Fetal Anomalies – The Geneticist's Approach

Introduction

The geneticist's approach to the unexpected finding of fetal structural malformations is to determine whether they constitute a recognizable abnormal pattern of morphogenesis. The pattern and nature of the anomalies can often suggest the timing and cause of an embryological insult and, together with information gleaned from family and parental medical histories, may be helpful in determining whether the insult was environmental or genetic. The rapid advances in molecular genetics may now allow a precise prenatal diagnosis. Hence close co-operation between the Fetal Medicine Unit and the genetics clinicians and laboratories has become more necessary.

This chapter outlines this approach and it includes a description and explanation of the modes of inheritance, including inherited chromosomal anomalies.

To determine a genetic origin for an anomaly it is necessary to:

determine if an anomaly is isolated or associated with other abnormal findings;
determine the underlying cause from the nature and pattern of anomalies;
collect information from family, pregnancy and personal medical histories;
attempt to make a diagnosis, assess prognosis and recurrence risks using information from as many sources as possible and advise on further testing during the pregnancy and at birth;
discuss all the information available and possible management options with the parents.

Determining if an Anomaly is Isolated or Not

When an unexpected structural anomaly is found on fetal ultrasound examination, the first step is to determine if the anomaly is an isolated single anomaly or whether there are other ultrasound findings.

Isolated Single Anomaly

Single malformations may occur in an otherwise normal child. Careful detailed scanning should be performed to confirm that all other fetal structural and growth parameters are normal because single anomalies can be markers for malformation syndromes.

The most common single primary defects in liveborns are shown in Table 7-1 .

TABLE 7-1

The Most Common Single Primary Defects in Liveborns

	Prevalence per 1000 births (UK)
Deformations
Congenital hip dislocation	3.2
Talipes equinovarus	6.2
Malformations
Cleft lip and/or cleft palate	1.2
Congenital cardiac defects	6.9
Defect in neural-tube closure	3.6

Studies from Kyoto and London on induced and spontaneous abortions have been used to show that congenital heart disease, cleft lip and palate, and neural-tube defects are at least twice as common in late embryos and early fetuses as in liveborns. The London series of spontaneous abortions at 8–28 weeks showed single malformations in 4.7% and multiple problems in a further 4.9%. It is impossible to be certain that an abnormality is isolated from ultrasound examinations, no matter how experienced the operator.

Multiple Malformations

A careful search should be made to determine if there are other structural malformations, growth disturbance or unusual movements.

If several anomalies are present, they may fall into a pattern that suggests a specific diagnosis. Common recognizable patterns of major anomalies are most likely to be due to chromosomal imbalance, but certain combinations of anomalies may also suggest rare single gene or dysmorphic syndromes, which can be diagnosed in utero in the absence of a previous family history. Abnormalities may develop with time and therefore repeat examinations may be required to make a diagnosis.

Determining the Underlying Cause from the Nature and Pattern of Anomalies

Reviewing the embryonic origin of the tissue or organ involved in a specific anomaly can be helpful in attempts to determine its cause or timing, particularly with multiple abnormalities, when such an approach may suggest a common embryological origin.

The nature of an anomaly is related to the stage of embryogenesis at which genetic and environmental factors acted during organogenesis or during maturation. During human development there are critical times when organ systems are susceptible ( Figure 7-1 ). The embryology of each organ system is described in the relevant chapter in this book.

FIGURE 7-1, Critical periods of development (purple shaded areas denote highly sensitive periods).

Table 7-2 gives a summary of the timing before which insults must have occurred to result in some major anomalies.

TABLE 7-2

Embryological Timing of Some Anomalies

Malformation	Defect in	Cause prior to
Holoprosencephaly	Prechordal mesoderm	23 days
Sirenomelia	Caudal axis	23 days
Anencephaly	Anterior neuropore	26 days
Meningomyelocoele	Posterior neuropore	28 days
Transposition of the great vessels	Direction of development of bulbous cordis septum	36 days
Radial aplasia	Development of radius	38 days
Cleft lip	Development of primary palate	6 weeks
Ventricular septal defect	Closure of ventricular septum	6 weeks
Diaphragmatic hernia	Closure of pleuropotential canal	6 weeks
Syndactyly	Programmed cell death between digits	6 weeks
Duodenal atresia	Recanalization of duodenum	7–8 weeks
Omphalocoele	Intestinal loop return to abdominal cavity	10 weeks
Bicornuate uterus	Fusion of lower portion of Mullerian ducts	10 weeks
Cleft palate	Development of secondary palate	10 weeks
Hypospadias	Fusion of urethral folds	12 weeks
Cryptorchidism	Descent of testes	7–9 months

