OTX2 microphthalmia syndrome: four novel mutations and delineation of a phenotype

Abstract

The OTX2 homeobox-containing transcription factor gene was shown to play a key role in the development of head structures in vertebrates. In humans, OTX2 mutations result in anophthalmia/microphthalmia (A/M) often associated with systemic anomalies. We screened fifty-two unrelated individuals affected with A/M and identified disease-causing variants in four families (8%), a higher frequency than previously reported. All four mutations are predicted to result in truncation of normal OTX2 protein sequence consistent with previously reported mechanisms; three changes occurred de novo and one mutation was inherited from an affected parent. Four out of the five OTX2-positive patients in our study displayed additional systemic findings, including two novel features, Wolf-Parkinson White syndrome and an anteriorly placed anus. Analysis of the phenotypic features of OTX2-positive A/M patients in this study and those previously reported suggests the presence of pituitary anomalies and lack of genitourinary and gastrointestinal manifestations as potential distinguishing characteristics from SOX2 anophthalmia syndrome. Interestingly, pituitary anomalies seem to be more strongly associated with mutations that occur in the second half of OTX2, after the homeodomain and SGQFTP motif. OTX2 patients also show a high rate of inherited mutations (36%), often from mildly or unaffected parents, emphasizing the importance of careful parental examination/testing.

Microphthalmia, late onset keratitis, and iris coloboma/aniridia in a family with a novelPAX6mutation

“…1 The genetic causes for most cases of microphthalmia are unknown, although mutations in a number of genes have been postulated to be responsible for the disease. [1][2][3] Genetic defects have been rarely reported in families with autosomal dominant micropthalmia across at least two generations, except for a few families with mutations in OTX2 4 or SOX2. 5 Autosomal dominant keratitis without aniridia has been reported in two families, 6,7 and the disease in one family is associated with a PAX6 mutation.…”

Midbrain-Hindbrain Involvement in Septo-Optic Dysplasia

“…12 However, no careful description of MH structures has been provided so far in these patients. We reviewed the available brain MR midline sagittal images including the posterior cranial fossa of previously reported patients with Otx2 mutations [35][36][37][38] or chromosome 14 deletions including Otx2, [39][40][41][42][43] and we recognized a similar midbrain hypoplasia with a long pons and large superior vermis in 5 patients. 35,36,40,41,43 We therefore suggest that MH abnormalities may have been underestimated in patients with Otx2 mutations or deletion; further studies on larger series are awaited to address this hypothesis.…”

Genes relacionados con microftalmia y anoftalmia hereditarias

“…Se han descrito diversas mutaciones dominantes en este gen en pacientes con anoftalmia o microftalmia asociadas a malformaciones del sistema nervioso central y discapacidad intelectual [25][26][27][28] , aunque también se han identificado casos con displasia retiniana 29 . Aproximadamente el 3% de los casos de anoftalmia/microftalmia bilateral se deben a mutaciones en OTX2 14 .…”