Because the causes of combined pituitary hormone deficiency (CPHD) are complex, the etiology of congenital CPHD remains unknown in most cases. The aim of the study was to identify the genetic etiology of CPHD in a well-defined single-center cohort. In total, 34 children (12 girls) with congenital CPHD (growth hormone (GH) deficiency and impaired secretion of at least one other pituitary hormone) treated with GH in our center were enrolled in the study. Their median age was 11.2 years, pre-treatment height was -3.2 s.d., and maximal stimulated GH was 1.4 ug/L. Of them, 30 had central adrenal insufficiency, 27 had central hypothyroidism, ten had hypogonadotropic hypogonadism, and three had central diabetes insipidus. Twenty-six children had a midline defect on MRI. Children with clinical suspicion of a specific genetic disorder underwent genetic examination of the gene(s) of interest via Sanger sequencing or array comparative genomic hybridization. Children without a detected causal variant after the first-tier testing or with no suspicion of a specific genetic disorder were subsequently examined using next-generation sequencing growth panel. Variants were evaluated by the American College of Medical Genetics standards. Genetic etiology was confirmed in 7/34 (21%) children. Chromosomal aberrations were found in one child (14q microdeletion involving the OTX2 gene). The remaining 6 children had causative genetic variants in the GLI2, PROP1, POU1F1, TBX3, PMM2, and GNAO1 genes, respectively. We elucidated the cause of CPHD in a fifth of the patients. Moreover, our study supports the PMM2 gene as a candidate gene for CPHD and suggests pathogenic variants in the GNAO1 gene as a potential novel genetic cause of CPHD.

Department of Pediatrics 2nd Faculty of Medicine Charles University and Motol University Hospital 5 Úvalu Prague Czech Republic

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Fang Q, George AS, Brinkmeier ML, Mortensen AH, Gergics P, Cheung LYM, Daly AZ, Ajmal A, Pérez Millán MI, Ozel AB, PubMed DOI PMC

Bando H Urai S Kanie K Sasaki Y Yamamoto M Fukuoka H Iguchi G & Camper SA. Novel genes and variants associated with congenital pituitary hormone deficiency in the era of next-generation sequencing. Frontiers in Endocrinology 2022131008306. ( 10.3389/fendo.2022.1008306) PubMed DOI PMC

Hietamaki J Karkinen J Iivonen AP Vaaralahti K Tarkkanen A Almusa H Huopio H Hero M Miettinen PJ & Raivio T. Presentation and diagnosis of childhood-onset combined pituitary hormone deficiency: a single center experience from over 30 years. EClinicalMedicine 202251101556 . ( 10.1016/j.eclinm.2022.101556) PubMed DOI PMC

Budny B Karmelita-Katulska K Stajgis M Żemojtel T Ruchała M & Ziemnicka K. Copy number variants contributing to combined pituitary hormone deficiency. International Journal of Molecular Sciences 2020211–10. ( 10.3390/ijms21165757) PubMed DOI PMC

Hage C Gan HW Ibba A Patti G Dattani M Loche S Maghnie M & Salvatori R. Advances in differential diagnosis and management of growth hormone deficiency in children. Nature Reviews. Endocrinology 202117608–624. ( 10.1038/s41574-021-00539-5) PubMed DOI

Chehadeh-Djebbar El S, Callier P, Masurel-Paulet A, Bensignor C, Méjean N, Payet M, Ragon C, Durand C, Marle N, Mosca-Boidron AL, PubMed DOI

Correa FA, Jorge AAL, Nakaguma M, Canton APM, Costa SS, Funari MF, Lerario AM, Franca MM, Carvalho LR, Krepischi ACV, PubMed DOI

Brisset S, Slamova Z, Dusatkova P, Briand-Suleau A, Milcent K, Metay C, Simandlova M, Sumnik Z, Tosca L, Goossens M, PubMed DOI PMC

Rienzo De F, Mellone S, Bellone S, Babu D, Fusco I, Prodam F, Petri A, Muniswamy R, Luca De F, Salerno M, PubMed DOI

Pérez Millán MI, Vishnopolska SA, Daly AZ, Bustamante JP, Seilicovich A, Bergadá I, Braslavsky D, Keselman AC, Lemons RM, Mortensen AH, PubMed DOI PMC

Obermannova B, Pfaeffle R, Zygmunt-Gorska A, Starzyk J, Verkauskiene R, Smetanina N, Bezlepkina O, Peterkova V, Frisch H, Cinek O, PubMed DOI

Zygmunt-Gorska A Starzyk J Adamek D Radwanska E Sucharski P Herman-Sucharska I & Pietrzyk JJ. Pituitary enlargement in patients with PROP1 gene inactivating mutation represents cystic hyperplasia of the intermediate pituitary lobe. Histopathology and over 10 years follow-up of two patients. Journal of Pediatric Endocrinology & Metabolism 200922653–660. ( 10.1515/jpem.2009.22.7.653) PubMed DOI

