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Costello syndrome: Phenotype, natural history, differential diagnosis, and possible cause
C
Costello syndrome: Phenotype, natural history, differential diagnosis, and possible cause
John P. Johnson, MD, Mahin Golabi, MD, Mary E. Norton, MD, Robert M. Rosenblatt, MD, Gary M. Feldman, MD, Samuel P. Yang, MD, Bryan D. Hall, MD, Melissa H. Fries, MD, and John C. Carey, MD
We describe 8 patients affected with Costello syndrome including an affected sib pair and review the literature on 29 previously reported cases. We emphasize an association with advanced parental age, which is consistent with autosomal dominant inheritance with germline mosaicism. The pathogenesis appears to involve metabolic dysfunction, with growth disturbance, storage disorder appearance, acanthosis nigricans, hypertrophic cardiomyopathy, and occasional abnormalities of glucose metabolism. Although the cause is currently unknown, Costello syndrome is interesting because of a potential genetic-metabolic etiology. (J Pediatr 1998;133:441-8)
In 1971 and 1977, Costello1,2 described a syndrome of mental and growth retardation, distinctive physical appearance, and verrucous papillomata of the nose. The condition involves prenatal overgrowth, postnatal failure to thrive, and a distinctive appearance, with craniofacial findings resembling those observed in lysosomal storage disorders. Dermatologic manifestations include soft skin with excess wrinkling over the dorsum of the hands and deep creases on the palms and soles, hyperextensibility of digits, generalized hyperpigmentation, pigmented nevi often on the palms and soles, vascular birthmarks, papillomata that develop at later ages around the nares, mouth, anus, or less commonly elsewhere on the body, and acanthosis nigricans. Affected individuals manifest
prenatal polyhydramnios and postnatal feeding difficulty, have severe short stature and mental retardation, and may have a silent or clinically significant hypertrophic cardiomyopathy. After the initial descriptions, there were no further reports of similarly affected patients until presentations in 1981, 1989, and 1990.3-5 However, a specific diagnosis was not made in these patients. Full reports of patients with diagnosed Costello syndrome occurred in 1991.6,7 Simultaneously, there was a preliminary report of 5 individuals with the so-called “Faciocutaneousskeletal” syndrome8,9 and subsequently recognition that all of the patients discussed previously likely had the same condition.10-16 Since this apparently relatively common syndrome was rediscovered, there have
From the Division of Medical Genetics, Children’s Hospital Oakland, California; the Department of Pediatrics, University of California, San Francisco, California; Sonoma Developmental Center, Eldridge, California; Tri-Counties Regional Center, Oxnard, California; Grace Pediatrics, Davis, California; the Department of Pediatrics, University of Kentucky, Lexington, Kentudky; and the Department of Pediatrics, University of Utah, Salt Lake City, Utah. Submitted for publication July 23, 1997; revisions received Nov 11, 1997, Feb 2, 1998, and May 12, 1998; accepted May 28, 1998. Reprint requests: John P. Johnson, MD, Medical Genetics, Shodair Hospital, PO Box 5539, Helena, MT 59604-5539. Copyright © 1998 by Mosby, Inc. 0022-3476/98/$5.00 + 0 9/21/92090
been numerous reports, primarily in the genetics literature.17-37 The varied manifestations of CS point toward a likely biochemical basis. In this report we describe 8 patients with CS, 2 of whom are siblings, and discuss the unique findings, course, differential diagnosis, and potential cause of this disorder. CS
Costello syndrome
CLINICAL REPORTS AND LITERATURE REVIEW Parental ages, pregnancy complications, birth weight and percentile, and previous patient presentations are detailed in Table I. Clinical findings are listed in Table II.
Patient 1 (Fig 1) This 8-year-old boy had early feeding problems and aspiration pneumonia requiring tracheostomy, gastrostomy, and Nissen fundoplication. A partial resection of salivary glands was performed because of hypersecretion. Laboratory studies and analyses of muscle and liver biopsy specimens were normal. Growth had decelerated to less than the third percentile for weight and length, with preservation of head circumference. On neurologic evaluation there was considerable developmental delay with nystagmoid eye movements in infancy, and IQ was estimated at 23. Hypertrophic cardiomyopathy with irregular conduction defects developed, and atrial fibrillation became significantly symptomatic. When not bedridden from cardiac fatigue, the patient was able to scoot around, use a wheelchair, or move with a special walker, and generally com441
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THE JOURNAL OF PEDIATRICS SEPTEMBER 1998 municated nonverbally in a sociable way. Heat intolerance was noted. A cataract developed in the left eye, and renal stones formed in the right kidney. The patient died after an episode of bowel obstruction with ileus and volvulus complicated by shock, congestive heart failure, and resulting multiple organ failure.
Patient 2 (Fig 2) This now 7 1⁄2-year-old boy had required 4 days of intubation after birth. Joint contractures and poor feeding were noted, and gastrostomy and Nissen procedures were performed at 5 months. Within the first year concentric left ventricular thickening and valvular insufficiency developed but did not limit activity. Peroneal hypertonicity required treatment with ankle orthotics and Achilles tendon lengthening. Brain magnetic resonance imaging showed mild cerebral atrophy. Laboratory studies showed minimal generalized aminoaciduria. At age 7 1⁄2 years speech has just progressed to 2-word phrases, but nonverbal communication, especially receptive, is good. The voice is normal. Increased sweating is present. Walking developed by age 3 1⁄2 years, but braces are used, assistance is required with stairs, and running is not possible. Small oral feedings are now accepted.
