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HESX1 Mutations Are an Uncommon Cause of Septooptic Dysplasia and Hypopituitarism

Biochemistry, Endocrinology, and Metabolism Unit (D.E.G.M., J.P.T., D.K., K.S.W., M.T.D.), Institute of Child Health, London WC1N 1EH, United Kingdom; Université Paris-Descartes, Assistance Publique Hopitaux de Paris, Hôpital Bicêtre (R.B.), 94275 Le Kremlin Bicêtre, France; Third Department of Pediatrics (A.P.), University of Athens School of Medicine, Athens, Greece; Hospital for Children and Adolescents (E.K., A.K.), University of Leipzig, Leipzig, Germany; Charite (N.H., H.K.), Institute of Experimental Pediatric Endocrinology, Augustenburgerplatz 1, D-13353 Berlin, Germany; and Department of Endocrinology (S.M.S.), Christie Hospital National Health Service Trust, Manchester, United Kingdom

Address all correspondence and requests for reprints to: Mehul T. Dattani, Biochemistry, Endocrinology, and Metabolism Unit, Institute of Child Health, London WC1N 1EH, United Kingdom. E-mail: m.dattani{at}ich.ucl.ac.uk.

Context: Mutations in the transcription factor HESX1 have previously been described in association with septooptic dysplasia (SOD) as well as isolated defects of the hypothalamic-pituitary axis.

Objective: Given that previous screening was carried out by SSCP detection alone and limited to coding regions, we performed an in-depth genetic analysis of HESX1 to establish the true contribution of HESX1 genetic defects to the etiology of hypopituitarism.

Design: Nonfamilial patients (724) with either SOD (n = 314) or isolated pituitary dysfunction, optic nerve hypoplasia, or midline neurological abnormalities (n = 410) originally screened by SSCP were rescreened by heteroduplex detection for mutations in the coding and regulatory regions of HESX1. In addition, direct sequencing of HESX1 was performed in 126 patients with familial hypopituitarism from 66 unrelated families and in 11 patients born to consanguineous parents.

Patients: All patients studied had at least one of the three classical features associated with SOD (optic nerve hypoplasia, hypopituitarism, midline forebrain defects).

Results: Novel sequence changes identified included a functionally significant heterozygous mutation at a highly conserved residue (E149K) in a patient with isolated GH deficiency and digital abnormalities. The overall incidence of coding region mutations within the cohort was less than 1%.

Conclusions: Mutations within HESX1 are a rare cause of SOD and hypopituitarism. However, the large number of familial patients with SOD in whom no mutations were identified is suggestive of an etiological role for other genetic factors. Furthermore, we have found that within our cohort SOD is associated with a reduced maternal age compared with isolated defects of the hypothalamopituitary axis.

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