).

150

OPITZ, SMITH, & SANTORO

that he or she can communicate directly with the child with a minimum of distraction. Many FGS children have difficulties writing or holding pencils because of weak or shaking hands. Schooling works best for these children if the class periods are short, crowding is avoided, and they are allowed to crawl safely into small, dark places. They need time to tune out or to relax, perhaps under their school desk with a blanket. All FGS children need one-on-one interaction in school. Attention needs to be paid to their toilet needs, depending on presence of constipation-obstipation or diarrhea. All lunch sessions must be supervised to prevent bolting and potential aspiration, and all school lunch personnel must know the Heimlich maneuver. Many FGS children do best if home-schooled. It is frequently reported that FGS boys have a genius at taking things apart, less so at putting them back together. Since writing is such a chore for these children, it is recommended to introduce the computer as early as possible. During adolescence, possible or apparent differences between FGS boys and girls may become evident, boys being more likely to be socially dysfunctional and asocial, or to avoid friends or neighbors. Girls may also have difficulties in their social interactions, but more commonly are troubled because of oppositional-defiant disorder and even more frequently with bipolar disorder (see Fig. 8B). Many young carrier women make impulsive (mate) choices, and attract attention because of their volatility, irresponsibility and unreliability. Boys and girls may develop or manifest sleep disturbance frequently with snoring, and are at risk for sleep apnea. There is a substantial tendency for adolescent boys and girls with FGS to become overweight, which may be correlated with sleep apnea. However, at this moment, the causal relationship between excess weight and sleep apnea is unknown. All FGS children need nutritional supervision and care; many are very good at learning to track their calorie intake on a PalmPilot or similar device. All FGS children and adults must be encouraged to exercise. If snoring and sleep apnea become a problem, then a sleep evaluation is required. Many of these children are found to require continuous positive airway pressure during the night.

DIAGNOSTIC CONSIDERATIONS At the moment, the diagnosis of FGS is mostly clinical and is made in children with FGS manifestations, with or without mutations in MED12 or FLNA. The absence of mutations in these genes does not rule out the diagnosis; if maternal X-inactivation is not skewed, that does not rule out the carrier state. At the moment FGS1 (so-called ‘‘Opitz-Kaveggia syndrome’’) is defined on the basis of the phenotype of the original FG family [3], our patient 4, an affected young man from Israel, and several others [10]. These individuals and families are characterized by the R961W mutation of MED12 [11]. A helpful diagnostic finding is the relatively small ears. Also, these young men tend to be relatively tall and more retarded than most FGS children.

FG SYNDROMES

151

Since the discovery of Filamin A (FLNA) mutions in some FGS boys ([1,2] and others), an FGS2 (sub)group has been established on the basis of their MRI finding of periventricular nodular heterotopias. With these exceptions, the extensive clinical overlap between the various linkage-defined forms of FGS is so extensive that differentiation between them is, at the moment, difficult, if not impossible. Ultimately another FGS2 form may be defined on the basis of associated factor VIII deficiency. The major criteria, minor criteria, and supporting criteria for FGS are summarized in Box 2. Care concerns for FGS children are summarized in Box 3. Genetics Prevalence, fitness, mutation rate Initially, the remarkable prevalence of FGS in Utah was viewed as a possible founder effect, whereby under polygamous ancestral circumstances a mildly affected man would transmit the gene to all of his daughters, who, in turn and under Mendelian expectations, would pass it to half of their sons (hemizygotes) and half of their daughters (heterozygous carriers). However, in our experience, transmission from fathers to daughters is far less common than from mother to offspring. The FGS appears to be common in other parts of the world as well. In Italy, it was one of the commonest conditions referred during a sabbatical year (2001–2002) in Rome, and the Stella Maris Institute in Pisa recently published 25 cases [12]. Thus, a founder-effect hypothesis seems unlikely at the moment. Also, while fetal losses and stillbirths are noted with considerable frequency in Utah FGS families, it is our impression that the overall fecundity in Utah kindreds is normal with an average of five children per sibship. Thus, the fitness (ability to have at least one surviving child per parent or two per couple) of carrier women seems not to be impaired. The fitness of adult hemizygotes has not been studied systematically. However, except for cases of great severity, fitness of adult hemizygotes does not seem to be substantially impaired either. If, theoretically, the fitness of a hemizygote is zero (as in Duchenne muscular dystrophy) and two thirds of X chromosomes in the human population reside in the females, then one third of Duchenne muscular dystrophy cases of the next generation are new mutations. Also, because new mutations in FGS seem to be extremely rare and most cases are inherited from carrier mothers, then, again, fitness in FGS cannot be substantially impaired. Another potential explanation for a high population frequency is a high mutation rate, especially if this is to be multiplied over seven or more loci. The exact prevalence of FGS is presently unknown, but ultimately will be determined most accurately on the basis of clinical/molecular data. At the moment it appears that the referral rate of FGS is far higher than that of Down syndrome. Furthermore, once clinicians begin to watch for a phenotype of relative shortness and megalencephaly, wide-set eyes, cowlicks, widow’s peaks,

152

OPITZ, SMITH, & SANTORO

Box 2: Major criteria, minor criteria, and supporting criteria for FGS Major criteria (present in 50% or more of FGS children) Congenital hypotonia, developmental delay with speech delay worse than motor delay Head circumference disproportionately large for length or height, with or without large anterior fontanelle Defects in sensory integration; oral tactile aversion Reflux/feeding difficulties, which may lead to Nissen fundoplication with or without G-button High, broad forehead with one or more cowlicks and abnormal hair whorls Reactive airway disease Multiple attacks of upper respiratory infections/otitis media leading to need for pressure-equalization tubes, tonsillectomy, and adenoidectomy Short sternum, telecanthus, short thick nasal septum Broad thumbs/halluces, with second toenails tending to curve over the tip of the toe Constipation/obstipation with or without diarrhea Characteristic behavior pattern with or without staring spells A family history of FGS manifestations Hypospadias, cryptorchidism, hernias MRI abnormalities of brain and/or tethered cord (see Fig. 7B and C, Fig. 9) Minor criteria The presence of one or more congenital heart defect, mostly patent foramen ovale, patent ductus arteriosus, atrial septal defect (atrial septal defect secundum), ventricular septal defect; almost all of these are self-limited; persistent left superior vena cava; some children have valvular or pheripheral pulmonic stenosis; severe congenital heart defects rare A characteristic combination of minor anomalies, including downward slant of palpebral fissures; hypertelorism or telecanthus, epicanthic folds; hypotonic, mouth-breathing facial appearance; highly arched palate; lower lip more prominent than upper lip; abnormal teeth with late eruption; abnormal sequence of eruption; small teeth; gaps between teeth; large upper central incisors with diastema; abnormal enamel frequently requiring capping of many baby teeth; short perineal body; sacral dimple Supporting criteria Coloboma (ocular) Cleft palate Choanal atresia Diaphragmatic defect Pyloric stenosis Laryngeal cleft (first degree) Imperforate anus, anal stenosis (rare)

