How to determine the causes and recurrence risks of congenital anomalies - a clinical approach
Professor P A Farndon4 What is the pattern of anomalies - isolated anomaly, malformation syndrome/sequence, or association?
Recognising into which group a patient’s anomalies fall can inform genetic risks, prognosis and appropriate management.
Is the anomaly an isolated finding in an otherwise normal person?
Consider the organ systems involved and ask if all the abnormalities can be explained by a single anomaly or problem which has led to a cascade of subsequent structural defects. If so, this is a malformation sequence.
Then, consider whether multiple defects appear to be independent embryologically, and cannot be attributed to a single initiating abnormality and its consequences. This is a malformation syndrome.
Malformation sequence
A sequence occurs when a primary anomaly itself determines additional defects. Examples are the oligohydramnios (Potter) sequence where facial appearance, lung hypoplasia, and joint contractures are all the result of constraint due to insufficient amniotic fluid (due to renal anomalies or urethral valves). The cleft palate in the Pierre Robin sequence is caused by the normally sized tongue pressing against the palate because of micrognathia which is the primary anomaly.
The cause of the original single localized 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 aetiology is ascribed to the latter, additional features consistent with a disruption - for instance, amniotic bands or orofacial clefting with amputations and ring constrictions - should be confirmed. 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.
Malformation syndrome
A recognisable 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 cause the structural defects. Causes include chromosomal abnormalities, teratogens and single gene defects. Examples are Down syndrome and fetal alcohol syndrome
Association
Some recognised patterns of malformations are described by the term "association" because the initiating cause has not been identified, and neither are the anomalies the results of a sequence.
An association is defined as a combination of anomalies which occur together more frequently than by chance alone, but which are not known to have a common cause. For example the VATER association involves Vertebral anomalies, Anal atresia, Tracheo-Esophageal fistula and Radial and renal anomalies.
When aetiology can be understood, "associations" may well be reclassified, either within existing groups, or in new embryological groups.