Malformation

A malformation is a primary structural defect of an organ, or part of an organ, that results from an inherent abnormality in development. This used to be known as a primary or intrinsic malformation. The presence of a malformation implies that the early development of a particular tissue or organ has been arrested or misdirected. Common examples include congenital heart abnormalities such as ventricular or atrial septal defects, cleft lip and/or palate, or neural tube defects (Figure 16.2). Most malformations involving only a single organ show multifactorial inheritance, implying an interaction of gene(s) with other factors (p. 143). Multiple malformations are more likely to be due to chromosomal abnormalities but may be due to single gene mutations.

FIGURE 16.2 Child with a large thoracolumbar myelomeningocele consisting of protruding spinal cord covered by meninges.

Disruption

The term disruption refers to an abnormal structure of an organ or tissue as a result of external factors disturbing the normal developmental process. This used to be known as a secondary or extrinsic malformation, and includes ischemia, infection, and trauma. An example of a disruption is the effect seen on limb development when a strand or band of amnion becomes entwined around a baby’s forearm or digits (Figure 16.3). By definition a disruption is not genetic, although occasionally genetic factors can predispose to disruptive events. For example, a small proportion of amniotic bands are caused by an underlying genetically determined defect in collagen that weakens the amnion, making it more liable to tear or rupture spontaneously.

FIGURE 16.3 Hand (A) and foot (B) of a baby with digital amputations resulting from amniotic bands showing residual strands of amnion.

(Courtesy Dr. Una MacFadyen, Leicester Royal Infirmary, UK.)

Deformation

A deformation is a defect resulting from an abnormal mechanical force that distorts an otherwise normal structure. Examples include dislocation of the hip and mild ‘positional’ talipes (‘clubfoot’) (Figure 16.4) resulting from reduced amniotic fluid (oligohydramnios) or intrauterine crowding from twinning or a structurally abnormal uterus. Deformations usually occur late in pregnancy and convey a good prognosis with appropriate treatment—for instance, gentle splinting for talipes, because the underlying organ is fundamentally normal in structure.

FIGURE 16.4 Lower limbs of a baby with talipes equinovarus.

Dysplasia

A dysplasia is an abnormal organization of cells into tissue. The effects are usually seen wherever that particular tissue is present. For example, in a skeletal dysplasia such as thanatophoric dysplasia, which is caused by mutations in FGFR3 (p. 93), almost all parts of the skeleton are affected (Figure 16.5). Similarly, in an ectodermal dysplasia, widely dispersed tissues of ectodermal origin, such as hair, teeth, skin, and nails, are involved (Figure 16.6). Most dysplasias are caused by single-gene defects and are associated with high recurrence risks for siblings and/or offspring.

FIGURE 16.5 A, Infant with thanatophoric dysplasia. B, Radiograph of the infant showing short ribs, flat vertebral bodies, and curved femora.

FIGURE 16.6 Hair (A) and teeth (B) of a male with ectodermal dysplasia.

Sequence

This concept describes the findings that occur as a consequence of a cascade of events initiated by a single primary factor and may result in a single organ malformation. In the ‘Potter’ sequence, chronic leakage of amniotic fluid or defective fetal urinary output results in oligohydramnios (Figure 16.7). This, in turn, leads to fetal compression, resulting in squashed facial features, dislocation of the hips, talipes, and pulmonary hypoplasia (Figure 16.8), usually resulting in neonatal death from respiratory failure.

FIGURE 16.7 The ‘Potter’ sequence showing the cascade of events leading to and resulting from oligohydramnios (reduced volume of amniotic fluid).

FIGURE 16.8 Facial appearance of a baby with Potter sequence from oligohydramnios as a consequence of bilateral renal agenesis. Note the squashed appearance caused by in utero compression.

Syndrome

In practice the term syndrome is used very loosely (e.g., the amniotic band ‘syndrome’), but in theory it should be reserved for consistent and recognizable patterns of abnormalities for which there will often be a known underlying cause. These underlying causes can include chromosome abnormalities, as in Down syndrome, or single gene defects, as in the Van der Woude syndrome, in which cleft lip and/or palate occurs in association with pits in the lower lip (Figure 16.9).

