Abstract
Background/Aims: Mutation frequencies of genes involved in combined pituitary hormone deficiency (CPHD) vary substantially between populations. The HYPOPIT study aims to obtain an overall picture of known and new genetic defects and variations in a nationwide cohort of Dutch (mostly) sporadic CPHD patients. Methods: We screened 79 CPHD patients from 78 families (regardless of MRI and hormonal phenotype) for mutations and deletions in PROP1, HESX1, POU1F1, LHX3 and LHX4, as well as the P89L and IVS3+1/+2 mutations in GH1, recently described to cause pituitary hormone impairment in addition to GH deficiency. Results: We did not find any mutation or deletion in PROP1, HESX1, LHX3 or LHX4, nor GH1 P89L and GH1 IVS3+1/+2 mutations. Among 12 patients with a typical ‘POU1F1 phenotype’, 1 patient was formerly known to have a POU1F1 mutation. This results in a POU1F1 mutation frequency in these patients of 8.3%. Conclusion: Thorough screening for mutations and deletions in PROP1, HESX1, POU1F1, LHX3, LHX4, as well as screening for GH1 P89L or GH1 IVS3+1/+2 mutations, did not reveal any genetic defect in our cohort of CPHD patients except for one formerly known POU1F1 mutation in 1 patient. Future research should focus on alternative explanations for CPHD, like other genes or environmental factors.
References
1.
Zhu X, Gleiberman AS, Rosenfeld MG: Molecular physiology of pituitary development: signaling and transcriptional networks. Physiol Rev 2007;87:933–963.
2.
Dattani MT, Martinez-Barbera JP, Thomas PQ, et al: Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nat Genet 1998;19:125–133.
3.
Duquesnoy P, Roy A, Dastot F, et al: Human Prop-1: cloning, mapping, genomic structure. Mutations in familial combined pituitary hormone deficiency. FEBS Lett 1998;437:216–220.
4.
Machinis K, Pantel J, Netchine I, et al: Syndromic short stature in patients with a germline mutation in the LIM homeobox LHX4. Am J Hum Genet 2001;69:961–968.
5.
Netchine I, Sobrier ML, Krude H, et al: Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency. Nat Genet 2000;25:182–186.
6.
Ohta K, Nobukuni Y, Mitsubuchi H, et al: Mutations in the Pit-1 gene in children with combined pituitary hormone deficiency. Biochem Biophys Res Commun 1992;189:851–855.
7.
Thomas PQ, Dattani MT, Brickman JM, et al: Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. Hum Mol Genet 2001;10:39–45.
8.
Wu W, Cogan JD, Pfaffle RW, et al: Mutations in PROP1 cause familial combined pituitary hormone deficiency. Nat Genet 1998;18:147–149.
9.
Mullis PE, Robinson IC, Salemi S, et al: Isolated autosomal dominant growth hormone deficiency: an evolving pituitary deficit? A multicenter follow-up study. J Clin Endocrinol Metab 2005;90:2089–2096.
10.
Pfaffle R, Kim C, Otten B, et al: Pit-1: clinical aspects. Horm Res 1996;45(suppl 1):25–28.
11.
Sloop KW, Meier BC, Bridwell JL, Parker GE, Schiller AM, Rhodes SJ: Differential activation of pituitary hormone genes by human Lhx3 isoforms with distinct DNA binding properties. Mol Endocrinol 1999;13:2212–2225.
12.
Pfaffle RW, DiMattia GE, Parks JS, et al: Mutation of the POU-specific domain of Pit-1 and hypopituitarism without pituitary hypoplasia. Science 1992;257:1118–1121.
13.
Turton JP, Reynaud R, Mehta A, et al: Novel mutations within the POU1F1 gene associated with variable combined pituitary hormone deficiency. J Clin Endocrinol Metab 2005;90:4762–4770.
14.
Reynaud R, Saveanu A, Barlier A, Enjalbert A, Brue T: Pituitary hormone deficiencies due to transcription factor gene alterations. Growth Horm IGF Res 2004;14:442–448.
15.
Kim SS, Kim Y, Shin YL, Kim GH, Kim TU, Yoo HW: Clinical characteristics and molecular analysis of PIT1, PROP1, LHX3, and HESX1 in combined pituitary hormone deficiency patients with abnormal pituitary MR imaging. Horm Res 2003;60:277–283.