Patient 3 (Fig 3) Fig 1. A, Patient 1 at age 18 months. B, Patient 1; hands at age 8 months. Note deep palmar creases. Table I. Parental age, pregnancy history, and previous presentations of 8 patients with CS*
Patient
Parental ages
Pregnancy
1 2
M 32 F 33 M 40 F 45
3 4
M 34 F 45 M 40 F 48
5
M 45 F 45
6 7
M 30 F 30 M 36 F 36
8
M 29
Term Excessive movement, polyhydramnios 36 wk Polyhydramnios, fetal arrhythmia Excessive movement, 36 wk Polyhydramnios Polyhydramnios, 36 wk twins Excessive movement, minimal weight gain
M, Mother’s age (years), F, father’s age (years); %ile, percentile. *Reported in published abstracts.3-5,15,16
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Birth weight (%ile) 10 lb 5 oz, >97% 8 lbs 5 oz, 75% 8 lb 6 oz, 90% 8 lb 10 oz, 75% 7 lb 13 oz, 75% 6 lb 3 oz, 10% 4 lb 15 oz, 75% 7 lb 15 oz, 50%
This now 5-year-old boy had a gastrostomy and Nissen fundoplication performed because of poor feeding after birth. Laboratory studies included normal lysosomal enzymes, long chain fatty acids, and urinary oligosaccharides but elevated hexosaminidase B of uncertain cause and mild increases in urinary amino acids (cysteine, lysine, ornithine). Skeletal radiographs and computed tomography scan of the brain were normal. Atrial flutter and fibrillation have been persistent. Resection of muscular subpulmonic stenosis was performed, but further hypertrophy of the left ventricle and septum has occurred. Development is delayed, with walking and talking by approximately age 4 years. The personality is outgoing, and the voice is hoarse. Linear and weight growth are poor with preservation of head circumference.
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Patient 4 (Fig 4) This now 11-year-old boy had fetal arrhythmias, and evaluation at birth found supraventricular tachycardia and bicuspid aortic valve. Left atrial and ventricular hypertrophy developed, as did pulmonic stenosis and mitral valve and aortic outflow obstruction. A rotatory nystagmus was present in infancy. Postnatal feeding difficulties were encountered. Pyloric stenosis was discovered and corrected at 7 weeks. Gastrostomy and Nissen fundoplication were required for feeding. Laboratory investigations were normal except for slightly increased prolactin. Skin and conjunctival biopsy specimens showed no storage material on electron microscopy studies. Growth in height and weight is well below the 3rd percentile with normal head circumference. At age 9 years papillomata developed around the nose. The boy is in school in special education classes.
Patient 5 This now 32-year-old man fed poorly after birth, and this has become a lifelong problem. A seizure disorder developed after an episode of varicella. Development was delayed with sitting by age 2 years and walking by age 4 years. In the teen years behavioral issues were prominent. Radiographs and electron microscopy of white cells were normal. Growth in height and weight have been significantly subnormal, with normal head circumference. A skin tag was present on the right buttocks, and a “wart” was present on the right knee. There was a cafe-au-lait spot on the right elbow, and multiple small dark nevi were present on the palms, soles, and face. The patient was last seen at age 18 years.
Fig 2. Patient 2 at age 3 years.
Patient 6 (Fig 5) This now 18-year-old male patient had poor feeding after birth attributed to a large tongue, with sucking being normal. Nasogastric feedings were instituted, but bottle and oral feeding of solids developed by 18 months. Significant failure to thrive developed, with weight, length, and head circumference all below the 3rd percentile despite adequate caloric intake. Laboratory investigations were normal, but EM of fibroblasts did show cytoplasmic vac-
Fig 3. A, Patient 3 at age 7 months; B, Patient 3; feet at age 3 months. Note positional deformity and deep creases.
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THE JOURNAL OF PEDIATRICS SEPTEMBER 1998 but generally uses a wheelchair at school. Orthopedic complications and corrective surgeries are many including for severe kyphosis (87 degrees). No cardiac involvement has occurred. Increased sweating and heat intolerance have been problematic. Speech is fluent and ample with hoarse character, but development and intellect have always indicated function at approximately half the chronologic age. The personality is outgoing and friendly. This patient continues to attend school at age 18 years and is experiencing late pubertal development.
Patient 7 (Fig 6) This is a sister born 6 years after patient 6. Severe failure to thrive developed after birth. There was a cataract in one eye. Increased sweating was noted. A persistent tachycardia, atrial in origin, did not respond to digoxin, and the patient eventually died of cardiomyopathy and malnutrition at approximately age 2 years. Weight at death was only 4 lbs, 9 oz, with a length of 15 in (with knee contractures). Autopsy showed only dilation of the right atrium. Brain neuropathology showed dilated cerebral ventricles, decreased white matter, small brainstem, and dysmyelination of the basal ganglia.
Fig 4. Patient 4 at age 5 years.
Patient 8 (Fig 7)
Fig 5. Patient 6 at age 16.5 years.
uoles. Development of motor milestones was especially delayed, with assisted sitting by age 3 years, and no walking has ever been possible. Truncal hypotonia has 444
generally been observed, although there is hypertonia in the lower extremities. Nasal and facial papillomata developed in the late teens. The patient scoots around
This now almost 15-year-old boy required a ventilator for 10 days after birth. He had seizures with abnormal electroencephalography, hypoglycemia, and poor feeding requiring gavage. A cranial computed tomography scan later showed leukomalacia. Cardiac catheterization at age 2 years showed subvalvular aortic stenosis, and ultrasonography showed systolic anterior motion of the mitral valve and asymmetric ventricular hypertrophy. Cardiac surgery was done at age 2 1⁄2 years, and residual aortic insufficiency is present. Acanthosis nigricans has developed in the neck region. Workup has included normal skin fibroblast analysis of collagen, mucopolysaccharides, mucolipids, and sphingolipids. When the patient was last seen at age 5 years, developmental progress included the use of approximately 2 dozen words and occasional 3word sentences. Walking occurred at ap-
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proximately age 2 years. Surgical lengthening of the Achilles tendon at age 9 years was required because of eversion on the right.
FREQUENT CLINICAL FINDINGS IN REPORTED PATIENTS WITH CS Signs, symptoms, and laboratory findings in 29 patients with CS described in the literature are summarized in Table II. Not listed is the peculiar finding of hoarse voice (patients 3 and 6), with laryngeal papillomata and webbing perhaps explaining this in 1 case.18 Radiographic studies and brain magnetic resonance imaging are generally normal, with the exception of delayed bone age and osteoporosis.21,31,34 Laboratory studies are generally unremarkable including karyotype, endocrine testing, and metabolic studies, with some exceptions described in the following text.
Fig 6. Patient 7 (sibling of patient 6) at age 18 months.
