Congenital Hypopituitarism: Various Genes, Various Phenotypes

Maria Xatzipsalti; Antonis Voutetakis; Lela Stamoyannou; George P. Chrousos; Christina Kanaka-Gantenbein

doi:10.1055/a-0822-3637

Hormone and Metabolic Research, Inhaltsverzeichnis

Horm Metab Res 2019; 51(02): 81-90
DOI: 10.1055/a-0822-3637

Review

Congenital Hypopituitarism: Various Genes, Various Phenotypes

Authors

Maria Xatzipsalti

¹Division of Endocrinology, Diabetes and Metabolism, First Department of Pediatrics, Medical School, National and Kapodistrian University of Athens, “Aghia Sofia” Children's Hospital, Athens, Greece

²First Department of Pediatrics, “Aglaia Kyriakou” Children's Hospital, Athens, Greece
Antonis Voutetakis

¹Division of Endocrinology, Diabetes and Metabolism, First Department of Pediatrics, Medical School, National and Kapodistrian University of Athens, “Aghia Sofia” Children's Hospital, Athens, Greece
Lela Stamoyannou

²First Department of Pediatrics, “Aglaia Kyriakou” Children's Hospital, Athens, Greece
George P. Chrousos

¹Division of Endocrinology, Diabetes and Metabolism, First Department of Pediatrics, Medical School, National and Kapodistrian University of Athens, “Aghia Sofia” Children's Hospital, Athens, Greece
Christina Kanaka-Gantenbein

¹Division of Endocrinology, Diabetes and Metabolism, First Department of Pediatrics, Medical School, National and Kapodistrian University of Athens, “Aghia Sofia” Children's Hospital, Athens, Greece

Abstract

The ontogenesis and development of the pituitary gland is a highly complex process that depends on a cascade of transcription factors and signaling molecules. Spontaneous mutations and transgenic murine models have demonstrated a role for many of these factors, including HESX1, PROP1, PIT1, LHX3, LHX4, SOX2, SOX3, OTX2, PAX6, FGFR1, SHH, GLI2, and FGF8 in the etiology of congenital hypopituitarism. Genetic mutations in any of these factors can lead to congenital hypopituitarism, which is characterized by the deficiency in one or more pituitary hormones. The phenotype can be highly variable, consisting of isolated hypopituitarism or more complex disorders. The same phenotype can be attributed to different gene mutations; while a given gene mutation can induce different phenotypes. This review highlights the genetic variations that lead to congenital hypopituitarism and their associated defects. The overall incidence of mutations in known transcription factors in patients with hypopituitarism is low; therefore many gene mutations or even gene- epigenetic interactions have to be unraveled in the future to explain the vast majority of still unclear cases of congenital hypopituitarism.

Key words

pituitary - combined pituitary hormone deficiency - congenital hypopituitarism - transcription factors - syndromic hypopituitarism - non-syndromic hypopituitarism

