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A distinctive autosomal recessive syndrome of severe disproportionate short stature with short long bones, brachydactyly, and hypotrichosis in two consanguineous Arab families
European Journal of Medical Genetics 55 (2012) 256e264
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European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Original article
A distinctive autosomal recessive syndrome of severe disproportionate short stature with short long bones, brachydactyly, and hypotrichosis in two consanguineous Arab families Stavit A. Shalev a, b, *, Ronen Spiegel a, b, Zvi U. Borochowitz b, c a b c
Genetic Institute, Emek Medical Center, Afula, Israel Rappaport Faculty of Medicine, Technion e Israel Institute of Technology, Haifa, Israel Simon Winter Institute for Human Genetics, Bnai-Zion Medical Center, Haifa, Israel
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 February 2011 Accepted 22 February 2012 Available online 3 March 2012
Disproportionate short stature is a heterogeneous group of hereditary disorders, which are classified according to their mode of inheritance, their clinical skeletal and non-skeletal manifestations, and their radiological characteristics. Herein, we inform on eight individuals with severe disproportionate short stature from two unrelated consanguineous families of Arab-Muslim ancestry. The adult height of the affected individuals is between 112 cm and127 cm, and is due to pre- and post-natal growth retardation, which probably manifests as early as the second trimester of pregnancy. At a young age, the phenotype is characterized by a short stature, a relatively large head, and a long triangular face, and this phenotype later evolves to one with in which the head is relatively small, the mandible is large and pointy. The affected individuals have normal cognitive abilities and lack any neurological deficits. Other typical features include a prominent nose, a voice with an unusual high-pitched sound, relatively small ears, clinodactyly, brachydactyly, small hands, hypoplastic fingernails, a waddling gait, and sparse hair postpubertally. Typical skeletal changes include short long bones, especially the femurs and humeri, with mild metaphyseal changes and very short femoral necks. After due consideration of the other hereditary causes of disproportionate short stature and close examination of the pedigrees of the two families, we concluded that these eight individuals have the same hitherto unreported form of severe disproportionate short stature that is inherited in the autosomal recessive mode. Ó 2012 Elsevier Masson SAS. All rights reserved.
Keywords: Autosomal recessive Disproportionate short stature Brachydactyly
1. Introduction Disproportionate short stature is a heterogeneous group of hereditary disorders, which are classified according to their mode of inheritance, their clinical skeletal and non-skeletal manifestations, and their radiological characteristics. Herein, we inform on eight individuals with severe disproportionate short stature that is inherited in the autosomal recessive mode in two unrelated consanguineous families.
familial relationship or kinship between the two families exists in the traceable history of each family. Family A has five affected individuals (three males) and family H has three affected individuals (two males). All affected individuals have a similar phenotype, which is predominately characterized by a severe disproportionate short stature, and the parents of the affected individuals are consanguineous and healthy with normal height.
2.1. Clinical summaries of the affected individuals in family A 2. Family histories The two families (family A and family H) are of Arab-Muslim ancestry, and live in non-neighbouring villages in northern Israel. Although each family has many consanguineous loops (Fig. 1), no * Corresponding author. Genetic Institute, Emek Medical Center, Afula, Israel. Tel.: þ972 4 6494430; fax: þ972 4 6494425. E-mail address: [email protected] (S.A. Shalev). 1769-7212/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmg.2012.02.011
2.1.1. Individual III-1 (Fig. 1A) This affected individual is a male, and his growth parameters at birth are displayed in Table 1. When he was 3-years-old, he was noted as having a disproportionate short stature with short limbs. He was diagnosed as having Silver-Russell syndrome (SRS) because of his severe growth retardation, his relatively large head with a prominent forehead, his blue sclerae, his clinodactyly, and having an undescended left testis.
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Fig. 1. (A) The pedigree of family A. (B) The pedigree of family H.
Table 1 also displays his growth parameters when he was 30years-old. On examination at this age, he was found to have a disproportionate short stature (Fig. 2d): the upper body segment measured 66 cm, the lower body segment measured 57 cm, and the upper segment: lower segment ratio was increased (1.16). His limbs were short: the upper arm length was 19.5 cm (5 standard deviations (SDS) below the mean for his age) and the lower arm length was 17.5 cm (5 SDS below the mean for his age). His skull is dolichocephalic, and he has a long thin triangular-shaped face with a large long nose and a pointy chin (Fig. 3i). He had sparse scalp and body hair and eyelashes (Fig. 9), and his voice had a peculiar highpitched sound. The inner and the outer canthal distances were 3 cm (50th centile) and 8 cm (10th centile), respectively. Other notable features included a short neck, a wide mouth with slightly small, widely-spaced teeth, some of which were coned-shaped. He had small hands and feet with short digits, all of which were rectangularly-shaped with hypoplastic fingernails (Fig. 4a), and bilateral transverse palmar lines that spanned the palms of his
hands. The extension of his elbows was limited to approximately 160 , and his gait was waddling. On neurological examination, he was found to have normal psychomotor development, hearing, and visual acuity. He was also found to have muscle cramps which were associated with a significantly elevated serum creatinine phosphokinase (CPK) activity. When he was 20-years-old, he was diagnosed as having type 2 diabetes mellitus (T2DM), which was not initially treated with insulin, and was now being treated with subcutaneous insulin in order to better control his glycaemia. Investigation of his infertility after marriage revealed that its cause was oligo-azospermia. He underwent a metabolic and an endocrinological assessment which included determination of serum activities of liver enzymes, serum electrolyte, calcium, and phosphate levels, serum adrenal, thyroid, and pituitary hormone levels, gastrointestinal absorption testing, renal function testing, and renal sonography. All results were found to be normal, except for decreased serum testosterone levels and increased serum
Table 1 Growth parameters at birth and at the last examination of the eight affected individuals from the two families. Individual
Family A III-1
Family A III-2
Family A III-3
Family A V-1
Family A V-2
Family H VII-1
Family H VII-2
Family H VII-3
Sex Birth weight (g) (50th centile equivalent) Birth length (50th centile equivalent) Birth HC (centile) Age at last examination Height at last examination (cm) (centile) HC at last examination (cm) (centile) Arm span at last examination (cm) Palm length at last examination (cm) (centile) Middle finger length at last examination (cm) (centile)
Male 1700 (32WG) NA
Female 2120 (33WG)
Female NA NA
NA 30y 124 cm (-7SDS) 51.5 cm (-3SDS) 122
35 (60) 23y 127 cm (-6SDS) 50 cm (-3SDS) NA
NA 33y 112 cm (-9SDS) 48 cm (-4SDS) 106
Male 1940 (33WG) 40 (30WG) NA 9mo 57 cm (-6SDS) 42 cm (2.5SDS) NA
Male NA
45 (34WG)
Male 1640 (32WG) 40.5 (30WG) NA 14y 112 cm (-6SDS) 47 cm (-4SDS) NA
Male 1700 (32WG) 41.5 (31WG) 34 (25) 33mo 69 cm (-7SDS) 47.5 cm (25)
9 cm (3)
NA NA
8 cm (-3SDS) 4.8 cm (-4SDS)
NA
5.5 cm (-3SDS)
7.5 cm (-4SDS) 5 cm (-4SDS)
NA
NA 24y 120 cm (-7SDS) 50 cm (3.5SD) NA
NA
Female 2080 (33WG) 41.5 (31WG) 31 (-2SD) 9y 85 cm (-8SDS) 48.3 cm (2.5SD) NA
8 cm (-3SDS) 5.2 cm (3.5SDS)
5 cm (-3SDS) 3 cm (3.5SDS)
6 cm (-4SDS) 4 cm (-4SDS)
NA
All affected individuals were born at term. HC e head circumference, mo e months, y e years, cm e centimetres, SDS e standard deviations, NA e data not available WG e weeks gestation. *Information in parentheses refers to either the centile or the number of standard deviations (SDS).
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Fig. 2. Photographs of (A) individual VII-3 from family H at age 7 years, (B) individual VII-1 from family H at age 8 years, and (C) at age 25 years, and (D) individual III-1 from family A at age 22 years when standing in an upright position in order to show their disproportionate short stature with limb shortness and small hands.
