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).