Congenital and genetic disorders

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18 Congenital and genetic disorders

Introduction

Congenital and genetic disorders are a major cause of morbidity and premature death in childhood. The presentation of these conditions may be at or before birth with congenital malformations, in early life with impaired development, or in the older child with learning difficulties or problems with growth or sexual development. Some disorders manifest as regressive conditions, with progressive loss of skills and functions, usually culminating in early death, such as Duchenne muscular dystrophy, or Rett’s syndrome. Some genetic disorders do not become evident until adult life, such as Huntington’s disease, or inherited forms of Parkinson’s or Alzheimer’s diseases.

The huge advances in genetics set in train by the Human Genome Project are now starting to feed into clinical practice, with better characterization of a range of disorders, and new diagnostic tools with ever more possibilities for diagnosis. Indeed, it is likely that, in the lifespan of this textbook, we will see a move towards whole-genome sequencing as a diagnostic aid.

Putting a label to a condition is very satisfying for a clinician. It may direct attention to key aspects of management (e.g. ultrasound surveillance for Wilms’ tumour in Beckwith syndrome); it may enable a prognosis – developmental, intellectual, physical – to be pronounced on. However, for some parents or children, a label may be devastating – few parents will share the clinician’s pleasure at an erudite diagnosis, particularly if there is the potential for future affected children (or grandchildren). Nevertheless, for many parents, a diagnosis is helpful in affirming the child’s problems, charting the likely future course, and facilitating appropriate support for their child.

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:

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 – women affected by congenital adrenal hyperplasia need to take suppressive doses of hydrocortisone in pregnancy (or a suitable alternative steroid, e.g. prednisolone) to prevent virilization of a female fetus by the action of maternal androgens.

Phenylketonuria (PKU) – phenylalanine is toxic to the fetus. Affected women must be scrupulous in their adherence to their diet and nutritional supplements to achieve near-normal phenylalanine concentrations. Spastic quadriplegia, microcephaly and mental retardation are the consequences of non-adherence. Use of supplemental tetrahydrobiopterin (a co-factor for phenylalanine hydroxylase, the deficient enzyme in PKU) may ease the dietary restriction, facilitating adherence.

Maternal disease arising from the fetus – a fetus affected by long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency produces toxic metabolites which cross the placenta and may result in severe maternal disease – severe pre-eclampsia, acute fatty liver of pregnancy, cholestasis of pregnancy and HELLP syndrome (Haemolysis, Elevated Liver enzymes and Low Platelets).

Fetal alcohol syndrome

As shown in Case 18.1, the fetus is very vulnerable to the effects of maternal alcohol ingestion. There is strong evidence that binge drinking is more detrimental than regular alcohol intake. The effects of alcohol on the fetus are threefold:

Impaired growth – resulting in reduced head size, intrauterine growth retardation (usually symmetrical), post-natal growth failure with poor catch-up growth (sometimes compounded by growth hormone deficiency)

Characteristic morphological abnormalities:

Cognitive impairmentwith subsequent learning disability, behaviour problems (notably attention deficit disorder).

More severe fetal malformations may occur, such as VSD, cleft palate, hypoplasia or agenesis of the corpus callosum, joint dislocations, scoliosis, myopia, sensorineural hearing loss, etc.

Morphological abnormalities may not be evident if the mother did not drink heavily in early pregnancy, making the diagnosis more problematic, unless it is disclosed. Conversely, some women stop drinking heavily once they realize they are pregnant, and consequently the child has the characteristic appearance of fetal alcohol syndrome, but has relatively normal intellectual functioning.

The keys to optimizing success in education are structure and consistency. The child has a short attention span, so brief messages, repeated until embedded, are more successful.

Long-term prognosis is poor. Most go on to have long-term mental health problems, with few (<20%) living independently, and relatively few able to gain employment.

Inheritance of genetic disease

It is important to understand the different patterns of inheritance of genetic disorders. There are four principle patterns of inheritance: autosomal recessive, autosomal dominant, sex-linked and mitochondrial. The inheritance pattern – and risk of recurrence – differs for each.

