title: Oral-facial-digital syndrome type 1 in males: Congenital heart defects are included in its phenotypic spectrum.
abstract: Oral-facial-digital syndrome type 1 (OFD1; OMIM# 311200) is an X-linked dominant ciliopathy caused by mutations in the OFD1 gene. This condition is characterized by facial anomalies and abnormalities of oral tissues, digits, brain, and kidneys. Almost all affected patients are female, as OFD1 is presumed to be lethal in males, mostly in the first or second trimester of pregnancy. Live born males with OFD1 are a rare occurrence, with only five reported patients to date. In four patients the presence of a congenital heart defect (CHD) was observed. Here, we report an affected male fetus with a hemizygous de novo mutation in OFD1 (c.2101C>T; p.(Gln701*)). Ultrasound examination demonstrated severe hydrocephalus, a hypoplastic cerebellum and a hypoplastic left ventricle of the heart. The pregnancy was terminated at 16 weeks of gestation because of poor prognosis. Post-mortem examination of the fetus confirmed severe hypoplasia of the left ventricle of the heart. We emphasize that CHDs should be included in the phenotypic spectrum of OFD1 in males. This justifies molecular analysis of OFD1 when CHD is encountered prenatally in combination with one or more phenotypic features previously described in the OFD1 gene alteration spectrum. The underlying pathogenesis of CHD in OFD1 (and other ciliopathies) probably involves dysfunction of the primary cilia regarding coordination of left-right signalling during early heart development. Whether these CHDs wholly or partly result from defective left right signalling, in which different types of cilia are known to play a critical role, remains a topic of research.
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Arjan
authors.identifier: http://orcid.org/0000-0003-3531-5136
authors.initials: A
authors.lastname: Bouman
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Mariëlle
authors.initials: M
authors.lastname: Alders
authors.affiliation: Department of Anatomy, Embryology and Physiology, Academic Medical Center, The Netherlands.
authors.forename: Roelof Jan
authors.initials: RJ
authors.lastname: Oostra
authors.affiliation: Department of Obstetrics and Gynaecology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: van Leeuwen
authors.affiliation: Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Nikki
authors.initials: N
authors.lastname: Thuijs
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: van der Kevie-Kersemaekers
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Merel
authors.initials: M
authors.lastname: van Maarle
mesh_terms: D037881:Aborted Fetus; D001344:Autopsy; D005260:Female; D050172:Genes, X-Linked; D006330:Heart Defects, Congenital / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D008297:Male; D009154:Mutation; D009958:Orofaciodigital Syndromes / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D010641:Phenotype; D011247:Pregnancy; D011506:Proteins / Q000235:genetics*; D015398:Signal Transduction
chemical_list: C115130:OFD1 protein, human; D011506:Proteins
keywords: OFD type 1; congenital heart defect; congenital heart disease; hypoplastic left heart syndrome; oral-facial-digital syndrome type 1