Handbook of Genetic Counseling/Down Syndrome - Trisomy 21-2

Down Syndrome - Trisomy 21 Genetics 3 possible etiologies: Full trisomy 21 (95% of the cases) Due to nondisjunction during meiosis Usually maternal nondisjunction (90-95% of these cases) 75% of maternal nondisjunction occurs during meiosis 1 1% recurrence risk, unless the mother's age related risk is higher than 1%, in which case the age-related risk is quoted Unbalanced translocation (3-4% of cases) 50% of cases a parent carries a balanced translocation 50% of the unbalanced translocations are de novo and occur during fertilization Recurrence risk is 100% for a parental 21:21 translocation For a 21:14 translocation, recurrence is 16% if in the mother and 5% if in the father Mosaicism (1-2% of cases) Due to nondisjunction during mitosis, early in embryonic development Only cells that descend from that specific cell where nondisjunction occurred will be trisomy 21 Usually associated with a less severe phenotype Molecular Genetics Ongoing effort to define Chromosome 21 critical region Narrowed to 21q22 DSCR1 is a candidate gene suspected to be involved in the pathogenesis of DS Incidence One in every 650-1,000 children is born with down syndrome Clinical Features Intelligence Mild to moderate mental retardation seen in most individuals (ranges from ~40-80) Language delays Cardiac >40% are born with congenital heart defects Av canal and VSD are common Gastrointestinal Duodenal atresia is the most common Duodenal web (partial obstruction) Tracheoesophageal fistula Pyloric stenosis Omphalocele Hirschprung's disease Imperforate anus Annular pancreas Celiac disease Associations with vomiting, diarrhea, constipation, and feeding difficulties may be associated Auditory Recurrent otitis media Some degree of hearing loss is present in ~90% of patients Conductive hearing loss due to fluid accumulation Sensorineural hearing loss is also seen Craniofacial Macroglossia (60%) May cause feeding difficulty Dental malocclusions (100%) Constellation of characteristic facial features Brachycephaly Low nasal root, flat nasal bridge Epicanthic folds Small and occasionally overfolded ears Short neck sometime seen with redundant skin at the nape Brushfield spots Skeletal 14% have increased mobility of the cervical spine at the level of the 1st and 2nd vertebrae (atlantoaxial instability) other Respiratory problems can be due to midfacial hypoplasia which results in narrow airways Infections (recurrent croup due to narrow trachea) Obstructive airway disease Sleep apnea Leukemia Risk of developing leukemia is 15-30 times higher in Down syndrome patients than in the general population Hypothyroidism (15%) Common during adolescence Yearly monitoring of TSH and T(subscript)4 levels recommended Alzheimer's Disease 15% of adults with average age of onset ~50 yrs Eye problems Strabismus cataracts Seizures (5-10%) Correlation between age and prevalence Peaks at infancy and 4th-5th decade of life Short stature (average at 3rd percentile) Obesity Wide gap between first and second toes Hypotonia Clinodactyly of the 5th fingers Natural History/Prognosis Life expectancy has significantly increased No congenital heart defects: >60 yrs old Congenital heart defects: 30-35 yrs old Causes of death Leukemia (malignancy) Infections Treatment and Management Echocardiograms, EKG, chest X-rays to monitor heart defects Surgery may be required Ophthalmology exams Hearing exams Abdominal X-rays, barium swallow or enema to follow digestive problems TSH levels to detect hypothyroidism Early intervention for MR and developmental delays Physical therapy for gross and fine motor skills Speech therapy References Jones KL (1997). Smith's Recognizable Patterns of Human Malformation. Philadelphia: W.B. Saunders Company Jorde LB, Carey JC, Bamshad MJ, White RL (1999). Medical Genetics. 2nd ed. Philadelphia: Mosby. Cohen WI (1999). Health Care Guidelines for Individuals with Down Syndrome: 1999 Revision (Down Syndrome Preventive Medical Check List). Down Syndrome Quarterly. Web References: OMIM Entry #190685 Notes The information in this outline was last updated in 2000.