Fig. 3. The distinct triangular faces and with a pointy chin and retrognathia noted in all affected individuals. a & b: Individual VII-2 from family H at age 1.5 years. c & d: Individual VII-1 from family H at age 8 years. e & f: Individual VII-3 from family H at age 6 years g: Individual V-1 from family A at age 17 years h: Individual III-2 from family A at age 18 years. i: Individual III-1 from family A at age 22 years. j & k: Individual VII-1 from family H at age 25 years.
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Fig. 4. The hands of three affected individuals. The hands are small with short fingers and hypoplastic fingernails. (a) Individual III-1 from family A at age 22 years. (b) Individual III2 from family A at age 18 years. (c) Individual VII-1 from family H at age 25 years.
luteinizing hormone and follicle-stimulating hormone levels, which were compatible with hypergonadotropic hypogonadism. His peripheral blood karyotype was normal. 2.1.2. Individual III-2 (Fig. 1A) This affected individual is a female, and her growth parameters at birth are displayed in Table 1. Her 1-min APGAR test score was 1, and her 5-min APGAR test score was 7. On clinical examination immediately after her birth, she was found to have a relatively large head with low-set ears and a small retrognathic chin, a head lag, a high palate, and limited abduction of her femurs. The results of serological tests that were done after her delivery did not indicate that these characteristics were due to an intrauterine infection. When she was 3-months-old, her length was 51 cm (3rd centile), her sitting height was 33 cm (3 SDS below the mean for her age), her weight was 3400 g (3rd centile), and her head circumference (HC) was 39 cm (50th centile). She was thought to have SRS due to her growth parameters, her triangular face with a prominent forehead, some asymmetry of her nipples, one café-au-lait spot in her left axilla, and her blue sclerae. When she was 7-years-old, her bone age was consistent that of a 5-year-old girl. When she was 13-years-old, all her long bones including her metacarpal bones were relatively short, and her bone age was consistent with that of a 7- to 8-year-old girl. On clinical examination when she was 23-years-old, her mental development, hearing, and visual acuity were found to be normal, and she had no clinical evidence of a neurological abnormality. Table 1 also displays her growth parameters when she was 23years-old. She reported having normal regular menses, and on clinical examination, her secondary sex characteristics were found to be at Tanner stage III, namely infantile breasts and no axillary hair. Her scalp hair was sparse, and the inner and outer canthal distances measured 2.8 cm (40th centile) and 8 cm (10th centile), respectively. Her palate and teeth were normal (Fig. 3h). She was able to extend her elbows fully, and she had no hyperextensible fingers. The examination of her hands revealed that she has a partial palmar transverse line, her fourth digits were short, and mild clinodactyly (Fig. 4b). On clinical laboratory investigation, which included a complete blood count, determination of serum immunoglobulin levels, liver and kidney function testing, and an extensive metabolic and endocrinological assessment, all results were found to be normal. 2.1.3. Individual V-1 (Fig. 1A) This affected individual is a male, and the result of an ultrasound study that was done during the 30th week of his mother’s pregnancy revealed that he had short limbs. He was born at term, and his growth parameters at birth are displayed in Table 1. His 1-min APGAR test score was 1, and his 5-min APGAR test score was 7.
When he was 1-month-old, his growth parameters were below the 3rd centile, and he was noted as having a triangular-shaped face, normal hair, a big nose, normally placed ears, retrognathia, and clinodactyly. When he was 13-months-old, all his growth parameters were between 4 and 6 SDS below the mean for his age: his body weight was 4300 g, his length was 56 cm, and his HC was 41 cm. On clinical examination, he was found to have dolicocephaly with a prominent metopic suture, a triangular-shaped face with a pointy chin and retrognathia, epicanthal folds, a high nasal bridge, and a big nose. He had normal teeth on the left side of his upper and lower jaw, and all the teeth of the right maxilla were missing. His limbs were short with brachydactyly, and he had hypoplastic distal phalanges and hypoplastic fingernails. No other physical abnormalities were noted. He was re-evaluated when he was 14-years-old, and his growth parameters at this age are displayed in Table 1. On clinical examination, he was found to have normal mental development, hearing, and vision. His voice was hoarse with a peculiar high-pitched sound. He had long face and a wide mouth, and the length of his neck was normal (Fig. 3g). The examination of his hands revealed that he had a partial palmar transverse line, clinodactyly, and hypoplastic fingernails. Although the extension of his elbows was limited to approximately 160 , he had full range of motion in both knees. He had a normal male karyotype. He reported that when he was 5-years-old, his mother became pregnant, and this pregnancy was terminated in its 19th week when the results of the ultrasound examination revealed that the foetus had severe limb shortening. The family declined a request to do a postmortem examination of the aborted foetus. Interestingly, a very low serum oestriol level (0.13 multiples of the median (MOM)) was found in the second trimester of this pregnancy when maternal serum marker screening was done. 2.1.4. Individual III-3 (Fig. 1A) This affected individual is a female and first presented herself when she was 33-years-old (Table 1). On clinical examination, she had a disproportionate short stature, a severe waddling gait, and normal intelligence, hearing, and vision. She was also found to have a marked lack of scalp hair, no eyelashes, sparse eyebrows, mid-face hypoplasia, a prominent nose, and an unusual hoarse high-pitched voice. The clinical examination of hands revealed brachydactyly, clinodactyly, and hypoplastic fingernails. 2.1.5. Individual V-2 (Fig. 1A) This affected individual is a male, who was born at term, and he was the first-born child to his consanguineous parents. His growth parameters are displayed in Table 1. At birth, he was diagnosed as having neonatal asphyxia because his 5-min Apgar score was 0.
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When he was 9-months-old, he was clinically evaluated, and found to have severe growth retardation (Table 1). Specifically, his HC was 42 cm (about 2.5 SDS below the mean for his age), his chest circumference was 32 cm (about 3 SDS below the mean for his age), and his weight was 4200 g (about 6 SDS below the mean for his age). He had high and narrow forehead with a prominent metopic suture, a high nasal bridge, and a haemangioma in the centre of his forehead. The inner canthal distance measured 1.6 cm (about 4 SDS below the mean for his age), and the outer canthal distance measured 5.6 cm (about 3 SDS below the mean for his age). He had malar hypoplasia, long eyelashes, a high palate and a pointy chin with retrognathia. His ears were posteriorly rotated, and their lengths were 4 cm (3rd centile). His neck and chest were short, and the inter-nipple distance measured 7.7 cm (approximately 2.5 SDS below the mean for his age). His limbs were short and his digits had hypoplastic fingernails. When he was 14-months-old, his skeletal survey was summarized as an infant with “translucent bones, flat acetabulum, brachydactyly, short distal phalanges”. These radiographs were not available for our evaluation. He died when he was 18-months-old due to severe pneumonia. 2.2. Clinical summaries of the affected individuals in family H 2.2.1. Individual VII-1 (Fig. 1B) This affected individual is a male (Fig. 2b, Fig. 3c and d), who was first examined at another hospital, and the documentation and results of this medical examination were not available for our assessment (Table 1). He was presented for examination at our hospital when he was 8-years-old. On clinical examination, he was of short stature with short long bones. Specifically, his height was 120 cm (6 SDS below the mean for his age), his weight was 41 kg (4 SDS below the mean for age), his hands were small, his fingers were short, and his fingernails were hypoplastic (Figs. 2c and 3j and k, and Fig. 4c). When he was 24-years-old, he was diagnosed as having T2DM. He was also referred for a chromosomal analysis by infertility experts because of oligo-azospermia, and he was found to have the normal male 46, XY karyotype.