Teratogenic influences (genetic or environmental) acting during the first 2 weeks of development are likely to result in the death of the embryo rather than cause malformations. The 3rd to the 8th week post-conception is the embryonic period during which organogenesis occurs and so most major malformations arise during this critical period. The final stage of development is from the 3rd month to birth. As this is the period of somatic growth and maturation of tissues, few malformations may be expected to arise, but the fetus may be at risk from extrinsic factors, such as fetal constraint and hypoxia.

Malformations initiated during early organogenesis tend to have more complex outcomes: a single malformation can result in a cascade of secondary and tertiary events, resulting in what appears to be multiple anomalies (see malformation sequence below). Some defects can be identified as having occurred in organs already normally developed, due to compression, constriction or immobility.

Nature of the Anomalies

Anomalies can be classified into three main types of abnormal morphogenesis:

malformations;
deformations;
disruptions.

Although it may appear academic to determine whether an anomaly is likely to be due to one of these causes, classifying anomalies in this way can suggest a differential diagnosis and direct subsequent investigations.

Malformation

A malformation is caused by an abnormality of morphogenesis due to an intrinsic problem within the developing structure. Underlying mechanisms include altered tissue formation, growth or differentiation caused by genetic or environmental factors or a combination of both. Examples include spina bifida, cleft lip/palate and congenital heart defects.

Deformation

A deformation is an abnormality of morphogenesis caused by extrinsic force being applied to a normally developing or developed structure. Deformations usually occur in late fetal life and are caused by lack of fetal movement through mechanical (uterine abnormalities and abnormal fetal positions) malformational (spina bifida and renal agenesis) or functional factors (fetal neuromuscular disorders). Examples of deformation include craniofacial asymmetry, arthrogryposis and talipes.

Disruption

A disruption is due to a destructive force acting upon an otherwise normal developing structure. Anomalies caused by disruptive forces can present a distinctive appearance because of the loss of tissue and aberrant differentiation of adjacent tissues with which adhesions may have developed. The mechanisms include cell death or tissue destruction because of vascular anomalies, anoxia, teratogens, infections or mechanical forces. Examples include some cases of porencephaly, facial clefts and missing digits or limbs.

Table 7-3 gives a comparison of the features of malformations, deformations and disruptions.

TABLE 7-3

Comparison of the Features of Malformations, Deformations and Disruptions

Features	Malformations	Deformations	Disruptions
Time of occurrence	Embryonic	Fetal	Embryonic/fetal
Level of disturbance	Organ	Region	Area
Perinatal mortality	+	–	+
Clinical variability of a given anomaly	Moderate	Mild	Extreme
Multiple causes of a given anomaly	Very frequent	Less common	Less common
Spontaneous correction	–	+	–
Correction by posture	–	+	–
Correction by surgery	+	±	+
Relative recurrence rate	Higher	Lower	Extremely low
Approximate frequency in newborns	2–3%	1–2%	1–2%

The Pattern of Anomalies

Isolated anomaly;
malformation syndrome/sequence;
association.

An anomaly may be an isolated malformation, or one of several in a malformation syndrome. Some anomalies may be secondary to a primary malformation, deformation or disruption resulting in a malformation sequence. Even if a precise aetiological agent cannot be identified, recognizing into which group a patient's anomalies fall can provide information about genetic risks, prognosis and appropriate management for the affected individual.

When trying to elucidate if a pattern of multiple malformations is the result of a sequence or represents a true malformation syndrome, it is helpful to consider the organ systems involved and ask if all the abnormalities can be explained by a single anomaly or problem that has led to a cascade of subsequent structural defects (a sequence). The converse is to consider whether the multiple structural defects present appear to be independent embryologically, and cannot be attributed to a single initiating abnormality and its consequences (malformation syndrome).

Malformation Sequence

A sequence occurs when a primary anomaly itself determines additional defects, e.g.

The oligohydramnios (Potter) sequence where facial appearance, lung hypoplasia and joint contractures are all the result of constraint because of insufficient amniotic fluid.
Micrognathia is the primary anomaly in the Pierre Robin sequence: the normally sized tongue pressing against the palate preventing its fusion.