FG SYNDROMES

153

Box 3: Care concerns for FGS children Neonatal stabilization and adaptation may be difficult in FGS children; almost all of them have jaundice requiring phototherapy. From the very beginning, children may have feeding difficulties and gastroesophageal reflux, rarely aspiration in the neonatal period to early infancy. The defects in sensory integration may be severe, and occupational therapy may be required, especially for the oral tactile aversion with feeding difficulties. All FGS children need to be followed carefully and treated for otitis media and other upper respiratory infections. Almost all children need surveillance for reactive airway disease and asthma. If there are seizures, oxcarbazepine and clonidine seem to be the best drugs. Constipation is best treated with a polyethylene glycol–based compound, such as MiraLax. Almost all FGS children have communication difficulties and require speech therapy, must be taught sign language, or need use-assisted communications devices. For hypotonia, occupational therapy is required; swimming therapy or hippotherapy has been found to be helpful. All FGS children require psychologic evaluation as to the level of cognitive impairment and need for additional special educational support. Almost all children with FGS require an individual education plan; however, they also need to be tested and observed carefully for unusual gifts, such as aptitude for using computers, ability to memorize, facility with numbers, and skills related to mechanical, numerical, and musical activities. Probably the most important aspect of dealing with an FGS child is to educate the professionals involved, including the mental health professionals, school professionals, and medical and genetic professionals. All parents are encouraged to join the FGS Family Alliance and to receive their publication, Flagstone. After a diagnosis of FGS has been made, it is probably prudent to take a careful look at close relatives, particularly those who are symptomatic.

abnormal hair whorls, short thick nasal septums, and prominent lower lips, evidence of possible FGS will be seen with surprising frequency in the ‘‘normal’’ population and even more commonly in pediatric gastroenterology clinics, special education classes in public schools, public health clinics for children with special health care needs, and pediatric genetics clinics. Signs of possible FGS are probably most common among groups of ‘‘autistic’’ children, although we have not yet confirmed this. Recessivity, carrier manifestations After Mary Lyon [13], medical geneticists came to doubt that there were such biological entities as completely recessive X-linked genes. However, even in the late 1960s and early 1970s, there were practical difficulties in making sure that a mother who had had two or more boys with an X-linked disorder and who claimed to be normal in all respects was in fact completely normal with respect

154

OPITZ, SMITH, & SANTORO

to that trait. We never examined Mrs. F. or Mrs. G. (see Fig. 1). Since 1974 many mothers have volunteered that they may be, or are in fact carriers on the basis of many manifestations, including growth, head size, minor anomalies, personality development and structure, emotional challenges, autoimmune disorders, constipation, and occasional Chiari I malformation or tethered cord. Fortunately most of these carrier manifestations are evident by history and by looking at face, scalp, hands, and feet. Also, because these mothers have had at least one affected child (the reason they are in the pediatric genetics clinics), their obstetrician or midwife will have told them about an unusually short perineal body, especially if an episiotomy was performed. After experience with several hundred FGS families, we have concluded that in spite of or because of Lyonization almost all FGS carriers are manifesting heterozygotes. That is, the FGS is an incompletely recessive/semidominant trait. This conclusion goes beyond genetics directly into the health and medical welfare concerns of the carrier mothers. They must know that in a subsequent pregnancy they may be at risk for hypertension/preeclampsia, even the HELLP syndrome (see Fig. 8A), premature labor, intrauterine growth retardation, rarely fetal death, poly- or oligohydramnios, PUP/PEP rashes, and, postnatally, a large number of potential autoimmune disorders. In other words, they are high-risk mothers. The carrier state appears also to predispose to bipolar disorder (see Fig. 8B). In any event, it would be to their greatest benefit to be as well informed as possible about the potential implications of their carrier state, and to be in contact with a health care provider expert in FGS and with the FGS Support Group [14,15] for information on virtually all aspects of FGS. Heterogeneity After the experience with the startling heterogeneity of such very pleiotropic autosomal traits as the syndromes of, for example, Meckel, Bardet-Biedl, and Fanconi, it is a little easier to accept extensive heterogeneity of an equally pleiotropic X-linked trait, such as FGS, given that heterogeneity of X-linked eye or central nervous system–related genes is common to begin with, X-linked retinitis pigmentosa (at least 9 genes) and X-linked mental retardation (over 217 known or mapped entities) being striking examples. FGS1. In 1991, Zhu and colleagues [16] found tentative linkage of FGS1 in the Keller and colleagues’ family to Xq21.31-Xq22. This family was also included in the study by Briault and colleagues [17] of 10 families who found heterogeneity, 7 kindreds mapping to Xq13 (FGS1) between DXS135 and DXSJ2 with linkage exclusion in 3 families (families 8,9, and 10). Graham and colleagues [18] confirmed linkage in 3 new families and found skewed X-inactivation in 5 carrier women (family A III-7: 70:30; family B I-2: 100:0; family C I-2: 100:0; II-2: 99:1; II-4: 80:20). However, skewed X-inactivation is not inevitable in FGS. Raynaud and colleagues [19] found nonskewing in 5 of 8 families, and Risheg and colleagues [11] in 6 of 9. The recent studies by Risheg and colleagues [11] showed that some 6.8% (6 of 45) of families with FGS1 have the consistent mutation 2881 C/T, leading

FG SYNDROMES

155

to R961W in MED12, not a part of the mediator complex but a member of the mediator module that ‘‘may act as an adaptor for specific transcription factors.’’ MED12-deficient zebra fish (Danio rerio) have defects in brain, neural crest, and kidney as an embryonically lethal condition. This gene product is also required as a coactivator for SOX9-dependent neural crest, cartilage, and ear development [11]. These investigators also quote two other studies showing physical and functional interactions between MED12 and the beta-catenin and Gli3 pathways. Since the mediator complex is also required for thyroid hormone–dependent activation and repression of transcription by RNA polymerase II, we are beginning to acquire a rudimentary understanding of the many complex functions of the MED12 protein in ontogeny and central nervous system functions. It has now been established that an additional base change in MED12 c.3020A/G in exon 22 gives rise to the Lujan-Fryns syndrome. Two additional mutations, c.617G > A (the missense mutation p.R206Q) and c.3425 G> A (the missense mutation p.R1142H) in MED12, were found in two families with manifestations sufficiently similar to those in the majority of FGS patients that we would not be inclined to place them in a separate nosologic category [20]. FGS2. A second FGS locus was postulated by Briault and colleagues [21,22] on the basis of large paracentric inversion of Xq with breakpoints at Xq11 and Xq28 in a French family segregating with apparent FGS over at least two generations. In situ hybridization of the breakpoints using yeast artificial chromosomes and cosmids did not show any genes in the proximal, approximately 600 Kb region [23]; distally the breakpoint lies between the color vision and G6PD loci, and close to the gene for factor VIII. Because all three affected sons and their adopted Chinese son in family 5 above have coagulation factor VIII deficiency, and red-green color blindness has been seen in several FGS families, we have strong hope that even in this gene-rich region it will be easy to locate and to clone FGS2. As mentioned above, FLNA mutations have been found in a few FGS2 patients/families [1]. FGS3. This locus was mapped by Dessay and colleagues [24] in a British and a Utah family from Salt Lake City and linked to DXS1060 at Xp22.22. Simultaneous occurrence of ocular albinism mapped to Xp22 in at least three FGS families suggests that the vicinity of that gene may be promising in locating FGS3. In the Utah FGS3 family, the carrier mother of the propositus, investigated for headaches, was found to have a Chiari I malformation. She has severe chronic constipation. The MID1 gene at Xp22.22 may be a candidate gene for FGS3. FGS4. In studies of this Neapolitan family with a severe form of apparent FGS, Piluso and colleagues [25] linked a gene to Xp11.4 between DXS8113 and sWxD805. A missense mutation in CASK: 83G/T (R28L) has been found but appears to be unique to this family [25,26]. FGS5. This gene is presumed to reside in a 4-megabase duplication at Xq22.3 studied by Jehee and colleagues [27] in a Brazilian boy with presumed FGS