Volltext

Referenzen

References
1 Alatzoglou KS, Dattani MT. Genetic forms of hypopituitarism and their manifestation in the neonatal period. Early Hum Dev 2009; 85: 705-712
2 Pfaeffle RW, Savage JJ, Hunter CS. et al. Four novel mutations of the LHX3 gene cause combined pituitary hormone deficiencies with or without limited neck rotation. J Clin Endocrinol Metab 2007; 92: 1909-1919
3 Savage JJ, Hunter CS, Clark-Sturm SL. et al. Mutations in the LHX3 gene cause dysregulation of pituitary and neural target genes that reflect patient phenotypes. Gene 2007; 400: 44-51
4 Bhangoo AP, Hunter CS, Savage JJ. et al. Clinical case seminar: A novel LHX3 mutation presenting as combined pituitary hormonal deficiency. J Clin Endocrinol Metab 2006; 91: 747-753
5 Sloop KW, Parker GE, Hanna KR. et al. LHX3 transcription factor mutations associated with combined pituitary hormone deficiency impair the activation of pituitary target genes. Gene 2001; 265: 61-69
6 Howard PW, Maurer RA. A point mutation in the LIM domain of Lhx3 reduces activation of the glycoprotein hormone alpha-subunit promoter. J Biol Chem 2001; 276: 19020-19026
7 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
8 Kristrom B, Zdunek AM, Rydh A. et al. A novel mutation in the LIM homeobox 3 gene is responsible for combined pituitary hormone deficiency, hearing impairment, and vertebral malformations. J Clin Endocrinol Metab 2009; 94: 1154-1161
9 Bonfig W, Krude H, Schmidt H. A novel mutation of LHX3 is associated with combined pituitary hormone deficiency including ACTH deficiency, sensorineural hearing loss, and short neck-A case report and review of the literature. Eur J Pediatr 2011; 170: 1017-1021
10 Rajab A, Kelberman D, de Castro SC. et al. Novel mutations in LHX3 are associated with hypopituitarism and sensorineural hearing loss. Hum Mol Genet 2008; 17: 2150-2159
11 Sobrier ML, Brachet C, Vié-Luton MP. et al. Symptomatic heterozygotes and prenatal diagnoses in a nonconsanguineous family with syndromic combined pituitary hormone deficiency resulting from two novel LHX3 mutations. J Clin Endocrinol Metab 2012; 97: E503-E509
12 Jullien N, Philippon M, Quentien MH. et al. Heterozygous LHX3 mutations may lead to a mild phenotype of combined pituitary hormone deficiency. Eur J Hum Genet 2018; [Epub ahead of print]
13 Bechtold-Dalla Pozza S, Hiedl S, Roeb J. et al. A recessive mutation resulting in a disabling amino acid substitution (T194R) in the LHX3 homeodomain causes combined pituitary hormone deficiency. Horm Res Paediatr 2012; 77: 41-51
14 Pfaeffle RW, Hunter CS, Savage JJ. et al. Three novel missense mutations within the LHX4 gene are associated with variable pituitary hormone deficiencies. J Clin Endocrinol Metab 2008; 93: 1062-1071
15 Tajima T, Yorifuji T, Ishizu K. et al. A novel mutation (V101A) of the LHX4 gene in a Japanese patient with combined pituitary hormone deficiency. Exp Clin Endocrinol Diabetes 2010; 118: 405-409
16 Dateki S, Fukami M, Uematsu A. et al. Mutation and gene copy number analyses of six pituitary transcription factor genes in 71 patients with combined pituitary hormone deficiency: Identification of a single patient with LHX4 deletion. J Clin Endocrinol Metab 2010; 95: 4043-4047
17 Takagi M, Ishii T, Inokuchi M. et al. Gradual loss of ACTH due to a novel mutation in LHX4: Comprehensive mutation screening in Japanese patients with congenital hypopituitarism. PLoS One 2012; 7: e46008
18 Castinetti F, Saveanu A, Reynaud R. et al. A novel dysfunctional LHX4 mutation with high phenotypical variability in patients with hypopituitarism. J Clin Endocrinol Metab 2008; 93: 2790-2799
19 Rochette C, Jullien N, Saveanu A. et al. Identifying the deleterious effect of rare LHX4 allelic variants, a challenging issue. PLoS One 2015; 10: e012664821
