Congenital malformations, deformations and chromosomal abnormalities
Congenital malformations and deformations of the musculoskeletal system
Autosomal recessive
16q11.2
Severe hypertelorism with midface prominence, myopia, mental retardation, and bone fragility is an extremely rare constellation of findings that have been reported to occur only in siblings from a single isolated family to date. The condition involves an extreme degree of hypertelorism, not seen in other conditions. Other differentiating craniofacial anomalies include abnormally modeled ears, enamel hypoplasia, high myopia, sensorineural deafness, and osteopenia with fractures.
Hamamy Syndrome follows an autosomal recessive mode of inheritance and is caused by homozygous mutation of the IRX5 gene. The gene encodes the Iroquois Homeobox Protein 5, a member of the Iroquois homeobox gene family which appears to play multiple roles during pattern formation of vertebrate embryos.
| Subject ID | Country | Sex | Family History | Parental Consanguinity | HPO Terms | Variant | Zygosity | Mode of Inheritance | Reference | Remarks |
|---|---|---|---|---|---|---|---|---|---|---|
| 611174.1.1 | Lebanon | Female | Yes | Yes | Abnormal facial shape; Recurrent fractur... Abnormal facial shape; Recurrent fractures; Intellectual disability, severe; Telecanthus; Dentinogenesis imperfecta  | NM_005853.6:c.503G>A | Homozygous | Autosomal, Recessive | Mégarbané et al. 2021 | |
| 611174.1.2 | Lebanon | Male | Yes | Yes | Abnormal facial shape; Recurrent fractur... Abnormal facial shape; Recurrent fractures; Intellectual disability, severe; Telecanthus; Dentinogenesis imperfecta | NM_005853.6:c.503G>A | Homozygous | Autosomal, Recessive | Mégarbané et al. 2021 | First cousin once re... |
Hamamy et al. (2007) described two brothers born to Jordanian double first cousin parents (inbreeding coefficient: 0.078), who were affected with a novel syndrome of severe hypertelorism, peculiar facial features, and bone fragility. At the time of examination, the patients were 10- and 8-years old. Both were born to normal pregnancies and had no neonatal problems. Speech, though comprehensible, was not clear. Their height and weight were normal, but the elder child had an OFC of 97th centile. Abnormal facial features included a prominent forehead with bitemporal narrowness, high and broad nasal bridge, pointed nasal tip, and anteverted nostrils, epicanthal folds, striking hypertelorism, prominent eyes with upward slant of palpebral fissures, large mouth with flat philtrum, highly arched palated, mild micrognathia, and thin enamel, webbing on the neck, and protruding ears. Both brothers had severe myopia and a moderate degree of sensorineural hearing loss. In addition, the younger brother was found to have mild mitral regurgitation and mild splenomegaly. They also had microcytic hypochromic iron deficiency anemia with an increased platelet count. Multiple long bone fractures were experienced by both, mostly in the femora. Radiological examination revealed generalized osteopenia, expansion of the medullary spaces, and hypoplastic ilial wings. The older sibling showed a thick skull vault with premature closure of major cranial sutures on CT-brain. The boys had a normal 46XY karyotype, and no telomeric rearrangements could be detected. There was no family history of a similar condition. The patients' father, however, showed mild hypertelorism. The parents have a normal, younger daughter. Hamamy et al. (2007) failed to document similar cases from literature and database searches, which prompted them to classify the condition as a novel syndrome. They proposed an autosomal or X-linked recessive mode of inheritance for the syndrome, with the father showing a heterozygote manifestation. They also conjectured that the condition could be the coincidental occurrence of two distinct recessive syndromes, made possible by the high degree of inbreeding within the family.