9
Birth defects and genetic disorders

The underlying etiologies of congenital anomalies and mechanisms by which they arise are shown in Table 9.1 and Figure 9.1. When confronted with a neonate with a congenital anomaly, there are a number of questions to ask (Table 9.2), features to look for (Table 9.3) and investigations to consider (Table 9.4). This evaluation process to establish a diagnosis is also appropriate when congenital anomalies are identified prenatally on antenatal ultrasound.

Table 9.1 Causes of congenital anomalies.

Teratogenic	Environmental agents during pregnancy – infections, drugs (particularly anticonvulsants), alcohol and radiation
Sporadic or multifactorial	Many single birth defects occur as isolated cases with low recurrence risk. These may be polygenic or due to faults in developmental pathways
Single-gene disorders	May be family history or previous pregnancy losses. Many multiple malformation syndromes follow autosomal recessive inheritance, but consider X-linked recessive disorders in males and new dominant mutations in isolated cases
Chromosomal	Usually cause multiple congenital malformations and learning difficulties

c9-fig-0001 — **Fig. 9.1** Mechanisms of birth defects.

Question. What to look for on clinical exam?

Table 9.3 What to look for.

Growth parameters	Intrauterine growth restriction, overgrowth, microcephaly
Movement and posture	Hypotonia, contractures, seizures
Minor anomalies	Features with little cosmetic or functional significance. The presence of 2 or more should prompt a search for major anomalies
Major birth defects	May represent an association (defects occurring together more often than by chance alone), e.g. VACTERL (vertebral, anal atresia, cardiac, tracheo-esophageal fistula, renal and limb)
	May represent a sequence (one initial malformation resulting in the development of others, e.g. renal agenesis resulting in Potter sequence)
	May represent a syndrome (defects occurring together which have a common, specific etiology)
Dysmorphic features	Unusual or distinctive external appearance of the face, hands, feet, etc.

Question. Which investigations to consider?

Table 9.4 Investigations to consider.

Clinical photographs	Provide a valuable record, especially if the phenotype changes with time
Chromosome analysis	Order chromosome analysis (karyotype) in all babies with multiple malformations or dysmorphic features. Consider requesting comparative micro-array test to analyze chromosomes in more detail.
Biochemical analysis	Examples are calcium (for suspected Williams syndrome or DiGeorge syndrome) and creatine kinase (for suspected congenital muscular dystrophy)
Skeletal survey	Suspected skeletal dysplasia, such as achondroplasia
Echocardiography	Suspected congenital heart disease
Renal ultrasound	If renal anomalies suspected, e.g. in some chromosomal disorders
Brain CT/MRI/ultrasound scan	Suspected CNS malformation
Specific gene tests	Specific disorders, e.g. cystic fibrosis, spinal muscular atrophy type 1

Chromosomal disorders

In addition to trisomy 21, 18 and 13 there are many hundreds of chromosomal deletions and rearrangements. Micro-array technology is increasingly able to detect them in fetal or neonatal DNA.

Trisomy 21 (Down syndrome)

Incidence is 1 in 650 live births. Most (94%) are due to non-disjunction of chromosome 21 during meiosis in the formation of eggs or sperm (Fig. 9.2). The risk increases with maternal age (Table 9.5) although most are born to mothers < 35 years old.

c9-fig-0002 — **Fig. 9.2** Trisomy 21 due to non-disjunction.

Table 9.5 Risk of trisomy 21 in liveborn infants by maternal age.

Maternal age at delivery (years)	Risk
All ages	1 in 650
30	1 in 900
35	1 in 400
37	1 in 250
40	1 in 100
44	1 in 40

Approximately 5% are due to translocation, in which chromosome 21 is relocated onto another chromosome (usually onto chromosome 14). The risk of trisomy 21 is about 10% when the balanced translocation is carried by the mother. Most are identified prenatally. Non-invasive prenatal testing (NIPT) – free fetal DNA recovered from maternal serum in the late first trimester has 99.5% sensitivity for trisomy 21.

Clinical features

The facial appearance and other clinical signs (Fig. 9.3) are usually recognizable at birth but diagnosis needs to be confirmed by chromosome analysis. Associated malformations include congenital heart disease, duodenal atresia and Hirschsprung disease.

c9-fig-0003 — **Fig. 9.3** Trisomy 21 (Down syndrome). (a) Facial features – upward slant of eyes, epicanthic folds, low set simple ears, flat occiput, third fontanel, short neck. (b) Hands – single palmar crease and short little finger. (c) Feet – wide gap between first and second toes. Other features – hypotonia.

Subsequently there is increased risk of:

learning difficulties
small stature
secretory otitis media and visual impairment
leukemia
hypothyroidism
Alzheimer disease.

Trisomy 18 (Edwards syndrome)

Incidence is 0.1/1000 live births. Most infants have intrauterine growth restriction. Dysmorphic features include prominent occiput, narrow forehead, small mouth and jaw, short sternum, clenched hands with overlapping digits (Fig. 9.4a), prominent heels and rocker-bottom feet (Fig. 9.4b). Major malformations include heart defects, neural tube defects, omphalocele, esophageal atresia and radial defects. Most die shortly after birth.

c9-fig-0004 — **Fig. 9.4** Characteristic abnormalities of trisomy 18 (Edwards syndrome). (a) Typical clenched hand with overlying digits. (b) Rocker-bottom feet.

Trisomy 13 (Patau syndrome)

Incidence is around 0.7/1000 live births. Dysmorphic features include scalp defects (Fig. 9.5a) and polydactyly. Major malformations include holoprosencephaly (brain is a single hemisphere), microcephaly, ocular malformations, cleft lip and palate (Fig. 9.5b), heart defects and renal abnormality. Most babies die within 1 month.

c9-fig-0005 — **Fig. 9.5** Characteristic abnormalities of trisomy 13 (Patau syndrome). (a) Scalp defect. (b) Cleft lip and palate.