Question

2] Craniofacial microsomias syndrome (CMS) presents with a spectrum of abnormalities mainly in the skull and face. It is characterized by facial asymmetries on the left and right sides in size and shape. This can cause dental problems as well as defects in feeding, speech and breathing in severe cases.

Imagine that you were to be presented with the following study of twins with this syndrome where the pair was identified by finding an CMS child: 20 pairs of identical twins were reported, where both twins showed CMS, and in all cases the parents were normal, while in 18 pairs of dizygotic twins, 5 of the twin pairs had both twins affected.

2b) Do these data allow you to postulate anything about whether CMS is genetic and if so what the mode of inheritance might be?

2c) Do you agree with the assertion that there must be families where both parents are carriers of CMS that have identical twins but the twins are unaffected? Why are there no families with identical twins where one or more of the children are unaffected?

Answer 1

2b. Craniofacial microsomias syndrome is a rare disease wherein there are malformations in structures derived from first and second branchial arches. The most prominent feature is the facial asymmetry. Mandibular hypoplasia, Preauricular or facial tags, Microtia and anotia in ear and mixed hearing loss are some other features of this condition.

In this case, all monozygotic twin pairs had the disease while only 5/18 pair had the disease. This does indicate that there may be a genetic basis for CMS. The parents of the monozygotic twins were not affected. Hence, they may be carriers who transferred one defective allele to their offspring. As parents are carriers, they do not exhibit symptoms of the disease. Hence, the mode of inheritance in the monozygotic twins is autosomal recessive. Very rare cases of CMS are autosomal recessive. As monozygotic (identical) twins are obtained due to splitting of the same embryo, their genetic makeup is identical. Hence, if there is chromosomal deletion/duplication (or defective alleles), both children in twin pair will be affected and exhibit the disease. If one child of the twin pair were only affected, then the cause would have been environmental, as epigenetics is responsible for differences in monozygotic twins. Such epigenetic changes are mostly environmental. CMS has also an environment dependent cause.

It is not clear that the parents of the diazygotic twins were carriers or displayed the syndrome. In 1-2% cases, it is autosomal dominant, where one copy is sufficient to cause the disease. This syndrome is caused by chromosomal deletions of duplication. However, the gene/genes are not yet identified. As dizygotic (fraternal) twins are from different embryos, it depends on whether the embryo inherited the defective mutation. However, as there are 5 twin pairs affected, it is may not be genetic in origin.

2c. If both the parents are carriers, then each carries a single defective allele. They don’t exhibit the condition, indicating a autosomal recessive mode of inheritance. If only one defective allele is inherited by the one parent, then the child will be a carrier and not inherit the disease. Hence, it is possible for the monozygotic twins of carriers to be normal as concordance rate for these twins is below 50%.

CMS is more common in twins than singletons. It is also more frequent in monozygotic twins than in dizygotic twins. In monozygotic twins, the conjoined vascular channels in monozygotic-twin placentas is mostly responsible for CMS. The stapedial and the external carotid artery is affected that alters structures developed from first and second branchial arched. A reduced blood flow and focal hemorrhage in first and second branchial arches in the blastogenesis period of development may be responsible. Environmental factors may a role in increasing the incidence of this syndrome in monozygotic twins with a single defective allele.