FIGURE 16.9 Posterior cleft palate and lower lip pits in a child with Van der Woude syndrome.

Several thousand multiple malformation syndromes are recognized, and their clinical study has been the discipline of dysmorphology. Clinical diagnosis has been greatly helped by the development of computerized databases (see Appendix) with a search facility based on key abnormal features. Even with the help of this extremely valuable diagnostic tool, there are many dysmorphic children for whom no diagnosis is reached, so that it can be very difficult to provide accurate information about the likely prognosis and recurrence risk (p. 266). The technique of microarray-CGH (p. 281) is making inroads into this large group of undiagnosed patients.

Association

The term association has been introduced in recognition of the fact that certain malformations tend to occur together more often than would be expected by chance, yet this non-random occurrence of abnormalities cannot be easily explained on the basis of a sequence or a syndrome. The main differences from a syndrome are the lack of consistency of abnormalities from one affected individual to another and the absence of a satisfactory underlying explanation. The names of associations are often acronyms; for example, the VATER association features vertebral, anal, tracheoesophageal, and renal abnormalities. Associations generally convey a low risk of recurrence and are generally thought not to be genetic. However, heterogeneity is likely and some cases are likely to be genetic.

This classification of birth defects is not perfect—it is far from being either fully comprehensive or mutually exclusive. For example, bladder outflow obstruction caused by a primary malformation such as a urethral valve will result in the oligohydramnios or Potter sequence, leading to secondary deformations such as dislocation of the hip and talipes. To complicate matters further, the absence of both kidneys, which will result in the same sequence of events, is usually erroneously referred to as Potter syndrome. Despite this semantic confusion, classifications can aid understanding of causes and recurrence risks (Chapter 17).

Noonan Syndrome

First described by Noonan and Ehmke in 1963, this well-known condition has incidence that may be as high as 1 : 2000 births, with equal sex ratio. The features resemble those of Turner syndrome in females—short stature, neck webbing, increased carrying angle at the elbow and congenital heart disease. Pulmonary stenosis is the most common lesion but atrial septal defect, ventricular septal defect, and occasionally hypertrophic cardiomyopathy occur. A characteristic mild pectus deformity may be seen, and the face shows hypertelorism, down-slanting palpebral fissures, and low-set ears (Figure 16.11). Some patients have a mild bleeding diathesis, and learning difficulties occur in about one-quarter.

FIGURE 16.11 Noonan syndrome: (A) In a baby presenting with cardiomyopathy at birth (which later resolved); (B) in a child; and (C) in a 57-year-old man.

In a three-generation Dutch family, Noonan syndrome (NS) was mapped to 12q22 in 1994, but it was not until 2001 that mutations were identified in the protein tyrosine phosphatase, non-receptor-type, 11 (PTPN11) gene. Attention has turned rapidly to phenotype–genotype correlation, and mutation-positive cases have a much higher frequency of pulmonary stenosis than mutation-negative cases, and very few mutations have been found in patients with cardiomyopathy. However, facial features are similar, whether or not a mutation is found. Mutations in PTPN11 account for about half of all cases of NS. Mutations in the SOS1, SHOC2, KRAS, and MAPZK1 genes have been found in a small proportion of PTPN11-negative cases. These genes belong to the same pathway, known as RAS-MAPK. The protein product of PTPN11 is SHP-2 and this, together with SOS1, positively transduces signals to Ras-GTP, a downstream effector (Figure 16.12). The KRAS mutations in NS appear to lead to K-ras proteins with impaired responsiveness to GTPase activating proteins (p. 213). Neurofibromatosis, the most common of this group, is dealt with in Chapter 18 (p. 298).