The cause of the original abnormality may be a malformation, deformation or disruption. Some anomalies, such as anencephaly, can be the result of a primary malformation or an early embryonic disruption. Before the lower recurrence risk associated with a disruption is given, it is important to search for confirmatory features, such as amniotic bands or orofacial clefting when amputations and ring constrictions are present. Monozygotic twins have a higher frequency of disruptions, which are likely to have a vascular cause related to arterial-to-venous anastomoses in the placenta. Monozygotic twins also have an increased risk of malformations related to the twinning process and epigenetic factors, which are separate from placental connections between the two fetal circulations.

Malformation Syndrome

A recognizable pattern of multiple defects is described as a ‘malformation syndrome’, when a common cause has resulted in a number of anatomically unrelated errors in morphogenesis. Primary developmental anomalies in two or more systems result in structural defects. Causes (and examples) include chromosomal abnormalities (Down syndrome), teratogens (fetal alcohol syndrome) and single-gene defects (Meckel–Gruber syndrome).

Association

An ‘association’ is a recognizable combination of anomalies that occur together more frequently than by chance, but that is known not to have a common cause nor to be the result of a sequence. Examples are the VATER, VACTERL and MURCS associations ( Table 7-4 ). It is likely that ‘associations’ will be reclassified into other existing or new groups when their aetiology can be determined. CHARGE syndrome used to be considered an association until the molecular aetiology of mutations in the CHD7 gene was identified.

TABLE 7-4

Examples of Recognized Associations

VATER	VACTERL	MURCS
V vertebral anomalies	V vertebral defects	MU Mullerian duct aplasia
A anal atresia	A anal atresia	R renal aplasia
TE tracheo-oesophageal fistula	C cardiovascular anomalies	CS cervico-thoracic somite dysplasia
R radial and renal anomalies	TE tracheo-oesophageal fistula
	R radial and renal anomalies
	L limb defects

Contributing Information from Family, Pregnancy and Personal Medical Histories

Family History

Documenting the family history is an essential step in trying to determine if the anomalies are likely to have a genetic cause, because autosomal dominant, X-linked and inherited chromosomal disorders may give a recognizable pedigree pattern of affected people. This is especially important for anomalies where the risk of recurrence would usually be low, e.g. congenital contractures or cleft palate. The absence of a family history does not necessarily rule out a genetic cause, however, because autosomal recessive inheritance or a new dominant mutation can result in an isolated case.

Drawing a pedigree is the best way to record genetic information about a family. The agreed pedigree notation is shown in Figure 7-2 .

FIGURE 7-2, Symbols used in the drawing of pedigrees.

It is important to record at least basic details on both sides of the family, even if it is obvious that a disorder is segregating on one side.

Interpreting the Pedigree

Table 7-5 summarizes pedigree patterns that would be suggestive of Mendelian inheritance.

TABLE 7-5

Summary of Pedigree Patterns for Single Gene Disorders

Autosomal Dominant Inheritance

1.
Males and females affected in equal proportions
2.
Transmitted from one generation to next (‘vertical transmission’)
3.
All forms of transmission are observed (i.e. male to male, female to female, male to female, female to male)

Autosomal Recessive Inheritance

1.
Males and females affected in equal proportions
2.
Individuals affected in a single sibship in one generation
3.
Consanguinity in the parents provides further support

X-Linked Recessive Inheritance

1.
Males affected almost exclusively
2.
Transmitted through carrier females to their sons (‘knight’s move’ pattern)
3.
Affected males cannot transmit the disorder to their sons

X-Linked Dominant Inheritance

1.
Males and females are affected although females are usually less severely affected than males
2.
While affected females can transmit the disorder to male and female children, affected males transmit the disorder only to their daughters, all of whom are affected

Other pointers include:

A history of miscarriages, stillbirths or early neonatal deaths, especially if the causes of death are unexplained or ambiguous. This pattern suggests the possibility of a parental balanced chromosome rearrangement.
Abnormal features in either parent in common with the fetus. This raises the possibility of an autosomal dominant disorder which can be very variable within the same family and hence careful examination of the parents may be necessary.
The presence of consanguinity. This does not prove autosomal recessive inheritance, but makes it more likely.
Similarly affected male relatives of a male patient on the maternal side. This pattern suggests an X-linked disorder. It may be necessary to confirm that the ultrasound sex is the same as the karytotypic sex if this is relevant.
Non-paternity and de novo mutations may explain discrepancies.

