Congenital bowel disorders

PhD ceremony: Ms. C.S. van der Werf, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Congenital bowel disorders

Promotor(s): prof. R.M.W. Hofstra

Faculty: Medical Sciences

This thesis focuses on two congenital bowel disorders, Congenital Short Bowel Syndrome (CSBS) and megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS). The main features of CSBS are a shortened small intestine and malrotation. In MMIHS, the main features are a giant bladder, a microcolon and hypoperistalsis, while a shortened small intestine is also seen in some patients. More than 40 cases of CSBS and more than 200 cases of MMIHS have been published in the literature. Both syndromes have been described in siblings of both sexes and in consanguineous families, and were therefore thought to have an autosomal recessive pattern of inheritance. The genetic cause of the disorders was unknown.

We identified loss-of-function mutations in CLMP in autosomal recessive CSBS and a two-base-pair deletion in FLNA in male CSBS patients. That there may well be more genes involved in CSBS is illustrated by a female patient who presented with persistent pulmonary hypertension of the newborn and CSBS but in whom no mutations in CLMP nor in FLNA were identified. Homozygosity mapping in a consanguineous family with one girl who was diagnosed with MMIHS revealed three homozygous regions on chromosomes 1, 2 and 8, respectively, in which the gene should reside. However, no pathogenic mutation was identified in these regions by exome sequencing. Clearly, more research is needed to identify the gene underlying MMIHS. The studies presented in this thesis provide more insight into the genetic factors involved in gastrointestinal development, in particular the small intestine. Furthermore, this work helped to improve genetic counseling of CSBS patients and their families.