156

OPITZ, SMITH, & SANTORO

(deceased) and his carrier mother. Studies with fluorescence in situ hybridization probes in metaphase suggest that this duplication is inverted. It is present in a heterozygous state in the mother; however, there is random inactivation of her two X chromosomes. The duplication involves mostly band Xq22.3 and includes some 16 genes, many without a known function. However, the thyroxine-binding globulin (TBG) gene SERPINA7 may be relevant here since thyroid dysfunction is very common in FGS, and this boy’s euthyroid mother had a 35% elevation in TBG level and an elevated thyroxine level. Also, the pathogenesis of FGS1 seems to involve a defect of thyroid hormone–dependent activation and repression of transcription by RNA polymerase II. The propositus in this Brazilian study had trigonocephaly due to metopic suture synostosis, and, since maternal or neonatal hyperthyroidism may cause craniosynostosis, he may have been predisposed to craniosynostosis by his mother’s elevated TBG levels. PRPS1 is another gene present in this inversion and codes for a ubiquitous form of phosphoribosyl phyrophosphate synthetase associated with an Xlinked form of hyperuricemia, gout, and nephrolithiasis. This patient’s mother had renal stones during her pregnancy and nephrolithiasis has been seen in several FGS boys. A third gene in the duplication is MID2, whose gene product may interact with that of MID1, which, when mutant, is responsible for the X-linked GBBB (‘‘Opitz’’) syndrome. Since at times the two conditions are clinically indistinguishable and both affect the midline, MID2 may be a reasonable candidate gene for FGS5. Also, it is perhaps indicated to test the serum uric acid and TBG levels in several non-FGS1 carrier mothers since FGS5 may be a contiguous gene syndrome. ‘‘FGS6’’. So-called FGS6 (Online Mendelian Inheritance in Man [OMIM] 300298, located at Xq25-26) involves truncating mutations of UPF3B, which may give rise either to FGS or Lujan-Fryns syndrome [20,28]. ‘‘FGS7’’. So-called FGS7 (OMIM 300553 at Xq21.1) was identified in two ‘‘nonsyndromic’’ X-linked mental retardation families, whose affected males manifest megalencephaly, mild to moderate developmental delay, early speech delay, and high broad forehead. In one family (family 322), the affected males had a mutation of the highly conserved þ1 position of the 5’ donor splice site of intron 29 of BRWD3, c.3325þG/T, also found in a carrier. In a second family (two half brothers) the frameshift mutation c.946-947 ins A was found. This leads to a predicted truncated protein p.R316KfsX21 [29]. Autosomal contribution? In 1992, Shapiro and colleagues (L. Shapiro, personal communication, 2003, 2008) reported on two brothers with apparent FGS (older brother developmentally delayed, but ‘‘cognitively normal’’ with imperforate anus, congenital heart disease, macrocephaly, broad thumbs and great toes, hypotonia, clinodactily, sacral dimple, and hydronephrosis; premature younger brother with identical

FG SYNDROMES

157

facial appearance). Subtelomeric testing showed a balanced t(2;11)(q37.3;q25) in their mother and a der(11)t(2;11)(q37.3;q25) in the brothers, who therefore have a telomeric monosomy 11q25 and telomeric trisomy 2q37.3 (ie, are aneuploid). Most likely this is not coincidence but a causal effect either due to the monosomy, the trisomy, or both. One robin does not necessarily make for spring. However, in Salt Lake City, we have followed for a long time a large Mormon family segregating for FGS, with premutation fra(X) repeats, bipolar disorder, and a balanced t(2;5)(q37.1;q15) present in the propositus, his younger (affected) carrier sister, and their mother. Thus, between 2q37.1 and 2q37.3, there may be a gene or genes contributing to the phenotype of X-linked FGS. To the best of our knowledge, the Shapiro and colleagues’ family has not been tested for a FGS1/MED12 mutation; and in the Utah family it has not been possible to obtain DNA from the youngest sister of the carrier mother of our propositi. Before the 2q37 hypothesis is dismissed, it must be remembered that, in the Wilhelm Johannsen Center for Functional Genome Research in Copenhagen, a dozen instances of translocations involving 2q37 are recorded with variable manifestations of bipolar disorder, mental retardation, short stature, abnormal hands or feet, seizures, imperforate anus, and other characteristics associated with FGS [30]. On several occasions we have also found FGS boys’ fathers with very broad halluces. Segregation When all sibs of an affected boy or FGS-manifesting girl are examined carefully and followed over the years, we commonly find deviation from a 50:50 segregation ratio in the offspring born to a carrier mother, such that more of them are affected than expected under a hypothesis of normal/regular (ie, Mendelian) segregation. The family in Fig. 10 is a classical example, one of many in our files—so many in fact that this phenomenon cannot be dismissed lightly. If thorough testing by human geneticists experienced in segregation analysis was to find it impossible (after ascertainment correction) to dismiss

Fig. 10. Pedigree of a Midwestern family (not previously published) with 10 FGS-affected children in generation III (P ¼ 1/1024, 0.0009765) and inheritance pattern suggestive of transmission ratio distortion.

158

OPITZ, SMITH, & SANTORO

this observation as apparent artifact, then it becomes imperative to search for an explanation for something of fundamental biological and genetic importance and for genetic counseling. For the moment we refer to this apparent phenomenon as transmission ratio distortion; it is also referred to as preferential segregation [31], meiotic drive [32], segregation distortion, and transmission distortion. Preferential segregation Preferential segregation was discovered by Rhoades [31] in corn (Zea mais) as a consequence of neocentromere formation caused by a large block (‘‘knob’’) of heterochromatin at the tip of the long arm of chromosome 10, with the astonishing effect of causing blocks of heterochromatin on all chromosomes to proceed to the poles of meiosis ahead of normal centromeres. Later it was shown by the Rhoades group that this preferential segregation results from an orientation of knobbed chromatids toward the outer poles of female meiosis [33]. Initial work involved the gene R/r, an anthocyanin pigment marker closely linked to the Abl0 knob. A test cross to the recessive r tester line produced an excess of colorless kernels in a 70:30 rather than an expected 50:50 ratio. Subsequent molecular studies have shown that the Ab10 and most other heterochromatic knobs are composed of thousands of an180-bp repeat with ability to increase recombination throughout the genome. All data to date suggest that at least four different loci are required for meiotic drive in corn [33]. The first case of what Sandler and Novitsky [32] referred to as meiotic drive was observed by Gershenson [34] in wild population of Drosophila obscura, noting that in certain crosses of this fruit fly with males carrying a special X chromosome many more females were produced than males, an effect not accounted for by zygote mortality. Subsequent work by Sturtevant and Dobzhansky [35] showed that, as a result of abnormal spermatogenesis in males with this X chromosome, all sperm (100%) carry an X chromosome [32]. In 1959, Sandler and colleagues [36] described a phenomenon in Drosophila melanogaster apparently analogous to that in corn, naming it segregation distortion due to the Sd gene on chromosome 2. In meiotic drive [32], one member of a pair of homologs, autosomal or X-linked, is preferentially recovered in the progeny of a heterozygote, a phenomenon equally explained by genetic selection (‘‘superiority’’ of a gamete carrying the favored allele) and meiotic drive (ie, an abnormality of the meiotic mechanism). When it was discovered that meiosis was normal in Sd males, it was necessary to redefine meiotic drive as including both gametic selection (with normal meiosis) and meiotic abnormalities preferentially favoring segregation of one allele (or chromosome) over its homolog. Recently, it was discovered that Sd encodes a mutant RanGap protein that normally is a key protein in the Ran signaling pathway required for nuclear transport and other nuclear functions [37]. The question must be asked as to why Ab10 has not swamped the populations of corn and teosinte in which it occurs naturally or has at least attained fixation. The answer seems to be that Ab10 has a deleterious male gamete effect