2.2.2. Individual VII-2 (Fig. 1B) This affected individual is a male, who was born at term, and his growth parameters at birth are displayed in Table 1. Throughout his mother’s pregnancy, sequential ultrasound examinations were performed, and the scans revealed a persistent and ever-increasing delayed growth of the femur: the delay in femoral growth in pregnancy week 19 was one week; the delay in pregnancy week 23 was three weeks; and the delay in pregnancy week 30 was seven weeks. When he was 2-months-old, his length was 46.5 cm and his weight was 2300 g, and both measurements were approximately 5 SDS below the mean for this age. His HC at this age was 36.2 cm, (2.5 SDS below the mean for his age). He had a triangular-shaped face with reduced amounts of periorbital sub-dermal fat, a prominent upturned nose, and pointy chin with micrognathia (Fig. 3a and b). His ears were normal, but relatively large (4 cm, 75th centile). His hands were small with short fingers. Specifically, the area of his palms and the lengths of his middle fingers were both at the 10th centile. In addition, the fingers looked like drumsticks, and he had clinodactyly. When he was 33-months-old, his length was 69 cm (6 SDS below the mean for his age), his HC was 47.5 cm (25th centile), and he had brachydactyly with hypoplastic fingernails. His psychomotor development was normal, as were the results of his chromosomal analysis. 2.2.3. Individual VII-3 Fig. 1B This affected individual was reported by Turnpenny and Thwaites [12], and her growth parameters at birth are displayed in Table 1. Briefly, this individual was characterized by her short stature of prenatal onset, dwarfism with limb shortness, and an unusual face. When she was 9-years-old (Fig. 2a), her height was 85 cm (8 SDs below the mean for her age), her HC was 48.3 cm (about 2.5 SDS below the mean for her age) (Table 1), her hands were small (7 cm, 4 SDS below the mean for her age), her fingers were short (middle finger lengths were 4 cm, a length which is about 4 SDS below the mean for her age) and rectangular-shaped, and her fingernails were hypoplastic. She had a triangular-shaped face with a protruding
Fig. 5. Radiographs taken at birth of individual III-1 from family A. This individual has (a) short long bones with no gross modelling defects, (b) sagittal clefting of the vertebral bodies when they are viewed in the anterior-posterior projection, and (c) normal vertebral bodies when they are viewed in the lateral projection.
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Fig. 6. Radiographs of the pelvis and proximal femurs of three affected individuals in order to show the hypoplasia of the proximal epiphyses and mild metaphyseal changes that are seen during childhood evolve into short femoral necks at adulthood. (a) Individual V-1 from family A at age 8 years. (b) Individual III-1 from family A at age 15- years. (c) Individual VII-1 from family H at age 25 years.
forehead and relatively deep-set eyes (Fig. 3e and f), a large nose, and a pointy chin with retrognathia. Her teeth were irregularly positioned and crowded, and she had severe dental decay due to a high level of dental carries. Her skin and hair were dry. The results of a clinical evaluation of her heart, which included echocardiography, revealed normal cardiac anatomy and function. Her mother had had five miscarriages whose reasons were unknown. Her mother also terminated a pregnancy in its 22nd week because the foetus was found to have severe retardation of femoral growth. The family declined a request to do a postmortem examination of the aborted foetus.
very noticeable in these bones during childhood (Fig. 6a). These epiphyseal and metaphyseal changes became less evident at adolescence, and these changes in the femur finally evolved into femurs with a short femoral necks in adulthood (Fig. 6c). The tubular bones of the hands, especially the metacarpals, were short (Fig. 7aec). These bones had cone-shaped epiphyses during childhood (Fig. 7a), and became even shorter towards adulthood (Fig. 7c). No skeletal changes were noted in the radiographs of the iliac wings and the acetabular roof that were taken during infancy, adolescence, and adulthood (Figs. 6 and 8a). 3. Discussion
2.3. Skeletal findings The skeletal findings in all affected individuals at all ages were similar. At birth, all the long bones were short for their age with no major modelling defects. The proximal epiphyses of the tibiae were not ossified (Fig. 5a). Radiologically, the vertebral bodies (Fig. 5b and c) appeared normal, although sagittal clefts were seen throughout the spine when they were viewed in the anterior-posterior projection (Fig. 5b). At infancy and childhood (Figs. 6a and 8b), all the long bones, especially the humeri and femurs, were still short for their age, and mild epiphyseal and metaphyseal changes were
The clinical and radiographic phenotype of the eight affected individuals from these two unrelated families suggests that these individuals were afflicted with a unique form of disproportionate short stature of an identical hereditary origin. To the best of our knowledge, this hereditary condition did not fulfil the diagnostic criteria of any known previously described disorder of disproportionate short stature. Since the differential diagnoses of the eight affected individuals is heterogeneous and includes several dwarfism syndromes, further diagnostic discussion is warranted (Table 2).
Fig. 7. Radiographs of the hands of three affected individuals in order to show their short tubular bones with mild cone-shape epiphyses (a) Individual VII-3 from family H at age 7 years. (b) Individual V-1 from family A at age 17 years. (c) Individual III-1 from family A at age 22 years.
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Fig. 8. (a) Lateral and anterior-posterior radiographs of the spine of individual VII-1 from family H at age 25 years in order to show that the spine has normal radiographic features. (b) Radiographs of the upper and lower limbs of individual V-1 from family A at age 8 years in order to show he shortening of the long bones without any major modelling defects.
A diagnosis of SRS was repeatedly considered in the five affected individuals from family A when they were examined at a young age. However, the consistent lack of body asymmetry, which is considered to be cardinal feature of SRS, as well as the facial phenotype and the evolving relative microcephaly [10], led us to conclude that SRS was probably not the underlying cause of their condition. Although the aetiology of SRS is heterogeneous, most
cases of SRS are sporadic, and most familial cases of SRS have an autosomal dominant mode of inheritance [2]. Notwithstanding, a few familial cases of SRS due to possible autosomal recessive inheritance have been reported, but only two of these reports contained convincing data that the mode of its inheritance was autosomal recessive inheritance. In 1992, Teebi reported six siblings with SRS due to autosomal recessive inheritance, who were
Fig. 9. Photographs of individual III-1 from family A at age 28 years in order to show generalized sparse hair (A) on the chest and abdomen, (B) in the axillae and on the back, and (C) around and on the genitalia.
Present Endocrine problems Present
Present Present Sparse hair Present Absent Absent
SRS ¼ Silver-Russell syndrome, AR ¼ autosomal recessive, AD ¼ autosomal dominant, ID ¼ intellectual disability.
Relative macrocephaly Other features
Present Limb asymmetry
Present Skeletal anomalies
Present
Absent Dental anomalies, behavioural problems
Absent Cardiac/valvular defects, deafness
Microcephaly Cardiac/GI/ immunologic
Absent Present Pigmentary anomalies Microcephaly Absent Present Skin eruptions Present Present Thickened skin Present Present Absent Absent Present Absent Absent Present Absent
Present Absent Absent
Presumably AR Yes Severe Absent Disproportionate AR No Moderate-severe Absent Disproportionate AR Yes Severe Mild Disproportionate Presumably AR Yes Moderate Mild to severe Proportionate AR Yes Moderate- severe Absent Disproportionate Sporadic No Moderate Mild-moderate Proportionate AD Usually no Mild-moderate Usually absent Disproportionate AR Yes Severe Absent Disproportionate Sporadic/AD Yes Moderate Absent Proportoinate
Mode of inheritance Prenatal onset post-natal short stature ID Proportionate/Disproportionate Short stature Brachydactyly Typical facial features Skin/hair involvement
Hypochondroplasia 3M syndrome SRS Syndrome
Table 2 The differential diagnosis of the eight affected individuals with disproportionate short stature.
