PMID- 31022718 OWN - NLM STAT- MEDLINE DCOM- 20200521 LR - 20200521 IS - 1663-2826 (Electronic) IS - 1663-2818 (Linking) VI - 92 IP - 2 DP - 2019 TI - Normal Growth despite Combined Pituitary Hormone Deficiency. PG - 133-142 LID - 10.1159/000499318 [doi] AB - BACKGROUND: The paradox of normal growth despite a lack of growth hormone (GH) is an unexplained phenomenon described in some pathological (sellar, suprasellar, and hypothalamic disorders) and overgrowth syndromes. It has been suggested that the paradoxical growth is due to other GH variants, GH-like moieties, prolactin, insulin, insulin-like growth factors (IGFs), and unidentified serum factors or growth mechanisms. The objective of this study was to determine the mechanism underlying this normal growth without GH. CASE DESCRIPTION: We describe here growth, hormonal, and genetic analyses for an adolescent boy with panhypopituitarism who achieved an adult height above his genetic potential. RESULTS: Normal growth was observed despite low serum GH, IGF-I, IGF-II, IGF binding protein 3 (IGFBP-3) and acid labile subunit (ALS) concentrations, but the IGF-II/IGFBP-3 molar ratio was slightly high. Panhypopituitarism was associated with a heterozygous missense mutation of HESX1, with variable penetrance in heterozygous relatives. Exome analysis detected heterozygous missense mutations of various genes involved in intracellular signaling pathways. The growth-promoting activity of the patient's serum was unable to induce AKT phosphorylation in the MCF-7 cell line. CONCLUSION: The high IGF-II/IGFBP-3 molar ratio was not the cause of the sustained high growth velocity, due to the low affinity of IGF-II for IGF type 1 receptor. The key finding was the HESX1 mutation, as similar cases have been described before, suggesting a common mechanism for growth without GH. However, the variable penetrance of this variant in heterozygous relatives suggests that modifier genes or mechanisms involving combinations with mutations of other genes involved in intracellular signaling pathways might be responsible. CI - (c) 2019 S. Karger AG, Basel. FAU - El Kholy, Mohamed AU - El Kholy M AD - Department of Pediatrics, Ain Shams University, Cairo, Egypt. FAU - Elsedfy, Heba AU - Elsedfy H AD - Department of Pediatrics, Ain Shams University, Cairo, Egypt. FAU - Perin, Laurence AU - Perin L AD - Explorations Fonctionnelles et genetique endocriniennes, Hopital Armand-Trousseau, AP-HP, Paris, France. FAU - Abi Habid, Walid AU - Abi Habid W AD - Unite Mixe Recherche Scientifique 938, Centre de Recherche St-Antoine (CRSA), Institut National de la Sante et de la Recherche Medicale, Universite Pierre et Marie Curie Paris 6, Sorbonne Universite, Paris, France. FAU - Thibaud, Nathalie AU - Thibaud N AD - Explorations Fonctionnelles et genetique endocriniennes, Hopital Armand-Trousseau, AP-HP, Paris, France. FAU - Bozzola, Mauro AU - Bozzola M AD - Unit of Pediatrics and Adolescentology, Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy. FAU - Rossignol, Sylvie AU - Rossignol S AD - Explorations Fonctionnelles et genetique endocriniennes, Hopital Armand-Trousseau, AP-HP, Paris, France. AD - Unite Mixe Recherche Scientifique 938, Centre de Recherche St-Antoine (CRSA), Institut National de la Sante et de la Recherche Medicale, Universite Pierre et Marie Curie Paris 6, Sorbonne Universite, Paris, France. FAU - Leneuve, Patricia AU - Leneuve P AD - Unite Mixe Recherche Scientifique 938, Centre de Recherche St-Antoine (CRSA), Institut National de la Sante et de la Recherche Medicale, Universite Pierre et Marie Curie Paris 6, Sorbonne Universite, Paris, France. FAU - Godeau, Francois AU - Godeau F AD - Unite Mixe Recherche Scientifique 938, Centre de Recherche St-Antoine (CRSA), Institut National de la Sante et de la Recherche Medicale, Universite Pierre et Marie Curie Paris 6, Sorbonne Universite, Paris, France. FAU - Chantot-Bastaraud, Sandra AU - Chantot-Bastaraud S AD - Departement de genetique et d'embryologie, Hopital Armand-Trousseau, AP-HP, Paris, France. FAU - Netchine, Irene AU - Netchine I AD - Explorations Fonctionnelles et genetique endocriniennes, Hopital Armand-Trousseau, AP-HP, Paris, France. AD - Unite Mixe Recherche Scientifique 938, Centre de Recherche St-Antoine (CRSA), Institut National de la Sante et de la Recherche Medicale, Universite Pierre et Marie Curie Paris 6, Sorbonne Universite, Paris, France. FAU - Le Bouc, Yves AU - Le Bouc Y AD - Explorations Fonctionnelles et genetique endocriniennes, Hopital Armand-Trousseau, AP-HP, Paris, France, yves.le-bouc@inserm.fr. AD - Unite Mixe Recherche Scientifique 938, Centre de Recherche St-Antoine (CRSA), Institut National de la Sante et de la Recherche Medicale, Universite Pierre et Marie Curie Paris 6, Sorbonne Universite, Paris, France, yves.le-bouc@inserm.fr. LA - eng PT - Case Reports DEP - 20190425 PL - Switzerland TA - Horm Res Paediatr JT - Hormone research in paediatrics JID - 101525157 RN - 0 (HESX1 protein, human) RN - 0 (Homeodomain Proteins) RN - 0 (IGF1 protein, human) RN - 0 (IGF2 protein, human) RN - 0 (IGFBP3 protein, human) RN - 0 (Insulin-Like Growth Factor Binding Protein 3) RN - 12629-01-5 (Human Growth Hormone) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - 67763-97-7 (Insulin-Like Growth Factor II) RN - Combined Pituitary Hormone Deficiency SB - IM MH - Adolescent MH - Adult MH - Homeodomain Proteins/blood/*genetics MH - Human Growth Hormone/*blood/genetics MH - Humans MH - *Hypopituitarism/blood/genetics/physiopathology MH - Insulin-Like Growth Factor Binding Protein 3/genetics/metabolism MH - Insulin-Like Growth Factor I/genetics/metabolism MH - Insulin-Like Growth Factor II/genetics/metabolism MH - MCF-7 Cells MH - Male MH - *Mutation OTO - NOTNLM OT - Combined pituitary hormone deficiency OT - Growth OT - IGF/IGFBP-3 molar ratio OT - Insulin-like growth factors EDAT- 2019/04/26 06:00 MHDA- 2020/05/22 06:00 CRDT- 2019/04/26 06:00 PHST- 2018/10/06 00:00 [received] PHST- 2019/02/27 00:00 [accepted] PHST- 2019/04/26 06:00 [pubmed] PHST- 2020/05/22 06:00 [medline] PHST- 2019/04/26 06:00 [entrez] AID - 000499318 [pii] AID - 10.1159/000499318 [doi] PST - ppublish SO - Horm Res Paediatr. 2019;92(2):133-142. doi: 10.1159/000499318. Epub 2019 Apr 25.