FG SYNDROMES

159

leading to an evolutionarily stable polymorphism as balance between meiotic drive and gametic selection. The Henikoff and colleagues [38] model for the evolution of centromeric repeats posits an ‘‘arms race’’ between ‘‘selfish’’ centromeres competing for access to the reproductive cells by interacting more efficiently with the kinetochore on one hand, and on the other a variant of histone 3 (CenH3) that associates with the centromeric DNA [38]. The consequences for such coevolution between centromeric DNA and histone are meiotic drive in females and infertility in males with or without distortion of sex ratio in offspring. This can be tested in the 10 nonhomologous human Robertsonian translocations (overwhelmingly dicentric) ascertained at prenatal diagnosis, thus eliminating the ascertainment bias of postnatally detected cases. Daniel [39] has shown that in maternal carriers, the actual ratio of balanced to normal segregants is 1.43:1 (v2 ¼ 6.2.1 df, P < .025, an almost 50% excess of balanced carriers over expectation) as evidence for a substantial meiotic drive. Also, Daniel found 2.5 times more pregnancies to female than to male carriers as indication of reduced male fertility. Thus, meiotic drive appears to be a reality in humans as well as in corn and fruit flies. In humans, Robertsonian translocations are relatively rare and involve only five chromosomes (13, 14, 15, 21, 22). However, there is some evidence for extensive transmission ratio distortion in the human genome. Zo¨llner and colleagues [40] examined genome screen data from 148 nuclear families collected without reference to phenotype and found a ‘‘modest but highly significant’’ genome-wide shift toward excess genetic sharing among sibs for most autosomes and involving many loci. Sex-specific meiotic drive may also be due to an imprinted locus [41]. Important work by de la Casa-Espero´n and colleagues [42] has shown that maternal meiotic drive favoring the inheritance of alleles at the OM locus on mouse chromosome 11 was strongly correlated with the X chromosome inactivation phenotype of (G57BL/6-Pgk1a  DDK) F, mothers. This phenomenon seems related to the well-documented effect of recombination or meiotic drive resulting from nonrandom segregation of chromosomes. The analysis indicates that an allelic difference at an X-linked locus is responsible for modulating levels of recombination in oocytes. Box 4 summarizes the neurodevelopmental phenotype of FGS for infancy and early childhood experienced to date. CLINICAL SPECULATION Autism So many children, mostly boys, with diagnostic criteria of FGS come into the clinic with a diagnosis of autism, mostly without fulfilling conventional diagnostic standards of the diagnosis [43], or as having PDD-NOS, Asperger syndrome, or ‘‘autistic-like manifestations.’’ In our clinics, most of these boys, when addressed engagingly by first name, are able to stop a moment from their perseverate activities, look you straight into the eyes, smile, and cooperate with the examination. However, the large population of such children seen in the

OPITZ, SMITH, & SANTORO

160

Box 4: Neurodevelopmental phenotype of FGS for infancy and early childhood experienced to date Hypotonia, delayed motor development; frequently do not learn to crawl Dysfunction in sensory integration for touch, sound, light, crowds, emotional pressure Oral tactile aversion leading to bolting, choking, aspiration Delayed speech development, frustration, inability to communicate; receptive language frequently much better than expressive abilities Cognitive impairment; mental retardation ([43,44]) Occasional seizures, intestinal migraines ADHD, distractibility, restlessness, inattentiveness, inability to stay on and to complete tasks Mechanical fascinations Loners, or preferring the company of younger playmates Affable, sweet-natured but lability may turn to aggression, self-injury, hurting others, cruelty to animals; Perseverative, attention-seeking Unsafe behavior (eg, getting out of cars and running into traffic, climbing out of windows, falling out of trees) Head banging, pulling hair Unusual tastes (eg, preference for hot spicy foods) Unraveling and eating rugs, sweaters High pain threshold or, less commonly, low pain threshold Obsessive-compulsive disorder, perseverations Oppositional defiant disorder (Before many FGS children learn to say ‘‘mama’’ or ‘‘dada,’’ their first word is an emphatic ‘‘no.’’ To cajole them into collaboration frequently is the parents’ most difficult challenge.) Ticlike disorders (eg, Tourette) aggravated by stress PDD/NOS, Asperger, autism (see below) Sleep disturbances, nightmares, talking in sleep, moving frequently in bed, snoring, sleep apnea, sleep walking Gifts (eg, strong aptitude in mathematics, music, memorization, history, science)

pediatric genetics clinic may not be representative of the ‘‘truly’’ autistic children seen in the pediatric psychiatry clinics. Nevertheless, some commonalities between these two patient groups deserve further study:  

A male preponderance Large head circumference suggested in the autistic children to arise during the first year of life, and in the FGS boys mostly known to be present at birth If

FG SYNDROMES



161

head measurements taken neonatally or at birth are reliable, then the head circumference measurement may be an objective means of discriminating between the two groups of conditions. Common occurrence of constipation and reactive airway disease in both groups of children.