Autosomal inheritance

Sex-linked inheritance

Sex-linked conditions arise from mutations on the X or, less commonly, Y chromosome. Females have two X chromosomes, and thus can compensate for the loss of a gene on one chromosome. Males, on the other hand, have only one X, and the loss of function is therefore manifest in males, but not usually in females. Examples include haemophilia A and B, fragile X (an important cause of learning disability in boys) and Duchenne muscular dystrophy. Occasionally females are affected, thus some female ‘carriers’ of fragile X have learning difficulties, but they are, nonetheless, much more mildly affected than males. Some sex-linked disorders are of such severity that male fetuses are not viable, thus only girls are known to have the condition. An example is Rett’s syndrome, a neurodegenerative disorder almost exclusively affecting girls, due to mutations in the MECP2 gene at Xq28.

Certain dominant or X-linked conditions appear to worsen with successive generations – a phenomenon referred to as anticipation. Commonly such disorders have triplet repeat sequences which become expanded in oocyte formation. Thus, anticipation occurs only with mother to child transmission, as no expansion of the triplet repeat sequence occurs during spermatogenesis. An example is myotonic dystrophy, caused by mutations in myotonic dystrophy protein kinase on chromosome 19. In this condition, a mildly affected mother may give birth to a much more severely affected child, who may have a long period of ventilator dependence, with attendant morbidity and mortality.

Genetic investigations

Antenatal testing

Sometimes, the need for genetic tests is evident before birth, due to a prior history of genetic disease, or the finding of morphological abnormalities on ultrasound, (see Chapter 17, p. 248). In early pregnancy, fetal sexing can be determined with high reliability on a maternal blood sample, between 7 and 9 weeks’ gestation. This may indicate the need for further investigations. For example, with a family history of haemophilia, an X-linked disorder, if the fetus is found to be a male, then chorionic villous sampling (CVS) at 10–12 weeks will permit molecular genetic diagnosis. For disorders that are not sex-specific, CVS is the initial investigation of choice. Later in pregnancy, amniocentesis and subsequent culture of fetal amniocytes will allow a detailed karyotype to be done. This is, however, more time consuming, and pregnancy is more advanced, making decisions about possible termination of pregnancy more problematic.

Neonatal testing

The newborn infant may be recognized to have dysmorphic features or abnormalities which indicate a possible genetic diagnosis. In this circumstance genetic investigation is indicated without delay as it may aid in management and decision-making, as in Case 18.2.

The finding of significant congenital abnormalities at birth should prompt genetic investigation. The nature of the problems will dictate the investigation performed (see Table 18.1).

Table 18.1 Genetic tests in the newborn infant

Clinical problem Test
Urgent confirmation of a suspected chromosomal aneuploidy (e.g. Down syndrome) Fluorescence in situ hybridization (FISH) using appropriate probes
Urgent confirmation of genetic sex in an infant with ambiguous genitalia FISH using appropriate probes
Confirmation of genetic status of a child born to a parent with a known balanced translocation Karyotype (if not done antenatally)
Investigation of a child with multiple congenital anomalies Low-resolution micro-array (or karyotype if array unavailable)*
Investigation of a specific genetic abnormality (e.g. cystic fibrosis) Specific molecular genetic testing

* Note that low-resolution micro-array is replacing the karyotype as a standard first-line investigation.

Genetic investigation of older children

Indications for genetic investigation of the older child are primarily:

As with any other part of medicine, genetic investigation begins with a careful history. This includes a careful family and pregnancy history, with careful inquiry into any illnesses and deaths. It is important to enquire specifically about miscarriages, as these may be an indication of a maternal balanced translocation.

The family tree should include both sets of grandparents, and any other first- or second-degree relatives. Exploring the family tree needs to done thoroughly and accurately, but with sensitivity. For an example of a complex family tree, see Figure 1.1, p. 4.

Careful physical examination may reveal clues as to the diagnosis, such as the typical hockey-stick palmar crease of fetal alcohol syndrome. It is very important to look closely at the face, hair line, ears and inside the mouth. Enquire about birth marks. Look at height, weight and body proportions – some conditions are characterized by asymmetry, e.g. Russell–Silver syndrome (see Table 18.2). Formal ophthalmological examination may be helpful for some conditions (see Case 18.3). For other cases, radiographic investigation may be decisive (see Case 18.4).