Natural History of CS The clinical course of patients with CS is interesting and provides some clues to the pathogenesis. Before birth there is polyhydramnios in almost 50%, increased (patients 2 and 5) or decreased2,27 fetal movement, and overgrowth, mainly in weight (generally exceeding 50th percentile) and often in head circumference. The polyhydramnios presumably reflects poor fetal swallowing,38 which continues after birth, with severe feeding problems and failure to thrive. Nissen fundoplication and gastrostomy have often been required (patients 1, 2, and 4). In patient 1 there was difficulty maintaining the airway with excessive secretions and aspiration pneumonia, consistent with reports of stridor and opisthotonos in other patients.22,29 The abnormal swallowing, feeding, and protection of the airway presumably reflect abnormal central nervous system function. This is also apparent in hypotonia, secondary joint contractures, severely delayed motor and intellectual milestones, nystagmus, and strabismus. Edema presenting at birth (30, patient 3) or evident by deeply set nails may also
Fig 7. Patient 8 at age 3.5 years.
indicate altered neurologic status.39 The biphasic growth pattern of prenatal overgrowth and postnatal failure to thrive indicates potential metabolic dysfunction, which is compensated in the intrauterine environment. Later growth is more normal, and development generally exceeds that expected early in life, with sociable personality an asset.29 The cardiac involvement includes the spectrum of congenital defects produced by abnormal
prenatal blood flow40 including atrial septal defects, pulmonic stenosis, bicuspid aortic valve, mitral valve anomalies, and ventricular septal defects. The cardiomyopathy that develops is almost exclusively hypertrophic, involving the subaortic region, septum, mitral valve,7,22 and occasionally the subpulmonic region. Arrhythmias are common before and after birth, and an abnormal conduction system has been found on au445
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Table II. Historical, physical, and laboratory findings in 37 patients with CS
Trait Sex Polyhydramnios BW ≥50th % Poor feeding Poor growth CNS Delay Atrophy Personality outgoing Craniofacial Birth OFC ≥50th % Coarse facial appearance Downslanting fissures Epicanthal folds Strabismus Flat nasal bridge Thick lips Macroglossia Macrostomia Low set ears Musculoskeletal Short neck Increased anteroposterior diameter-chest Hernia Elbow limitation Extensible fingers Wide phalanges Ulnar deviation-hand Abnormal foot position Tight Achilles tendon Skin Curly hair Dysplastic nails Loose skin Hyperkeratotosis-palms Deep creases-palms/soles Hyperpigmentation Nevus flammeus Acanthosis nigricans Sparse hair Thick eyebrows Papillomatosis Cardiovascular HCM Dysrhythmia CHD Laboratory Abnormal amino acids Bone age delayed
Pt 1
Pt 2
Pt 3
Pt 4
Pt 5
Pt 6
Pt 7
Pt 8
Lit
Total
%
M – + + +
M + + + +
M + + + +
M + + + +
M + + + +
M + – + +
F + + + +
M – + + +
12M17F 11/27 25/28 26/26 29/29
19M18F 17/35 32/36 34/34 37/37
M:F 1.1 49 89 100 100
+ – +
+ + +
+ – +
+ – +
+
+
+
+
+ + +
+ + +
29/29 8/17 20/22
37/37 11/23 28/30
100 48 93
+ + + + + + + + + +
+ + + – + + + + + +
+ + + + – + + + – +
+ + + + – + + + + +
+ + + + + + + + + +
– + + + + + + + + +
– + + + + + + + +
– + + + – + + + + +
25/29 27/27 15/27 20/23 13/19 23/25 25/27 6/10 20/23 26/26
30/37 35/35 23/35 27/31 17/26 31/33 33/35 14/18 27/31 34/34
81 100 66 87 65 94 94 78 87 100
+ –
+ +
+ +
+ +
+ +
+ +
+ –
+ –
26/26 19/20
34/34 24/28
100 86
– – + + – –
+ + + – + + +
– + – + – + +
+ + + + – +
– + + +
– + + +
– + +
+ + + + + + +
11/15 13/21 19/20 17/18 5/12 20/22 12/14
14/23 20/29 26/28 23/25 7/17 25/28 15/17
61 69 93 92 41 89 88
+ – + – + + – – + + –
+
+
+
+
+
+ + + + + – + + +
+ + + + – – + + +
+ + + + – – + + –
+ + + + + + – + + + –
24/27 11/16 25/25 12/16 21/21 19/19 6/14 5/19 20/24 15/22 14/24
31/34 12/18 33/33 17/23 29/29 25/25 9/22 6/27 28/32 23/30 17/32
91 67 100 74 100 100 41 22 88 77 53
+ – –
8/16 8/16 11/14
15/23 13/23 15/19
65 56 79
– +
1/11 13/16
4/17 17/20
24 85
+
+ – +
+
+ – + + –
+ – + + –
+ + + + – – + + +
+ + +
+ – +
+ + +
+ + +
+ +
– +
+
+
– +
+
+
+ +
+
BW, Birth weight; ≥50th %, greater than or equal to 50th percentile; CNS, central nervous system; OFC, head circumference; HCM, hypertrophic cardiomyopathy; CHD, congenital heart disease; +, present; –, absent; Lit, literature patients; Pt, patients in this report. Blank in individual cell indicates that the finding is not noted to be either present or absent. Numerator = finding present or ascertained; denominator = finding mentioned on examination.
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THE JOURNAL OF PEDIATRICS VOLUME 133, NUMBER 3 topsy.33 It is remarkable that cardiac symptoms have been essentially minor and nonprogressive, with the exception of patients 1 and 7 and the patient described by Fukao et al,36 who were significantly compromised by their involvement. Management of the cardiac disease has little clinical impact. The distinctive and almost pathognomonic skin papillomata seem to appear later in life24 and have a predilection for areas around mucous membranes (nose, mouth, anus). As in patient 1, orthopedic complications can become severe. Seven deaths have occurred in reported patients9,20,33,36 and in our patients 1 and 7, with different causes and no consistent pattern. The oldest patient in this series is patient 5, last seen at age 18 years and presumably alive at age 32 years. Costello37 has recently revisited cases 1 and 2 at ages 32 and 27 years, respectively. Case 1 has developed hypertension, a ruptured cornea with keratoconus, and duodenal ulcer with gastroesophageal reflux. Case 2 developed fibroadenomata in the breast, lichenified eczema of the neck, and hypertrophic cardiomyopathy with supraventricular tachycardia.
DISCUSSION The diagnosis in all the previously described patients, 4 of whom had been presented at multiple genetics meetings,3-5,15,16 was made after the rediscovery of the CS in 1991.6,7 The disorder has been difficult to recognize until the recent reports, and many diagnoses have been entertained as discussed in the following text.