Thus, it would seem reasonable to begin conducting a case control study of both groups of children from two major perspectives: comparative clinical manifestations and analysis of family history. In almost all FGS children, it is possible to document related manifestations in close relatives. In our experience, clear-cut X-linked autism is rare. This disparity between the number of people with documented manifestations and the number of people with clear-cut Xlinked autism invites two possible explanations: (1) We are dealing with two causally different groups of entities, one familial with less severe manifestations, the other mostly sporadic; or (2) the zealous clinical geneticists, a` la Sherlock Holmes, may be seeing FGS manifestations ‘‘under every rock’’ (which has been the suggestion by so many clinical and pediatrics genetics colleagues as communicated to us over the past 35 years in writing or verbally by the parents). Autoimmune disorder One of the most astonishing and common phenomena reported by so many evident or presumed carrier women and an occasional hemizygote is the frequency and variety of autoimmune disorders in themselves and in closely related female (less commonly male) relatives. These include, in order of frequency, ‘‘fibromyalgia/chronic fatigue disorder’’ (with or without elevated erythrocyte sedimentation rate); hypothyroidism requiring thyroid replacement therapy rarely with preceding history of Hashimoto thyroiditis; Crohn disease; rheumatoid arthritis (sometimes severe); lupus erythematosus; (linear) scleroderma; multiple sclerosis/retrobulbar neuritis (at least four times in the authors’ experience); autoimmune inflammatory pericarditis (life-threatening, requiring pericardectomy in one case); autoimmune ‘‘sick sinus’’ syndrome requiring cardiac pacemaker insertion in several members of one family; and many others. NOSOLOGIC ASPECTS Not all short, developmentally delayed boys with hypertelorism and a relatively big head have FGS. Even in those with the additional medical, neurologic, psychologic, and physical findings characteristic of FGS, it is recommended to perform an array–comparative genomic hybridization analysis at least once in a family. A rare FGS-like boy or girl will turn out to have a minute chromosomal deletion or duplication not detectable on a high-resolution banding analysis unrelated to FGS, thus defining a new, private, rarely heritable syndrome (see below). FGS, like virtually all Mendelian traits, has over time undergone false splitting. Thus, the neurofaciodigitorenal syndrome [45] surely is FGS. We also

162

OPITZ, SMITH, & SANTORO

suspect that the so-called ‘‘Neuha¨user-megalocornea syndrome’’ [46] largely represents FGS. We are convinced that at least the first three familial cases and perhaps also some of the sporadic cases of Neuha¨user-megalocornea syndrome represent FGS. The most difficult nosologic challenge in this context involves FGS and the GBBB (so-called ‘‘Opitz’’) syndrome. In at least two-dozen ‘‘cases’’ in our experience, it is impossible, on a clinical basis, to make the distinction between these two entities. Presently, our view is that GBBB is uncommon or rare, while FGS is common. True mental retardation is more common and reflux more severe in the former than in the latter. The minor facial anomalies and physiognomy in GBBB are subtly different and more pronounced than in FGS; the high rather than the flat bridge of nose more likely indicating G/BBB as does cleft lip and palate, uni- or bilateral. To date, severe heart defects, such as tetralogy of Fallot or unilateral pulmonary agenesis, have not been seen in FGS. Hypertelorism, hypospadias, imperforate anus do not distinguish GBBB from FGS. However, so far, laryngeal clefts more severe than grade I have not been recorded in FGS. Normal results of MID1 testing for X-linked ‘‘Opitz’’ syndrome do not rule out GBBB; clear-cut male-to-male transmission is seen only in autosomal dominant ‘‘Opitz’’ syndrome, linked to 22q11.2, gene as yet unidentified. The Atkin-Flaitz syndrome [47] shares many traits with FGS and comprises X-linked mental retardation with multiple congenital anomalies. However, the facial phenotype differs from that seen in FGS, supraorbital ridge being prominent in Atkin-Flaitz syndrome together with obesity and macro-orchidism. So far as is known, Atkin-Flaitz syndrome patients do not manifest the anogenital malformations, constipation, broad thumbs and halluces, deep pilonidal dimple, reflux, recurrent otitis, cowlicks and hair whorl abnormalities, and congenital hypotonia so characteristic of children with FGS. The Jonas-Kimonis-Morales syndrome [48] comprises partial agenesis of corpus callosum, pontine hypoplasia, focal white matter changes, megalencephaly, hypotonia, frontal bossing, hypertelorism, mental retardation, or minor anomalies in a sister and brother, the latter also manifesting a Duane II anomaly and an ectopic right ureter. MRI studies also showed external hydrocephalus. Parents were normal. Autosomal recessive inheritance was postulated. In some fra(X) boys, minor anomalies like those in FGS are seen [49]. However, macro-orchidism and the fra(X) molecular findings clearly differentiate this entity from FGS. Patient 1, a girl, in the report by Dumic and colleagues [50] of the so-called ‘‘Keipert syndrome’’ [51–54] has a facial appearance strikingly reminiscent of that seen in FGS. In that family, there are four instances of male-to-male transmission ruling out X-linked inheritance. However, all the other patients (six so far) of Keipert syndrome reported were males (two sets of brothers and two isolated cases), suggesting involvement of an X-linked gene. That entity consists of sensorineural hearing loss, broad terminal phalanges, hypertelorism,

FG SYNDROMES

163

epicanthic folds, broad nose with high bridge, frontal prominence, and other facultative anomalies, such as pulmonary stenosis, developmental delay, behavior disturbance, and prominent columella. Sensorineural deafness in FGS is uncommon and, if present, tends to be quite severe. The Say-Meyer [55] syndrome is an X-linked recessive condition of intrauterine growth retardation seen in two first cousins with metopic, sagittal, and lambdoid suture synostosis; ventricular septal defect; mild development delay; seizures in one; and, on photographs, high bridge of nose and hypertelorism (not hypotelorism) for head circumference. This entity can probably be differentiated from FGS by appearance alone. The Donnai-Barrow [56] syndrome delineated on the basis of three propositi (one male, two female) and two subsequently affected fetuses comprises greater-than-normal weight at birth, large anterior fontanelle, pronounced hypertelorism with prominent eyes, iris coloboma (in one of five cases), short nose, posteriorly angulated ears, pronounced sensorineural deafness, diaphragmatic hernia (two left, one right), exomphalos/cord hernia, malrotation of bowel, absent corpus callosum (in three of four cases). Overall phenotype and the striking facial appearance are the bases for differentiating Donnai-Barrow syndrome from FGS. There is no excuse anymore for misdiagnosing Sotos or Pelizaeus-Merzbacher syndrome as FGS. Overall phenotype, pointed chin, and the strikingly ruddy cheeks in Sotos syndrome are now amenable to diagnosis on a molecular basis. Any spastic, developmentally delayed boy with large head and nystagmus must be presumed to have Pelizaeus-Merzbacher syndrome. Recent more sophisticated molecular approaches are much more sensitive than the proteolipid protein (PLP) assay formerly available at Indiana University, which caused us to miss the diagnosis in one case. The so-called ‘‘Opitz C-trigonocephaly syndrome’’ is sometimes considered in FGS cases because of the presence of metopic suture synostosis. However, overall phenotype with more severe mental retardation and the presence of multiple buccal frenula serves to distinguish this sporadic (rarely familial) entity from FGS. The Dubowitz syndrome is a more difficult matter. It is the suggested diagnosis in some two-dozen cases in our files referred for small size, craniosynostosis (mostly metopic suture), and blepharophimosis. Craniosynostosis with a small head is an uncommon finding in FGS, however, it was described already in the first reported FG family. Asymmetric blepharophimosis in the original Madison, Wisconsin, prototypic Dubowitz patient together with severe eczema and small size seemed to set this entity apart as a newly delineated causal genesis syndrome (in view of its occurrence in the two sisters described by Victor Dubowitz). Since studies by Grosse and colleagues [57] and Tsukahara and Opitz [58], most Dubowitz cases have been sporadic occurrences. However, in the original Madison ‘‘case,’’ a dramatic genetic development was the birth to the normal sister of the proposita of an identically affected girl. Since there is no such thing in malformation syndromes as an obligatory anomaly that must be present to allow diagnosis of a given entity, occurrence of

