Craniosynostosis Syndrome, Autosomal Recessive

Clinical Features

Blair et al. (2000) described a consanguineous family of Pakistani origin in which 3 of 5 sibs had craniosynostosis of variable presentation. In addition, they had other congenital abnormalities, principally affecting ocular and limb development. The eldest daughter had global developmental delay from an early age, long face with a prominent nasal bridge, inner canthal distance of 3.2 cm, short philtrum with narrow upper lip, highly arched palate, cleft uvula, and a left divergent squint with abnormal eye movements and associated elevation of each eye on adduction. The next oldest daughter also had global developmental delay from an early age, long face with a prominent nasal bridge, short philtrum and narrow upper lip, asymmetric, low-set, and posteriorly rotated ears, bilateral colobomata of the iris, choroid, and optic disc associated with microphthalmia, horizontal pendular nystagmus, convergent squint, long and narrow fingers, and bilateral postaxial duplication of the fifth toe.

Mapping

Using intragenic and flanking microsatellite markers, Blair et al. (2000) developed linkage evidence that the disorder in this family was not caused by a mutation in any of the then-known craniosynostosis loci, including FGFR1 (136350), FGFR2 (176943), FGFR3 (134934), MSX2 (123101), and TWIST1 (601622).

Inheritance

Given the clinical novelty of the disorder and parental consanguinity in this family, Blair et al. (2000) hypothesized that the affected individuals were homozygous for a recessively inherited mutation at a novel locus predisposing to craniosynostosis.