title: Unusual phenotypic features in a patient with a novel splice mutation in the GHRHR gene.
abstract: Isolated growth hormone deficiency (IGHD) may be of genetic origin. One of the few genes involved in that condition encodes the growth hormone releasing hormone receptor (GHRHR) that, through its ligand (GHRH), plays a pivotal role in the GH synthesis and secretion by the pituitary. Our objective is to describe the phenotype of two siblings born to a consanguineous union presenting with short stature (IGHD) and Magnetic Resonance Imaging (MRI) abnormalities, and to identify the molecular basis of this condition. Our main outcome measures were clinical and endocrinological investigations, MRI of the pituitary region, study of the GHRHR gene sequence and transcripts. In both patients, the severe growth retardation (-5SD) was combined with anterior pituitary hypoplasia. In addition to these classical phenotypic features for IGHD, one of the patients had a Chiari I malformation, an arachnoid cyst, and a dysmorphic anterior pituitary. A homozygous sequence variation in the consensus donor splice site of intron 1 (IVS1 + 2T > G) of the GHRHR gene was identified in both patients. Using in vitro transcription assay, we showed that this mutation results in abnormal splicing of GHRHR transcripts. In this report, which broadens the phenotype associated with GHRHR defects, we discuss the possible role of the GHRHR in the proper development of extrapituitary structures, through a mechanism that could be direct or secondary to severe GH deficiency.
authors.affiliation: Laboratoire de Génétique et de Physiologie Neuroendocrinienne, Equipe des Bases Moléculaires de Maladies Génétiques, UFR de Génétique et Biologie Moléculaire, Université Ibn Tofaïl, Faculté des Sciences, Kenitra, Maroc.
authors.forename: Latifa
authors.initials: L
authors.lastname: Hilal
authors.forename: Yassir
authors.initials: Y
authors.lastname: Hajaji
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Vie-Luton
authors.forename: Zeina
authors.initials: Z
authors.lastname: Ajaltouni
authors.forename: Bouchra
authors.initials: B
authors.lastname: Benazzouz
authors.forename: Maha
authors.initials: M
authors.lastname: Chana
authors.forename: Adelmajid
authors.initials: A
authors.lastname: Chraïbi
authors.forename: Abdelkrim
authors.initials: A
authors.lastname: Kadiri
authors.forename: Serge
authors.initials: S
authors.lastname: Amselem
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Sobrier
mesh_terms: D017398:Alternative Splicing; D002648:Child; D004252:DNA Mutational Analysis; D004393:Dwarfism, Pituitary / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D005260:Female; D013006:Growth Hormone / Q000627:therapeutic use; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D022821:RNA Splice Sites / Q000235:genetics*; D018013:Receptors, Neuropeptide / Q000235:genetics* / Q000502:physiology; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000235:genetics* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D022821:RNA Splice Sites; D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D013006:Growth Hormone; C048250:somatotropin releasing hormone receptor