FIGURE 16.12 The RAS-MAPK pathway. HRAS and KRAS are activated by SPH-2 and SOS1 (red arrows). Orange arrows = inhibition. The pathway is dysregulated by mutations in key components, resulting in the distinct but related phenotypes of Noonan syndrome, CFC syndrome, Costello syndrome, and neurofibromatosis (see Table 16.5). Neurofibromin is a GAP (GTPase activating) protein that functions as a tumor-suppressor. Mutant RAS proteins display impaired GTPase activity and are resistant to GAPs. The effect is for RAS to bind GTP, which results in activation of the pathway (gain of function).

For years dysmorphologists recognized overlapping features between NS and the rarer conditions known as cardio-facio-cutaneous and Costello syndromes. These conditions are now recognized to form part of a spectrum of disorders explained by mutations in different components of the RAS-MAPK pathway, with each syndrome displaying considerable genetic heterogeneity (Table 16.5). Many of the mutations are gain-of-function missense mutations, which may explain the increase in solid tumors in Costello syndrome as well as cellular proliferation in some tissues in cardio-facio-cutaneous syndrome (e.g., hyperkeratosis). The effect is for RAS to bind GTP, which results in activation of the pathway (gain-of-function). Neurofibromin is a GTPase activating protein, and functions as a tumor-suppressor.

Sotos Syndrome

First described in 1964, this is one of the ‘overgrowth’ syndromes, previously known as cerebral gigantism. Birth weight is usually increased and macrocephaly noted. Early feeding difficulties and hypotonia may prompt many investigations and there is often motor delay and ataxia. Height progresses along the top of, or above, the normal centile lines, but final adult height is not necessarily markedly increased. Advanced bone age may be present, as well as large hands and feet, and the cerebral ventricles may be mildly dilated on imaging. The face is characteristic (Figure 16.13), with a high prominent forehead, hypertelorism with down-slanting palpebral fissures, a characteristic nose in early childhood, and a long pointed chin. Scoliosis develops in some cases during adolescence. Parent–child transmission is rare, probably because most patients have learning difficulties. However, the author has seen a three-generation family including individuals with above average intelligence.

FIGURE 16.13 Sotos syndrome. A, In a young child who has the typical high forehead, large head, and characteristic tip to the nose. B, The same individual at age 18 years, with learning difficulties and a spinal curvature (scoliosis).

Among patients with Sotos syndrome reported to have balanced chromosome translocations were two with breakpoints at 5q35. From these crucial patients a Japanese group in 2002 went on to identify a 2.2-Mb deletion in a series of Sotos syndrome cases. The deletion takes out a gene called NSD1, an androgen receptor-associated co-regulator with 23 exons. The Japanese found a small number of frameshift mutations in their patients but, interestingly, a study of European cases found that mutations were far more common than deletions. For the large majority of cases the mutations and deletions occur de novo.

Holoprosencephaly

This severe and often fatal malformation is caused by a failure of cleavage of the embryonic forebrain or prosencephalon. Normally this divides transversely into the telencephalon and the diencephalon. The telencephalon divides in the sagittal plane to form the cerebral hemispheres and the olfactory tracts and bulbs. The diencephalon develops to form the thalamic nuclei, the pineal gland, the optic chiasm, and the optic nerves. In holoprosencephaly, there is incomplete or partial failure of these developmental processes, and in the severe alobar form this results in an abnormal facial appearance (see Figure 6.7, p. 88) with profound neurodevelopmental impairment.

Etiologically, holoprosencephaly can be classified as chromosomal, syndromal, or isolated. Chromosomal causes account for around 30% to 40% of all cases, with the most common abnormality being trisomy 13 (p. 275). Other chromosomal causes include deletions of 18p, 2p21, 7q36, and 21q22.3, duplication of 3p24-pter, duplication or deletion of 13q, and triploidy (p. 276). Syndromal causes of holoprosencephaly are numerous and include relatively well known conditions such as the deletion 22q11 (DiGeorge) syndrome (p. 282) and a host of much rarer multiple malformation syndromes, some of which show autosomal recessive inheritance. One of these, Smith-Lemli-Opitz syndrome (p. 87), is associated with low levels of cholesterol; this is relevant in that it is known that cholesterol is necessary for normal functioning of the sonic hedgehog pathway (p. 86).