20 Tajima T, Hattori T, Nakajima T. et al. A novel missense mutation (P366T) of the LHX4 gene causes severe combined pituitary hormone deficiency with pituitary hypoplasia, ectopic posterior lobe and a poorly developed sella turcica. Endocr J 2007; 54: 637-641
21 Filges I, Bischof-Renner A, Röthlisberger B. et al. Panhypopituitarism presenting as life-threatening heart failure caused by an inherited microdeletion in 1q25 including LHX4. Pediatrics 2012; 129: e529-e534
22 Gregory LC, Humayun KN, Turton JP. et al. Lethal form of congenital hypopituitarism associated with the first recessive LHX4 mutation. J Clin Endocrinol Metab 2015; 100: 2158-2164
23 Cohen E, Maghnie M, Collot N. et al. Contribution of LHX4 mutations to pituitary deficits in a cohort of 417 unrelated patients. J Clin Endocrinol Metab 2017; 102: 290-301
24 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
25 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
26 Brickman JM, Clements M, Tyrell R. et al. Molecular effects of novel mutations in Hesx1/HESX1 associated with human pituitary disorders. Development 2001; 128: 5189-5199
27 Vivenza D, Godi M, Faienza MF. et al. A novel HESX1 splice mutation causes isolated GH deficiency by interfering with mRNA processing. Eur J Endocrinol 2011; 164: 705-713
28 Takagi M, Takahashi M, Ohtsu Y. et al. A novel mutation in HESX1 causes combined pituitary hormone deficiency without septo optic dysplasia phenotypes. Endocr J 2016; 63: 405-410
29 Fang Q, Benedetti AF, Ma Q. et al. HESX1 mutations in patients with congenital hypopituitarism: Variable phenotypes with the same genotype. Clin Endocrinol (Oxf) 2016; 85: 408-414
30 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
31 Kelberman D, Rizzoti K, Avilion A. et al. Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans. J Clin Invest 2006; 116: 2442-2455
32 Kelberman D, de Castro SC, Huang S. et al. SOX2 plays a critical role in the pituitary, forebrain, and eye during human embryonic development. J Clin Endocrinol Metab 2008; 93: 1865-1873
33 Sato N, Kamachi Y, Kondoh H. et al. Hypogonadotropic hypogonadism in an adult female with a heterozygous hypomorphic mutation of SOX2. Eur J Endocrinol 2007; 156: 167-171
34 Stark Z, Storen R, Bennetts B. et al. Isolated hypogonadotropic hypogonadism with SOX2 mutation and anophthalmia/microphthalmia in offspring. Eur J Hum Genet 2011; 19: 753-756
35 Errichiello E, Gorgone C, Giuliano L. et al. SOX2: Not always eye malformations. Severe genital but no major ocular anomalies in a female patient with the recurrent c.70del20 variant. Eur J Med Genet 2018; 61: 335-340
36 Macchiaroli A, Kelberman D, Auriemma RS. et al. A novel heterozygous SOX2 mutation causing congenital bilateral anophthalmia, hypogonadotropic hypogonadism and growth hormone deficiency. Gene 2014; 534: 282-285
37 Alatzoglou KS, Andoniadou CL, Kelberman D. et al. SOX2 haploinsufficiency is associated with slow progressing hypothalamo-pituitary tumours. Hum Mutat 2011; 32: 1376-1380
38 Takagi M, Ishii T, Torii C. et al. A novel mutation in SOX3 polyalanine tract: A case of Kabuki syndrome with combined pituitary hormone deficiency harboring double mutations in MLL2 and SOX3. Pituitary 2014; 17: 569-574
39 Laumonnier F, Ronce N, Hamel BC. et al. Transcription factor SOX3 is involved in X-linked mental retardation with growth hormone deficiency. Am J Hum Genet 2002; 71: 1450-1455
40 Stankiewicz P, Thiele H, Schlicker M. Duplication of Xq26.2-q27.1, including SOX3, in a mother and daughter with short stature and dyslalia. Am J Med Genet A 2005; 138: 11-17
41 Dateki S, Kosaka K, Hasegawa K. et al. Heterozygous orthodenticle homeobox 2 mutations are associated with variable pituitary phenotype. J Clin Endocrinol Metab 2010; 95: 756-764
