Pituitary Transcription Factor Mutations Leading to Hypopituitarism

  • Peter GergicsEmail author
Part of the Experientia Supplementum book series (EXS, volume 111)


Congenital pituitary hormone deficiency is a disabling condition. It is part of a spectrum of disorders including craniofacial midline developmental defects ranging from holoprosencephaly through septo-optic dysplasia to combined and isolated pituitary hormone deficiency. The first genes discovered in the human disease were based on mouse models of dwarfism due to mutations in transcription factor genes. High-throughput DNA sequencing technologies enabled clinicians and researchers to find novel genetic causes of hypopituitarism for the more than three quarters of patients without a known genetic diagnosis to date. Transcription factor (TF) genes are at the forefront of the functional analysis of novel variants of unknown significance due to the relative ease in in vitro testing in a research lab. Genetic testing in hypopituitarism is of high importance to the individual and their family to predict phenotype composition, disease progression and to avoid life-threatening complications such as secondary adrenal insufficiency.

This chapter aims to highlight our current understanding about (1) the contribution of TF genes to pituitary development (2) the diversity of inheritance and phenotype features in combined and select isolated pituitary hormone deficiency and (3) provide an initial assessment on how to approach variants of unknown significance in human hypopituitarism. Our better understanding on how transcription factor gene variants lead to hypopituitarism is a meaningful step to plan advanced therapies to specific genetic changes in the future.


Pituitary hormone deficiency Transcription factor Inheritance Genetic testing Variants of unknown significance 

List of Abbreviations


Adrenocorticotropic hormone


Anterior lobe of pituitary


Bone morphogenetic protein


Choriogonadotropin alpha subunit


Central nervous system


Combined pituitary hormone deficiency


Fibroblast growth factor


Follicle-stimulating hormone


Growth hormone


Growth hormone deficiency


Glucocorticoid receptor


Hypogonadotropic hypogonadism


Isolated ACTH deficiency


Isolated growth hormone deficiency


Intermediate lobe of pituitary


Luteinizing hormone


Melanocyte-stimulating hormone, alpha


Optic nerve hypoplasia


Proprotein convertase (subtilisin/kexin)


Posterior lobe of pituitary






Retinoic acid receptor


Sonic hedgehog


Transcription factor


Thyroid hormone receptor


Thyroid-stimulating hormone


Variants of unknown significance


Whole exome sequencing


Wingless-type MMTV integration site family/beta-catenin



This work was supported by the grant entitled “Cell specific expression in the pituitary gland” awarded to Sally A Camper (PI) by the National Institutes of Health (R01 HD034283) with Peter Gergics as co-investigator on this grant. The author apologizes to other colleagues whose work was not cited due to space limitations. The author would like to thank Sally A. Camper for her careful review and feedback on the manuscript, to the members of her lab collecting information on specific genes/variants, and to his family for their continued support toward his research productivity.