The third group, isolated holoprosencephaly, is sometimes explained by heterozygous mutations in three genes. The effects can be very variable, ranging from very mild with minimal features such as anosmia, to the full-blown, lethal, alobar form. The genes Sonic hedgehog (SHH) on chromosome 7q36, ZIC2 on chromosome 13q32, and SIX3 on chromosome 2p21. Of these SHH is thought to make the greatest contribution, accounting for up to 20% of all familial cases and between 1% and 10% of isolated cases. Some sibling recurrences of holoprosencephaly, not because of recessive Smith-Lemli-Opitz syndrome, have been shown to be due to germline mutations in these genes.

That so many familial cases remain unexplained indicates that more holoprosencephaly genes await identification. Causal heterogeneity is further illustrated by its association with poorly controlled maternal diabetes mellitus (p. 261).

Neural Tube Defects

Neural tube defects (NTDs), such as spina bifida and anencephaly, illustrate many of the underlying principles of multifactorial inheritance and emphasize the importance of trying to identify possible adverse environmental factors. These conditions result from defective closure of the developing neural tube during the first month of embryonic life. A defect occurring at the upper end of the developing neural tube results in either exencephaly/anencephaly or an encephalocele (Figure 16.14). A defect occurring at the lower end of the developing neural tube leads to a spinal lesion such as a lumbosacral myelocele or meningomyelocele (see Figure 16.2), and a defect involving the head plus cervical and thoracic spine leads to craniorachischisis. These different entities relate to the different embryological closure points of the neural tube. Most NTDs have serious consequences. Anencephaly and craniorachischisis are not compatible with survival for more than a few hours after birth. Large lumbosacral lesions usually cause partial or complete paralysis of the lower limbs with impaired bladder and bowel continence.

FIGURE 16.14 A baby with a large occipital encephalocele.

As with many malformations, NTDs can be classified etiologically under the headings of chromosomal, syndromal, and isolated. Chromosomal causes include trisomy 13 and trisomy 18, in both of which NTDs show an incidence of around 5% to 10%. Syndromal causes include the relatively rare autosomal recessive disorder Meckel-Gruber syndrome, characterized by encephalocele in association with polycystic kidneys and polydactyly. However, most NTDs represent isolated malformations in otherwise normal infants, and appear to show multifactorial inheritance.

The empirical recurrence risks to first-degree relatives (siblings and offspring) vary according to the local population incidence and are as high as 4% to 5% in areas where NTDs are common. The incidence in the United Kingdom is highest in people of Celtic origin. If such individuals move from their country of origin to another part of the world, the incidence in their offspring declines but remains higher than among the indigenous population. These observations suggest a relatively high incidence of susceptibility genes in the Celtic populations.

No single NTD susceptibility genes have been identified in humans, although there is some evidence that the common 677C > T polymorphism in the Methylenetetrahydrofolate reductase (MTHFR) gene can be a susceptibility factor in some populations. Reduction in MTHFR activity results in decreased plasma folate levels, which are known to be causally associated with NTDs (see the following section). Research efforts have also focused on developmental genes, such as the PAX family (p. 91), which are expressed in the embryonic neural tube and vertebral column. In mouse models, about 80 genes have been linked to exencephaly, about 20 genes to lumbosacral meningomyelocele, and about 5 genes to craniorachischisis. One example is an interaction between mutations of PAX1 and the Platelet-derived growth factor α gene (PDGFRA) that results in severe NTDs in 100% of double-mutant embryos. This rare example of digenic inheritance (p. 119) serves as a useful illustration of the difficulties posed by a search for susceptibility genes in a multifactorial disorder. However, to date there have been no equivalent breakthroughs in understanding the processes in human NTDs.

