A 36-year-old woman with little prenatal care delivers a 3900 g girl. The infant has decreased tone, upslanting palpebral fissures, epicanthal folds, redundant nuchal skin, fifth finger clinodactyly and brachydactyly, and a single transverse palmar crease.
What is the most likely diagnosis?
What is the next step in the evaluation?
ANSWERS TO CASE 3: Down Syndrome
Summary: A newborn with dysmorphic features is born to a woman of advanced maternal age.
• Most likely diagnosis: Down syndrome (trisomy 21).
• Next step in evaluation: Infant chromosomal evaluation to confirm diagnosis, evaluation for other features of the syndrome, counseling, and family support.
1. Know the physical features and problems associated with Down syndrome (DS) and other common trisomy conditions.
2. Understand the evaluation of a child with dysmorphic features consistent with DS.
3. Appreciate the counseling and support required by a family with a special-needs child.
This newborn has many DS features; confirmation is made with a chromosome evaluation. Upon identification of a child with possible DS, the health-care provider attempts to identify potentially life-threatening features, including cardiac or gastrointestinal (GI) anomalies. A thorough evaluation of the family’s psychosocial environment is warranted; these children can be physically, emotionally, and financially challenging.
Note: This woman of advanced maternal age had limited prenatal care but was at high risk for pregnancy complications. Adequate care may have included a serum triple screen between the 15th and 20th weeks of pregnancy or a “genetic” ultrasound, which could have demonstrated a DS pattern. Further evaluation (amniocentesis for chromosomal analysis) then could have been offered.
The Dysmorphic Child
ADVANCED MATERNAL AGE: The incidence of DS increases each year beyond the age of 35 years. At 35 years, the incidence is 1 in 378 live born infants, increasing to 1 in 106 by the age of 40 and to 1 in 11 by the age of 49 years.
BRACHYDACTYLY: Excessive shortening of hand and foot tubular bones resulting in a boxlike appearance.
CLINODACTYLY: Incurving of one of the digits (in DS the fifth digit curves toward the fourth digit due to midphalanx dysplasia).
DYSMORPHIC CHILD: A child with problems of generalized growth or body structure formation. These children can have a syndrome (a constellation of features from a common cause; ie, DS features caused by extra chromosome 21 material), an association (two or more features of unknown cause occurring together more commonly than expected; ie, VATER [Vertebral problems, Anal anomalies, Trachea problems, Esophageal abnormalities, and Radius or renal anomalies]), or a sequence (a single defect that leads to subsequent abnormalities; ie, Potter disease’s lack of normal infant kidney function, causing reduced urine output, oligohydramnios, and constraint deformities; common facial features include wide-set eyes, flattened palpebral fissures, prominent epicanthus, flattened nasal bridge, mandibular micrognathia, and large, low-set, cartilage-deficient ears).
SERUM TRISOMY SCREENING: Measurements of α-fetoprotein (AFP), human chorionic gonadotropin (hCG), inhibin A, and estriol levels, usually performed at 15 to 20 weeks’ gestation. These tests screen for a variety of genetic problems. Approximately 75% of DS babies and 80% to 90% of babies with neural tube defects will be identified by this testing.
The first newborn evaluation occurs in the delivery room where attempts are made to successfully transition the infant from an intrauterine to an extrauterine environment; it focuses primarily on the ABCs of medicine—Airway, Breathing, and Circulation. The infant is then evaluated for possible abnormalities, including those that might fit into a pattern such as DS.
The prenatal history and course provide some important clues in the evaluation of a dysmorphic child. The parents’ age (increased chromosomal abnormalities with increased maternal and sometimes paternal age), degree of fetal movement, maternal drug or teratogen exposure, family history of dysmorphia, and prenatal testing results, including triple screening and chorioamnionic or chorionic villus testing, may prove helpful. For instance, an older mother with a low AFP on her triple screen is at higher risk for having a DS child.
The physical examination is critical to the diagnosis of a dysmorphic child. For DS, a distinctive pattern can lead to a presumptive diagnosis; more than 90% of such children have features, including upslanting palpebral fissures, Brushfield spots (white or grey spots in the periphery of the iris), flat facial profile, small and rounded ears, excess nuchal skin, widespread nipples, pelvic dysplasia, joint hyperflexibility, fifth finger clinodactyly, a single transverse palmar (simian) crease, hypotonia, and a poor Moro reflex. Other features include brachycephaly (disproportionate shortness of the head), epicanthal folds, brachydactyly, wide spacing between first and second toes, and short stature.