42 Shimada A, Takagi M, Nagashima Y. et al. A novel mutation in OTX2 Causes combined pituitary hormone deficiency, bilateral microphthalmia, and agenesis of the left internal carotid artery. Horm Res Paediatr 2016; 86: 62-69
43 Jones GE, Robertson L, Warman P. et al. 14q22.3 Microdeletion encompassing OTX2 in a five-generation family with microphthalmia, pituitary abnormalities, and intellectual disability. Ophthalmic Genet 2016; 37: 352-353
44 Lonero A, Delvecchio M, Primignani P. et al. OTX2 gene frameshift mutation in a child with microphthalmia, ectopic pituitary and growth hormone deficiency. J Pediatr Endocrinol Metab 2016; 29: 603-605
45 Diaczok D, Romero C, Zunich J. et al. A novel dominant negative mutation of OTX2 associated with combined pituitary hormone deficiency. J Clin Endocrinol Metab 2008; 93: 4351-4359
46 Dateki S, Fukami M, Sato N. et al. OTX2 mutation in a patient with anophthalmia, short stature, and partial growth hormone deficiency: Functional studies using the IRBP, HESX1, and POU1F1 promoters. J Clin Endocrinol Metab 2008; 93: 3697-3702
47 Ashkenazi-Hoffnung L, Lebenthal Y, Wyatt AW. et al. A novel loss-of-function mutation in OTX2 in a patient with anophthalmia and isolated growth hormone deficiency. Hum Genet 2010; 127: 721-729
48 Henderson RH, Williamson KA, Kennedy JS. et al. A rare de novo nonsense mutation in OTX2 causes early onset retinal dystrophy and pituitary dysfunction. Mol Vis 2009; 15: 2442-2447
49 Gorbenko Del Blanco D, Romero CJ, Diaczok D. et al. A novel OTX2 mutation in a patient with combined pituitary hormone deficiency, pituitary malformation, and an underdeveloped left optic nerve. Eur J Endocrinol 2012; 167: 441-452
50 Kioussi C, O'Connell S, St-Onge L. et al. Pax6 is essential for establishing ventral-dorsal cell boundaries in pituitary gland development. Proc Natl Acad Sci U S A 1999; 96: 14378-14382
51 Hergott-Faure L, Borot S, Kleinclauss C. et al. Pituitary function and glucose tolerance in a family with a PAX6 mutation. Ann Endocrinol (Paris) 2012; 73: 510-514
52 Shimo N, Yasuda T, Kitamura T. et al. Aniridia with a heterozygous PAX6 mutation in which the pituitary function was partially impaired. Intern Med 2014; 53: 39-42
53 Takagi M, Nagasaki K, Fujiwara I. et al. Heterozygous defects in PAX6 gene and congenital hypopituitarism. Eur J Endocrinol 2015; 172: 37-45
54 Bakrania P, Efthymiou M, Klein JC. et al. Mutations in BMP4 cause eye, brain, and digit developmental anomalies: Overlap between the BMP4 and hedgehog signaling pathways. Am J Hum Genet 2008; 82: 304-319
55 Breitfeld J, Martens S, Klammt J. et al. Genetic analyses of bone morphogenetic protein 2, 4 and 7 in congenital combined pituitary hormone deficiency. BMC Endocr Disord 2013; 13: 56
56 Koika V, Varnavas P, Valavani H. et al. Comparative functional analysis of two fibroblast growth factor receptor 1 (FGFR1) mutations affecting the same residue (R254W and R254Q) in isolated hypogonadotropic hypogonadism (IHH). Gene 2013; 516: 146-151
57 Raivio T, Avbelj M, McCabe MJ. et al. Genetic overlap in Kallmann syndrome, combined pituitary hormone deficiency, and septo-optic dysplasia. J Clin Endocrinol Metab 2012; 97: E694-E699
58 Fukami M, Iso M, Sato N. et al. T.Submicroscopic deletion involving the fibroblast growth factor receptor 1 gene in a patient with combined pituitary hormone deficiency. Endocr J 2013; 60: 1013-1020
59 Webb EA, AlMutair A, Kelberman D. et al. ARNT2 mutation causes hypopituitarism, post-natal microcephaly, visual and renal anomalies. Brain 2013; 136 Pt 10 3096-3105
60 Paulo SS, Fernandes-Rosa FL, Turatti W. et al. Sonic Hedgehog mutations are not a common cause of congenital hypopituitarism in the absence of complex midline cerebral defects. Clin Endocrinol (Oxf) 2015; 82: 562-569
