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Expanding the Spectrum of Mutations in GH1 and GHRHR: Genetic Screening in a Large Cohort of Patients with Congenital Isolated Growth Hormone Deficiency

Developmental Endocrinology Research Group (K.S.A., J.P.T., D.K., A.M., P.C.H., M.T.D.), Clinical and Molecular Genetics Unit, University College London Institute of Child Health, London WC1N 1EH, United Kingdom; Endocrine Sciences Research Group (P.E.C.), University of Manchester, Manchester M13 9PL, United Kingdom; Departments of Child Health and Endocrinology (C.B., S.A.), King’s College Hospital, London SE5 9RS, United Kingdom; Department of Pediatric Diabetes and Endocrinology (E.C.C.), Bristol Royal Hospital for Children, University Hospitals Bristol NHS Foundation Trust, Bristol BS2 8BJ, United Kingdom; Department of Pediatrics (H.T.C., N.T.H.), H. C. Andersen Children’s Hospital, Odense University Hospital, 5000 Odense, Denmark; Department of Endocrinology (P.J.T.), Christie Hospital, Manchester M20 4BX, United Kingdom; Department of Pediatric Endocrinology (M.O.S.), William Harvey Research Institute, Barts and The London Queen Mary’s School of Medicine and Dentistry, London EC1M 6BQ, United Kingdom; Department of Endocrinology (J.R.), National Institute of Child Health, Karachi, 75510, Pakistan; Department of Paediatrics (K.B.), Whipps Cross University Hospital, London E11 1NR, United Kingdom; Division of Pediatric Endocrinology (S.K.S., S.T.), Maimonides Infants’ and Children Hospital of Brooklyn and Children’s Hospital of SUNY Downstate, Brooklyn, New York 11203; Department of Pediatric Endocrinology (T.M.), Leeds University Teaching Hospitals, Leeds General Infirmary, Leeds LS9 7TF, United Kingdom; Department of Pediatric Endocrinology (R.B.), Hôpital Bicêtre, Université Paris Descartes, 75006 Paris, France; Institute of Human Genetics (T.D.C.), Newcastle University, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, United Kingdom; and Pediatric Endocrinology (P.E.M.), University Children’s Hospital Inselspital, CH-3010 Bern, Switzerland

Address all correspondence and requests for reprints to: Professor Mehul T. Dattani, Clinical and Academic Lead in Endocrinology, Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, University College of London Institute of Child Health, 30 Guilford Street, London WC1N 1EH, United Kingdom. E-mail: m.dattani{at}ich.ucl.ac.uk.

Context: It is estimated that 3–30% of cases with isolated GH deficiency (IGHD) have a genetic etiology, with a number of mutations being reported in GH1 and GHRHR. The aim of our study was to genetically characterize a cohort of patients with congenital IGHD and analyze their characteristics.

Patients and Methods: A total of 224 patients (190 pedigrees) with IGHD and a eutopic posterior pituitary were screened for mutations in GH1 and GHRHR. To explore the possibility of an association of GH1 abnormalities with multiple pituitary hormone deficiencies, we have screened 62 patients with either multiple pituitary hormone deficiencies (42 pedigrees), or IGHD with an ectopic posterior pituitary (21 pedigrees).

Results: Mutations in GH1 and GHRHR were identified in 41 patients from 21 pedigrees (11.1%), with a higher prevalence in familial cases (38.6%). These included previously described and novel mutations in GH1 (C182X, G120V, R178H, IVS3+4nt, a>t) and GHRHR (W273S, R94L, R162W). Autosomal dominant, type II IGHD was the commonest form (52.4%), followed by type IB (42.8%) and type IA (4.8%). Patients with type II IGHD had highly variable phenotypes. There was no difference in the endocrinology or magnetic resonance imaging appearance between patients with and without mutations, although those with mutations presented with more significant growth failure (height, –4.7 ± 1.6 SDS vs. –3.4 ± 1.7 SDS) (P = 0.001). There was no apparent difference between patients with mutations in GH1 and GHRHR.

Conclusions: IGHD patients with severe growth failure and a positive family history should be screened for genetic mutations; the evolving endocrinopathy observed in some of these patients suggests the need for long-term follow-up.