# 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.