In newborns with suspected DS, at least two potentially life-threatening conditions must be addressed. Approximately 50% of DS infants have cardiac defects—most commonly an endocardial cushion defect (60%),ventricular septal defect (VSD, 32%), and tetralogy of Fallot (6%). A cardiology consultation and echocardiogram usually are indicated. Approximately 12% of DS infants have intestinal (usually duodenal) atresia, some presenting with a history of polyhydramnios. All DS infants have hypotonia and sometimes slower feeding. Should an infant with presumed DS develop persistent vomiting after feeds (especially if bilious), an upper GI study likely will reveal the characteristic “double-bubble” pattern of duodenal atresia; surgical intervention is warranted.
Confirmation of DS requires chromosomal analysis. A complete, extra chromosome 21 (nondisjunction, ie, failure to segregate during meiosis) occurs in almost 95% of cases. Two percent of cases are caused by translocations (breakage and removal of a large DNA segment from one chromosome and attachment to a different one), and 3% are mosaics (more than one cell type; usually described as an abnormal cell percentage). Parents of a child with translocation-caused DS are evaluated for chromosomal aberrations; the recurrence risk can approach 100% in some cases.
Other newborn conditions associated with DS include hearing loss, strabismus, cataracts, nystagmus, and congenital hypothyroidism. Hearing is evaluated by the age of 3 months. An ophthalmologist evaluates the eyes by the age of 6 months, and thyroid function is assessed as part of the routine newborn screening program. Longer-term DS consequences include obesity, a higher leukemia risk, acquired hypothyroidism, atlantoaxial (cervical spine) instability, and premature aging with an increased risk of Alzheimer disease. All DS children are mentally retarded, but the intelligence quotients vary widely (mosaics can exhibit near-normal intelligence).
“Well-child care” takes on special meaning for DS children. In addition to providing routine care based on the American Academy of Pediatrics (AAP) guidelines for health supervision that apply to all children, the AAP has promulgated DS-specific guidelines (see www.aap.org). Periodic objective thyroid, hearing, and vision screenings are focal points of concern. Equally important in successful DS management is appropriate psychosocial intervention. Proper home or environmental, educational, and vocational interventions can improve the DS child’s functioning level, facilitating his or her transition to adulthood. Providing family support and assisting with financial and medical support program applications are within the pediatrician’s realm.
3.1 A small-for-gestational age infant is born to a 35-year-old woman. He has low-set and malformed ears, microcephaly, rocker-bottom feet, inguinal hernias, cleft lip and palate, and micrognathia. Chromosomal analysis is likely to reveal which of the following?
A. Down syndrome (trisomy 21)
B. Edwards syndrome (trisomy 18)
C. Holt-Oram syndrome
D. Patau syndrome (trisomy 13)
E. Turner syndrome
3.2 A 15-day-old infant has respiratory distress. A quick observation suggests she has slight cyanosis, hepatosplenomegaly, and features consistent with DS. The cardiac examination demonstrates a loud first heart sound, a wide and fixed split second heart sound, a low-pitched, mid-diastolic murmur at the lower left sternal border, and a harsh apical holosystolic murmur in the mitral area. An echocardiogram is likely to demonstrate which of the following?
A. Complete atrioventricular (AV) canal (endocardial cushion defect)
B. Hypoplastic left heart
C. Total anomalous venous return
D. Transposition of the great vessels
E. Tricuspid atresia
3.3 A small-for-gestational age, dysmorphic newborn infant has microcephaly and sloping forehead, cutis aplasia (missing portion of the skin and hair) of the scalp, polydactyly, microphthalmia, and omphalocele. Which of the following is the most likely diagnosis?
A. Down syndrome (trisomy 21)
B. Edwards syndrome (trisomy 18)
C. Holt-Oram syndrome
D. Patau syndrome (trisomy 13)
E. Turner syndrome
3.4 The parents of an 8-year-old DS boy arrive for his annual well-child visit. He wants to participate in sports, including the Special Olympics. Until further evaluation can be completed, which of the following sports would you suggest as being safe?