Differential Diagnosis of CS Many diagnoses have been considered in these patients. Notable is Cutis Laxa, considered in our patient 1 and in other reports.29,30 Two patients in whom CS was later diagnosed18,27,41 had originally been included in a report of Cutis Laxa.34 The occasional abnormalities of glucose metabolism and the presence of acanthosis nigricans bring the possibility of Donahue Syndrome, or Leprechaunism, to mind (patient 8),9,20,21,27,29 in addition to Berardinelli-type lipodystro-
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phy.20 Diagnoses of Noonan or cardiofaciocutaneous syndromes have been entertained6,9,36 because of the similarity of cardiac involvement with abnormal appearance and ectodermal type findings. In fact, ectodermal dysplasias have also been considered.19,29 However, CS is distinguished from these conditions by a characteristic prenatal and postnatal history and by the distinctive physical appearance and examination findings. The findings in patients with CS are usually more extensive than those observed in the previously mentioned conditions.
Cause of CS The cause of CS is as yet unknown. The possibility of causation by an autosomal recessive gene has been raised because of the affected siblings described in this report (patients 6 and 7), in the report of Zampino et al,20 and because of parental consanguinity in 2 of the 5 patients described by Borochowitz et al.9 This also would be consistent with a recessive enzyme deficiency to account for the possible metabolic basis of the disorder (see following text). However, Lurie42 has pointed out that there is a deficiency of affected siblings and has suggested an alternate possibility of autosomal dominant de novo mutations to explain the generally sporadic occurrence of the syndrome, with germline mosaicism for such mutations accounting for families with recurrences. This hypothesis is attractive based on the advanced paternal age in the families analyzed by Lurie (38 years), with an average paternal age of 40.3 years in our study (mean maternal age 35.8 years). Advanced parental age is a finding in new mutation dominant conditions, with apparent mutation of the paternal allele. Assuming the disorder to be metabolic in origin, a gain-of-function or regulatory mutation could be hypothesized. The single case with a chromosomal translocation of 1q and 22q31 may provide a clue to gene localization. At this point, assuming a genetic cause, resolution of the mode of inheritance and whether there is genetic heterogeneity with both autosomal dominant and recessive forms of the condition is not possible. Assuming that CS is indeed a genetic disorder, many findings point toward a meta-
bolic basis for the condition. These include prenatal overgrowth and postnatal failure to thrive, a physical appearance consistent with a storage disorder, occasional hepatosplenomegaly,2,9,18,36 cataracts (patients 1, 7), heat intolerance and increased sweating (patients 1, 6, 7), graying of hair (29, patient 1), acanthosis nigricans, hypertrophic cardiomyopathy with valve dysfunction (65%), and delayed bone age (85%). Biochemical alterations have been common including nonspecific, generalized aminoaciduria (2, patients 2, 3, and 5), low maternal serum α-fetoprotein in 1 pregnancy,9 prolactin elevation in patient 4, and sialuria in 2 patients, the first of whom also had fasting hypoglycemia and postprandial hyperglycemia with normal insulin levels and binding to receptors in fibroblasts.21 Hypoglycemia was found in 2 other patients,5,24 a flat glucose tolerance test in 1,34 and normal glucose and insulin ratios in 1.9 Neonatal IgM levels were elevated in 1 patient26 who also had growth hormone deficiency, and the latter has been found in a second patient.35 Growth hormone therapy had a limited effect in 126 but at least an early beneficial response in 2 other patients.18,35 Finally, our patient 3 had an unexplained elevation of hexosaminidase B. Many patients have undergone biopsy and various sites have been sampled without evidence for storage disease except for the vacuoles in fibroblasts in patient 6 and the metachromatic granules in lymphocytes in another patient.20 However, there have been some additional abnormalities, with a decrease in visualized collagen fibers in 1 patient18 and alterations of elastic fibers. Although 3 patients have clearly had normal elastic fibers,18,27,36 there are 2 recent reports of elastin abnormalities in patients with CS. Increased fragmentation and loss of connections of elastin fibers were observed in 1 patient28 and disrupted and loosely organized fibers in a second.33 Elastin mRNA from the second patient was studied and was normal in size and expression. These authors33 point out that CS is similar to Williams syndrome, which is caused by a deletion of elastin and probably of contiguous genes.43 We have recently had the opportunity to test patient 1 for a deletion of the Williams syndrome critical region,44 and results were normal. Although there are many reported minor 447
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biochemical alterations in affected patients, there is no clear pattern to provide clues to the cause and pathogenesis of CS. We thank the patients, families, and other clinicians, especially Martha Berberich, MD, involved in the care of these patients for their kindness in providing data for the report. Physicians and parents may be interested in the availability of a support group, sponsored by Colin and Cath Stone, 90 Parkfield Road North, New Moston, Manchester, M40 3RQ, England (Email: c.a.stone@ mmu.ac.uk).
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13.
14.
15.
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44.
