A Collage of Hereditary Childhood Disorders

Fragile X Syndrome

This 7-year-old boy presented with mental retardation and delayed gross motor milestones: he first sat up at 12 months, walked at 18 months, and ran at 2 years. His level of speech development was that of a 5-year-old; his IQ was 75.

Physical examination revealed typical features of fragile X syndrome: large, prominent ears; a long, narrow face; a high-arched palate; and a prominent jaw. Macroorchidism is usually not noted until puberty. Physical and behavioral abnormalities are common; they include hyperactivity, short attention span, poor eye contact, poor gross motor coordination, and echolalia.

Fragile X syndrome is inherited as an X-linked trait; it results from allelic expansion that begins as a small increase in the copy number of trinucleotide repeats. The number of repeats may increase from one generation to the next.

Earlier cytogenetic techniques for diagnosis used the presence of a fragile site on the X chromosome at band q27.3 and depended on folic acid-deficient tissue culture medium. This test was not very reliable; it detected almost half of obligate carriers. The diagnosis of fragile X syndrome is now made by direct DNA analysis, which demonstrates an expanded segment of DNA from the q27.3 region.

Next to Down syndrome, fragile X syndrome is the most common cause of mental retardation that can be specifically diagnosed.

Horner Syndrome

This 5-year-old girl had drooping of the left upper eyelid and a small left pupil at birth. At around 1 year, a blue iris was noted in the left eye and a brown iris in the right eye. She also had a decrease in facial sweating and occasional flushing on the left side of the face.

Miosis, ptosis, apparent enophthalmos (with or without anhidrosis), flushing on the side of the lesion, and heterochromia iridis are typical features of Horner syndrome, which results from an obstruction of sympathetic outflow from the hypothalamus to the orbit. The condition may be inherited as an autosomal dominant trait. An acquired form may result from birth trauma, thoracic surgery, neuroblastoma, ganglioneuroma, and congenital Cytomegalovirus infection.

The sympathetic nervous system is intimately associated with the development of normal eye color. If paralysis of the ocular sympathetic fibers occurs before age 2, hypopigmentation of the iris on the affected side may result. Since pigmentation of the iris is completed by about age 2, injury to the sympathetic nervous system after this time does not result in heterochromia.

Prader-Willi Syndrome

Morbid obesity and developmental delay were the presenting features of this 8-year-old boy. He was the product of an uncomplicated pregnancy and a full-term normal, spontaneous delivery. His weight at birth was 6 lb 2 oz. Decreased fetal movements were noted in the third trimester of the pregnancy. In the neonatal period, he was observed to have a weak cry, hypotonia, micropenis, hypoplastic scrotum, and undescended testicles. Gross motor milestones of sitting, crawling, walking, and running were delayed, as was speech development.

Bilateral orchidopexy was performed when the boy was 2; he became a voracious eater at about this time. He had microdontia and numerous dental caries that required a number of dental restorations and extractions.

Physical examination revealed that the boy weighed 100 lb (15 lb above the 95th percentile) and was 126 cm tall (50th percentile). He had a relatively narrow forehead, with low-set and slightly rotated ears. His hands and feet were both very small and he had down-slanting palpebral fissures. He also had a small penis, hypoplastic scrotum, and rudimentary testicles. His IQ was 70.

This patient has Prader-Willi syndrome, which is characterized by hypotonia, hypomentality, hypogonadism, and obesity (H₃O syndrome). Other manifestations include microdontia, enamel hypoplasia, high-arched palate, small hands and feet, scoliosis, compulsive snacking, and compulsive skin-picking.

More than 50% of patients with Prader-Willi syndrome have anomalies of chromosome 15, notably a deletion of the proximal part of the long arm (del 15q11 - q13), and at times, an unbalanced translocation in that region. Less frequently, a 15;15 translocation or isodicentric chromosome 15 is found.

Potential complications in patients with Prader-Willi syndrome include dental caries, diabetes mellitus, hypertension, atherosclerosis, joint contracture, osteoporosis, glomerulosclerosis, and development of a pickwickian or obesity-hypoventilation syndrome.

Down Syndrome

This 3-month-old girl has typical features of Down syndrome: upward-slanting palpebral fissures; protruding tongue; flat nasal bridge; flat occiput; short neck with redundant skinfolds; Brushfield spots; short, broad hands and fingers; clinodactyly of the fifth fingers; simian creases; wide spaces between first and second toes; and hypotonia.

Most persons with Down syndrome (trisomy 21) have an extra chromosome 21. In 95% of cases, this results from meiotic nondisjunction--a condition that increases with advancing maternal age: nearly half of affected persons are born to women older than 35 years. Approximately 1% of affected persons are mosaic, with a mixture of normal and trisomic cells. The remaining 4% have a translocation involving chromosome 21.

Children with Down syndrome have varying degrees of mental retardation; their IQs usually range from 20 to 80. Approximately 45% have congenital heart disease, notably endocardial cushion defect. A higher than normal incidence of other disorders is seen in children with Down syndrome. These include atlantoaxial instability, duodenal atresia, Hirschsprung disease, imperforate anus, Hashimoto thyroiditis, and acute leukemia.

Ehlers-Danlos Syndrome

This 2-year-old girl had hyperelastic skin (A), very elastic and pliable ears (B), and hyperextensible joints. Her mother and grandmother had similar clinical features; the mother's hyperextensible joints are seen in photograph C.

The child has Ehlers-Danlos syndrome, an inherited connective tissue disorder. At least 11 types of this genetically heterogeneous condition have been described. The essential defect is a quantitative deficiency of collagen.

Children with Ehlers-Danlos syndrome are prone to poor wound healing with "cigarette paper" scars; easy bruisability; Raynaud phenomenon; inguinal, umbilical, incisional, and hiatal hernia; diverticula and perforation of the GI tract; joint effusion and recurrent dislocation; kyphoscoliosis; joint contracture; mitral valve prolapse; and dissecting aneurysm.