Floating-Harbor syndrome
Geleophysic dysplasia
Dubowitz syndrome
Osteodysplastic proimordial dwarfism
Acrocapitofemoral dysplasia
Our patients
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born to healthy first-cousin Arab parents [12]. More than a decade later, Ounap et al reported two sisters with SRS due to possible autosomal recessive inheritance [9]. Even if our affected individuals were diagnosed as having SRS while they were still infants, we eliminated this diagnosis as a possibility because of its subsequent clinical course. The skeletal findings in the affected individuals resemble those that are described in hypochondroplasia. The radiological features that are commonly seen in hypochondroplasia include shortening of long bones with mild metaphyseal flare, brachydactyly, and short and broad femoral necks that are associated with spinal and pelvic changes. Although the clinical and radiological diagnostic criteria remain controversial, a definite diagnosis of hypochondroplasia relies on analysis of the FGFR3 gene [1]. The clinical and radiological features of the eight affected individuals in the two unrelated families were not sufficiently convincing that they had hypochondroplasia. Moreover, hypochondroplasia was excluded as the diagnosis because the mode of inheritance of this form of disproportionate short stature isautosomal recessive whereas hypochondroplasia has an autosomal dominant mode of inheritance. Another diagnostic possibility was the 3-M syndrome, which is a heritable low birth weight dwarfism, has an autosomal recessive mode of inheritance, and is caused by mutations in either CUL7 gene [7] or the recently identified OBSTL1 gene [4]. We excluded this diagnosis because this syndrome is characterized by its clinical and skeletal features that include a distinctive face, slender ribs, short long bones, and tall vertebral bodies [15]. In addition, we performed a whole genome single nucleotide polymorphism analysis in several affected individuals, and we did not find any homozygosity in the chromosomal regions that harbour the CUL7 and OBSTL1 genes. Individual VII-3 from family H was reported by Turnpenny and Thwaites when she was 14-months-old [14]. To our best knowledge, there are no familial links between her family and family A, and the two families do not share common ancestors. In addition, the two families live in different regions of northern Israel. Of note, the clinical description of this girl’s phenotype by Turnpenny and Thwaites, which was short stature of prenatal onset, relative macrocephaly, and frontal balding, has significant clinical overlap with the phenotype of the affected individuals from family A, when they were younger. Turnpenny and Thwaites felt that this phenotype shared typical features with Robinow syndrome, a condition that seems mostly unlikely in view of the phenotype and clinical and radiological findings in the other seven affected individuals. The Dubowitz syndrome is characterized by intrauterine growth retardation, and a post-natal short stature that is associated with microcephaly and sparse hair. Other cardinal features of Dubowitz syndrome also include distinctive facial dysmorphic changes, such as ptosis, blepharophimosis, hypertelorism, and an unusual form of severe eczema [13]. Since none of these features were noted in the eight affected individuals, we excluded the Dubowitz syndrome as the underlying cause of the condition on these grounds. Geleophysic dysplasia is a proportionate short stature syndrome with an autosomal recessive mode of inheritance, and is caused by mutations in ADAMTSL2 gene [8]. Our eight patients share several features of this syndrome, which include intrauterine and postnatal growth retardation, very small hands and feet, and normal intelligence. However, our cases lacked several cardinal features of this syndrome that include cardiac and joint anomalies. Nevertheless, we performed linkage analysis with four polymorphic markers around the ADAMTSL2 gene in three patients from both families, and found no homozygous haplotype in this genomic region. The Floating-Harbor syndrome is characterized by a short statute, brachydactyly, and a distinctive face with a small mandible and a prominent nose. These features were present in the affected
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individuals. However, the usual facial appearance of an individual with Floating-Harbor syndrome differed from the facial appearance of the affected individuals that we describe in this report. Recently, heterozygous truncating mutations in the SRCAP gene were reported to cause Floating-Harbor syndrome [6]. The association of short stature, short limbs, brachydactyly, and normal intelligence with autosomal recessive inheritance in our patients may suggest acrocapitofemoral dysplasia. This syndrome is characterized by skeletal findings of which the most typical are cone-shaped epiphyses. Mutations in the IHH gene were found to underlie the syndrome [5]. Linkage analysis performed on 5 individuals ruled out several candidate genes including IHH and SRCAP, implicated in acrocapitofemoral dysplasia and Floating-Harbor syndrome respectively. The metaphyseal dysplasia that characterizes cartilage-hair hypoplasia is typically associated with a fine and sparse hair and a variable degree of immunodeficiency [3]. The lack of any immunological abnormalities in the eight affected individuals, together with the various skeletal changes makes the diagnosis of cartilagehair hypoplasia most unlikely. The two types of osteodysplastic primordial dwarfism have some phenotypic features that are also found in the eight affected individuals. These common phenotypic features include short stature and changes in the proximal femoral metaphyses. Since the two types of osteodysplastic primordial dwarfism are typically associated with extreme microcephaly, a ’bird-face’, and mental retardation [11] it makes the diagnosis of osteodysplastic primordial dwarfism extremely unlikely. In order to diagnose a previously unreported genetic disease, one must (a) meticulously and comprehensively describe the phenotype of the affected individual(s) at all stages of growth, development, and ages, (b) establish its mode of inheritance, and (c) use molecular biological techniques to identify the heritable mutations of the causative gene(s). In this report, we have described eight individuals from two unrelated consanguineous families with a severe form of disproportionate short stature that is associated with hypotrichosis, brachydactyly and peculiar facial features. Examination of the ancestry and pedigrees of the two families suggests that the mode of inheritance is an autosomal recessive mode of inheritance. Although we have not yet done a complete molecular analysis of the genome of the affected individuals, the results of some molecular tests for known heritable forms of disproportionate short stature were able to eliminate some of the other known potential causes of this condition. From the results of the clinical and laboratory examinations, careful analysis of the pedigrees of the two families, and the limited molecular analyses, we conclude that the phenotype of these affected individuals did not fulfil the diagnostic criteria of other known genetic disorders of disproportionate short stature. Moreover, the close clinical and radiographic resemblance of the affected individuals with one another suggests that their disease is caused by the same gene defect. Acknowledgements We would like to thank the family members for their cooperation and patience, and in particular Dr. Abdelhadi Zouabi, the
family physician, for his long- standing helpful collaboration. We are also grateful for the fruitful discussions with Prof. Judy Hall, Emeritus Professor of Pediatrics and Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. The authors also wish to thank Dr. Arieh Bomzon, Consulwrite (www. consulwrite.com) for his editorial assistance in preparing this manuscript.