diagnosis of cutis laxa. J Med Genet 1994;31:486-9. Torres JV, Marfa MP, Ensenat MAG, Trull JL. Pathology of the elastic tissue of the skin in Costello syndrome. Analyt Quant Cytol Histol 1994;16:421-9. Fryns JP, Bogels A, Haegeman J, Effermont E. Van Den Berghe H. Costello syndrome: a postnatal growth retardation syndrome with distinct phenotype. Genet Counsel 1994;5:337-43. Umans S, Decock P, Fryns JP. Costello syndrome: the natural history of a true postnatal growth retardation syndrome. Genet Counsel 1995;6:121-5. Czeizel AE, Timar L. Hungarian case with Costello syndrome and translocation t(1,22) [letter]. Am J Med Genet 1995;57:501-3. Torrelo A, Lopez-Avila A, Mediero IG, Zambrano A. Costello syndrome. J Am Acad Dermatol 1995;32:904-7. Mori M, Yamagata T, Mori Y, Mitsuhiro N, Saito K, Fukushima Y, et al. Elastic fiber degeneration in Costello syndrome. Am J Med Genet 1996;61:304-9. Patton MA, Tolmie J, Ruthnum P, Bamforth S, Baraitser M, Pembrey M. Congenital cutis laxa with retardation of growth and development. J Med Genet 1987;24:556-61. Schimke RN, Donaldson D, Moore W. Growth hormone deficiency in Costello syndrome (abstract). Proc Greenwood Genet Ctr 1996;15:195. Fukao T, Sakai S, Shimozawa N, Kuwahara T, Kano M, Goto E, et al. Life-threatening cardiac involvement throughout life in a case of Costello syndrome. Clin Genet 1996;50:244-7. Costello JM. Costello syndrome: update on the original cases and commentary. Am J Med Genet 1996;62:199-201. Scott JS. The volume and circulation of liquor amnii: clinical observations. Proc R Soc Med 1966;59:1128-31. Larroche JC, Aubry MC, Narcy F. Intrauterine brain damage in nonimmune hydrops fetalis. Biol Neonate 1992;61:273. Clark EB. Cardiac embryology. Its relevance to congenital heart disease. Am J Dis Child 1986;140:41-4. Davies SJ, Hughes HE. Cutis laxa: a feature of Costello syndrome [letter]. J Med Genet 1994;31:85. Lurie IW. Genetics of the Costello syndrome. Am J Med Genet 1994;52:358-9. Tassabehji M, Metcalfe K, Gergusson WD, Carette MJA, Dore JK, Donnai D, et al. LIM-kinase deleted in Williams syndrome [letter]. Nature Genet 1996;13:272-3. Lowery MC, Morris CA, Ewart A, Brothman LJ, Zhu XL, Leonard CO, et al. Strong correlation of elastin deletions, detected by FISH, with Williams syndrome: evaluation of 235 patients. Am J Hum Genet 1995;57:49-53.
Costello syndrome: Phenotype, natural history, differential diagnosis, and possible cause
John P. Johnson, MD, Mahin Golabi, MD, Mary E. Norton, MD, Robert M. Rosenblatt, MD, Gary M. Feldman, MD, Samuel P. Yang, MD, Bryan D. Hall, MD, Melissa H. Fries, MD, and John C. Carey, MD
We describe 8 patients affected with Costello syndrome including an affected sib pair and review the literature on 29 previously reported cases. We emphasize an association with advanced parental age, which is consistent with autosomal dominant inheritance with germline mosaicism. The pathogenesis appears to involve metabolic dysfunction, with growth disturbance, storage disorder appearance, acanthosis nigricans, hypertrophic cardiomyopathy, and occasional abnormalities of glucose metabolism. Although the cause is currently unknown, Costello syndrome is interesting because of a potential genetic-metabolic etiology. (J Pediatr 1998;133:441-8)
In 1971 and 1977, Costello1,2 described a syndrome of mental and growth retardation, distinctive physical appearance, and verrucous papillomata of the nose. The condition involves prenatal overgrowth, postnatal failure to thrive, and a distinctive appearance, with craniofacial findings resembling those observed in lysosomal storage disorders. Dermatologic manifestations include soft skin with excess wrinkling over the dorsum of the hands and deep creases on the palms and soles, hyperextensibility of digits, generalized hyperpigmentation, pigmented nevi often on the palms and soles, vascular birthmarks, papillomata that develop at later ages around the nares, mouth, anus, or less commonly elsewhere on the body, and acanthosis nigricans. Affected individuals manifest
prenatal polyhydramnios and postnatal feeding difficulty, have severe short stature and mental retardation, and may have a silent or clinically significant hypertrophic cardiomyopathy. After the initial descriptions, there were no further reports of similarly affected patients until presentations in 1981, 1989, and 1990.3-5 However, a specific diagnosis was not made in these patients. Full reports of patients with diagnosed Costello syndrome occurred in 1991.6,7 Simultaneously, there was a preliminary report of 5 individuals with the so-called “Faciocutaneousskeletal” syndrome8,9 and subsequently recognition that all of the patients discussed previously likely had the same condition.10-16 Since this apparently relatively common syndrome was rediscovered, there have
From the Division of Medical Genetics, Children’s Hospital Oakland, California; the Department of Pediatrics, University of California, San Francisco, California; Sonoma Developmental Center, Eldridge, California; Tri-Counties Regional Center, Oxnard, California; Grace Pediatrics, Davis, California; the Department of Pediatrics, University of Kentucky, Lexington, Kentudky; and the Department of Pediatrics, University of Utah, Salt Lake City, Utah. Submitted for publication July 23, 1997; revisions received Nov 11, 1997, Feb 2, 1998, and May 12, 1998; accepted May 28, 1998. Reprint requests: John P. Johnson, MD, Medical Genetics, Shodair Hospital, PO Box 5539, Helena, MT 59604-5539. Copyright © 1998 by Mosby, Inc. 0022-3476/98/$5.00 + 0 9/21/92090
been numerous reports, primarily in the genetics literature.17-37 The varied manifestations of CS point toward a likely biochemical basis. In this report we describe 8 patients with CS, 2 of whom are siblings, and discuss the unique findings, course, differential diagnosis, and potential cause of this disorder. CS
Costello syndrome
CLINICAL REPORTS AND LITERATURE REVIEW Parental ages, pregnancy complications, birth weight and percentile, and previous patient presentations are detailed in Table I. Clinical findings are listed in Table II.
Patient 1 (Fig 1) This 8-year-old boy had early feeding problems and aspiration pneumonia requiring tracheostomy, gastrostomy, and Nissen fundoplication. A partial resection of salivary glands was performed because of hypersecretion. Laboratory studies and analyses of muscle and liver biopsy specimens were normal. Growth had decelerated to less than the third percentile for weight and length, with preservation of head circumference. On neurologic evaluation there was considerable developmental delay with nystagmoid eye movements in infancy, and IQ was estimated at 23. Hypertrophic cardiomyopathy with irregular conduction defects developed, and atrial fibrillation became significantly symptomatic. When not bedridden from cardiac fatigue, the patient was able to scoot around, use a wheelchair, or move with a special walker, and generally com441
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THE JOURNAL OF PEDIATRICS SEPTEMBER 1998 municated nonverbally in a sociable way. Heat intolerance was noted. A cataract developed in the left eye, and renal stones formed in the right kidney. The patient died after an episode of bowel obstruction with ileus and volvulus complicated by shock, congestive heart failure, and resulting multiple organ failure.
