Vol. 16: Summer, 1998

Management of Common Genetic Disorders

Down Syndrome / Trisomy 21

Introduction
Trisomy 21 is the most common autosomal chromosome abnormality with an incidence of 1/800 live births. It occurs in all ethnic groups. Ninety-five percent are due to meiotic non-disjunction. Most of the time the extra chromosome is of maternal origin and the risk increases with increasing maternal age. A translocation is seen in 3-4% of cases, about half of which are de novo and half familial. Mosaicism is seen in 1-2% of children and the clinical picture correlates somewhat with the percentage of normal cells.
The recurrence risk depends upon the etiology. In cases with non-disjunction and de novo translocations, the risk is about 1% plus the maternal age risk. Familial 21/21 translocations have a 100% recurrence risk. Other translocations have a lower recurrence risk with a 2-5% risk if the carrier is the father and a 10-15% risk if the mother is the carrier.
Clinical Features
Individuals with Down syndrome have characteristic facies and typical minor anomalies. Most striking in the newborn are the upslanting palpebral fissures, protruding tongue, abnormal palmar creases, and hypotonia. Once the diagnosis is suspected, it should be confirmed by a chromosomal analysis on cultured lymphocytes.
The family should be referred for genetic counseling to discuss the diagnosis, the recurrence risks, and the options for prenatal diagnosis (amniocentesis, chorionic villus sampling, maternal serum triple screen, and/or ultrasound) in future pregnancies.
Common Medical Complications
The child with trisomy 21 is at risk for other abnormalities and complications. The most common is congenital heart disease, typically a VSD although endocardial cushion defects are also common in Down syndrome. Cardiac defects require SBE prophylaxis for dental work or other invasive procedures. An echocardiogram is recommended for all infants with Down syndrome. The presence of Down syndrome per se does not adversely affect the outcome of surgery in the absence of pulmonary hypertension. Gastrointestinal anomalies are present in about 12% of individuals with Down syndrome including duodenal atresia/stenosis, TE fistula, Meckel diverticulum, Hirschsprung disease, imperforate anus and omphalocele. Hypotonia can lead to poor suck as well as constipation. Genitourinary involvement can include renal malformations, hypospadias, micropenis and undescended testes. The risk for leukemia is 10 to 30% higher than the general population risk, but is less than 1%. Neonatal leukemoid reactions are common.
Children should be referred for an ophthalmologic examination by 9 months of age. Common eye problems include congenital nystagmus or alternating esotropia (which often resolves), congenital cataracts, glaucoma, strabismus, refractive errors, and nasolacrimal duct obstruction.
The incidence of hearing loss approaches 75% with most cases being conductive due to serous otitis media. However, there may also be middle ear anomalies and/or sensorineural hearing loss. Therefore, all children should have formal audiograms by 6 months of age and hearing should be monitored at each office visit. In addition to otitis media, there is also a higher incidence of sinusitis and obstructive sleep apnea.
The major musculoskeletal abnormalities are hypotonia and hyperextensibility which contribute to gross motor delays. Atlantoaxial instability is seen on X-ray in 14% but only 1-2% develop signs of cord compression. Lateral neck films are recommended at 3 to 5 years of age (before participating in Special Olympics), before engaging in contact sports, or if symptoms of spinal cord compression develop. It is important to remember, however, that individuals can be symptomatic with normal neck films and, therefore, a thorough neurologic examination should be done at each office visit.
A variety of endocrine abnormalities may occur in Down syndrome. Thyroid dysfunction develops in 15% of children with Down syndrome and the signs and symptoms can mimic trisomy 21. Therefore, Down syndrome individuals should be screened at birth, 6 months, 12 months, and then annually.
Sexual maturation is essentially normal with 15-30% of females being fertile. Appropriate contraceptive counseling should be given as the risk of having a child with Down syndrome is 50%. Males are usually infertile. In monitoring growth, it is important to use Down syndrome growth charts.
Obesity becomes a problem with age and nutritional counseling and an activity program should be started early to keep weight under control.
Routine dental care is also important as crowding, periodontal disease, and caries can develop.
Other Medical Considerations
The major question raised by families has to do with the intellectual potential of a child with Down syndrome. The average IQ is 40-77, but this is a poor indication of their ability to function in society. Early developmental intervention and appropriate therapies are recommended. In general, children with Down syndrome are better with visual processing and right brain functions. Many are capable of working and living semi-independently.
There have been a variety of controversial therapies which have been advocated, but none have been scientifically validated. Such therapies include sicca cell therapy, patterning treatment and craniosacral manipulation. The latter is potentially harmful if there is any vertebral subluxation. The most wide-spread nontraditional therapy includes vitamin and mineral supplementation as well as piracetam. Also controversial is plastic surgery to "normalize" facial features.
Although the life span for an individual with trisomy 21 is less than the general population, many are living into adulthood and present some unique health problems. In general, they have an accelerated aging process. Both hearing and vision should be tested annually because of the incidence of high frequency hearing loss and cataracts. Annual thyroid screening should also continue as 40% of adults with Down syndrome have thyroid dysfunction. There should be clinical monitoring for mitral valve prolapse and aortic regurgitation with an echocardiogram as indicated. SBE prophylaxis should continue in patients with cardiac defects.
The major concerns with aging are related to dementia and an Alzheimer-like picture. Nearly all Down syndrome adults over 40 years of age have increased senile plaques and neurofibrillary tangles. By 50 years of age, about 25% of adults with trisomy 21 will have some signs of dementia. Seizures may also begin as early as the third decade.
Psychiatric disorders, particularly depression, can occur and need to be differentiated from dementia. In addition, routine medical and dental care is needed to monitor weight, nutrition, physical activity, socialization, and vocational placement.
Conclusion
The overall outlook for individuals with Down syndrome has changed markedly over the past 25 years. They are healthier, have increased longevity, are better integrated into society, and may be cared for in all types of medical settings.
References:
- Health Supervision for Children with Down Syndrome. Committee on Genetics. Pediatrics 93 (5): 855-859, 1994
- AAP issues guidelines on health supervision for children with Down syndrome. Am Fam Physician 50(3):695-697, 1994

Contributed by Janet Stewart, MD (CO)

The Genetic Drift Newsletter is not copyrighted. Readers are free to duplicate all or parts of its contents. The Genetic Drift Newsletter is published semiannually by the Mountain States Genetics Network for associates & those interested in Human Genetics. In accordance with accepted publication standards, we request acknowledgement in print of any article reproduced in another publication. The views expressed in the newsletter do not necessarily reflect local, state, or federal policy. For additional information, contact Carol Clericuzio, M.D., Editor, Department of Pediatrics, The University of New Mexico, Albuquerque, NM, 87131

Table of Contents:
Management of Common Genetic Disorders

Introduction
Achondropasia
Down Syndrome / Trisomy 21
Fragile X Syndrome
Marfan Syndrome
Neurofibromatosis
Turner Syndrome
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