Genetic Disorders: 4-Day-Old Boy With Multiple Abnormalities

Consultant for PediatriciansConsultant for Pediatricians Vol 4 No 9
Volume 4
Issue 9

A 4-day-old boy was transferred to our institution for evaluation of multiple anomalies. He was born to a gravida 2 para 1 mother at 38 weeks of gestation. He weighed 3288 g at birth. Antenatal ultrasonograms at 5, 6, and 7 months had revealed short bones in the legs. The mother was subsequently lost to follow-up--until now.

A 4-day-old boy was transferred to our institution for evaluation of multiple anomalies. He was born to a gravida 2 para 1 mother at 38 weeks of gestation. He weighed 3288 g at birth. Antenatal ultrasonograms at 5, 6, and 7 months had revealed short bones in the legs. The mother was subsequently lost to follow-up--until now.

Both parents were of Amish ancestry, with no history of consanguinity between them. They both were of normal stature, as was their firstborn son.

The neonate weighed 3400 g (90th percentile), head circumference was 33 cm (50th percentile), and length was 46 cm (25th percentile). The ratio of upper segment to lower segment was 1.78 (normal, 1.70). He had low-set ears, normal eyes, and 2 natal teeth (mandibular). The upper lip frenulum was attached to the gum line.

Examination of the hands revealed axial polydactyly (7 digits on the left hand and 6 on the right) and syndactyly (fifth and sixth fingers of both hands) (Figure 1). In addition, the patient had hypoplasia of fingernails, bilateral simian creases, bilateral short arms and forearms, and overlapping toes. He had a narrow, bell-shaped thoracic cage (Figure 2), which was demonstrated on chest films. Results of the abdominal and neurologic examination were normal.

The cardiac echocardiogram revealed an atrioventricular canal defect, atrial septal defect, ventricular septal defect, a large patent ductus arteriosis, and coarctation of the aorta. The skeletal survey also revealed widened coronal sutures, multiple wormian bones, clavicular hooking, short ribs with widened ends, deep costophrenic angles, shortening of the extremities (mostly of the hands and feet, and the arms and legs to a lesser degree), the absence of multiple distal phalanges of toes (Figure 3), flared iliac wings, and normal vertebrae.

The infant required ventilatory support: multiple attempts at extubation were unsuccessful. His cardiac lesions were repaired, but eventually, chylous ascites developed, as did recurrent infections and bronchospasm. Coagulation abnormalities also developed; therapy to prevent disseminated intravascular coagulation was started. Analysis of the methylene tetrahydrofolate reductase gene showed heterozygous mutation, which therefore had no connection to the coagulation problem.

Tracheostomy was finally done because of prolonged ventilatory support. The infant's health continued to deteriorate. Support was withdrawn on the 96th day of his life. His parents declined autopsy.



The clinical and radiographic findings of thoracic dystrophy and shortening of the ribs led to the following differential diagnostic considerations:

• Ellis-van Creveld (EVC) syndrome.

• Short rib polydactyly syndrome--an autosomal recessive disorder with lethal skeletal dysplasia, markedly short ribs, short limbs, postaxial polydactyly, and multiple anomalies of major organs.

• Jeune syndrome--also called asphyxiating thoracic dystrophy-- which is associated with micromelic limbs, retinal degeneration, and renal failure. Polydactyly or abnormalities of hair/nails/teeth have not been reported.

• Weyers acrodental dysostosis--an autosomal dominant condition that is a milder phenotype of EVC syndrome. In most cases, this condition is nonfamilial.

• Thanatophoric dysplasia--an autosomal dominant condition (mostly newly occurring mutations) with severe growth deficiency, clover-shaped skull, narrow thorax with small ribs, and severely micromelic limbs.

• Barnes syndrome--an autosomal dominant condition characterized by thoraco-laryngo-pelvic dysplasia. This syndrome is not associated with limb abnormalities, polydactyly, or shortening of the ribs.

We based our diagnosis of EVC syndrome on the following:

• The parents' Amish ancestry.

• The ectodermal involvement.

• The presence of thoracic dystrophy.

• The skeletal abnormalities.

Ellis and van Creveld first described this syndrome, which is also known as mesoectodermal dysplasia or chondroectodermal dysplasia, in 1940. The chondrodysplasia affects the long bones--mainly the distal end of extremities. The result is short limb dwarfism and hexadactyly of the fingers and (less frequently) toes. The ectodermal dysplasia causes hair and nail abnormalities. Affected children also have multiple congenital heart defects and may have epispadias, cryptorchidism, talipes equinovalgus, and Dandy-Walker syndrome.


The highest incidence of EVC syndrome is seen in the Amish population: there are an estimated 5 cases per 1000 live births. The frequency of carriers in this population may be as high as 13%. Males and females are equally affected.

Histopathologic studies of fetuses with EVC syndrome show chondrocyte disorganization in the physeal growth zone of the cartilage of long bones.

The EVC gene has been mapped to chromosome 4p16, but clinical use for diagnosis is not yet available. The transmission is mainly autosomal recessive. Another gene, EVC2, may be responsible in persons of Ashkenazi descent.


Because EVC syndrome is an autosomal recessive disease, the family history may reveal parental consanguinity and siblings who also have EVC syndrome. Routine prenatal ultrasonography may show intrauterine growth retardation, skeletal malformations, and cardiac defects. Natal teeth may be present.