Environmental factors include poor socioeconomic status, multiparity, and valproic acid embryopathy (p. 261). Firm evidence has also emerged that periconceptional multivitamin supplementation reduces the risk of recurrence by a factor of 70% to 75% when a woman has had one affected child. Several studies have shown that folic acid is likely to be the effective constituent in multivitamin preparations. In both the United Kingdom and the United States, it is recommended that all women who have had a previous child with a NTD should take 4 to 5 mg folic acid daily both before and during the early stages of all subsequent pregnancies. Similarly, in the United Kingdom, it has been recommended that all women who are trying to conceive should take 0.4 mg folic acid daily. In the United States, where bread is fortified with folic acid, this recommendation applies to all women of reproductive age throughout their reproductive years. In the United Kingdom, this recommendation has not as yet resulted in a noticeable decline in the incidence of NTDs.

The Thalidomide Tragedy

Thalidomide was used widely in Europe during 1958 to 1962 as a sedative. In 1961 an association with severe limb anomalies in babies whose mothers had taken the drug during the first trimester was recognized and the drug was subsequently withdrawn from use. It is possible that more than 10,000 babies were damaged over this period. Review of these babies’ records indicated that the critical period for fetal damage was between 20 and 35 days postconception (i.e., 34 to 50 days after the beginning of the last menstrual period).

The most characteristic abnormality caused by thalidomide was phocomelia (Figure 16.15). This is the name given to a limb that is malformed due to absence of some or all of the long bones, with retention of digits giving a ‘flipper’ or ‘seal-like’ appearance. Other external abnormalities included ear defects, microphthalmia and cleft lip/palate. In addition, approximately 40% died in early infancy from severe internal abnormalities affecting the heart, kidneys, or gastrointestinal tract. Some ‘thalidomide babies’ have grown up and had children of their own, and in some cases these offspring have also had similar defects. It is therefore most likely, not surprisingly, that thalidomide was wrongly blamed in a proportion of cases that were in fact from single-gene conditions following autosomal dominant inheritance (e.g., SALL4 mutations [see Figure 6.21, C, p. 99] in Okihiro syndrome).

FIGURE 16.15 A child with thalidomide embryopathy. There is absence of the upper limbs (amelia). The lower limbs show phocomelia and polydactyly.

(Courtesy Emeritus Professor R. W. Smithells, University of Leeds, UK)

The thalidomide tragedy focused attention on the importance of avoiding all drugs in pregnancy as far as is possible, unless absolute safety has been established. Drug manufacturers undertake extensive research trials before releasing a drug for general use, and invariably urge caution about the use of any new drug in pregnancy. Monitoring systems, in the form of congenital abnormality registers, have been set up in most Western countries so that it is unlikely that an ‘epidemic’ on the scale of the thalidomide tragedy could ever happen again.

Fetal Alcohol Syndrome

Children born to mothers who have consistently consumed large quantities of alcohol during pregnancy tend to show a degree of microcephaly, a distinctive facial appearance with short palpebral fissures, and a long smooth philtrum (Figure 16.16). They also show developmental delay with hyperactivity and clumsiness. This condition is referred to as fetal alcohol syndrome, but if the physical aspects are lacking the term ‘alcohol-related neurodevelopmental defects’ may be applied. There is uncertainty about the ‘safe’ level of alcohol consumption in pregnancy and there is evidence that mild-to-moderate ingestion can be harmful. Generally, total abstinence from alcohol is advised throughout pregnancy.

FIGURE 16.16 A child with fetal alcohol syndrome. The child has short palpebral fissures and a long, smooth philtrum.

Rubella

The rubella virus, which damages 15% to 25% of all babies infected during the first trimester, causes cardiovascular malformations such as patent ductus arteriosus and peripheral pulmonary artery stenosis. Congenital rubella infection can be prevented by the widespread use of immunization programs based on administration of either the measles, mumps, rubella vaccine in early childhood or rubella vaccine alone to young adult women.

Cytomegalovirus

At present no immunization is available against cytomegalovirus and naturally occurring infection does not always produce long-term immunity. The risk of abnormality is greatest when infection occurs during the first trimester. Overall this virus causes damage in about 5% of infected pregnancies.

