18 Congenital and genetic disorders
Congenital abnormalities
Congenital abnormalities range from trivial morphological abnormalities, such as a rudimentary extra digit, to lethal conditions such as major brain malformations. At birth, 2–3% of infants are recognized to have a congenital malformation. By age 5, this rises to 4–6%, as abnormalities not initially evident become manifest. In 40–60%, the cause is unknown. A chromosomal/genetic cause is found in 10–15%. Environmental factors, such as congenital infections (see Chapter 17, p. 256), maternal disease (e.g. diabetes), nutritional deficiencies, hypoxia, drug and alcohol exposure contribute about 10%. The remainder arise from a combination of genetic and environmental factors.
Congenital abnormalities may be categorized as:
• Malformations – something occurs to disturb the normal development of an organ or structure. It may result in complete or partial absence, as occurs in most cases of congenital hypothyroidism, or alteration of structure, as occurs in congenital heart disease
• Disruptions – a disruption arises when the normal structure is affected by a process (usually destructive) after formation of the organ. For example, intestinal atresias are believed to result from a transient vascular insult during fetal life
• Deformations – the fetus is in a confined space. To develop normally, the fetus needs to move. Conditions which impair movement may lead to multiple postural deformities (arthrogryposis multiplex), as may occur in infants born to mothers with myasthenia gravis. Other ‘packaging defects’ are less severe, such as talipes (see Chapter 6, p. 44)
• Syndromes – a constellation of findings, which may themselves appear unrelated, may point to a syndromal diagnosis. Down syndrome (trisomy 21), is such an example. Other syndromes may not have a genetic origin, such as VACTERL (Vertebral anomalies, imperforate Anus, congenital Cardiac disease, Tracheo-oesophageal fistula, oEsophageal atresia, Renal anomalies and radial Limb defects). This arises from defective mesodermal development during embryogenesis.
Environmental factors
A number of environmental factors are implicated in the development of congenital abnormalities:
• Congenital infection, notably the ToRCH infections (Toxoplasma, Rubella, Cytomegalovirus and Herpes simplex), varicella and HIV (see Chapter 17, p. 256)
• Hyperthermia – fever secondary to infection, or use of hot tubs and sauna
• Radiation – studies of pregnant Japanese women exposed to radiation in Hiroshima and Nagasaki in World War 2 found that 28% miscarried, 25% of live born children died in infancy and 25% of survivors had CNS abnormalities – principally microcephaly and mental retardation
• Environmental chemicals – there is little definitive evidence about chemical exposure and congenital malformations, but growing circumstantial evidence implicates a number of chemicals as potential teratogens (e.g. arsenic, insecticides, lead, mercury, organic solvents, paint, polychlorinated biphenyls, toluene)
• Alcohol – fetal alcohol syndrome/fetal alcohol spectrum disorder may result from alcohol exposure (see below)
• Prescribed drugs – a number of drugs are known teratogens in pregnancy, but the severity of the underlying medical condition precludes their withdrawal. In general, drug use in pregnancy should be minimized, and known teratogens should be stopped prior to conception if at all possible (see Table 17.2, p. 249)
• Recreational drugs – drug use in pregnancy is often not disclosed, and often multiple drug exposures occur. Poor nutrition and concurrent alcohol use make attributing particular outcomes difficult. The best evidence is for cocaine use in pregnancy. Cocaine is a potent vasoconstrictor. Use is associated with miscarriage, intrauterine growth retardation, microcephaly, gastroschisis and genitourinary abnormalities.
Maternal disease
A number of maternal conditions have the potential to cause fetal malformations:
• Maternal diabetes – 2–5% of pregnancies are complicated by gestational diabetes mellitus (GDM), which accounts for 85–90% of diabetes in pregnancy. Often this is associated with maternal obesity. GDM arises during pregnancy, and is not associated with increased fetal malformations, but there is a high rate of miscarriage and fetal death, and neonatal morbidity and mortality from increased preterm birth, and complications of prematurity, coupled with macrosomia or growth retardation. Type 2 diabetes accounts for about 8–10%, with the remainder having type 1 diabetes. In contrast to GDM, hyperglycaemia during organogenesis may cause a x of 5–15%:
• Congenital adrenal hyperplasia