References [1] G.A. Bellus, E.B. Spector, P.W. Speiser, C.A. Weaver, A.T. Garber, C.R. Bryke, J. Israel, S.S. Rosengren, M.K. Webster, D.J. Donoghue, C.A. Francomano, Distinct missense mutations of the FGFR3 Lye650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype, Am. J. Hum. Genet. 67 (2000) 1411e1421. [2] T. Eggermann, M. Begemann, G. Binder, S. Spengler, SilvereRussell syndrome. Genetic basis and molecular genetic testing, Orphanet. J. Rare. Dis. 19 (2010) 5e10. [3] R.B.J. Glass, C.J. Tifft, Radiological changes in infancy in McKusick cartilage hair hypoplasia, Am. J. Med. Genet. 86 (1999) 312e315. [4] D. Hanson, P.G. Murray, A. Sud, S.A. Temtamy, M. Aglan, A. Superti-Furga, S.E. Holder, J. Urquhart, E. Hilton, F.D. Manson, P. Scambler, G.C. Black, P.E. Clayton, The primordial growth disorder 3-M syndrome connects ubiquitination to the cytoskeletal adaptor OBSL1, Am. J. Hum. Genet. 84 (2009) 801e806. [5] J. Hellemans, P.J. Coucke, A. Giedion, A. De Paepe, P. Kramer, F. Beemer, G.R. Mortier, Homozygous mutations in IHH cause acrocapitofemoral dysplasia, an autosomal recessive disorder with cone-shaped epiphyses in hands and hips, Am. J. Hum. Genet. 72 (2003) 1040e1046. [6] R.L. Hood, M.A. Lines, S.M. Nikkel, J. Schwartzentruber, C. Beaulieu, M.J. Nowaczyk, J. Allanson, C.A. Kim, D. Wieczorek, J.S. Moilanen, D. Lacombe, G. Gillessen-Kaesbach, M.L. Whiteford, C.R. Quaio, I. Gomy, D.R. Bertola, B. Albrecht, K. Platzer, G. McGillivray, R. Zou, D.R. McLeod, A.E. Chudley, B.N. Chodirker, J. Marcadier, FORGE Canada Consortium, J. Majewski, D.E. Bulman, S.M. White, K.M. Boycott, Mutations in SRCAP, encoding SNF2related CREBBP activator protein, cause Floating-Harbor syndrome, Am. J. Hum. Genet. 90 (2012) 308e313. [7] C. Huber, D. Dias-Santagata, A. Glaser, J. O’Sullivan, R. Brauner, K. Wu, X. Xu, K. Pearce, R. Wang, M.L. Uzielli, N. Dagoneau, W. Chemaitilly, A. Superti- Furga, H. Dos Santos, A. Mégarbané, G. Morin, G. Gillessen-Kaesbach, R. Hennekam, I. Van der Burgt, G.C. Black, P.E. Clayton, A. Read, M. Le Merrer, P.J. Scambler, A. Munnich, Z.Q. Pan, R. Winter, V. Cormier-Daire, Identification of mutations in CUL7 in 3-M syndrome, Nat. Genet. 37 (2005) 1119e1124. [8] C. Le Goff, F. Morice-Picard, N. Dagoneau, L.W. Wang, C. Perrot, Y.J. Crow, F. Bauer, E. Flori, C. Prost-Squarcioni, D. Krakow, G. Ge, D.S. Greenspan, D. Bonnet, M. Le Merrer, A. Munnich, S.S. Apte, V. Cormier-Daire, ADAMTSL2 mutations in geleophysic dysplasia demonstrate a role for ADAMTS- like proteins in TGF-beta bioavailability regulation, Nat. Genet. 40 (2008) 1119e1123. [9] K. Ounap, T. Reimand, M.L. Magi, O. Bartsch, Two sisters with SilvereRussell phenotype, Am. J. Med. Genet. 131 (2004) 301e306. [10] S.M. Price, R. Stanhope, C. Garrett, M.A. Preece, R.C. Trembath, The spectrum of SilvereRussell syndrome: a clinical and molecular genetic study and new diagnostic criteria, J. Med. Genet. 36 (1999) 837e842. [11] S. Sigaudy, A. Toutain, A. Moncla, C. Fredouille, B. Bourliere, S. Ayme, N. Philip, Microcephalic osteodysplastic primordial dwarfism TaybieLinder type: report of four new cases and review of the literature, Am. J. Med. Genet. 80 (1998) 16e24. [12] A.S. Teebi, Autosomal recessive SilvereRussell syndrome, Clin. Dysmorphol. 1 (1992) 151e156. [13] M. Tsukahara, J.M. Opitz, Dubowitz syndrome: review of 141 cases including 36 previously unreported patients, Am. J. Med. Genet. 63 (1996) 277e289. [14] P.D. Turnpenny, R.J. Thwaites, Dwarfism, rhizomelic limb shortness, and abnormal face: new short stature syndrome sharing some manifestations with Robinow syndrome, Am. J. Med. Genet. 42 (1992) 724e727. [15] G. van der Wal, B.J. Otten, H.G. Brunner, I. van der Burgt, 3-M syndrome: description of six new patients with review of the literature, Clin. Dysmorphol. 10 (2001) 241e252.
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European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Original article
A distinctive autosomal recessive syndrome of severe disproportionate short stature with short long bones, brachydactyly, and hypotrichosis in two consanguineous Arab families Stavit A. Shalev a, b, *, Ronen Spiegel a, b, Zvi U. Borochowitz b, c a b c
Genetic Institute, Emek Medical Center, Afula, Israel Rappaport Faculty of Medicine, Technion e Israel Institute of Technology, Haifa, Israel Simon Winter Institute for Human Genetics, Bnai-Zion Medical Center, Haifa, Israel
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 February 2011 Accepted 22 February 2012 Available online 3 March 2012
Disproportionate short stature is a heterogeneous group of hereditary disorders, which are classified according to their mode of inheritance, their clinical skeletal and non-skeletal manifestations, and their radiological characteristics. Herein, we inform on eight individuals with severe disproportionate short stature from two unrelated consanguineous families of Arab-Muslim ancestry. The adult height of the affected individuals is between 112 cm and127 cm, and is due to pre- and post-natal growth retardation, which probably manifests as early as the second trimester of pregnancy. At a young age, the phenotype is characterized by a short stature, a relatively large head, and a long triangular face, and this phenotype later evolves to one with in which the head is relatively small, the mandible is large and pointy. The affected individuals have normal cognitive abilities and lack any neurological deficits. Other typical features include a prominent nose, a voice with an unusual high-pitched sound, relatively small ears, clinodactyly, brachydactyly, small hands, hypoplastic fingernails, a waddling gait, and sparse hair postpubertally. Typical skeletal changes include short long bones, especially the femurs and humeri, with mild metaphyseal changes and very short femoral necks. After due consideration of the other hereditary causes of disproportionate short stature and close examination of the pedigrees of the two families, we concluded that these eight individuals have the same hitherto unreported form of severe disproportionate short stature that is inherited in the autosomal recessive mode. Ó 2012 Elsevier Masson SAS. All rights reserved.
Keywords: Autosomal recessive Disproportionate short stature Brachydactyly
1. Introduction Disproportionate short stature is a heterogeneous group of hereditary disorders, which are classified according to their mode of inheritance, their clinical skeletal and non-skeletal manifestations, and their radiological characteristics. Herein, we inform on eight individuals with severe disproportionate short stature that is inherited in the autosomal recessive mode in two unrelated consanguineous families.
familial relationship or kinship between the two families exists in the traceable history of each family. Family A has five affected individuals (three males) and family H has three affected individuals (two males). All affected individuals have a similar phenotype, which is predominately characterized by a severe disproportionate short stature, and the parents of the affected individuals are consanguineous and healthy with normal height.
2.1. Clinical summaries of the affected individuals in family A 2. Family histories The two families (family A and family H) are of Arab-Muslim ancestry, and live in non-neighbouring villages in northern Israel. Although each family has many consanguineous loops (Fig. 1), no * Corresponding author. Genetic Institute, Emek Medical Center, Afula, Israel. Tel.: þ972 4 6494430; fax: þ972 4 6494425. E-mail address: [email protected] (S.A. Shalev). 1769-7212/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmg.2012.02.011
2.1.1. Individual III-1 (Fig. 1A) This affected individual is a male, and his growth parameters at birth are displayed in Table 1. When he was 3-years-old, he was noted as having a disproportionate short stature with short limbs. He was diagnosed as having Silver-Russell syndrome (SRS) because of his severe growth retardation, his relatively large head with a prominent forehead, his blue sclerae, his clinodactyly, and having an undescended left testis.
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Fig. 1. (A) The pedigree of family A. (B) The pedigree of family H.