16.
McLennan K, Jeske Y, Cotterill A, et al: Combined pituitary hormone deficiency in Australian children: clinical and genetic correlates. Clin Endocrinol (Oxf) 2003;58:785–794.
17.
Rainbow LA, Rees SA, Shaikh MG, et al: Mutation analysis of POUF-1, PROP-1 and HESX-1 show low frequency of mutations in children with sporadic forms of combined pituitary hormone deficiency and septo-optic dysplasia. Clin Endocrinol (Oxf) 2005;62:163–168.
18.
Turton JP, Mehta A, Raza J, et al: Mutations within the transcription factor PROP1 are rare in a cohort of patients with sporadic combined pituitary hormone deficiency (CPHD). Clin Endocrinol (Oxf) 2005;63:10–18.
19.
Dobson-Stone C, Cox RD, Lonie L, et al: Comparison of fluorescent single-strand conformation polymorphism analysis and denaturing high-performance liquid chromatography for detection of EXT1 and EXT2 mutations in hereditary multiple exostoses. Eur J Hum Genet 2000;8:24–32.
20.
Ellis LA, Taylor CF, Taylor GR: A comparison of fluorescent SSCP and denaturing HPLC for high throughput mutation scanning. Hum Mutat 2000;15:556–564.
21.
Gross E, Arnold N, Goette J, Schwarz-Boeger U, Kiechle M: A comparison of BRCA1 mutation analysis by direct sequencing, SSCP and DHPLC. Hum Genet 1999;105:72–78.
22.
Jones AC, Austin J, Hansen N, et al: Optimal temperature selection for mutation detection by denaturing HPLC and comparison to single-stranded conformation polymorphism and heteroduplex analysis. Clin Chem 1999;45:1133–1140.
23.
Liu WO, Oefner PJ, Qian C, Odom RS, Francke U: Denaturing HPLC-identified novel FBN1 mutations, polymorphisms, and sequence variants in Marfan syndrome and related connective tissue disorders. Genet Test 1997;1:237–242.
24.
O’Donovan MC, Oefner PJ, Roberts SC, et al: Blind analysis of denaturing high-performance liquid chromatography as a tool for mutation detection. Genomics 1998;52:44–49.
25.
Osorio MG, Marui S, Jorge AA, et al: Pituitary magnetic resonance imaging and function in patients with growth hormone deficiency with and without mutations in GHRH-R, GH-1, or PROP-1 genes. J Clin Endocrinol Metab 2002;87:5076–5084.
26.
Reynaud R, Gueydan M, Saveanu A, et al: Genetic screening of combined pituitary hormone deficiency: experience in 195 patients. J Clin Endocrinol Metab 2006;91:3329–3336.
27.
Lebl J, Vosáhlo J, Pfaeffle RW, et al: Auxological and endocrine phenotype in a population-based cohort of patients with PROP1 gene defects. Eur J Endocrinol 2005;153:389–396.
28.
Vallette-Kasic S, Barlier A, Teinturier C, et al: PROP1 gene screening in patients with multiple pituitary hormone deficiency reveals two sites of hypermutability and a high incidence of corticotroph deficiency. J Clin Endocrinol Metab 2001;86:4529–4535.
29.
Lemos MC, Gomes L, Bastos M, et al: PROP1 gene analysis in Portuguese patients with combined pituitary hormone deficiency. Clin Endocrinol (Oxf) 2006;65:479–485.
30.
Deladoey J, Fluck C, Buyukgebiz A, et al: ‘Hot spot’ in the PROP1 gene responsible for combined pituitary hormone deficiency. J Clin Endocrinol Metab 1999;84:1645–1650.
31.
Fofanova OV, Takamura N, Kinoshita E, et al: A mutational hot spot in the Prop-1 gene in Russian children with combined pituitary hormone deficiency. Pituitary 1998;1:45–49.
32.
McNay DE, Turton JP, Kelberman D, et al: HESX1 mutations are an uncommon cause of septooptic dysplasia and hypopituitarism. J Clin Endocrinol Metab 2007;92:691–697.
33.
Fofanova OV, Takamura N, Kinoshita E, et al: Rarity of PIT1 involvement in children from Russia with combined pituitary hormone deficiency. Am J Med Genet 1998;77:360–365.
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2010
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