Pregnancy and Personal Medical Histories

Pregnancy history is of crucial importance because it may reveal a specific non-genetic cause, such as drug therapy or misuse, or maternal illness, such as an infection. Severe hyperemesis may cause a skeletal disorder similar to chondrodysplasia punctata. An abnormal fetal intrauterine position may suggest a mechanical uterine factor, such as fibroids or uterine anomalies causing deformation or disruption. Pre-existing risk factors may be suggested from information on parental ages, occupations, past medical and drug history.

Maternal Disease

Autoimmune disorders such as myasthenia gravis and systemic lupus erythematosis may cause fetal abnormalities.
Diabetes mellitus is increasingly common with the rising incidence of obesity and delayed motherhood: sacral agenesis and caudal regression are strongly associated with maternal diabetes and may be due to deranged maternal metabolism.
Phenylketouria may result in microcephaly in the fetus.

Occupations such as a primary school teacher may make fetal infection a more likely underlying cause of fetal abnormality.

Making a Diagnosis; Assessing Prognosis and Recurrence Risks

A definitive diagnosis depends on recognizing the particular pattern of anomalies. Even with the additional information available after birth, a diagnosis cannot be made in about half the patients with dysmorphic syndromes seen in tertiary referral genetic clinics. Prenatal diagnosis presents even greater challenges, particularly as individual anomalies are often non-specific and even rare defects may be found in several conditions. In addition, there may be variable expression of features associated with a particular disorder. However, the diagnosis of a malformation syndrome or being able to place a group of anomalies in a likely aetiological category can inform management plans.

Sources of Information

A particularly useful source of advice is available from clinical geneticists with specialist skills in the diagnosis of dysmorphic and multiple malformation syndromes and many ultrasound services have formal links with their local clinical genetics services. Clinical geneticists have access to specialist literature and can also advise on DNA diagnosis for single-gene disorders, risks associated with familial chromosome rearrangements and for organ/system anomalies.

Further Investigations

Chromosome analysis is always indicated where multiple malformations affecting several different organ systems are identified when there is no obvious diagnosis. Certain combinations of defects may suggest a small chromosomal deletion; close links between clinical and laboratory staff will help when determining if specific additional studies are needed such as fluorescence in-situ hybridization (FISH) or comparative genomic hybridization (CGH). For example, the identification of a conotruncal defect on cardiac ultrasound will always require the karyotype to be examined for a 22q11.1 deletion. It is important to request this information at the time the sample arrives in the laboratory, as it may be possible to undertake a rapid investigation at this stage rather than wait for the cultured chromosomes which will take approximately 2 weeks.

Extraction of DNA from an amniocentesis may require a further 3 weeks to grow the cells for an adequate volume of DNA to be available. CGH (comparative genomic hybridization) is increasingly used prenatally for unexplained multiple malformation syndromes, but it is necessary to discuss with the parents the possibility of finding variations of unknown significance.

DNA analysis during the pregnancy is becoming increasingly useful for specific malformations to confirm the underlying cause, for example a single rhabdomyoma is associated with tuberous sclerosis in 50% of cases and analyses of the genes TSC1 and TSC2 will identify the majority of affected babies. Multiple rhabodmyomas are always associated with tuberous sclerosis and therefore DNA diagnosis does not add information for the parents. Free fetal DNA extracted from the maternal circulation is increasingly used in a diagnostic setting.

Biochemical studies currently prove helpful in only a small proportion of dysmorphic infants (e.g. peroxisomal disorders such as Zellweger syndrome). Fetal hydrops with hepatosplenomegaly may suggest a lysosymal storage disorder and enzyme analysis can be helpful.

Further maternal tests maybe indicated, for example looking for steroid ratios in maternal urine and serum in a fetus with a suspected diagnosis of Smith–Lemli–Opitz syndrome.

Fetal MRI may help clarify fetal brain malformations, providing additional information over ultrasound after 22 weeks’ gestation.

Whilst the majority of congenital malformation syndromes are diagnosed from recognition of external malformations, autopsy by an experienced paediatric pathologist may be extremely helpful.