61 Roessler E, Du YZ, Mullor JL. et al. Loss-of-function mutations in the human GLI2 gene are associated with pituitary anomalies and holoprosencephaly-like features. Proc Natl Acad Sci USA 2003; 100: 13424-13429
62 Roessler E, Ermilov AN, Grange DK. et al. A previously unidentified amino-terminal domain regulates transcriptional activity of wild-type and disease-associated human GLI2. Hum Mol Genet 2005; 14: 2181-2188
63 Bear KA, Solomon BD, Antonini S. et al. Pathogenic mutations in GLI2 cause a specific phenotype that is distinct from holoprosencephaly. J Med Genet 2014; 51: 413-418
64 Bertolacini CD, Ribeiro-Bicudo LA, Petrin A. et al. Clinical findings in patients with GLI2 mutations--phenotypic variability. Clin Genet 2012; 81: 70-75
65 Franca MM, Jorge AA, Carvalho LR. et al. Novel heterozygous nonsense GLI2 mutations in patients with hypopituitarism and ectopic posterior pituitary lobe without holoprosencephaly. J Clin Endocrinol Metab 2010; 95: E384-E391
66 Gregory LC, Gaston-Massuet C, Andoniadou CL. et al. The role of the sonic hedgehog signalling pathway in patients with midline defects and congenital hypopituitarism. Clin Endocrinol (Oxf) 2015; 82: 728-738
67 McCabe MJ, Gaston-Massuet C, Tziaferi V. et al. Novel FGF8 mutations associated with recessive holoprosencephaly, craniofacial defects, and hypothalamo-pituitary dysfunction. J Clin Endocrinol Metab 2011; 96: E1709-E1718
68 Tatsi C, Sertedaki A, Voutetakis A. et al. Pituitary stalk interruption syndrome and isolated pituitary hypoplasia may be caused by mutations in holoprosencephaly-related genes. J Clin Endocrinol Metab 2013; 98: E779-E784
69 Reynaud R, Jayakody SA, Monnier C. et al. PROKR2 variants in multiple hypopituitarism with pituitary stalk interruption. J Clin Endocrinol Metab 2012; 97: E1068-E1073
70 Reynaud R, Albarel F, Saveanu A. et al. Pituitary stalk interruption syndrome in 83 patients: Novel HESX1 mutation and severe hormonal prognosis in malformative forms. Eur J Endocrinol 2011; 164: 457-465
71 McCabe MJ, Gaston-Massuet C, Gregory LC. et al. Variations in PROKR2, but not PROK2, are associated with hypopituitarism and septo-optic dysplasia. J Clin Endocrinol Metab 2013; 98: E547-E557
72 Correa FA, Trarbach EB, Tusset C. et al. FGFR1 and PROKR2 rare variants found in patients with combined pituitary hormone deficiencies. Endocr Connect 2015; 4: 100-107
73 Karaca E, Buyukkaya R, Pehlivan D. et al. Whole-exome sequencing identifies homozygous GPR161 mutation in a family with pituitary stalk interruption syndrome. J Clin Endocrinol Metab 2015; 100: E140-E147
74 Sun Y, Bak B, Schoenmakers N. et al. Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement. Nat Genet 2012; 44: 1375-1381
75 Joustra SD, Schoenmakers N, Persani L. et al. ASThe IGSF1 deficiency syndrome: Characteristics of male and female patients. J Clin Endocrinol Metab 2013; 98: 4942-4952
76 Van Hulle S, Craen M, Callewaert B. et al. Adrenarche may be an Additional Feature of Immunoglobulin Super Family Member 1 Deficiency Syndrome. J Clin Res Pediatr Endocrinol 2016; 8: 86-91
77 Quentien MH, Delemer B, Papadimitriou DT. et al. Deficit in anterior pituitary function and variable immune deficiency (DAVID) in children presenting with adrenocorticotropin deficiency and severe infections. J Clin Endocrinol Metab 2012; 97: E121-E128
78 Chen K, Coonrod EM, Kumánovics A. et al. Germline mutations in NFKB2 implicate the noncanonical NF-kappaB pathway in the pathogenesis of common variable immunodeficiency. Am J Hum Genet 2013; 93: 812-824
79 Lee CE, Fulcher DA, Whittle B. et al. Autosomal-dominant B-cell deficiency with alopecia due to a mutation in NFKB2 that results in nonprocessable p100. Blood 2014; 124: 2964-2672
