Craniosynostosis associated with ocular and distal limb defects is very likely caused by mutations in a gene different from FGFR, TWIST, and MSX2

Abstract

Craniosynostosis caused by genetic factors includes a heterogeneous group of over 100 syndromes, most with autosomal dominant inheritance. Mutations in five genes (FGFR1-, -2, -3, TWIST, and MSX2) causing craniosynostosis as the main clinical feature were described. In most of these conditions, there are also limb malformations. We report a two-generation kindred segregating microcornea, optic nerve alterations and cataract since childhood, craniosynostosis, and distal limb alterations, with a great clinical intrafamilial variability. The ophthalmological problems here described seem to be unique to this genealogy while similar feet alterations were apparently only described in two other affected siblings with acro-cranial-facial dysostosis syndrome (ADS). However, ADS has an autosomal recessive inheritance instead of the dominant pattern of the present genealogy. The candidate exons of the five genes previously mentioned were tested through sequencing analysis presenting normal results in all cases. Therefore, clinical and laboratory analyses in our patients suggest that their phenotype represents a new syndrome very likely caused by mutation in a gene different from those studied.

Anomalous bilateral lateral rectus muscles and anterior polar cataract with dysmorphic features

“…One variant, described as acro-cranial-facial dysostosis syndrome, is characterized by limb malformations, ocular manifestations (microcornea, optic nerve alterations, and cataract) in addition to craniosynostosis, although lateral rectus abnormalities have not been identified with this variant. 6 Clinically, the patient had some features of Apert syndrome, a sporadic form of craniosynostosis. Apert syndrome is characterized by asymmetrical facies and syndactyly of the hands and the feet; ocular findings are characterized by hypertelorism, cataract, strabismus, and partial ophthalmoplegia.…”

Estudo molecular das craniossinostoses sindrômicas: Crouzon, Pfeiffer e Saethre-Chotzen"

“…Isto leva a um ganho de função desses genes e é provavelmente o principal mecanismo responsável pela maior parte dos sintomas de craniosinostose sindrômicas. (Baroni et al, 2002;Passos-Bueno et al, 2002).…”

Investigação de fatores genéticos na etiologia de fendas orofaciais típicas

“…Entretanto, tem se relatado também o envolvimento do gene FGF8 em casos desta síndrome (186,187,188,189). Mutações no gene FGFR1 são frequentes em casos de craniossinostose (190,191,192). Além disso, mutações também foram encontradas em casos de FL/P e FP não-sindrômica ( 54) e, no gene FGF8, em casos de FL/P não-sindrômica (54,193).…”