Table 1 also displays his growth parameters when he was 30years-old. On examination at this age, he was found to have a disproportionate short stature (Fig. 2d): the upper body segment measured 66 cm, the lower body segment measured 57 cm, and the upper segment: lower segment ratio was increased (1.16). His limbs were short: the upper arm length was 19.5 cm (5 standard deviations (SDS) below the mean for his age) and the lower arm length was 17.5 cm (5 SDS below the mean for his age). His skull is dolichocephalic, and he has a long thin triangular-shaped face with a large long nose and a pointy chin (Fig. 3i). He had sparse scalp and body hair and eyelashes (Fig. 9), and his voice had a peculiar highpitched sound. The inner and the outer canthal distances were 3 cm (50th centile) and 8 cm (10th centile), respectively. Other notable features included a short neck, a wide mouth with slightly small, widely-spaced teeth, some of which were coned-shaped. He had small hands and feet with short digits, all of which were rectangularly-shaped with hypoplastic fingernails (Fig. 4a), and bilateral transverse palmar lines that spanned the palms of his
hands. The extension of his elbows was limited to approximately 160 , and his gait was waddling. On neurological examination, he was found to have normal psychomotor development, hearing, and visual acuity. He was also found to have muscle cramps which were associated with a significantly elevated serum creatinine phosphokinase (CPK) activity. When he was 20-years-old, he was diagnosed as having type 2 diabetes mellitus (T2DM), which was not initially treated with insulin, and was now being treated with subcutaneous insulin in order to better control his glycaemia. Investigation of his infertility after marriage revealed that its cause was oligo-azospermia. He underwent a metabolic and an endocrinological assessment which included determination of serum activities of liver enzymes, serum electrolyte, calcium, and phosphate levels, serum adrenal, thyroid, and pituitary hormone levels, gastrointestinal absorption testing, renal function testing, and renal sonography. All results were found to be normal, except for decreased serum testosterone levels and increased serum
Table 1 Growth parameters at birth and at the last examination of the eight affected individuals from the two families. Individual
Family A III-1
Family A III-2
Family A III-3
Family A V-1
Family A V-2
Family H VII-1
Family H VII-2
Family H VII-3
Sex Birth weight (g) (50th centile equivalent) Birth length (50th centile equivalent) Birth HC (centile) Age at last examination Height at last examination (cm) (centile) HC at last examination (cm) (centile) Arm span at last examination (cm) Palm length at last examination (cm) (centile) Middle finger length at last examination (cm) (centile)
Male 1700 (32WG) NA
Female 2120 (33WG)
Female NA NA
NA 30y 124 cm (-7SDS) 51.5 cm (-3SDS) 122
35 (60) 23y 127 cm (-6SDS) 50 cm (-3SDS) NA
NA 33y 112 cm (-9SDS) 48 cm (-4SDS) 106
Male 1940 (33WG) 40 (30WG) NA 9mo 57 cm (-6SDS) 42 cm (2.5SDS) NA
Male NA
45 (34WG)
Male 1640 (32WG) 40.5 (30WG) NA 14y 112 cm (-6SDS) 47 cm (-4SDS) NA
Male 1700 (32WG) 41.5 (31WG) 34 (25) 33mo 69 cm (-7SDS) 47.5 cm (25)
9 cm (3)
NA NA
8 cm (-3SDS) 4.8 cm (-4SDS)
NA
5.5 cm (-3SDS)
7.5 cm (-4SDS) 5 cm (-4SDS)
NA
NA 24y 120 cm (-7SDS) 50 cm (3.5SD) NA
NA
Female 2080 (33WG) 41.5 (31WG) 31 (-2SD) 9y 85 cm (-8SDS) 48.3 cm (2.5SD) NA
8 cm (-3SDS) 5.2 cm (3.5SDS)
5 cm (-3SDS) 3 cm (3.5SDS)
6 cm (-4SDS) 4 cm (-4SDS)
NA
All affected individuals were born at term. HC e head circumference, mo e months, y e years, cm e centimetres, SDS e standard deviations, NA e data not available WG e weeks gestation. *Information in parentheses refers to either the centile or the number of standard deviations (SDS).
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Fig. 2. Photographs of (A) individual VII-3 from family H at age 7 years, (B) individual VII-1 from family H at age 8 years, and (C) at age 25 years, and (D) individual III-1 from family A at age 22 years when standing in an upright position in order to show their disproportionate short stature with limb shortness and small hands.
Fig. 3. The distinct triangular faces and with a pointy chin and retrognathia noted in all affected individuals. a & b: Individual VII-2 from family H at age 1.5 years. c & d: Individual VII-1 from family H at age 8 years. e & f: Individual VII-3 from family H at age 6 years g: Individual V-1 from family A at age 17 years h: Individual III-2 from family A at age 18 years. i: Individual III-1 from family A at age 22 years. j & k: Individual VII-1 from family H at age 25 years.
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Fig. 4. The hands of three affected individuals. The hands are small with short fingers and hypoplastic fingernails. (a) Individual III-1 from family A at age 22 years. (b) Individual III2 from family A at age 18 years. (c) Individual VII-1 from family H at age 25 years.
luteinizing hormone and follicle-stimulating hormone levels, which were compatible with hypergonadotropic hypogonadism. His peripheral blood karyotype was normal. 2.1.2. Individual III-2 (Fig. 1A) This affected individual is a female, and her growth parameters at birth are displayed in Table 1. Her 1-min APGAR test score was 1, and her 5-min APGAR test score was 7. On clinical examination immediately after her birth, she was found to have a relatively large head with low-set ears and a small retrognathic chin, a head lag, a high palate, and limited abduction of her femurs. The results of serological tests that were done after her delivery did not indicate that these characteristics were due to an intrauterine infection. When she was 3-months-old, her length was 51 cm (3rd centile), her sitting height was 33 cm (3 SDS below the mean for her age), her weight was 3400 g (3rd centile), and her head circumference (HC) was 39 cm (50th centile). She was thought to have SRS due to her growth parameters, her triangular face with a prominent forehead, some asymmetry of her nipples, one café-au-lait spot in her left axilla, and her blue sclerae. When she was 7-years-old, her bone age was consistent that of a 5-year-old girl. When she was 13-years-old, all her long bones including her metacarpal bones were relatively short, and her bone age was consistent with that of a 7- to 8-year-old girl. On clinical examination when she was 23-years-old, her mental development, hearing, and visual acuity were found to be normal, and she had no clinical evidence of a neurological abnormality. Table 1 also displays her growth parameters when she was 23years-old. She reported having normal regular menses, and on clinical examination, her secondary sex characteristics were found to be at Tanner stage III, namely infantile breasts and no axillary hair. Her scalp hair was sparse, and the inner and outer canthal distances measured 2.8 cm (40th centile) and 8 cm (10th centile), respectively. Her palate and teeth were normal (Fig. 3h). She was able to extend her elbows fully, and she had no hyperextensible fingers. The examination of her hands revealed that she has a partial palmar transverse line, her fourth digits were short, and mild clinodactyly (Fig. 4b). On clinical laboratory investigation, which included a complete blood count, determination of serum immunoglobulin levels, liver and kidney function testing, and an extensive metabolic and endocrinological assessment, all results were found to be normal. 2.1.3. Individual V-1 (Fig. 1A) This affected individual is a male, and the result of an ultrasound study that was done during the 30th week of his mother’s pregnancy revealed that he had short limbs. He was born at term, and his growth parameters at birth are displayed in Table 1. His 1-min APGAR test score was 1, and his 5-min APGAR test score was 7.
When he was 1-month-old, his growth parameters were below the 3rd centile, and he was noted as having a triangular-shaped face, normal hair, a big nose, normally placed ears, retrognathia, and clinodactyly. When he was 13-months-old, all his growth parameters were between 4 and 6 SDS below the mean for his age: his body weight was 4300 g, his length was 56 cm, and his HC was 41 cm. On clinical examination, he was found to have dolicocephaly with a prominent metopic suture, a triangular-shaped face with a pointy chin and retrognathia, epicanthal folds, a high nasal bridge, and a big nose. He had normal teeth on the left side of his upper and lower jaw, and all the teeth of the right maxilla were missing. His limbs were short with brachydactyly, and he had hypoplastic distal phalanges and hypoplastic fingernails. No other physical abnormalities were noted. He was re-evaluated when he was 14-years-old, and his growth parameters at this age are displayed in Table 1. On clinical examination, he was found to have normal mental development, hearing, and vision. His voice was hoarse with a peculiar high-pitched sound. He had long face and a wide mouth, and the length of his neck was normal (Fig. 3g). The examination of his hands revealed that he had a partial palmar transverse line, clinodactyly, and hypoplastic fingernails. Although the extension of his elbows was limited to approximately 160 , he had full range of motion in both knees. He had a normal male karyotype. He reported that when he was 5-years-old, his mother became pregnant, and this pregnancy was terminated in its 19th week when the results of the ultrasound examination revealed that the foetus had severe limb shortening. The family declined a request to do a postmortem examination of the aborted foetus. Interestingly, a very low serum oestriol level (0.13 multiples of the median (MOM)) was found in the second trimester of this pregnancy when maternal serum marker screening was done. 2.1.4. Individual III-3 (Fig. 1A) This affected individual is a female and first presented herself when she was 33-years-old (Table 1). On clinical examination, she had a disproportionate short stature, a severe waddling gait, and normal intelligence, hearing, and vision. She was also found to have a marked lack of scalp hair, no eyelashes, sparse eyebrows, mid-face hypoplasia, a prominent nose, and an unusual hoarse high-pitched voice. The clinical examination of hands revealed brachydactyly, clinodactyly, and hypoplastic fingernails. 2.1.5. Individual V-2 (Fig. 1A) This affected individual is a male, who was born at term, and he was the first-born child to his consanguineous parents. His growth parameters are displayed in Table 1. At birth, he was diagnosed as having neonatal asphyxia because his 5-min Apgar score was 0.