  1. Abali ZY, Yesil G, Kirkgoz T et al (2019) Evaluation of growth and puberty in a child with a novel TBX19 gene mutation and review of the literature. Hormones (Athens). CrossRefGoogle Scholar
  2. Accornero S, Danesino C, Bastianello S, D’Errico I, Guala A, Chiovato L (2010) Duplication of the pituitary stalk in a patient with a heterozygous deletion of chromosome 14 harboring the thyroid transcription factor-1 gene. J Clin Endocrinol Metab 95:3595–3596. CrossRefPubMedGoogle Scholar
  3. Alatzoglou KS, Dattani MT (2010) Genetic causes and treatment of isolated growth hormone deficiency-an update. Nat Rev Endocrinol 6:562–576. CrossRefPubMedGoogle Scholar
  4. Alatzoglou KS, Dattani MT (2012) Phenotype-genotype correlations in congenital isolated growth hormone deficiency (IGHD). Indian J Pediatr 79:99–106. CrossRefPubMedGoogle Scholar
  5. Alatzoglou KS, Kelberman D, Cowell CT et al (2011) Increased transactivation associated with SOX3 polyalanine tract deletion in a patient with hypopituitarism. J Clin Endocrinol Metab 96:E685–E690. CrossRefPubMedGoogle Scholar
  6. Ando M, Goto M, Hojo M et al (2018) The proneural bHLH genes Mash1, Math3 and NeuroD are required for pituitary development. J Mol Endocrinol 61:127–138. CrossRefPubMedGoogle Scholar
  7. Andrioli M, Pecori Giraldi F, Cavagnini F (2006) Isolated corticotrophin deficiency. Pituitary 9:289–295. CrossRefPubMedGoogle Scholar
  8. Asakura Y, Abe K, Muroya K et al (2015) Combined growth hormone and thyroid-stimulating hormone deficiency in a Japanese patient with a novel frameshift mutation in IGSF1. Horm Res Paediatr 84:349–354. CrossRefPubMedGoogle Scholar
  9. Ashkenazi-Hoffnung L, Lebenthal Y, Wyatt AW (2010) A novel loss-of-function mutation in OTX2 in a patient with anophthalmia and isolated growth hormone deficiency. Hum Genet 127:721–729. CrossRefPubMedGoogle Scholar
  10. Aslan IR, Ranadive SA, Valle I, Kollipara S, Noble JA, Vaisse C (2014) The melanocortin system and insulin resistance in humans: insights from a patient with complete POMC deficiency and type 1 diabetes mellitus. Int J Obes 38:148–151. CrossRefGoogle Scholar
  11. Avbelj Stefanija M, Kotnik P, Bratanič N et al (2015) Novel mutations in HESX1 and PROP1 genes in combined pituitary hormone deficiency. Horm Res Paediatr 84:153–158. CrossRefPubMedGoogle Scholar
  12. Babu D, Fanelli A, Mellone S et al (2019) Novel GLI2 mutations identified in patients with Combined Pituitary Hormone Deficiency (CPHD): evidence for a pathogenic effect by functional characterization. Clin Endocrinol 90:449–456. CrossRefGoogle Scholar
  13. Bakrania P, Robinson DO, Bunyan DJ et al (2007) SOX2 anophthalmia syndrome: 12 new cases demonstrating broader phenotype and high frequency of large gene deletions. Br J Ophthalmol 91:1471–1476. CrossRefPubMedPubMedCentralGoogle Scholar
  14. Balicza P, Grosz Z, Molnár V et al (2018) NKX2-1 new mutation associated with myoclonus, dystonia, and pituitary involvement. Front Genet 9:335. CrossRefPubMedPubMedCentralGoogle Scholar
  15. Bartholin L, Powers SE, Melhuish TA, Lasse S, Weinstein M, Wotton D (2006) TGIF inhibits retinoid signaling. Mol Cell Biol 26:990–1001. CrossRefPubMedPubMedCentralGoogle Scholar
  16. Bauters M, Frints SG, Van Esch H et al (2014) Evidence for increased SOX3 dosage as a risk factor for X-linked hypopituitarism and neural tube defects. Am J Med Genet A 164a:1947–1952. CrossRefPubMedGoogle Scholar
  17. Bear KA, Solomon BD, Antonini S et al (2014) Pathogenic mutations in GLI2 cause a specific phenotype that is distinct from holoprosencephaly. J Med Genet 51:413–418. CrossRefPubMedPubMedCentralGoogle Scholar
  18. Bechtold-Dalla Pozza S, Hiedl S, Roeb J et al (2012) A recessive mutation resulting in a disabling amino acid substitution (T194R) in the LHX3 homeodomain causes combined pituitary hormone deficiency. Horm Res Paediatr 77:41–51. CrossRefPubMedPubMedCentralGoogle Scholar
  19. Bertolino E, Reimund B, Wildt-Perinic D, Clerc RG (1995) A novel homeobox protein which recognizes a TGT core and functionally interferes with a retinoid-responsive motif. J Biol Chem 270:31178–31188. CrossRefPubMedGoogle Scholar