164

OPITZ, SMITH, & SANTORO

Dubowitz syndrome without eczema was to be expected. Blepharophimosis has been seen in FGS, as has small head (usually with metopic suture prominence) and an occasional patch of eczema. The cervical vertebral malformations described in Dubowitz syndrome [59] have also been seen in FGS and are not a differentiating criterion. Parents of apparent Dubowitz syndrome children have approached us pointing out that, except for the small head, their child fitted all the criteria of FGS. Cautiously, this suggests that there exists a ‘‘pseudoDubowitz’’ form of FGS in which it may not be necessary to monitor regularly for aplastic anemias/leukemias. This matter evidently requires much additional study. There is considerable phenotypic overlap between FGS and the Lujan-Fryns syndrome. Because both may be due to MED12 mutations, this similarity is a result of allelism [20]. Finally, regarding FG-like ‘‘private’’ aneuploidy syndromes, we recently were privileged to see an infant girl with many FGS manifestations, including congenital hypotonia, developmental delay, sacral dimple, short perineal body, and neurogenic bladder due to tethered cord (operated), constipation, absence of tears with xerophthalmia, congenital torticollis/plagiocephaly, reflux, patent ductus arteriosus (closed spontaneously), lingual frenulum, immune deficiency treated with intravenous immunoglobulin, pigmentary dysplasia, supernumerary nipple (on right side), and skewed X-inactivation (84:16). At the Children’s Hospital of Philadelphia, microarray studies showed a de novo microdeletion 17p3.1. In retrospect, what set her apart from FGS was the presence of multiple cysts (ovary, kidney, supraorbital ridge, a scalp nevus, and a retinal hamartoma in the right eye) and of a wide congenital separation of nasal bones never reported previously in FGS. The phenotype of the type of X-linked mental disability caused by mutations in the polyglutamine-binding-protein 1 [60], also known as Sutherland-Haan syndrome (MRXS3), may be considered nosologically in this context because it comprises developmental delay, shortness of stature, brachycephaly, small testes, and anal stenosis or atresia, with ‘‘complete situs inversus’’ in one. However, consistent microcephaly and spastic diplegia serve to distinguish this entity from FGS. SUMMARY Rarely in the history of medicine has an X-linked mental retardation syndrome so thoroughly entered every branch of medicine, at least of pediatrics, but also of internal medicine, on account of its protean manifestations. In such countries as Zambia, malaria, tuberculosis, HIV, and other infections diseases, and many environmental and nutritional disorders still top the list of childhood morbidity and mortality. However, in the more developed nations of the Old and New Worlds, prematurity, birth defects, and genetic conditions constitute the major burden of infant mortality and chronic childhood handicaps. One of the most pervasive of these is the group of FG syndromes seen in every pediatric clinic and mental health service.

FG SYNDROMES

165

A partial list includes: Peri- and neonatology: prematurity, breech and cesarean section delivery, intrauterine growth retardation, congenital hypotonia, difficulties in neonatal adaptation, feeding difficulties, reflux with or without aspiration, failure to thrive, single umbilical artery, infant death Otology/otorhinolaryngology: severe congenital sensorineural deafness; chronic recurrent otitis; sinusitis and tonsillitis (tonsillectomy and adenoidectomy), stridor/laryngomalacia; grade 1 laryngeal cleft with or without subglottic stenosis; cleft palate; rare choanal stenosis; almost universal narrowing of ear canals with frequent need to remove wax; short lingual frenulum, labiogingival frenulum; conductive hearing loss Ophthalmology: strabismus, congenital nystagmus; large corneae; stenosis of nasolacrymal ducts; lack of tearing; ptosis; blepharophimosis with inturned eyelashes and corneal irritation; errors of refraction, cobolomata Allergy: almost universal reactive airway disease; sometimes eczema, generally rather mild Pulmonology: aspiration pneumonia, atelectasis; sleep apneas and other sleep disturbances that may require continuous positive airway pressure. Gastroenterology: reflux (Nissen), feeding difficulties and failure to thrive (G-button), constipation, diarrhea, pyloric stenosis, and rectal stenosis Urology [61]: hypospadias, inguinal hernia(e), cryptorchidism, hydrocele, renal anomalies, neurogenic bladder, nephrolithiasis Cardiology: patent ductus arteriosus, patent foramen ovale, atrial septal defect, ventricular septal defect, (peripheral) pulmonic stenosis, left superior vena cava, conduction defects, autonomic vascular problems, postnatal hypotension, acrocyanosis/Raynaud General surgery: umbilical hernia, rare diaphragmatic hernia Neurosurgery: Chiari I (beyond 10 mm [62]), syringomyelia, tethered cord, cervical vertebral malformations, rarely true hydrocephalus Radiology: for ‘‘everything,’’ brain MRI and cine-MRI of lower cord recommended in all FGS children, boys and girls Orthopedics: ectrodactyly, polysyndactyly, duplication of thumb, congenital clubfeet, syndactyly, patellar subluxation, hypotonic scoliosis, hypotonic pectus excavatum, unstable hips Plastic surgery: helmet for congenital plagiocephaly/torticollis; occasional hemangiomata Dermatology: pigmentary dysplasias, nevi, warts, melanoma surveillance Physical therapy: hypotonia, hypotonic diplegia, motor delay Occupational therapy: defects of sensory integration (especially oral tactile aversion), feeding therapy, autistic manifestations. Speech therapy: virtually universal speech delay Psychology: evaluation of behavior, autism, cognitive/psychomotor development; psychologic therapy Psychiatry: evaluation for ‘‘autism,’’ behavior and emotional problems (ADHD, oppositional defiant disorder, obsessive-compulsive disorder; bipolar disorder), psychopharmacology, psychotherapy Hematology: follow-up of those with neonatal anemia, neutropenia/leucopenia, thrombocytopenia, and other platelet disorders

166

OPITZ, SMITH, & SANTORO

Infectious disease and rheumatology: immune deficiencies toward potential intravenous immunoglobulin treatment [63], recurrent viral infections, respiratory syncytial virus, rotavirus, bronchiolitis. Pediatric genetics: cytogenetics, molecular genetics, FGS carrier testing, genetic counseling Obstetrics and gynecology: Pregnancies in known FGS carriers require most careful surveillance and such women must be considered at high risk after a prior complicated outcome. In the process, the carrier woman may be discovered to have a uterine malformation (uterus bicornis, septate, duplex) and an unusually short perineal body. There is a much higher probability of cesarean delivery for hypotonia, cephalic dystocia, fetal distress, breech or transverse presentation, failure to progress, and other reasons. Soon molecular prenatal diagnosis will be possible. Pathology: At autopsy a stillborn male infant or fetus with evident congenital hypotonia, hypertelorism, hypospadias, broad thumbs, and halluces. Parents are not present to give a family history and the case may end up being coded ‘‘multiple congenital anomalies, chromosomes (apparently) normal,’’ with no further causal analysis. In the fetal genetic pathology service at the University of Utah, we have begun to add the sentence: ‘‘Consider possibility of FG syndrome and referral to genetics.’’ This takes into account the frequent note of fetal or infant death in FGS sibships evaluated in the pediatric genetics, and the findings in the last three syndromal infant cases referred by the Utah medical examiner, one dying of overwhelming sepsis with dehydration, failure to thrive, and severe constipation after formula change to Neocate with over 100 rock-hard sciboli in colon, and several affected sibs with FGS. Another male died suddenly 1 day after cochlear implant with pronounced congenital hypotonia and megalencephaly. Another was a ‘‘sudden infant death’’ in a male with congenital hypotonia, large head, and urethral megameatus.

