Common Chromosomal Trisomies 21, 18, and 13
INTRODUCTION
Chromosome abnormalities account for a significant portion of genetic disease and are important causes of congenital malformations and pregnancy loss. Cytogenetic disorders are found in nearly 1% of live births; thus, performing a karyotype on a newborn with multiple congenital anomalies can provide valuable information with respect to management questions and prognosis counseling. Chromosome analysis is indicated as a diagnostic procedure in a number of different general clinical situations, such as problems with early growth, development, stillbirth, and neonatal death. For infants in the neonatal period, performing a chromosome analysis may be considered if any of the following features are demonstrated:
• Abnormal growth parameters
• At least 1 major malformation
• 2 or more minor anomalies
• Abnormal neurologic findings
The most common chromosome abnormalities a care provider is likely to encounter in the newborn nursery are trisomies for chromosomes 21, 18, and 13. It is important to be able to recognize characteristic features of these conditions in order to initiate the most appropriate evaluations. For children who have had the diagnosis made prenatally, a formal copy of the chromosome report should be obtained. This report allows the clinician to confirm the diagnosis, review the results with the family, and add the formal diagnosis to the child’s medical record. If the results of prenatal testing are not available, a blood sample can be obtained for postnatal cytogenetic analysis to confirm the diagnosis and rule out a chromosome translocation.
TRISOMY 21 (DOWN SYNDROME)
Introduction
Down syndrome (DS) is the most common autosomal trisomy seen in live births. Incidence is estimated to be 1/600–1/800. The facial appearance of individuals with DS is characteristic and can be the first noticeable sign on physical examination to suggest this diagnosis. Other minor anomalies (eg, small ears, single transverse palmar crease, increased sandal gap), hypotonia, and malformations of other body systems (most importantly the cardiovascular and gastrointestinal systems) can be appreciated in the newborn period. DS is also associated with developmental delay/cognitive impairment, hearing loss, eye anomalies, thyroid dysfunction, atlantoaxial instability, and transient myeloproliferative disorder (TMD)/leukemia.
Diagnosis
Clinical Findings
History
The first step in evaluating a newborn infant suspected of having trisomy 21 is a careful review of the family history and prenatal information, including prenatal screening, chromosome studies done via amniocentesis or chorionic villi sampling (CVS), or any other genetic testing performed. Previous children born with trisomy 21, developmental differences, or pregnancies that ended in miscarriage may be significant clues that a family may carry a balanced translocation that predisposes them to having children with trisomy 21.
Physical Examination
A physical examination is the most sensitive test in the first 24 hours of life to diagnose trisomy 21 in an infant. If the clinician feels that enough criteria are present on physical examination, then a blood sample should be sent for chromosome evaluation. The clinician should alert the laboratory and request rapid results.
Common physical features are the following:
• Hypotonia
• Small brachycephalic head with large fontanelle
• Epicanthal folds
• Flat nasal bridge/flattened midface
• Upward-slanting palpebral fissures
• Small mouth, small ears with overfolded pinnae
• Redundant nuchal folds
• Single transverse palmar crease
• Brachydactyly, short fifth finger with clinodactyly
• Wide space, often with a deep fissure, between the first and second toes (“sandal gap”)
• Hypoplastic nipples/breast buds
Confirmatory Testing
Routine blood karyotype may be ordered STAT. If the patient’s mother has had prenatal testing, amniocentesis or CVS that identified trisomy 21, there is no need to repeat testing. High-resolution chromosome analysis is not indicated. Comparative genomic hybridization (CGH) is not an appropriate first-line test to rule out a trisomy.
Differential Diagnosis
Sometimes, features of trisomy 21 can be subtle, depending on factors such as the clinical status and ethnic background. A chromosome analysis will rule out common aneuploidies as well as major structural anomalies that can present with overlapping signs and symptoms to trisomy 21. Consultation by a medical genetics specialist may provide additional insight into additional disorders (eg, single gene) to consider.
Treatment
Ethical Considerations
Although overall survival for children with DS may be reduced in the first 5 years of life when compared to the general pediatric population (likely from heart defects, respiratory infections), withholding care to a newborn with this diagnosis is not appropriate. Thus, evaluation for associated medical issues is important prior to discharge.
Initiation
There are a number of medical issues common to trisomy 21 that present in the newborn period. Surveillance for these problems is warranted.
Associated medical issues in the newborn period are the following:
• Congenital heart defect (50%): Endocardial cushion defects are the most common.
• Gastrointestinal atresias (12%).
• Thyroid disease (15%).
• Atlantoaxial instability (1%–2%).
• TMD. TMD is an uncontrolled proliferation of myeloblasts occurring only in infants with DS. The majority of infants present from birth to 2–3 weeks of life with elevated white blood cell counts and blasts, very rarely with anemia or thrombocytopenia. The incidence of TMD in DS is around 10%. Most cases of TMD are asymptomatic, with spontaneous resolution by 3 months of age. However, 20% of cases progress to life-threatening organomegaly, hepatic fibrosis, liver failure, or cardiopulmonary disease (caused by blast infiltration).
• Approximately 30% of all cases develop acute megakaryoblastic leukemia between the ages of 1 and 4 years. If TMD is diagnosed in a neonate with DS, the infant should be followed closely by hematology.
• Hirschsprung disease (<1%).
Tests/Evaluations
Evaluation for the common associated medical conditions includes the following:
• Complete blood cell count (CBC) with differential (will detect polycythemia, leukemoid reaction)
• Echocardiogram
• Intestinal obstruction monitoring
• Hearing screen (routine, prior to discharge)
• Newborn screen (will detect congenital hypothyroidism)
• Genetics consult at earliest convenience
Conclusion/Follow-up Discharge Planning
When formulating the discharge plans for a patient with trisomy 21, a comprehensive team approach is appropriate.
The following are general recommendations:
• Referral for specialty follow-up (eg, cardiology, gastrointestinal [GI], endocrinology, ear-nose-throat [ENT], hematology/oncology) as appropriate
• RSV (respiratory syncytial virus) prophylaxis (if appropriate)
• Cervical spine precautions
• Referral to early intervention programs
• Hearing screen (if abnormal, arrange for outpatient follow-up)
• Parent resources: national DS support groups, local support groups
Clinical Follow-up
Follow-up recommendations are dictated by issues identified in the nursery (eg, cardiology if heart defect is diagnosed). However, the family should be counseled regarding other common medical and developmental problems that can be seen over time and for which the primary care physician should monitor.
Associated medical issues presenting after newborn period include
• Cognitive impairment (100%)
• Hearing loss (75%)
• Otitis media (50%–75%)
• Obstructive sleep apnea (50%–75%)
• Eye disease (60%)
• Thyroid disease (15%)
• Seizures (6%–8%)
• Hip dislocation (6%)
• Atlantoaxial instability (1%–2%)
• Leukemia (<1%)
Long-Term Outcome/Implications for Patient/Family
1. Early intervention: Evidence shows that enrollment in early intervention programs providing physical, occupational, and speech therapies are beneficial for helping patients with DS meet their maximum developmental potential. Referral to local programs should be part of the discharge plan.
2. Genetic counseling: Families should receive basic counseling regarding the type of DS their baby has and the chance for recurrence within the family.
• Of trisomy 21 cases, 95% are caused by nondisjunction resulting in 3 separate copies of chromosome 21.
• Robertsonian translocations between chromosome 21 and another acrocentric chromosome (usually chromosome 14) cause 3%–4% of cases. Approximately three-quarters of these unbalanced translocations are de novo, and approximately one-quarter are the result of familial translocations.
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