  20. Bharti K, Gasper M, Bertuzzi S, Arnheiter H (2011) Lack of the ventral anterior homeodomain transcription factor VAX1 leads to induction of a second pituitary. Development 138:873–878. CrossRefPubMedPubMedCentralGoogle Scholar
  21. Blackburn PR, Chacon-Camacho OF, Ortiz-González XR et al (2018) Extension of the mutational and clinical spectrum of SOX2 related disorders: description of six new cases and a novel association with suprasellar teratoma. Am J Med Genet A 176:2710–2719. CrossRefPubMedGoogle Scholar
  22. Boda H, Miyata M, Inagaki H, Shinkai Y, Kato T, Yoshikawa T, Kurahashi H (2018) FOXA2 gene mutation in a patient with congenital complex pituitary hormone deficiency. Eur J Med Genet.
  23. Boehm U, Bouloux PM, Dattani MT et al (2015) Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment. Nat Rev Endocrinol 11:547–564. CrossRefPubMedGoogle Scholar
  24. Bogeas A, Morvan-Dubois G, El-Habr EA et al (2018) Changes in chromatin state reveal ARNT2 at a node of a tumorigenic transcription factor signature driving glioblastoma cell aggressiveness. Acta Neuropathol 135:267–283. CrossRefPubMedGoogle Scholar
  25. Bonfig W, Krude H, Schmidt H (2011) 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 170:1017–1021. CrossRefPubMedGoogle Scholar
  26. Bonomi M, Proverbio MC, Weber G, Chiumello G, Beck-Peccoz P, Persani L (2001) Hyperplastic pituitary gland, high serum glycoprotein hormone alpha-subunit, and variable circulating thyrotropin (TSH) levels as hallmark of central hypothyroidism due to mutations of the TSH beta gene. J Clin Endocrinol Metab 86:1600–1604. CrossRefPubMedGoogle Scholar
  27. Brinkmeier ML, Davis SW, Carninci P et al (2009) Discovery of transcriptional regulators and signaling pathways in the developing pituitary gland by bioinformatic and genomic approaches. Genomics 93:449–460. CrossRefPubMedPubMedCentralGoogle Scholar
  28. Brue T (2018) Lessons from screening of genetic causes of hypopituitarism in session S54—“New developments of pituitary disease”, session 54 edn. In: The Endocrine Society’s 100th Annual Meeting and Expo (ENDO 2018), Chicago, ILGoogle Scholar
  29. Brue T, Quentien MH, Khetchoumian K et al (2014) Mutations in NFKB2 and potential genetic heterogeneity in patients with DAVID syndrome, having variable endocrine and immune deficiencies. BMC Med Genet 15:139. CrossRefPubMedPubMedCentralGoogle Scholar
  30. Brue T, Saveanu A, Jullien N et al (2017) Lessons from monogenic causes of growth hormone deficiency. Ann Endocrinol (Paris) 78:77–79. CrossRefGoogle Scholar
  31. Budry L, Couture C, Balsalobre A, Drouin J (2011) The Ets factor Etv1 interacts with Tpit protein for pituitary pro-opiomelanocortin (POMC) gene transcription. J Biol Chem 286:25387–25396. CrossRefPubMedPubMedCentralGoogle Scholar
  32. Budry L, Balsalobre A, Gauthier Y et al (2012) The selector gene Pax7 dictates alternate pituitary cell fates through its pioneer action on chromatin remodeling. Genes Dev 26:2299–2310. CrossRefPubMedPubMedCentralGoogle Scholar
  33. Castinetti F, Reynaud R, Saveanu A et al (2008a) [Clinical and genetic aspects of combined pituitary hormone deficiencies]. Ann Endocrinol (Paris) 69:7–17. CrossRefGoogle Scholar
  34. Castinetti F, Saveanu A, Reynaud R et al (2008b) A novel dysfunctional LHX4 mutation with high phenotypical variability in patients with hypopituitarism. J Clin Endocrinol Metab 93:2790–2799. CrossRefPubMedGoogle Scholar
  35. Castinetti F, Reynaud R, Saveanu A, Barlier A, Brue T (2012) Genetic causes of combined pituitary hormone deficiencies in humans. Ann Endocrinol (Paris) 73:53–55. CrossRefGoogle Scholar
  36. Catania A, Legati A, Peverelli L et al (2019) Homozygous variant in OTX2 and possible genetic modifiers identified in a patient with combined pituitary hormone deficiency, ocular involvement, myopathy, ataxia, and mitochondrial impairment. Am J Med Genet A 179(5):827–831. CrossRefPubMedGoogle Scholar
