Abstract：This paper reports the clinical and genetic characteristics of a case of combined pituitary hormone deficiency type I (CPHD1) caused by POU domain, class 1, transcription factor 1 (POU1F1) gene variation. A 2 years and 3 months old girl mainly presented with short stature, special facial features of prominent forehead, enophthalmos, and short mandible, loose skin, central hypothyroidism, complete growth hormone deficiency, and anterior pituitary hypoplasia. Gene analysis identified a novel heterozygous mutation, c.889C > T (p.R297W), in POU1F1 gene, and this locus of her parents was wild-type. This mutation was analyzed as a possible pathogenic variant according to the guidelines of the American College of Medical Genetics and Genomics, which has not been previously reported in the literature and conforms to the autosomal dominant inheritance. This child was diagnosed with CPHD1. Her height increased by 19.8 cm and showed a catch-up growth trend after one year of combined treatment with growth hormone and euthyrox. This study enriches the mutation spectrum of POU1F1 gene and has important significance for the diagnosis and classification of combined pituitary hormone deficiency.
CHEN Jie,ZHANG Xing-Xing,WU Xiao-Chuan et al. Clinical and genetic characteristics of a young child with combined pituitary hormone deficiency type I caused by POU1F1 gene variation[J]. CJCP, 2019, 21(7): 685-689.
Otto AP, França MM, Correa FA, et al. Frequent development of combined pituitary hormone deficiency in patients initially diagnosed as isolated growth hormone deficiency:a long term follow-up of patients from a single center[J]. Pituitary, 2015, 18(4):561-567.
[2]
Turton JP, Strom M, Langham S, et al. Two novel mutations in the POU1F1 gene generate null alleles through different mechanisms leading to combined pituitary hormone deficiency[J]. Clin Endocrinol (Oxf), 2012, 76(3):387-393.
[3]
Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants:a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5):405-424.
[4]
Bertko E, Klammt J, Dusatkova P, et al. Combined pituitary hormone deficiency due to gross deletions in the POU1F1(PIT-1) and PROP1 genes[J]. J Hum Genet, 2017, 62(8):755-762.
[5]
Tatsumi K, Miyai K, Notomi T, et al. Cretinism with combined hormone deficiency caused by a mutation in the PIT1 gene[J]. Nat Genet, 1992, 1(1):56-58.
[6]
Fang Q, George AS, Brinkmeier ML, et al. Genetics of combined pituitary hormone deficiency:roadmap into the genome era[J]. Endocr Rev, 2016, 37(6):636-675.
[7]
Bancalari RE, Gregory LC, McCabe MJ, et al. Pituitary gland development:an update[J]. Endocr Dev, 2012, 23:1-15.
[8]
Davis SW, Ellsworth BS, Peréz Millan MI, et al. Pituitary gland development and disease:from stem cell to hormone production[J]. Curr Top Dev Biol, 2013, 106:1-47.
[9]
Pfäffle R, Klammt J. Pituitary transcription factors in the aetiology of combined pituitary hormone deficiency[J]. Best Prac Res Clin Endocrinol Metab, 2011, 25(1):43-60.
[10]
Simm F, Griesbeck A, Choukair D, et al. Identification of SLC20A1 and SLC15A4 among other genes as potential risk factors for combined pituitary hormone deficiency[J]. Genet Med, 2018, 20(7):728-736.
[11]
Elizabeth M, Hokken-Koelega ACS, Schuilwerve J, et al. Genetic screening of regulatory regions of pituitary transcription factors in patients with idiopathic pituitary hormone deficiencies[J]. Pituitary, 2018, 21(1):76-83.
[12]
Birla S, Khadgawat R, Jyotsna VP, et al. Identification of novel PROP1 and POU1F1 mutations in patients with combined pituitary hormone deficiency[J]. Horm Metab Res, 2016, 48(12):822-827.
[13]
De Rienzo F, Mellone S, Bellone S, et al. Frequency of genetic defects in combined pituitary hormone deficiency:a systematic review and analysis of a multicentre Italian cohort[J]. Clin Endocrinol (Oxf), 2015, 83(6):849-860.
Andersen B, Rosenfeld MG. POU domain factors in the neuroendocrine system:lessons from developmental biology provide insights into human disease[J]. Endocr Rev, 2001, 22(1):2-35.
[16]
Theill LE, Hattori K, Lazzaro D, et al. Differential splicing of the GHF1 primary transcript gives rise to two functionally distinct homeodomain proteins[J]. EMBO J, 1992, 11(6):2261-2269.
[17]
Jonsen MD, Duval DL, Gutierrez-Hartmann A. The 26-amino acid β-motif of the Pit-1β transcription factor is a dominant and independent repressor domain[J]. Mol Endocrinol, 2009, 23(9):1371-1384.
[18]
Konzak KE, Moore DD. Functional isoforms of Pit-1 generated by alternative messenger RNA splicing[J]. Mol Endocrinol, 1992, 6(2):241-247.
[19]
Haugen BR, Gordon DF, Nelson AR, et al. The combination of Pit-1 and Pit-1T have a synergistic stimulatory effect on the thyrotropin β-subunit promoter but not the growth hormone or prolactin promoters[J]. Mol Endocrinol, 1994, 8(11):1574-1582.
[20]
Inoue H, Mukai T, Sakamoto Y, et al. Identification of a novel mutation in the exon 2 splice donor site of the POU1F1/PIT-1 gene in Japanese identical twins with mild combined pituitary hormone deficiency[J]. Clin Endocrinol (Oxf), 2012, 76(1):78-87.
[21]
Cohen LE, Wondisford FE, Salvatoni A, et al. A "hot spot" in the the Pit-1 gene responsible for combined pituitary hormone deficiency:clinical and molecular correlates[J]. J Clin Endocrinol Metab, 1995, 80(2):679-684.
[22]
Mortensen AH, Fang Q, Fleming MT, et al. Genetic variation in thyroid folliculogenesis influences susceptibility to hypothyroidism-induced hearing impairment[J]. Mamm Genome, 2019, 30(1-2):5-22.