Extremities. Affected children are of small stature with disproportionately short extremities. Polydactyly of fingers is a consistent finding. Only about 10% of patients have polydactyly of the toes. The 7 fingers seen in our patient have never been described before (Figure 4). Polydactyly is usually bilateral and postaxial (an extra digit is located next to the fifth digit). Affected patients have short middle phalanges, hypoplastic distal phalanges, malformed carpals, fused capitate and hamate bones, and extra carpal bones. The nails are hypoplastic, dysplastic, or sometimes complete-ly absent.

Oropharynx. Many affected patients have natal teeth, partial anodontia, small teeth, and delayed eruption. Enamel hypoplasia is common and can result in abnormally shaped teeth, with frequent malocclusion. The labiogingival frenulum sometimes binds the upper lip to the alveolar ridge.

Cardiorespiratory. Cardiac anomalies are reported in about 60% of patients with EVC syndrome and are a major cause of shortened life expectancy. The most common anomaly is either a single atrium or a large atrial septal defect. Pectus carinatum with a long narrow bell-shaped chest may lead to respiratory difficulties.

Genitourinary. Anomalies are found in about 22% of those affected. These include hypospadias, epispadias, hypoplastic penis, cryptorchidism, vulvar atresia, focal tubulomedullary dilatation, nephrocalcinosis, and agenesis of kidneys.

CNS. Most persons with EVC syndrome are of normal intelligence. Occasional CNS anomalies and mental retardation have been reported.


The diagnosis of EVC syndrome depends on clinical findings. Karyotyping is not helpful because this is a single-gene disorder.

Once this diagnosis is suspected, the child should undergo cardiac echocardiography, chest roentgenography, a skeletal survey, and renal ultrasonography. A multidisciplinary approach is necessary.

Cardiorespiratory care. Although the bell-shaped thorax and other congenital heart defects are serious, they may not always be lethal. Cardiology and cardiothoracic services will be needed to manage the patient's congenital heart defects.

The unique shape of the chest in children with EVC syndrome may predispose them to poor respiratory function. Surgery can do little to correct this condition. Management involves adequate oxygenation and keeping a close watch on the lung function test results. The usual time of decompensation is early infancy. The condition tends to improve as the patient grows.

Dental care. An oral and maxillofacial surgeon will be needed to treat the hypertrophic upper frenulum. A dentist usually treats the oligodontia of the frontal region and the conical crowns with laminated veneers and a dental adhesive cement that facilitates simultaneous etching of both the enamel and dentin.

Orthopedic/plastic surgery care. Whether a patient will need such care depends on the complexity of the deformity. Postaxial polydactyly of the foot is most commonly treated with surgical removal of extra digits. Surgery is best deferred, when possible, until the child is 9 to 12 months old in an effort to decrease the risk of anesthesia.

Urologic care. Because about 25% of affected patients have genitourinary abnormalities, a pediatric urologist may need to get involved.

Genetic counseling. Parents should receive appropriate counseling and risk assessment. They should also be advised that the recurrence rate of EVC syndrome in future siblings is about 25%.

Prognosis. EVC syndrome is usually nonlethal. However, complications may be fatal. The overall prognosis is guarded.



Howard TD,Guttmacher AE, McKinnon W, et al. Autosomal dominant postaxial polydactyly, nail dystrophy, and dental abnormalities map to chromosome 4p16, in the region containing the Ellis-van Creveld syndrome locus. Am J Hum Genet. 1997;61: 1405-1412.

Ide SE, Ortiz de Luna RI, Francomano CA, Polymeropoulos MH. Exclusion of the MSX1 homeobox gene as the gene for the Ellis van Creveld syndrome in the Amish. Hum Genet. 1996;98:572-575.

Jones KL. Chondroectodermal dysplasia. In: Jones KL, Smith DW, eds. Smith's Recognizable Patterns of Human Malformation. 5th ed. Philadelphia: WB Saunders Co; 1997:374-375.

Mahoney MJ, Hobbins JC. Prenatal diagnosis of chondroectodermal dysplasia (Ellis-van Creveld syndrome) with fetoscopy and ultrasound. N Engl J Med. 1977;297:258-260.

McKusick VA, Egeland JA, Eldridge R, Krusen DE. Dwarfism in the Amish, I: the Ellis-van Creveld syndrome. Bull Johns Hopkins Hosp. 1964;115: 306-336.

Polymeropoulos MH, Ide SE, Wright M, et al. The gene for the Ellis-van Creveld syndrome is located on chromosome 4p16. Genomics. 1996;35:1-5.

Qureshi F, Jacques SM, Evans MI, et al. Skeletal histopathology in fetuses with chondroectodermal dysplasia (Ellis-van Creveld syndrome). Am J Med Genet. 1993;45:471-476.

Rosemberg S, Carneiro PC, Zerbini MC, Gonzalez CH. Brief clinical report: chondroectodermal dysplasia (Ellis-van Creveld) with anomalies of CNS and urinary tract. Am J Med Genet. 1983;15:291-295.

Ruiz-Perez VL, Ide SE, Strom TM, et al. Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis. Nat Genet. 2000; 24:283-286.

Torrente I, Mangino M, De Luca A, et al. First-trimester prenatal diagnosis of Ellis-van Creveld syndrome using linked microsatellite markers. Prenat Diagn. 1998;18:504-506.

Zangwill KM, Boal DK, Ladda RL. Dandy-Walker malformation in Ellis-van Creveld syndrome. Am J Med Genet. 1988;31:123-129.

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