title: Familial isolated growth hormone deficiency due to a novel homozygous missense mutation in the growth hormone releasing hormone receptor gene: clinical presentation with hypoglycemia.
abstract: BACKGROUND
  Mutations in the growth hormone releasing hormone receptor (GHRHR) gene are a relatively rare cause of isolated growth hormone deficiency (IGHD).
  
  
  OBJECTIVE
  This study aimed to understand the biochemical basis of hypoglycemia in the index case and the molecular basis of severe short stature in a large consanguineous family with IGHD.
  
  
  METHODS
  The index case presented with a hypoglycemic convulsion, following which eight members in two related consanguineous Turkish families were identified with IGHD. Homozygosity mapping identified the homozygous regions shared only among the affected individuals. Sanger sequencing of GHRHR, which resided in the shared homozygous region, was performed. In silico analysis of the pathogenic GHRHR variant was performed.
  
  
  RESULTS
  The clinical presentation and hormonal analysis confirmed GH deficiency in all affected individuals. Magnetic resonance imaging scan of the pituitary gland showed anterior pituitary hypoplasia in five affected individuals in which the youngest was only 0.4 years old, but with normal pituitary size in three affected individuals. Homozygosity mapping showed two large homozygous regions on chromosome 7 shared only among affected individuals. Sanger sequencing of GHRHR gene present in one of these shared regions identified a novel homozygous missense mutation (p.C64G) segregating with the disease phenotype. In silico analysis predicted the mutation to be deleterious and disease causing.
  
  
  CONCLUSIONS
  We describe a large consanguineous Turkish kindred with IGHD due to a novel homozygous missense GHRHR mutation. This is the first description of presentation with hypoglycemia and the earliest reported occurrence of anterior pituitary hypoplasia in patients with GHRHR mutation.
authors.affiliation: Developmental Endocrinology Research Group (H.D., S.T., M.S., P.S., V.B.A., K.H.), Clinical and Molecular Genetics Unit, Institute of Child Health, University College London, WC1N 1EH London, United Kingdom; Department of Paediatric Endocrinology (H.D., P.S., V.B.A., K.H.), Great Ormond Street Hospital for Children, NHS Foundation Trust, WC1N 3JH London, United Kingdom; Department of Paediatric Endocrinology (H.D., R.T.B., M.N.O.) and Department of Radiology (N.H., A.B.), Diyarbakir Children's State Hospital, 21100 Diyarbakir, Turkey.
authors.forename: Huseyin
authors.initials: H
authors.lastname: Demirbilek
authors.forename: Sophia
authors.initials: S
authors.lastname: Tahir
authors.forename: Riza Taner
authors.initials: RT
authors.lastname: Baran
authors.forename: Maha
authors.initials: M
authors.lastname: Sherif
authors.forename: Pratik
authors.initials: P
authors.lastname: Shah
authors.forename: Mehmet Nuri
authors.initials: MN
authors.lastname: Ozbek
authors.forename: Nebahat
authors.initials: N
authors.lastname: Hatipoglu
authors.forename: Ahmet
authors.initials: A
authors.lastname: Baran
authors.forename: Ved Bhushan
authors.initials: VB
authors.lastname: Arya
authors.forename: Khalid
authors.initials: K
authors.lastname: Hussain
mesh_terms: D001827:Body Height / Q000235:genetics; D001921:Brain / Q000473:pathology; D002874:Chromosome Mapping; D005190:Family; D005260:Female; D019382:Human Growth Hormone / Q000172:deficiency* / Q000235:genetics*; D006801:Humans; D007003:Hypoglycemia / Q000150:complications / Q000235:genetics*; D007223:Infant; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D010903:Pituitary Gland, Anterior / Q000473:pathology; D011247:Pregnancy; D018013:Receptors, Neuropeptide / Q000235:genetics*; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000235:genetics*
chemical_list: D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D019382:Human Growth Hormone; C048250:somatotropin releasing hormone receptor