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When he was 9-months-old, he was clinically evaluated, and found to have severe growth retardation (Table 1). Specifically, his HC was 42 cm (about 2.5 SDS below the mean for his age), his chest circumference was 32 cm (about 3 SDS below the mean for his age), and his weight was 4200 g (about 6 SDS below the mean for his age). He had high and narrow forehead with a prominent metopic suture, a high nasal bridge, and a haemangioma in the centre of his forehead. The inner canthal distance measured 1.6 cm (about 4 SDS below the mean for his age), and the outer canthal distance measured 5.6 cm (about 3 SDS below the mean for his age). He had malar hypoplasia, long eyelashes, a high palate and a pointy chin with retrognathia. His ears were posteriorly rotated, and their lengths were 4 cm (3rd centile). His neck and chest were short, and the inter-nipple distance measured 7.7 cm (approximately 2.5 SDS below the mean for his age). His limbs were short and his digits had hypoplastic fingernails. When he was 14-months-old, his skeletal survey was summarized as an infant with “translucent bones, flat acetabulum, brachydactyly, short distal phalanges”. These radiographs were not available for our evaluation. He died when he was 18-months-old due to severe pneumonia. 2.2. Clinical summaries of the affected individuals in family H 2.2.1. Individual VII-1 (Fig. 1B) This affected individual is a male (Fig. 2b, Fig. 3c and d), who was first examined at another hospital, and the documentation and results of this medical examination were not available for our assessment (Table 1). He was presented for examination at our hospital when he was 8-years-old. On clinical examination, he was of short stature with short long bones. Specifically, his height was 120 cm (6 SDS below the mean for his age), his weight was 41 kg (4 SDS below the mean for age), his hands were small, his fingers were short, and his fingernails were hypoplastic (Figs. 2c and 3j and k, and Fig. 4c). When he was 24-years-old, he was diagnosed as having T2DM. He was also referred for a chromosomal analysis by infertility experts because of oligo-azospermia, and he was found to have the normal male 46, XY karyotype.
2.2.2. Individual VII-2 (Fig. 1B) This affected individual is a male, who was born at term, and his growth parameters at birth are displayed in Table 1. Throughout his mother’s pregnancy, sequential ultrasound examinations were performed, and the scans revealed a persistent and ever-increasing delayed growth of the femur: the delay in femoral growth in pregnancy week 19 was one week; the delay in pregnancy week 23 was three weeks; and the delay in pregnancy week 30 was seven weeks. When he was 2-months-old, his length was 46.5 cm and his weight was 2300 g, and both measurements were approximately 5 SDS below the mean for this age. His HC at this age was 36.2 cm, (2.5 SDS below the mean for his age). He had a triangular-shaped face with reduced amounts of periorbital sub-dermal fat, a prominent upturned nose, and pointy chin with micrognathia (Fig. 3a and b). His ears were normal, but relatively large (4 cm, 75th centile). His hands were small with short fingers. Specifically, the area of his palms and the lengths of his middle fingers were both at the 10th centile. In addition, the fingers looked like drumsticks, and he had clinodactyly. When he was 33-months-old, his length was 69 cm (6 SDS below the mean for his age), his HC was 47.5 cm (25th centile), and he had brachydactyly with hypoplastic fingernails. His psychomotor development was normal, as were the results of his chromosomal analysis. 2.2.3. Individual VII-3 Fig. 1B This affected individual was reported by Turnpenny and Thwaites [12], and her growth parameters at birth are displayed in Table 1. Briefly, this individual was characterized by her short stature of prenatal onset, dwarfism with limb shortness, and an unusual face. When she was 9-years-old (Fig. 2a), her height was 85 cm (8 SDs below the mean for her age), her HC was 48.3 cm (about 2.5 SDS below the mean for her age) (Table 1), her hands were small (7 cm, 4 SDS below the mean for her age), her fingers were short (middle finger lengths were 4 cm, a length which is about 4 SDS below the mean for her age) and rectangular-shaped, and her fingernails were hypoplastic. She had a triangular-shaped face with a protruding
Fig. 5. Radiographs taken at birth of individual III-1 from family A. This individual has (a) short long bones with no gross modelling defects, (b) sagittal clefting of the vertebral bodies when they are viewed in the anterior-posterior projection, and (c) normal vertebral bodies when they are viewed in the lateral projection.
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Fig. 6. Radiographs of the pelvis and proximal femurs of three affected individuals in order to show the hypoplasia of the proximal epiphyses and mild metaphyseal changes that are seen during childhood evolve into short femoral necks at adulthood. (a) Individual V-1 from family A at age 8 years. (b) Individual III-1 from family A at age 15- years. (c) Individual VII-1 from family H at age 25 years.
forehead and relatively deep-set eyes (Fig. 3e and f), a large nose, and a pointy chin with retrognathia. Her teeth were irregularly positioned and crowded, and she had severe dental decay due to a high level of dental carries. Her skin and hair were dry. The results of a clinical evaluation of her heart, which included echocardiography, revealed normal cardiac anatomy and function. Her mother had had five miscarriages whose reasons were unknown. Her mother also terminated a pregnancy in its 22nd week because the foetus was found to have severe retardation of femoral growth. The family declined a request to do a postmortem examination of the aborted foetus.
very noticeable in these bones during childhood (Fig. 6a). These epiphyseal and metaphyseal changes became less evident at adolescence, and these changes in the femur finally evolved into femurs with a short femoral necks in adulthood (Fig. 6c). The tubular bones of the hands, especially the metacarpals, were short (Fig. 7aec). These bones had cone-shaped epiphyses during childhood (Fig. 7a), and became even shorter towards adulthood (Fig. 7c). No skeletal changes were noted in the radiographs of the iliac wings and the acetabular roof that were taken during infancy, adolescence, and adulthood (Figs. 6 and 8a). 3. Discussion
2.3. Skeletal findings The skeletal findings in all affected individuals at all ages were similar. At birth, all the long bones were short for their age with no major modelling defects. The proximal epiphyses of the tibiae were not ossified (Fig. 5a). Radiologically, the vertebral bodies (Fig. 5b and c) appeared normal, although sagittal clefts were seen throughout the spine when they were viewed in the anterior-posterior projection (Fig. 5b). At infancy and childhood (Figs. 6a and 8b), all the long bones, especially the humeri and femurs, were still short for their age, and mild epiphyseal and metaphyseal changes were
The clinical and radiographic phenotype of the eight affected individuals from these two unrelated families suggests that these individuals were afflicted with a unique form of disproportionate short stature of an identical hereditary origin. To the best of our knowledge, this hereditary condition did not fulfil the diagnostic criteria of any known previously described disorder of disproportionate short stature. Since the differential diagnoses of the eight affected individuals is heterogeneous and includes several dwarfism syndromes, further diagnostic discussion is warranted (Table 2).
Fig. 7. Radiographs of the hands of three affected individuals in order to show their short tubular bones with mild cone-shape epiphyses (a) Individual VII-3 from family H at age 7 years. (b) Individual V-1 from family A at age 17 years. (c) Individual III-1 from family A at age 22 years.
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Fig. 8. (a) Lateral and anterior-posterior radiographs of the spine of individual VII-1 from family H at age 25 years in order to show that the spine has normal radiographic features. (b) Radiographs of the upper and lower limbs of individual V-1 from family A at age 8 years in order to show he shortening of the long bones without any major modelling defects.
A diagnosis of SRS was repeatedly considered in the five affected individuals from family A when they were examined at a young age. However, the consistent lack of body asymmetry, which is considered to be cardinal feature of SRS, as well as the facial phenotype and the evolving relative microcephaly [10], led us to conclude that SRS was probably not the underlying cause of their condition. Although the aetiology of SRS is heterogeneous, most
cases of SRS are sporadic, and most familial cases of SRS have an autosomal dominant mode of inheritance [2]. Notwithstanding, a few familial cases of SRS due to possible autosomal recessive inheritance have been reported, but only two of these reports contained convincing data that the mode of its inheritance was autosomal recessive inheritance. In 1992, Teebi reported six siblings with SRS due to autosomal recessive inheritance, who were
Fig. 9. Photographs of individual III-1 from family A at age 28 years in order to show generalized sparse hair (A) on the chest and abdomen, (B) in the axillae and on the back, and (C) around and on the genitalia.