80 Liu Y, Hanson S, Gurugama P. et al. Novel NFKB2 mutation in early-onset CVID. J Clin Immunol 2014; 34: 686-690
81 Hassed SJ, Li S, Xu W. et al. Mutation in PITX2 in a Patient with Axenfeld-Rieger Syndrome. Mol Syndromol 2017; 8: 107-109
82 Gregory LC, Gevers EF, Baker J. et al. Structural pituitary abnormalities associated with CHARGE syndrome. J Clin Endocrinol Metab 2013; 98: E737-E743
83 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. Clin Endocrinol (Oxf) 2015; 83: 849-860
84 Nose O, Tatsumi K, Nakano Y. et al. Congenital combined pituitary hormone deficiency attributable to a novel PROP1 mutation (467insT). J Pediatr Endocrinol Metab 2006; 19: 491-498
85 Abrao MG, Leite MV, Carvalho LR. et al. Combined pituitary hormone deficiency (CPHD) due to a complete PROP1 deletion. Clin Endocrinol (Oxf) 2006; 65: 294-300
86 Lebl J, Vosáhlo J, Pfaeffle RW. Auxological and endocrine phenotype in a population-based cohort of patients with PROP1 gene defects. Eur J Endocrinol 2005; 153: 389-396
87 Tatsumi KI, Kikuchi K, Tsumura K. et al. A novel PROP1 gene mutation (157delA) in Japanese siblings with combined anterior pituitary hormone deficiency. Clin Endocrinol (Oxf) 2004; 61: 635-640
88 Reynaud R, Chadli-Chaieb M, Vallette-Kasic S. et al. A familial form of congenital hypopituitarism due to a PROP1 mutation in a large kindred: Phenotypic and in vitro functional studies. J Clin Endocrinol Metab 2004; 89: 5779-5786
89 Paracchini R, Giordano M, Corrias A. et al. Two new PROP1 gene mutations responsible for compound pituitary hormone deficiency. Clin Genet 2003; 64: 142-147
90 Wu W, Cogan JD, Pfäffle RW. et al. Mutations in PROP1 cause familial combined pituitary hormone deficiency. Nat Genet 1998; 18: 147-149
91 Arroyo A, Pernasetti F, Vasilyev VV. A unique case of combined pituitary hormone deficiency caused by a PROP1 gene mutation (R120C) associated with normal height and absent puberty. Clin Endocrinol (Oxf) 2002; 57: 283-291
92 Voutetakis A, Maniati-Christidi M, Kanaka-Gantenbein C. et al. A Prolonged jaundice and hypothyroidism as the presenting symptoms in a neonate with a novel Prop1 gene mutation (Q83X). Eur J Endocrinol 2004; 150: 257-264
93 Deladoey J, Büyükgebiz A, Kuhlmann BV. et al. “Hot spot” in the PROP1 gene responsible for combined pituitary hormone deficiency. J Clin Endocrinol Metab 1999; 84 p 1645-1650
94 Asteria C, Oliveira JH, Abucham J. et al. Central hypocortisolism as part of combined pituitary hormone deficiency due to mutations of PROP-1 gene. Eur J Endocrinol 2000; 143: 347-352
95 Pernasetti F, Toledo SP, Vasilyev VV. et al. Impaired adrenocorticotropin-adrenal axis in combined pituitary hormone deficiency caused by a two-base pair deletion (301-302delAG) in the prophet of Pit-1 gene. J Clin Endocrinol Metab 2000; 85: 390-397
96 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
97 Voutetakis A, Sertedaki A, Livadas S. et al. Pituitary size fluctuation in long-term MR studies of PROP1 deficient patients: A persistent pathophysiological mechanism?. J Endocrinol Invest 2006; 29: 462-466
98 Romero CJ, Pine-Twaddell E, Sima DI. et al. Insulin-like growth factor 1 mediates negative feedback to somatotroph GH expression via POU1F1/CREB binding protein interactions. Mol Cell Biol 2012; 32: 4258-4569
99 Szeto DP, Ryan AK, O'Connell SM. et al. P-OTX: A PIT-1-interacting homeodomain factor expressed during anterior pituitary gland development. Proc Natl Acad Sci USA 1996; 93: 7706-7710
100 Cohen LE, Wondisford FE, Salvatoni A. et al. A “hot spot” in the Pit-1 gene responsible for combined pituitary hormone deficiency: Clinical and molecular correlates. J Clin Endocrinol Metab 1995; 80: 679-684