Patient 2 (Fig 2) This now 7 1⁄2-year-old boy had required 4 days of intubation after birth. Joint contractures and poor feeding were noted, and gastrostomy and Nissen procedures were performed at 5 months. Within the first year concentric left ventricular thickening and valvular insufficiency developed but did not limit activity. Peroneal hypertonicity required treatment with ankle orthotics and Achilles tendon lengthening. Brain magnetic resonance imaging showed mild cerebral atrophy. Laboratory studies showed minimal generalized aminoaciduria. At age 7 1⁄2 years speech has just progressed to 2-word phrases, but nonverbal communication, especially receptive, is good. The voice is normal. Increased sweating is present. Walking developed by age 3 1⁄2 years, but braces are used, assistance is required with stairs, and running is not possible. Small oral feedings are now accepted.
Patient 3 (Fig 3) Fig 1. A, Patient 1 at age 18 months. B, Patient 1; hands at age 8 months. Note deep palmar creases. Table I. Parental age, pregnancy history, and previous presentations of 8 patients with CS*
Patient
Parental ages
Pregnancy
1 2
M 32 F 33 M 40 F 45
3 4
M 34 F 45 M 40 F 48
5
M 45 F 45
6 7
M 30 F 30 M 36 F 36
8
M 29
Term Excessive movement, polyhydramnios 36 wk Polyhydramnios, fetal arrhythmia Excessive movement, 36 wk Polyhydramnios Polyhydramnios, 36 wk twins Excessive movement, minimal weight gain
M, Mother’s age (years), F, father’s age (years); %ile, percentile. *Reported in published abstracts.3-5,15,16
442
Birth weight (%ile) 10 lb 5 oz, >97% 8 lbs 5 oz, 75% 8 lb 6 oz, 90% 8 lb 10 oz, 75% 7 lb 13 oz, 75% 6 lb 3 oz, 10% 4 lb 15 oz, 75% 7 lb 15 oz, 50%
This now 5-year-old boy had a gastrostomy and Nissen fundoplication performed because of poor feeding after birth. Laboratory studies included normal lysosomal enzymes, long chain fatty acids, and urinary oligosaccharides but elevated hexosaminidase B of uncertain cause and mild increases in urinary amino acids (cysteine, lysine, ornithine). Skeletal radiographs and computed tomography scan of the brain were normal. Atrial flutter and fibrillation have been persistent. Resection of muscular subpulmonic stenosis was performed, but further hypertrophy of the left ventricle and septum has occurred. Development is delayed, with walking and talking by approximately age 4 years. The personality is outgoing, and the voice is hoarse. Linear and weight growth are poor with preservation of head circumference.
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Patient 4 (Fig 4) This now 11-year-old boy had fetal arrhythmias, and evaluation at birth found supraventricular tachycardia and bicuspid aortic valve. Left atrial and ventricular hypertrophy developed, as did pulmonic stenosis and mitral valve and aortic outflow obstruction. A rotatory nystagmus was present in infancy. Postnatal feeding difficulties were encountered. Pyloric stenosis was discovered and corrected at 7 weeks. Gastrostomy and Nissen fundoplication were required for feeding. Laboratory investigations were normal except for slightly increased prolactin. Skin and conjunctival biopsy specimens showed no storage material on electron microscopy studies. Growth in height and weight is well below the 3rd percentile with normal head circumference. At age 9 years papillomata developed around the nose. The boy is in school in special education classes.
Patient 5 This now 32-year-old man fed poorly after birth, and this has become a lifelong problem. A seizure disorder developed after an episode of varicella. Development was delayed with sitting by age 2 years and walking by age 4 years. In the teen years behavioral issues were prominent. Radiographs and electron microscopy of white cells were normal. Growth in height and weight have been significantly subnormal, with normal head circumference. A skin tag was present on the right buttocks, and a “wart” was present on the right knee. There was a cafe-au-lait spot on the right elbow, and multiple small dark nevi were present on the palms, soles, and face. The patient was last seen at age 18 years.
Fig 2. Patient 2 at age 3 years.
Patient 6 (Fig 5) This now 18-year-old male patient had poor feeding after birth attributed to a large tongue, with sucking being normal. Nasogastric feedings were instituted, but bottle and oral feeding of solids developed by 18 months. Significant failure to thrive developed, with weight, length, and head circumference all below the 3rd percentile despite adequate caloric intake. Laboratory investigations were normal, but EM of fibroblasts did show cytoplasmic vac-
Fig 3. A, Patient 3 at age 7 months; B, Patient 3; feet at age 3 months. Note positional deformity and deep creases.
443
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THE JOURNAL OF PEDIATRICS SEPTEMBER 1998 but generally uses a wheelchair at school. Orthopedic complications and corrective surgeries are many including for severe kyphosis (87 degrees). No cardiac involvement has occurred. Increased sweating and heat intolerance have been problematic. Speech is fluent and ample with hoarse character, but development and intellect have always indicated function at approximately half the chronologic age. The personality is outgoing and friendly. This patient continues to attend school at age 18 years and is experiencing late pubertal development.
Patient 7 (Fig 6) This is a sister born 6 years after patient 6. Severe failure to thrive developed after birth. There was a cataract in one eye. Increased sweating was noted. A persistent tachycardia, atrial in origin, did not respond to digoxin, and the patient eventually died of cardiomyopathy and malnutrition at approximately age 2 years. Weight at death was only 4 lbs, 9 oz, with a length of 15 in (with knee contractures). Autopsy showed only dilation of the right atrium. Brain neuropathology showed dilated cerebral ventricles, decreased white matter, small brainstem, and dysmyelination of the basal ganglia.
Fig 4. Patient 4 at age 5 years.
Patient 8 (Fig 7)
Fig 5. Patient 6 at age 16.5 years.
uoles. Development of motor milestones was especially delayed, with assisted sitting by age 3 years, and no walking has ever been possible. Truncal hypotonia has 444
generally been observed, although there is hypertonia in the lower extremities. Nasal and facial papillomata developed in the late teens. The patient scoots around
This now almost 15-year-old boy required a ventilator for 10 days after birth. He had seizures with abnormal electroencephalography, hypoglycemia, and poor feeding requiring gavage. A cranial computed tomography scan later showed leukomalacia. Cardiac catheterization at age 2 years showed subvalvular aortic stenosis, and ultrasonography showed systolic anterior motion of the mitral valve and asymmetric ventricular hypertrophy. Cardiac surgery was done at age 2 1⁄2 years, and residual aortic insufficiency is present. Acanthosis nigricans has developed in the neck region. Workup has included normal skin fibroblast analysis of collagen, mucopolysaccharides, mucolipids, and sphingolipids. When the patient was last seen at age 5 years, developmental progress included the use of approximately 2 dozen words and occasional 3word sentences. Walking occurred at ap-
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proximately age 2 years. Surgical lengthening of the Achilles tendon at age 9 years was required because of eversion on the right.