Toxoplasmosis

Maternal infection with the parasite causing toxoplasmosis conveys a risk of 20% that the fetus will be infected during the first trimester, rising to 75% in the second and third trimesters. Vaccines against toxoplasmosis are not available.

Investigation for possible congenital infection can be made by sampling fetal blood to look for specific immunoglobulin-M antibodies. Fetal blood analysis can also reveal generalized evidence of infection, such as abnormal liver function and thrombocytopenia.

There is some evidence to suggest that maternal infection with Listeria can cause a miscarriage, and a definite association has been established between maternal infection with this agent and neonatal meningitis. Maternal infection with parvovirus can cause severe anemia in the fetus, resulting in hydrops fetalis and pregnancy loss.

Ionizing Radiation

Heavy doses of ionizing radiation, far in excess of those used in routine diagnostic radiography, can cause microcephaly and ocular defects in the developing fetus. The most sensitive time of exposure is 2 to 5 weeks post-conception. Ionizing radiation can also have mutagenic (p. 26) and carcinogenic effects and, although the risks associated with low-dose diagnostic procedures are minimal, radiography should be avoided during pregnancy if possible.

Prolonged Hyperthermia

There is evidence that prolonged hyperthermia in early pregnancy can cause microcephaly and microphthalmia as well as neuronal migration defects. Consequently, it is recommended that care should be taken to avoid excessive use of hot baths and saunas during the first trimester.

Diabetes Mellitus

Maternal diabetes mellitus is associated with a two- to threefold increase in the incidence of congenital abnormalities in offspring. Malformations that occur most commonly in such infants include congenital heart disease, neural tube defects, vertebral segmentation defects and sacral agenesis, femoral hypoplasia, holoprosencephaly, and sirenomelia (‘mermaidism’). The likelihood of an abnormality is inversely related to the control of the mother’s blood glucose levels during early pregnancy. This can be assessed by regular monitoring of blood glucose and glycosylated hemoglobin levels.

Phenylketonuria

Another maternal metabolic condition that conveys a risk to the fetus is untreated phenylketonuria (p. 167). A high serum level of phenylalanine in a pregnant woman with phenylketonuria will almost invariably result in serious damage (e.g., mental retardation). Structural abnormalities may include microcephaly and congenital heart defects. All women with phenylketonuria should be strongly advised to adhere to a strict and closely monitored low phenylalanine diet before and throughout pregnancy.

Maternal Epilepsy

There is a large body of literature devoted to the question of maternal epilepsy, the link with congenital abnormalities, and the teratogenic effects of antiepileptic drugs (AEDs). The largest and best controlled studies suggest that maternal epilepsy itself is not associated with an increased risk of congenital abnormalities. However, all studies have shown an increased incidence of birth defects in babies exposed to AEDs. The risks are in the region of 5% to 10%, which is two to five times the background population risk. These figures apply mainly to single drug therapy, and may be doubled if the fetus is exposed to more than one AED. Some drugs are more teratogenic than others, with the highest risks applying to sodium valproate. The range of abnormalities occurring in the ‘fetal anticonvulsant syndromes’ (FACS) are wide, including neural tube defect (about 2%), oral clefting, genitourinary abnormalities such as hypospadias, congenital heart disease, and limb defects. The abnormalities themselves are not specific to FACS, and making a diagnosis in an individual case can therefore be difficult. Sometimes characteristic facial features are seen, particularly in fetal valproate syndrome (Figure 16.17).

FIGURE 16.17 A child with fetal valproate syndrome. She has a broad nasal root, blunt nasal tip, and a thin upper lip.

The most controversial aspect of AEDs and FACS is the risk of learning difficulties and behavioral problems. Controlled studies are problematic but evidence points to a higher incidence than in the general population—again, particularly in relation to sodium valproate. For practical purposes, potential risks to the fetus have to be weighed against the dangers of stopping AED treatment and risking seizures during pregnancy. If the patient has been seizure-free for at least 2 years, she can be offered withdrawal of anticonvulsant medication before proceeding with a pregnancy. If therapy is essential, then single-drug treatment is much preferred and sodium valproate should be avoided if possible.