Use of Databases

Computerized databases are useful diagnostic tools. The Winter–Baraitser Dysmorphology Database (WBDD) (formerly London Dysmorphology Database, LDDB) and POSSUM are two in common use. The WBDD, for example, contains information on over 4700 multiple congenital anomaly syndromes, including single-gene disorders, sporadic conditions and those caused by environmental agents. Although WBDD mainly contains information about non-chromosomal multiple congenital anomaly syndromes, it also includes information about distinctive microdeletion syndromes and those resulting from uniparental disomy.

The database generates a list of possible diagnoses by searching on combinations of clinical features. As it is often impossible to assess which are the most characteristic or constant features of a rare syndrome, some clinical experience is required to assess the likelihood of the diagnoses suggested.

The clinical features chosen for the computer search should be those anomalies that are easily recognizable as being abnormal, do not merge with normal variation and are not common to a large number of syndromes. It is also important to consider that a feature might not be a primary phenomenon, but perhaps the end result in a sequence, e.g. a high-arched palate may be the result of long-standing hypotonia and may not be an important feature in itself. On the other hand, some secondary features are extremely important, such as joint contractures resulting from fetal akinesia secondary to neuromuscular abnormalities. The features of a patient selected for database searching should be the most unusual, clear-cut and unequivocal . Above all, the approach must be flexible, using different combinations of features during searches, as patients described in the literature may not have had all the features found in the patient awaiting diagnosis. The aim is to find a small number of possible diagnoses and then to review the features, photographs and abstracts on the database, followed by the original references to see whether the overall features of the condition fit the pattern in the patient. The pattern may not fit exactly with those patients with the same syndrome in the literature, as syndromes can be so variable. Equally, it is important that the patient should not be forced into a diagnostic category that is not correct, as this may have important management consequences. Although the computer may suggest diagnoses, clinical skill and experience in assessing normal variability and those with syndromes are required. The databases have been created on postnatal data which may be inappropriate antenatally as a key feature such as mental retardation cannot be used antenatally.

OMIM (On-Line Mendelian Inheritance in Man) is a useful summary of genetic phenotypes and limited searches can be made. It has the advantage of online free access and links to gene databases which, with the advent of CGH, allows information to be obtained on potential abnormalities that might affect the fetus.

Discussing Available Information and Diagnostic Dilemmas with Parents

The unexpected diagnosis of a malformation syndrome or serious genetic disorder during pregnancy may leave the family with little time to understand the severity and consequences of the disorder, the options open to them (including any treatments available) or to discuss genetic implications. Families report that they find the support offered during this time by specially trained nurses in fetal medicine departments, or clinical genetics units, to be extremely valuable.

Discussions with families have to be honest: too often definitive answers cannot be found during pregnancy, even with the best information and facilities available. This uncertainty can be difficult to accept in an age when medical investigations are widely expected to be able to answer all questions. In such cases, a discussion of the various possibilities and outcomes takes considerable time, but it is vital that the family members fully understand the certainties or uncertainties of the collective medical opinion. The geneticist may be able to offer an opinion separate from the fetal medicine specialist. Discussions with paediatric surgeons or neonatologists about treatments available and the likelihood of success can help parents to reach decisions. Decisions may have to be taken rapidly when the couple are emotionally traumatized by the information they have been given, hence time offered by the medical professionals is essential and it is frequently necessary to offer a second appointment.

Families particularly want to know if a condition is lethal or severely disabling, and if the burden of the disease could be very high they may have a lower threshold for deciding whether or not they will continue with pregnancy. For example, if a baby survives following the repair of a diaphragmatic hernia, the future quality of life is likely to be good even though the survival may only be 50%. If a fetus has multiple rhabdomyoma, and therefore tuberous sclerosis, there is an approximate 10% risk of severe mental retardation and therefore the long-term burden of disease may be much greater, even though the risk of serious outcome is less. Unless the diagnosis is certain the risk to future pregnancies should await discussion until after delivery as it may be inaccurate, and it is unlikely that the couple will be able to look rationally at the future at this time of grief. The increasing use of CGH antenatally will result in the diagnosis of many very rare microdeletion/duplication syndromes. The support of organizations such as UNIQUE is invaluable.

Couples with a family history of abnormality who have received this information before embarking upon a pregnancy, have time to decide the options that they consider correct for them.

Options available to a couple for future pregnancies may include:

having no (more) children;
accepting the risk;
undertaking prenatal diagnosis (if available);
seeking adoption;
gamete donation;
pre-implantation diagnosis.

A couple's choice will depend on many factors: social, economic, moral and practical.

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