FREQUENT CLINICAL FINDINGS IN REPORTED PATIENTS WITH CS Signs, symptoms, and laboratory findings in 29 patients with CS described in the literature are summarized in Table II. Not listed is the peculiar finding of hoarse voice (patients 3 and 6), with laryngeal papillomata and webbing perhaps explaining this in 1 case.18 Radiographic studies and brain magnetic resonance imaging are generally normal, with the exception of delayed bone age and osteoporosis.21,31,34 Laboratory studies are generally unremarkable including karyotype, endocrine testing, and metabolic studies, with some exceptions described in the following text.
Fig 6. Patient 7 (sibling of patient 6) at age 18 months.
Natural History of CS The clinical course of patients with CS is interesting and provides some clues to the pathogenesis. Before birth there is polyhydramnios in almost 50%, increased (patients 2 and 5) or decreased2,27 fetal movement, and overgrowth, mainly in weight (generally exceeding 50th percentile) and often in head circumference. The polyhydramnios presumably reflects poor fetal swallowing,38 which continues after birth, with severe feeding problems and failure to thrive. Nissen fundoplication and gastrostomy have often been required (patients 1, 2, and 4). In patient 1 there was difficulty maintaining the airway with excessive secretions and aspiration pneumonia, consistent with reports of stridor and opisthotonos in other patients.22,29 The abnormal swallowing, feeding, and protection of the airway presumably reflect abnormal central nervous system function. This is also apparent in hypotonia, secondary joint contractures, severely delayed motor and intellectual milestones, nystagmus, and strabismus. Edema presenting at birth (30, patient 3) or evident by deeply set nails may also
Fig 7. Patient 8 at age 3.5 years.
indicate altered neurologic status.39 The biphasic growth pattern of prenatal overgrowth and postnatal failure to thrive indicates potential metabolic dysfunction, which is compensated in the intrauterine environment. Later growth is more normal, and development generally exceeds that expected early in life, with sociable personality an asset.29 The cardiac involvement includes the spectrum of congenital defects produced by abnormal
prenatal blood flow40 including atrial septal defects, pulmonic stenosis, bicuspid aortic valve, mitral valve anomalies, and ventricular septal defects. The cardiomyopathy that develops is almost exclusively hypertrophic, involving the subaortic region, septum, mitral valve,7,22 and occasionally the subpulmonic region. Arrhythmias are common before and after birth, and an abnormal conduction system has been found on au445
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Table II. Historical, physical, and laboratory findings in 37 patients with CS
Trait Sex Polyhydramnios BW ≥50th % Poor feeding Poor growth CNS Delay Atrophy Personality outgoing Craniofacial Birth OFC ≥50th % Coarse facial appearance Downslanting fissures Epicanthal folds Strabismus Flat nasal bridge Thick lips Macroglossia Macrostomia Low set ears Musculoskeletal Short neck Increased anteroposterior diameter-chest Hernia Elbow limitation Extensible fingers Wide phalanges Ulnar deviation-hand Abnormal foot position Tight Achilles tendon Skin Curly hair Dysplastic nails Loose skin Hyperkeratotosis-palms Deep creases-palms/soles Hyperpigmentation Nevus flammeus Acanthosis nigricans Sparse hair Thick eyebrows Papillomatosis Cardiovascular HCM Dysrhythmia CHD Laboratory Abnormal amino acids Bone age delayed
Pt 1
Pt 2
Pt 3
Pt 4
Pt 5
Pt 6
Pt 7
Pt 8
Lit
Total
%
M – + + +
M + + + +
M + + + +
M + + + +
M + + + +
M + – + +
F + + + +
M – + + +
12M17F 11/27 25/28 26/26 29/29
19M18F 17/35 32/36 34/34 37/37
M:F 1.1 49 89 100 100
+ – +
+ + +
+ – +
+ – +
+
+
+
+
+ + +
+ + +
29/29 8/17 20/22
37/37 11/23 28/30
100 48 93
+ + + + + + + + + +
+ + + – + + + + + +
+ + + + – + + + – +
+ + + + – + + + + +
+ + + + + + + + + +
– + + + + + + + + +
– + + + + + + + +
– + + + – + + + + +
25/29 27/27 15/27 20/23 13/19 23/25 25/27 6/10 20/23 26/26
30/37 35/35 23/35 27/31 17/26 31/33 33/35 14/18 27/31 34/34
81 100 66 87 65 94 94 78 87 100
+ –
+ +
+ +
+ +
+ +
+ +
+ –
+ –
26/26 19/20
34/34 24/28
100 86
– – + + – –
+ + + – + + +
– + – + – + +
+ + + + – +
– + + +
– + + +
– + +
+ + + + + + +
11/15 13/21 19/20 17/18 5/12 20/22 12/14
14/23 20/29 26/28 23/25 7/17 25/28 15/17
61 69 93 92 41 89 88
+ – + – + + – – + + –
+
+
+
+
+
+ + + + + – + + +
+ + + + – – + + +
+ + + + – – + + –
+ + + + + + – + + + –
24/27 11/16 25/25 12/16 21/21 19/19 6/14 5/19 20/24 15/22 14/24
31/34 12/18 33/33 17/23 29/29 25/25 9/22 6/27 28/32 23/30 17/32
91 67 100 74 100 100 41 22 88 77 53
+ – –
8/16 8/16 11/14
15/23 13/23 15/19
65 56 79
– +
1/11 13/16
4/17 17/20
24 85
+
+ – +
+
+ – + + –
+ – + + –
+ + + + – – + + +
+ + +
+ – +
+ + +
+ + +
+ +
– +
+
+
– +
+
+
+ +
+
BW, Birth weight; ≥50th %, greater than or equal to 50th percentile; CNS, central nervous system; OFC, head circumference; HCM, hypertrophic cardiomyopathy; CHD, congenital heart disease; +, present; –, absent; Lit, literature patients; Pt, patients in this report. Blank in individual cell indicates that the finding is not noted to be either present or absent. Numerator = finding present or ascertained; denominator = finding mentioned on examination.
