Severe hypertelorism, midface prominence, prominent/simple ears, severe myopia, borderline intelligence, and bone fragility in two brothers: New syndrome?†

Abstract

We report on two brothers, born to double first cousin Jordanian Arab parents, with a syndrome comprising severe hypertelorism with upslanted palpebral fissures, brachycephaly, abnormal ears, sloping shoulders, enamel hypoplasia, and osteopenia with repeated fractures. Both have severe myopia, mild to moderate sensori-neural hearing loss and borderline intelligence. Results of chromosome analysis were normal as was a FISH assay for subtelomeric rearrangements. The father has mild hypertelorism but the family history is otherwise unremarkable. We think that this represents a previously unrecognized autosomal or X-linked recessive syndrome.

New oral findings in Hamamy syndrome

“…Oro‐dental findings in Hamamy syndrome are not well documented in the literature, but reported features include loss of lamina dura, deep palate, enamel hypoplasia, and dilacerated roots . We report, for the first time, the occurrence of dentinogenesis imperfecta type III (Brandywine variant or shell teeth), tooth impaction, and multiple gingival polyps in Hamamy syndrome.…”

“…Hamamy syndrome is a rare autosomal recessive disorder first described in 2007 in a Jordanian family . The syndrome is caused by missense mutations in the IRX5 gene on chromosome 16q12.2‐q21 .…”

Modeling Human Craniofacial Disorders in Xenopus

“…Only 5 affected individuals have been described in two consanguineous families, a Turkish and a Jordanian family [94], [95]. It is an autosomal recessive craniofacial syndrome characterized by severe hypertelorism with upslanted palpebral fissures, brachycephaly, abnormal ears, enamel hypoplasia and sensorineural deafness.…”

Loss of Iroquois homeobox transcription factors 3 and 5 in osteoblasts disrupts cranial mineralization

“…Two mutations in human IRX5, Ala150Pro and Asn166Lys occur in patients with Hamamy syndrome (OMIM MIM611174; Bonnard et al, 2012 ), who present with craniofacial dysmorphism, osteopenia, tooth eruption defects, and hip dysplasia, along with cardiac defects and microcytic hypochromic anemia ( Bonnard et al, 2012 , Hamamy et al, 2007a , Hamamy et al, 2007b ). The function of IRX5 seems to differ in mice and humans as the human phenotype is not observed in Irx 5 −/− mice ( Costantini et al, 2005 ).…”

“…Irx 3 −/− and Irx 5 −/− mice do not show any Hamamy syndrome characteristics ( Costantini et al, 2005 , Smemo et al, 2014 ), but several aspects of the Hamamy syndrome phenotype are recapitulated in Irx 3 and Irx 5 double knockout mice ( Irx 3 −/− / Irx 5 −/− mice), including the cardiac defects and craniofacial dysmorphisms ( Hiroi et al, 2001 ). Furthermore, the hind limb skeletal hypoplasia reported in Irx 3 −/− / Irx 5 −/− mouse embryos and the femoral fragility observed in Hamamy syndrome patients suggest that IRX3 and IRX5 are important for limb development in vertebrates ( Gaborit et al, 2012 , Hamamy et al, 2007a ). Although the Irx 3 −/− / Irx 5 −/− mice have a complete loss of protein in comparison to the point mutations found in humans with Hamamy syndrome, the finding that multiple features of Hamamy syndrome phenotype are recapitulated in Irx 3 −/− / Irx 5 −/− mice indicates that this mouse model may be useful for understanding the role of Iroquois proteins in vivo .…”