Present Endocrine problems Present
Present Present Sparse hair Present Absent Absent
SRS ¼ Silver-Russell syndrome, AR ¼ autosomal recessive, AD ¼ autosomal dominant, ID ¼ intellectual disability.
Relative macrocephaly Other features
Present Limb asymmetry
Present Skeletal anomalies
Present
Absent Dental anomalies, behavioural problems
Absent Cardiac/valvular defects, deafness
Microcephaly Cardiac/GI/ immunologic
Absent Present Pigmentary anomalies Microcephaly Absent Present Skin eruptions Present Present Thickened skin Present Present Absent Absent Present Absent Absent Present Absent
Present Absent Absent
Presumably AR Yes Severe Absent Disproportionate AR No Moderate-severe Absent Disproportionate AR Yes Severe Mild Disproportionate Presumably AR Yes Moderate Mild to severe Proportionate AR Yes Moderate- severe Absent Disproportionate Sporadic No Moderate Mild-moderate Proportionate AD Usually no Mild-moderate Usually absent Disproportionate AR Yes Severe Absent Disproportionate Sporadic/AD Yes Moderate Absent Proportoinate
Mode of inheritance Prenatal onset post-natal short stature ID Proportionate/Disproportionate Short stature Brachydactyly Typical facial features Skin/hair involvement
Hypochondroplasia 3M syndrome SRS Syndrome
Table 2 The differential diagnosis of the eight affected individuals with disproportionate short stature.
Floating-Harbor syndrome
Geleophysic dysplasia
Dubowitz syndrome
Osteodysplastic proimordial dwarfism
Acrocapitofemoral dysplasia
Our patients
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born to healthy first-cousin Arab parents [12]. More than a decade later, Ounap et al reported two sisters with SRS due to possible autosomal recessive inheritance [9]. Even if our affected individuals were diagnosed as having SRS while they were still infants, we eliminated this diagnosis as a possibility because of its subsequent clinical course. The skeletal findings in the affected individuals resemble those that are described in hypochondroplasia. The radiological features that are commonly seen in hypochondroplasia include shortening of long bones with mild metaphyseal flare, brachydactyly, and short and broad femoral necks that are associated with spinal and pelvic changes. Although the clinical and radiological diagnostic criteria remain controversial, a definite diagnosis of hypochondroplasia relies on analysis of the FGFR3 gene [1]. The clinical and radiological features of the eight affected individuals in the two unrelated families were not sufficiently convincing that they had hypochondroplasia. Moreover, hypochondroplasia was excluded as the diagnosis because the mode of inheritance of this form of disproportionate short stature isautosomal recessive whereas hypochondroplasia has an autosomal dominant mode of inheritance. Another diagnostic possibility was the 3-M syndrome, which is a heritable low birth weight dwarfism, has an autosomal recessive mode of inheritance, and is caused by mutations in either CUL7 gene [7] or the recently identified OBSTL1 gene [4]. We excluded this diagnosis because this syndrome is characterized by its clinical and skeletal features that include a distinctive face, slender ribs, short long bones, and tall vertebral bodies [15]. In addition, we performed a whole genome single nucleotide polymorphism analysis in several affected individuals, and we did not find any homozygosity in the chromosomal regions that harbour the CUL7 and OBSTL1 genes. Individual VII-3 from family H was reported by Turnpenny and Thwaites when she was 14-months-old [14]. To our best knowledge, there are no familial links between her family and family A, and the two families do not share common ancestors. In addition, the two families live in different regions of northern Israel. Of note, the clinical description of this girl’s phenotype by Turnpenny and Thwaites, which was short stature of prenatal onset, relative macrocephaly, and frontal balding, has significant clinical overlap with the phenotype of the affected individuals from family A, when they were younger. Turnpenny and Thwaites felt that this phenotype shared typical features with Robinow syndrome, a condition that seems mostly unlikely in view of the phenotype and clinical and radiological findings in the other seven affected individuals. The Dubowitz syndrome is characterized by intrauterine growth retardation, and a post-natal short stature that is associated with microcephaly and sparse hair. Other cardinal features of Dubowitz syndrome also include distinctive facial dysmorphic changes, such as ptosis, blepharophimosis, hypertelorism, and an unusual form of severe eczema [13]. Since none of these features were noted in the eight affected individuals, we excluded the Dubowitz syndrome as the underlying cause of the condition on these grounds. Geleophysic dysplasia is a proportionate short stature syndrome with an autosomal recessive mode of inheritance, and is caused by mutations in ADAMTSL2 gene [8]. Our eight patients share several features of this syndrome, which include intrauterine and postnatal growth retardation, very small hands and feet, and normal intelligence. However, our cases lacked several cardinal features of this syndrome that include cardiac and joint anomalies. Nevertheless, we performed linkage analysis with four polymorphic markers around the ADAMTSL2 gene in three patients from both families, and found no homozygous haplotype in this genomic region. The Floating-Harbor syndrome is characterized by a short statute, brachydactyly, and a distinctive face with a small mandible and a prominent nose. These features were present in the affected
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individuals. However, the usual facial appearance of an individual with Floating-Harbor syndrome differed from the facial appearance of the affected individuals that we describe in this report. Recently, heterozygous truncating mutations in the SRCAP gene were reported to cause Floating-Harbor syndrome [6]. The association of short stature, short limbs, brachydactyly, and normal intelligence with autosomal recessive inheritance in our patients may suggest acrocapitofemoral dysplasia. This syndrome is characterized by skeletal findings of which the most typical are cone-shaped epiphyses. Mutations in the IHH gene were found to underlie the syndrome [5]. Linkage analysis performed on 5 individuals ruled out several candidate genes including IHH and SRCAP, implicated in acrocapitofemoral dysplasia and Floating-Harbor syndrome respectively. The metaphyseal dysplasia that characterizes cartilage-hair hypoplasia is typically associated with a fine and sparse hair and a variable degree of immunodeficiency [3]. The lack of any immunological abnormalities in the eight affected individuals, together with the various skeletal changes makes the diagnosis of cartilagehair hypoplasia most unlikely. The two types of osteodysplastic primordial dwarfism have some phenotypic features that are also found in the eight affected individuals. These common phenotypic features include short stature and changes in the proximal femoral metaphyses. Since the two types of osteodysplastic primordial dwarfism are typically associated with extreme microcephaly, a ’bird-face’, and mental retardation [11] it makes the diagnosis of osteodysplastic primordial dwarfism extremely unlikely. In order to diagnose a previously unreported genetic disease, one must (a) meticulously and comprehensively describe the phenotype of the affected individual(s) at all stages of growth, development, and ages, (b) establish its mode of inheritance, and (c) use molecular biological techniques to identify the heritable mutations of the causative gene(s). In this report, we have described eight individuals from two unrelated consanguineous families with a severe form of disproportionate short stature that is associated with hypotrichosis, brachydactyly and peculiar facial features. Examination of the ancestry and pedigrees of the two families suggests that the mode of inheritance is an autosomal recessive mode of inheritance. Although we have not yet done a complete molecular analysis of the genome of the affected individuals, the results of some molecular tests for known heritable forms of disproportionate short stature were able to eliminate some of the other known potential causes of this condition. From the results of the clinical and laboratory examinations, careful analysis of the pedigrees of the two families, and the limited molecular analyses, we conclude that the phenotype of these affected individuals did not fulfil the diagnostic criteria of other known genetic disorders of disproportionate short stature. Moreover, the close clinical and radiographic resemblance of the affected individuals with one another suggests that their disease is caused by the same gene defect. Acknowledgements We would like to thank the family members for their cooperation and patience, and in particular Dr. Abdelhadi Zouabi, the
family physician, for his long- standing helpful collaboration. We are also grateful for the fruitful discussions with Prof. Judy Hall, Emeritus Professor of Pediatrics and Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. The authors also wish to thank Dr. Arieh Bomzon, Consulwrite (www. consulwrite.com) for his editorial assistance in preparing this manuscript.
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