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THE JOURNAL OF PEDIATRICS VOLUME 133, NUMBER 3 topsy.33 It is remarkable that cardiac symptoms have been essentially minor and nonprogressive, with the exception of patients 1 and 7 and the patient described by Fukao et al,36 who were significantly compromised by their involvement. Management of the cardiac disease has little clinical impact. The distinctive and almost pathognomonic skin papillomata seem to appear later in life24 and have a predilection for areas around mucous membranes (nose, mouth, anus). As in patient 1, orthopedic complications can become severe. Seven deaths have occurred in reported patients9,20,33,36 and in our patients 1 and 7, with different causes and no consistent pattern. The oldest patient in this series is patient 5, last seen at age 18 years and presumably alive at age 32 years. Costello37 has recently revisited cases 1 and 2 at ages 32 and 27 years, respectively. Case 1 has developed hypertension, a ruptured cornea with keratoconus, and duodenal ulcer with gastroesophageal reflux. Case 2 developed fibroadenomata in the breast, lichenified eczema of the neck, and hypertrophic cardiomyopathy with supraventricular tachycardia.
DISCUSSION The diagnosis in all the previously described patients, 4 of whom had been presented at multiple genetics meetings,3-5,15,16 was made after the rediscovery of the CS in 1991.6,7 The disorder has been difficult to recognize until the recent reports, and many diagnoses have been entertained as discussed in the following text.
Differential Diagnosis of CS Many diagnoses have been considered in these patients. Notable is Cutis Laxa, considered in our patient 1 and in other reports.29,30 Two patients in whom CS was later diagnosed18,27,41 had originally been included in a report of Cutis Laxa.34 The occasional abnormalities of glucose metabolism and the presence of acanthosis nigricans bring the possibility of Donahue Syndrome, or Leprechaunism, to mind (patient 8),9,20,21,27,29 in addition to Berardinelli-type lipodystro-
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phy.20 Diagnoses of Noonan or cardiofaciocutaneous syndromes have been entertained6,9,36 because of the similarity of cardiac involvement with abnormal appearance and ectodermal type findings. In fact, ectodermal dysplasias have also been considered.19,29 However, CS is distinguished from these conditions by a characteristic prenatal and postnatal history and by the distinctive physical appearance and examination findings. The findings in patients with CS are usually more extensive than those observed in the previously mentioned conditions.
Cause of CS The cause of CS is as yet unknown. The possibility of causation by an autosomal recessive gene has been raised because of the affected siblings described in this report (patients 6 and 7), in the report of Zampino et al,20 and because of parental consanguinity in 2 of the 5 patients described by Borochowitz et al.9 This also would be consistent with a recessive enzyme deficiency to account for the possible metabolic basis of the disorder (see following text). However, Lurie42 has pointed out that there is a deficiency of affected siblings and has suggested an alternate possibility of autosomal dominant de novo mutations to explain the generally sporadic occurrence of the syndrome, with germline mosaicism for such mutations accounting for families with recurrences. This hypothesis is attractive based on the advanced paternal age in the families analyzed by Lurie (38 years), with an average paternal age of 40.3 years in our study (mean maternal age 35.8 years). Advanced parental age is a finding in new mutation dominant conditions, with apparent mutation of the paternal allele. Assuming the disorder to be metabolic in origin, a gain-of-function or regulatory mutation could be hypothesized. The single case with a chromosomal translocation of 1q and 22q31 may provide a clue to gene localization. At this point, assuming a genetic cause, resolution of the mode of inheritance and whether there is genetic heterogeneity with both autosomal dominant and recessive forms of the condition is not possible. Assuming that CS is indeed a genetic disorder, many findings point toward a meta-
bolic basis for the condition. These include prenatal overgrowth and postnatal failure to thrive, a physical appearance consistent with a storage disorder, occasional hepatosplenomegaly,2,9,18,36 cataracts (patients 1, 7), heat intolerance and increased sweating (patients 1, 6, 7), graying of hair (29, patient 1), acanthosis nigricans, hypertrophic cardiomyopathy with valve dysfunction (65%), and delayed bone age (85%). Biochemical alterations have been common including nonspecific, generalized aminoaciduria (2, patients 2, 3, and 5), low maternal serum α-fetoprotein in 1 pregnancy,9 prolactin elevation in patient 4, and sialuria in 2 patients, the first of whom also had fasting hypoglycemia and postprandial hyperglycemia with normal insulin levels and binding to receptors in fibroblasts.21 Hypoglycemia was found in 2 other patients,5,24 a flat glucose tolerance test in 1,34 and normal glucose and insulin ratios in 1.9 Neonatal IgM levels were elevated in 1 patient26 who also had growth hormone deficiency, and the latter has been found in a second patient.35 Growth hormone therapy had a limited effect in 126 but at least an early beneficial response in 2 other patients.18,35 Finally, our patient 3 had an unexplained elevation of hexosaminidase B. Many patients have undergone biopsy and various sites have been sampled without evidence for storage disease except for the vacuoles in fibroblasts in patient 6 and the metachromatic granules in lymphocytes in another patient.20 However, there have been some additional abnormalities, with a decrease in visualized collagen fibers in 1 patient18 and alterations of elastic fibers. Although 3 patients have clearly had normal elastic fibers,18,27,36 there are 2 recent reports of elastin abnormalities in patients with CS. Increased fragmentation and loss of connections of elastin fibers were observed in 1 patient28 and disrupted and loosely organized fibers in a second.33 Elastin mRNA from the second patient was studied and was normal in size and expression. These authors33 point out that CS is similar to Williams syndrome, which is caused by a deletion of elastin and probably of contiguous genes.43 We have recently had the opportunity to test patient 1 for a deletion of the Williams syndrome critical region,44 and results were normal. Although there are many reported minor 447
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biochemical alterations in affected patients, there is no clear pattern to provide clues to the cause and pathogenesis of CS. We thank the patients, families, and other clinicians, especially Martha Berberich, MD, involved in the care of these patients for their kindness in providing data for the report. Physicians and parents may be interested in the availability of a support group, sponsored by Colin and Cath Stone, 90 Parkfield Road North, New Moston, Manchester, M40 3RQ, England (Email: c.a.stone@ mmu.ac.uk).
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13.
14.
15.
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