Grimberg A DiVall SA Polychronakos C Allen DB Cohen LE Quintos JB Rossi WC Feudtner C & Murad MH. Guidelines for growth hormone and insulin-like growth factor-I treatment in children and adolescents: growth hormone deficiency, idiopathic short stature, and primary insulin-like growth factor-I deficiency. Hormone Research in Paediatrics 201786361–397. ( 10.1159/000452150) PubMed DOI

Growth Hormone Research Society. Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society 1. Journal of Clinical Endocrinology and Metabolism 2000853990–3993. ( 10.1210/jcem.85.11.6984) PubMed DOI

Persani L Brabant G Dattani M Bonomi M Feldt-Rasmussen U Fliers E Gruters A Maiter D Schoenmakers N & Paul Van Trotsenburg ASP. 2018 European Thyroid Association (ETA) guidelines on the diagnosis and management of central hypothyroidism. European Thyroid Journal 20187225–237. ( 10.1159/000491388) PubMed DOI PMC

Bornstein SR, Allolio B, Arlt W, Barthel A, Don-Wauchope A, Hammer GD, Husebye ES, Merke DP, Murad MH, Stratakis CA, PubMed DOI PMC

Gruber LM & Bancos I. Secondary adrenal insufficiency: recent updates and new directions for diagnosis and management. Endocrine Practice 202228110–117. ( 10.1016/j.eprac.2021.09.011) PubMed DOI

Nordenström A, Ahmed SF, Akker van den E, Blair J, Bonomi M, Brachet C, Broersen LHA, Claahsen-van der Grinten HL, Dessens AB, Gawlik A, PubMed DOI PMC

Mishra G & Chandrashekhar SR. Management of diabetes insipidus in children. Indian Journal of Endocrinology and Metabolism 201115(Supplement 3) S180–S187. ( 10.4103/2230-8210.84858) PubMed DOI PMC

Voigt M Fusch C Olbertz D Hartmann K Rochow N Renken C & Schneider K. Analyse des Neugeborenenkollektivs der Bundesrepublik Deutschland. Geburtshilfe und Frauenheilkunde 200666956–970. ( 10.1055/s-2006-924458) DOI

Kobzová J Vignerová J Bláha P Krejćovsky L & Riedlová J. The 6th nationwide anthropological survey of children and adolescents in the Czech Republic in 2001. Central European Journal of Public Health 200412126–130. PubMed

Pruhova S Dusatkova P Sumnik Z Kolouskova S Pedersen O Hansen T Cinek O & Lebl J. Glucokinase diabetes in 103 families from a country-based study in the Czech Republic: geographically restricted distribution of two prevalent GCK mutations. Pediatric Diabetes 201011529–535. ( 10.1111/j.1399-5448.2010.00646.x) PubMed DOI

Plachy L, Strakova V, Elblova L, Obermannova B, Kolouskova S, Snajderova M, Zemkova D, Dusatkova P, Sumnik Z, Lebl J, PubMed DOI

Plachy L, Dusatkova P, Maratova K, Petruzelkova L, Zemkova D, Elblova L, Kucerova P, Toni L, Kolouskova S, Snajderova M, PubMed DOI

Plachy L, Dusatkova P, Maratova K, Petruzelkova L, Elblova L, Kolouskova S, Snajderova M, Obermannova B, Zemkova D, Sumnik Z, PubMed DOI

Plachy L, Amaratunga SA, Dusatkova P, Maratova K, Neuman V, Petruzelkova L, Zemkova D, Obermannova B, Snajderova M, Kolouskova S, PubMed DOI PMC

Fowler A.DECoN: a detection and visualization tool for exonic copy number variants. In: Variant Calling. Methods in Molecular Biology, vol 2493. New York, NY, USA: Humana, 2022. ( 10.1007/978-1-0716-2293-3_6) PubMed DOI

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, PubMed DOI PMC

Jarvik GP & Browning BL. Consideration of cosegregation in the pathogenicity classification of genomic variants. American Journal of Human Genetics 2016981077–1081. ( 10.1016/j.ajhg.2016.04.003) PubMed DOI PMC

Reynaud R Gueydan M Saveanu A Vallette-Kasic S Enjalbert A Brue T & Barlier A. Genetic screening of combined pituitary hormone deficiency: experience in 195 patients. Journal of Clinical Endocrinology and Metabolism 2006913329–3336. ( 10.1210/jc.2005-2173) PubMed DOI