Thus, in our experience FGS emerges as the most common yet the least known developmental disabilities condition in our society. FGS imposes a tremendous burden of morbidity, and to some extent also of mortality, on society and families. After successful neonatal adaptation, such recurring problems as otitis, reactive airway disease, and constipation can be routinely treated symptomatically. However, the neurodevelopmental burden represents the greatest challenge that FGS presents for families and to society. Under the best of circumstances, motor and speech development catch up. However, virtually all FGS children, boys and girls, have difficulties in psychologic development, school performance, and ultimate emotional adaptation to adult life and social integration. The many such cases added to those with outright psychiatric disturbances are overwhelming social, psychologic, and psychiatric services and, above all, public and private school systems, which are understaffed, underfunded, beyond formulating individual educational plans, and helpless to deal with the enormous burden of special service needs of these children. It’s time that handicapped children receive care according to needs and not according to diagnosis. However, the near absence of information on FGS available to these professionals is a handicap in arriving at a specific diagnosis (allowing

FG SYNDROMES

167

state and federal support for special services) and in understanding the prognosis, natural history, and such complications as ‘‘autism,’’ seizures, and tethered cord that affect the child’s success at home, in school, and out in society. The FGS parent support group has been of enormous help in informing families about all of these ‘‘issues,’’ and to this day remains the greatest repository of knowledge on FGS. As they say in baseball, it is time at long last for the professionals ‘‘to step up to the plate.’’ Acknowledgments We are profoundly grateful to all FGS patients and families for their gifts of educating us in all aspects of FGS, for their courageous and insightful research into the conditions of their children and relatives, and for sharing that information with us. We thank all collaborating physicians, scientists and other professionals for gradually enlarging over the years our body of knowledge on FGS. We offer deepest appreciation to Feliz Martinez and Meg Weist at the American Journal of Medical Genetics for research support and expert document preparation. We also acknowledge the contributions to the field of Kim Peek and his father, who have made extraordinary efforts to spread knowledge on agenesis of the corpus callosum and associated manifestations to millions of persons throughout the world. References [1] Hehr U, Hehr A, Uyanik G, et al. A filamin A splice mutation resulting in a syndrome of facial dysmorphism, periventricular nodular heterotopia, and severe constipation reminiscent of cerebro-fronto-facial syndrome. J Med Genet 2006;43(6):541–4 [Epub 2005 Nov 18]. [2] Unger S, Mainberger A, Spitz C, et al. Filamin A mutation is one cause of FG syndrome. Am J Med Genet 2007;143A:1876–9. [3] Opitz JM, Kaveggia EG. Studies of malformation syndromes of man 33: the FG syndrome. An X-linked recessive syndrome of multiple congenital anomalies and mental retardation. Z Kinderheilkd 1974;117(1):1–18. [4] Riccardi VM, Ha ¨ ssler E, Lubinsky MS. The FG syndrome: further characterization, report of a third family, and of a sporadic case. Am J Med Genet 1977;1(1):47–58. [5] Opitz JM, Kaveggia EG, Adkins WN, et al. Studies of malformation syndromes of humans XXXIIIC: the FG syndrome-further studies on three affected individuals from the FG family. Am J Med Genet 1982;12(2):147–54. [6] Opitz JM, Rauch AM, Poss A, et al. The FG syndrome: perspective in 2001. Ital J Pediatr 2001;27(5):715–29. [7] Peek F. ‘‘The Real Rain Man.’’ Salt lake City, UT: Harkness; 1996. [8] Treffert DA, Christensen DD. Inside the mind of a savant. Sci Am 2005;108–13. [9] Ozonoff S, Williams BJ, Rauch AM, et al. Behavior phenotype of FG syndrome: cognition, personality, and behavior in eleven affected boys. Am J Med Genet 2000;97(2):112–8 [Summer]. [10] Graham JM, Visootsak J, Ykens E. Clinical and behavioral features in patients with FG (Opitz-Kaveggia) syndrome and a recurrent mutation, p.R961W, in the MED12 gene. Presented at the 13th International Workshop on Fragile X and X-linked Mental Retardation. Venice, Italy, October 3–6, 2007, abstract. [11] Risheg H, Graham JM Jr, Clark RD, et al. A recurrent mutation in MED12 leading to R961W causes Opitz-Kaveggia syndrome. Nat Genet 2007;39(4):451–3.

168

OPITZ, SMITH, & SANTORO

[12] Battaglia A, Chines C, Carey JC. The FG syndrome: report of a large Italian series. Am J Med Genet 2006;140(19):2075–9. [13] Lyon MF. Sex chromatin and gene action in the mammalian X-chromosome. Am J Hum Genet 1962;14:135–48. [14] Available at: www.fg-syndrome.org. [15] email Available at: infofg-syndrome.org. [16] Zhu D, Mitchell TN, Maumenee IH. Mapping of the X-linked FG syndrome to Xq21.31Xq22. Cytogenet Cell Genet 1991;58:2091 [(only) abstract]. [17] Briault S, Hill R, Shrimpton A, et al. A gene for FG syndrome maps in the Xq12-q21.31 region. Am J Med Genet 1997;73(1):87–90. [18] Graham JM Jr, Tackels D, Dibbern K, et al. FG syndrome: report of three new families with linkage to Xq12-q22.1. Am J Med Genet 1998;80(2):145–56. [19] Raynaud M, Dessay S, Ronce N, et al. Skewed X chromosome inactivation in carriers is not a constant finding in FG syndrome. Eur J Hum Genet 2003;11(4):352–6. [20] Schwartz C, Tarpey PS, Herbert AL, et al. The original Lujan syndrome family has a novel missense mutation (p.N1007S) in the MED12 gene. J Med Genet 2007;44:472–7. [21] Briault S, Odent S, Lucas J, et al. Paracentric inversion of the X chromosome [inv(X)(q12q28)] in familial FG syndrome. Am J Med Genet 1999;86(2):112–4. [22] Briault S, Villard L, Rogner U, et al. Mapping of X chromosome inversion breakpoints [inv(X)(q11q28)] associated with FG syndrome: a second FG locus [FGS2]? Am J Med Genet 2000;95(2):178–81. [23] Lossi AM, Colleaux L, Chiaroni P, et al. Exclusion of nine candidate genes for their involvement in X-linked FG syndrome (FGS1) in three families. Am J Med Genet 2000;94(5): 386–8. [24] Dessay S, Moizard MP, Opitz JM. FG syndrome: linkage analysis in two families supporting a new gene localization at Xp22.3 [FGS3]. Am J Med Genet 2002;112(1):6–11. [25] Piluso G, Carella M, D’Avanzo M, et al. Genetic heterogeneity of FG syndrome: a fourth locus (FGS4) maps to Xp11.4-p11.3 in an Italian family. Hum Genet 2003;112(2): 124–30. [26] Piluso G, D’Amico F, Saccone V, et al. A missense mutation in CASK gene causes FG syndrome in an Italian FGS family. Presented at the 13th International Workshop on Fragile X and X-linked Mental Retardation. Venice, Italy, October 3–6, 2007, abstract. [27] Jehee FS, Rosenberg C, Krepischi-Santos AC, et al. An Xq22.3 duplication detected by comparative genomic hybridization microarray (Array-CGH) defines a new locus (FGS5) for FG syndrome. Am J Med Genet 2005;139(3):221–6. [28] Tarpey PS, Raymond FL, Nguyen LS, et al. Mutations in UPF3B, a member of the nonsensemediated mRNA decay complex, cause syndromic and nonsyndromic mental retardation. Nat Genet 2007;39(9):1127–33. [29] Field M, Tarpey PS, Smith R, et al. Mutations in the BRWD3 gene cause X-linked mental retardation associated with macrocephaly. Am J Hum Genet 2007;81:367–74. [30] Available at: www.mcndb.org/browse.fsp?stateid. [31] Rhoades MM. Preferential segregation in maize. Genetics 1942;27(4):395–407. [32] Sandler L, Novitski E. Meiotic drive as an evolutionary force. Am Naturalist 1957;91: 105–10. [33] Birchler JA, Dawe RK, Doebley JF. Marcus Rhoades, preferential segregation and meiotic drive. Genetics 2003;164(3):835–41. [34] Gershenson S. A new sex-ratio abnormality in Drosophila obscura. Genetics 1928;13(6): 488–507. [35] Sturtevant AH, Dobzhansky T. Geographical distribution and cytology of ‘‘sex ratio’’ in Drosophila pseudoobscura and related species. Genetics 1936;21(4):473–90. [36] Sandler L, Hiraizumi Y, Sandler I. Meiotic drive in natural populations of Drosophila melanogaster. I. The Cytogenetic basis of segregation-distortion. Genetics 1959;44(2):233–50.