3.1 B. The child has trisomy 18. Other features include clenched hands with overlapping digits, small palpebral fissures, prominent occiput, short sternum, and cardiac defects (ventricular septal defect [VSD], atrial septal defect [ASD], patent ductus arteriosus [PDA], or coarctation of the aorta).
3.2 A. Although VSDs are common in DS, the most characteristic lesion is endocardial cushion defect (or atrioventricular [AV] canal defect). Slight cyanosis occurs because of the mixing of deoxygenated with oxygenated blood. In the AV canal, a range of defects involving the atrial septum, the ventricular septum, and one or both of the AV valves can be seen. A complete AV canal includes ASDs and VSDs with a common AV valve. A partial AV canal includes defects of the atrial septum and separate mitral and tricuspid valve orifices.
3.3 D. The appearance of cutis aplasia and polydactyly suggests trisomy 13. Other common features include holoprosencephaly (failure of growth of the forebrain), cleft lip or palate, postaxial polydactyly, flexed and overlapping fingers, coloboma, and cardiac defects (VSD, ASD, PDA, dextrocardia).
3.4 C. Until lateral cervical flexion–extension films confirm normal anatomy, contact sports and other activities that may result in forceful flexion of the neck should be avoided.
Down syndrome is the most common autosomal chromosome abnormality in live born infants, increasing in incidence with advanced maternal age.
The most common neonatal Down syndrome features are hypotonia with poor Moro reflex, flat faces, slanted palpebral fissures, laxity of joints, and excessive skin on the back of the neck.
Common problems associated with Down syndrome include cardiac defects and duodenal atresia.
Common features of trisomy 18 (Edwards) syndrome include weak cry, single umbilical artery, micrognathia with small mouth and high arched palate, clenched hand with overlapping of index finger over the third finger, simian crease, rocker-bottom feet, small pelvis, and short sternum.
Common features of trisomy 13 (Patau) syndrome include microcephaly and sloping forehead, deafness, scalp cutis aplasia, microphthalmia, coloboma, cardiac defect (especially ventricular septal defect), omphalocele, single umbilical artery, and hypersensitivity to agents containing atropine and pilocarpine.
American Academy of Pediatrics. Health supervision for children with Down syndrome. Pediatrics. 2001: 107; 442-449.
Bacino CA, Lee B. Cytogenetics. In: Kleigman RM, Stanton BF, St. Geme JW, Schor NF Behrman RE, eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia, PA: WB Saunders; 2011:394-415.
Bernstein D. Atrioventricular septal defects (ostium primum and atrioventricular canal or endocardial cushion defects). In: Kleigman RM, Stanton BF, St. Geme JW, Schor NF, Behrman RE, eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia, PA: WB Saunders; 2011:1554-1556.
Carey JC. Chromosome disorders. In: Rudolph CD, Rudolph AM, Lister G, First LR, Gershon AA, eds. Rudolph’s Pediatrics. 22nd ed. New York, NY: McGraw-Hill; 2011:691-697.
Lewanda AF, Boyadjiev SA, Jabs EW. Dysmorphology: genetic syndromes and associations. In: McMillan JA, Feigin RD, DeAngelis CD, Jones MD, eds. Oski’s Pediatrics: Principles and Practice. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:2629-2630.
South ST, Carey JC. Human cytogenetics. In: Rudolph CD, Rudolph AM, Lister G, First LR, Gershon AA, eds. Rudolph’s Pediatrics. 22nd ed. New York, NY: McGraw-Hill; 2011:688-691.
Sponseller PD. Cervical spine. In: McMillan JA, Feigin RD, DeAngelis CD, Jones MD, eds. Oski’s Pediatrics: Principles and Practice. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:2491.
Tsai AC-H, Manchester DK, Elias ER. Genetics & dysmorphology. In: Hay WW, Levin MJ, Sondheimer JM, Deterding RR. Current Diagnosis & Treatment: Pediatrics. 20th ed. New York, NY: McGraw-Hill; 2011:1037-1038.
Vick GW, Bezoild LI. Defects of the atrial septum, including the atrioventricular canal. In: McMillan JA, Feigin RD, DeAngelis CD, Jones MD, eds. Oski’s Pediatrics: Principles and Practice. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:1565-1574.