Coya R, Vela A, Perez de Nanclares G, Rica I, Castano L, Busturia MA, Martul P. & GEDPIT group. Panhypopituitarism: genetic versus acquired etiological factors. Journal of Pediatric Endocrinology and Metabolism 20072027–36 . ( 10.1515/JPEM.2007.20.1.27) PubMed DOI

Vieira TC Boldarine VT & Abucham J. Molecular analysis of PROP1, PIT1, HESX1, LHX3, and LHX4 shows high frequency of PROP1 mutations in patients with familial forms of combined pituitary hormone deficiency. Arquivos Brasileiros de Endocrinologia e Metabologia 2007511097–1103. ( 10.1590/S0004-27302007000700012) PubMed DOI

Navardauskaite R Dusatkova P Obermannova B Pfaeffle RW Blum WF Adukauskiene D Smetanina N Cinek O Verkauskiene R & Lebl J. High prevalence of PROP1 defects in Lithuania: phenotypic findings in an ethnically homogenous cohort of patients with multiple pituitary hormone deficiency. Journal of Clinical Endocrinology and Metabolism 201499299–306. ( 10.1210/jc.2013-3090) PubMed DOI

Lebl J, Vosáhlo J, Pfaeffle RW, Stobbe H, Černá J, Novotná D, Zapletalová J, Kalvachová B, Hána V, Weiss V, PubMed DOI

Halász Z, Toke J, Patócs A, Bertalan R, Tömböl Z, Sallai A, Hosszú E, Muzsnai A, Kovács L, Sólyom J, PubMed DOI

Plachy L, Petruzelkova L, Dušátková P, Maratova K, Zemkova D, Elblova L, Neuman V, Kolouskova S, Obermannova B, Snajderova M, PubMed DOI PMC

Toni L, Plachy L, Dusatkova P, Amaratunga SA, Elblova L, Sumnik Z, Kolouskova S, Snajderova M, Obermannova B, Pruhova S, PubMed DOI

Hauer NN, Popp B, Schoeller E, Schuhmann S, Heath KE, Hisado-Oliva A, Klinger P, Kraus C, Trautmann U, Zenker M, PubMed DOI PMC

Homma TK, Freire BL, Honjo Kawahira RS, Dauber A, Funari MFA, Lerario AM, Nishi MY, Albuquerque EV, Vasques GA, Collett-Solberg PF, PubMed DOI

Freire BL Homma TK Funari MFA Lerario AM Vasques GA Malaquias AC Arnhold IJP & Jorge AAL. Multigene sequencing analysis of children born small for gestational age with isolated short stature. Journal of Clinical Endocrinology and Metabolism 20191042023–2030. ( 10.1210/jc.2018-01971) PubMed DOI

Miller BS Duffy MM Addo OY & Sarafoglou K. rhIGF-1 therapy for growth failure and IGF-1 deficiency in congenital disorder of glycosylation Ia (PMM2 deficiency). Journal of Investigative Medicine High Impact Case Reports 201312324709613503316. ( 10.1177/2324709613503316) PubMed DOI PMC

Apuzzo D Cappuccio G Vaisanen T Alagia M Pignataro P Genesio R & Brunetti-Pierri N. Two cases of 16q12.1q21 deletions and refinement of the critical region. European Journal of Medical Genetics 202063103878. ( 10.1016/j.ejmg.2020.103878) PubMed DOI

Girisha KM Bidchol AM Graul-Neumann L Gupta A Hehr U Lessel D Nader S Shah H Wickert J & Kutsche K. Phenotype and genotype in patients with Larsen syndrome: clinical homogeneity and allelic heterogeneity in seven patients. BMC Medical Genetics 20161727. ( 10.1186/s12881-016-0290-6) PubMed DOI PMC

Brauner R Bignon-Topalovic J Bashamboo A & McElreavey K. Pituitary stalk interruption syndrome is characterized by genetic heterogeneity. PLoS One 202015e0242358 . ( 10.1371/journal.pone.0242358) PubMed DOI PMC

Čechová A, Honzík T, Edmondson AC, Ficicioglu C, Serrano M, Barone R, Lonlay De P, Schiff M, Witters P, Lam C, PubMed DOI PMC

Saitsu H, Fukai R, Ben-Zeev B, Sakai Y, Mimaki M, Okamoto N, Suzuki Y, Monden Y, Saito H, Tziperman B, PubMed DOI PMC

Hong M & Krauss RS. Cdon mutation and fetal ethanol exposure synergize to produce midline signaling defects and holoprosencephaly spectrum disorders in mice. PLoS Genetics 20128e1002999. ( 10.1371/journal.pgen.1002999) PubMed DOI PMC

Simeone P & Alberti S. Epigenetic heredity of human height. Physiological Reports 20142e12047. ( 10.14814/phy2.12047) PubMed DOI PMC