FG SYNDROMES

169

[37] Kusano A, Staber C, Chan HY, et al. Closing the (Ran) GAP on segregation distortion in Drosophila. Bioessays 2003;25(2):108–15. [38] Henikoff S, Ahmad K, Malik HS. The centromere paradox: stable inheritance with rapidly evolving DNA. Science 2001;293(5532):1098–102. [39] Daniel A. Distortion of female meiotic segregation and reduced male fertility in human Robertsonian translocations: consistent with the centromere model of co-evolving centromere DNA/centromeric histone (CENP-A). Am J Med Genet 2002;111(4):450–2. [40] Zo ¨ llner S, Wen X, Hanchard NA, et al. Evidence for extensive transmission distortion in the human genome. Am J Hum Genet 2004;74(1):62–72. [41] Ubeda F, Haig D. Sex-specific meiotic drive and selection at an imprinted locus. Genetics 2004;167(4):2083–95. [42] de la Casa-Espero´n E, Loredo-Osti JC, Pardo-Manuel de Villena F, et al. X chromosome effect on maternal recombination and meiotic drive in the mouse. Genetics 2002;161(4): 1651–9. [43] Ozonoff S, Williams BJ, Rauch AM, et al. Behavior phenotype of FG syndrome: cognition, personality, and behavior in eleven affected boys. Am J Med Genet 2000;97(2):112–8. [44] Graham JM, Wheeler P. A new X-linked syndrome with agenesis of the corpus callosum, mental retardation, coloboma, micrognatha, and a mutation in the Alpha 4 gene at Xq13. Am J Med Genet A 2003;123(1):37–44. [45] Freire-Maia N, Pinheiro M, Opitz JM. The neurofaciodigitorenal (NFDR) syndrome. Am J Med Genet 1982;11(3):329–36. [46] Neuha ¨ user G, Kaveggia EG, France TD, et al. Syndrome of mental retardation, seizures, hypotonic cerebral palsy and megalocorneae, recessively inherited. Z Kinderheilkd 1975;120(1):1–18. [47] Atkin JF, Flaitz K, Patil S, et al. A new X-linked mental retardation syndrome. Am J Med Genet 1985;21(4):697–705. [48] Jonas RE, Kimonis E, Morales A. Possible new autosomal recessive syndrome of partial agenesis of the corpus callosum, pontine hypoplasia, focal white matter changes, hypotonia, mental retardation, and minor anomalies. Am J Med Genet 1997;73:184–8. [49] Loesch DZ, Hay DA, Sheffield LJ. Fragile X family with unusual digital and facial abnormalities, cleft lip and palate, and epilepsy. Am J Med Genet 1992;44(5):543–50. [50] Dumic M, Kokic DD, Matic T, et al. Daughter and her mildly affected father with Keipert syndrome. Am J Med Genet 2006;140(22):2488–92. [51] Keipert JA, Fitzgerald MG, Danks DM. A new syndrome of broad terminal phalanges and facial abnormalities. Aust Paediatr J 1973;9(1):10–3. [52] Balci S, Dagli S. Keipert syndrome in two brothers from Turkey. Clin Genet 1996;50(4): 223–8. [53] Cappon SM, Khalifa MM. Additional case of Keipert syndrome and review of the literature. Med Sci Monit 2000;6(4):776–8. [54] Reardon W, Hall CM. Broad thumbs and halluces with deafness: a patient with Keipert syndrome. Am J Med Genet 2003;118(1):86–9. [55] Say B, Meyer J. Familial trigonocephaly associated with short stature and developmental delay. Am J Dis Child 1981;135(8):711–2. [56] Donnai D, Barrow M. Diaphragmatic hernia, exomphalos, absent corpus callosum, hypertelorism, myopia, and sensorineural deafness: a newly recognized autosomal recessive disorder? Am J Med Genet 1993;47(5):679–82. [57] Grosse R, Gorlin J, Opitz JM. The Dubowitz syndrome. Z Kinderheilkd 1971;110(3): 175–87. [58] Tsukahara M, Opitz JM. Dubowitz syndrome: review of 141 cases including 36 previously unreported patients. Am J Med Genet 1996;63(1):277–89. [59] Swartz KR, Resnick DK, Iskandar BJ, et al. Craniocervical anomalies in Dubowitz syndrome. Pediatr Neurosurg 2003;38:238–43.

170

OPITZ, SMITH, & SANTORO

[60] Kalscheuer VM, Freude K, Musante L, et al. Mutations in the polyglutamine binding protein 1 gene cause X-linked mental retardation. Nat Genet 2003;35(4):313–5. [61] Smith JF, Wayment RO, Cartwright PC, et al. Genitourinary anomalies in pediatric FG syndrome. J Urol 2007;178:656–9. [62] Gottfried ON, Hedlund GL, Opitz JM, et al. Chiari I malformations in patients with FG syndrome. J Neurosurg 2005;103:148–55. [63] Finocchi A, Palma P, Rossi P, et al. Research letter: transitory hypogammaglobulinemia of infancy in FG syndrome. Am J Med Genet 2005;138A:396–8.