  37. Chassaing N, Sorrentino S, Davis EE et al (2012) OTX2 mutations contribute to the otocephaly-dysgnathia complex. J Med Genet 49:373–379. CrossRefPubMedGoogle Scholar
  38. Chen K, Coonrod EM, Kumánovics A et al (2013) Germline mutations in NFKB2 implicate the noncanonical NF-kappaB pathway in the pathogenesis of common variable immunodeficiency. Am J Hum Genet 93:812–824. CrossRefPubMedPubMedCentralGoogle Scholar
  39. Cheung LYM, George AS, McGee SR, Daly AZ, Brinkmeier ML, Ellsworth BS, Camper SA (2018) Single-cell RNA sequencing reveals novel markers of male pituitary stem cells and hormone-producing cell types. Endocrinology 159:3910–3924. CrossRefPubMedGoogle Scholar
  40. Chinoy A, Murray PG (2016) Diagnosis of growth hormone deficiency in the paediatric and transitional age. Best Pract Res Clin Endocrinol Metab 30:737–747. CrossRefPubMedGoogle Scholar
  41. Cogan JD, Wu W, Phillips JA 3rd et al (1998) The PROP1 2-base pair deletion is a common cause of combined pituitary hormone deficiency. J Clin Endocrinol Metab 83:3346–3349. CrossRefPubMedGoogle Scholar
  42. Cohen LE, Zanger K, Brue T, Wondisford FE, Radovick S (1999) Defective retinoic acid regulation of the Pit-1 gene enhancer: a novel mechanism of combined pituitary hormone deficiency. Mol Endocrinol 13:476–484. CrossRefPubMedGoogle Scholar
  43. Cohen RN, Cohen LE, Botero D, Yu C, Sagar A, Jurkiewicz M, Radovick S (2003) Enhanced repression by HESX1 as a cause of hypopituitarism and septooptic dysplasia. J Clin Endocrinol Metab 88:4832–4839. CrossRefPubMedGoogle Scholar
  44. Cohen RN, Brue T, Naik K, Houlihan CA, Wondisford FE, Radovick S (2006) The role of CBP/p300 interactions and Pit-1 dimerization in the pathophysiological mechanism of combined pituitary hormone deficiency. J Clin Endocrinol Metab 91:239–247. CrossRefPubMedGoogle Scholar
  45. Cohen E, Maghnie M, Collot N et al (2017) Contribution of LHX4 mutations to pituitary deficits in a cohort of 417 unrelated patients. J Clin Endocrinol Metab 102:290–301. CrossRefPubMedGoogle Scholar
  46. Collu R, Tang J, Castagné J et al (1997) A novel mechanism for isolated central hypothyroidism: inactivating mutations in the thyrotropin-releasing hormone receptor gene. J Clin Endocrinol Metab 82:1561–1565. CrossRefPubMedGoogle Scholar
  47. Corneli G, Vivenza D, Prodam F et al (2008) Heterozygous mutation of HESX1 causing hypopituitarism and multiple anatomical malformations without features of septo-optic dysplasia. J Endocrinol Investig 31:689–693. CrossRefGoogle Scholar
  48. Correa FA, Jorge AA, Nakaguma M et al (2018) Pathogenic copy number variants in patients with congenital hypopituitarism associated with complex phenotypes. Clin Endocrinol 88:425–431. CrossRefGoogle Scholar
  49. Couture C, Saveanu A, Barlier A et al (2012) Phenotypic homogeneity and genotypic variability in a large series of congenital isolated ACTH-deficiency patients with TPIT gene mutations. J Clin Endocrinol Metab 97:E486–E495. CrossRefPubMedGoogle Scholar
  50. Coya R, Vela A, Perez de Nanclares G, Rica I, Castano L, Busturia MA, Martul P (2007) Panhypopituitarism: genetic versus acquired etiological factors. J Pediatr Endocrinol Metab 20:27–36. CrossRefPubMedGoogle Scholar
  51. Dasen JS, O’Connell SM, Flynn SE et al (1999) Reciprocal interactions of Pit1 and GATA2 mediate signaling gradient-induced determination of pituitary cell types. Cell 97:587–598. CrossRefPubMedGoogle Scholar
  52. Dateki S, Fukami M, Sato N, Muroya K, Adachi M, Ogata T (2008) 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 93:3697–3702. CrossRefPubMedGoogle Scholar
  53. Dateki S, Fukami M, Uematsu A et al (2010a) 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 95:4043–4047. CrossRefPubMedGoogle Scholar
  54. Dateki S, Kosaka K, Hasegawa K et al (2010b) Heterozygous orthodenticle homeobox 2 mutations are associated with variable pituitary phenotype. J Clin Endocrinol Metab 95:756–764. CrossRefPubMedGoogle Scholar
  55. Dattani MT (2005) Growth hormone deficiency and combined pituitary hormone deficiency: does the genotype matter? Clin Endocrinol 63:121–130. CrossRefGoogle Scholar
  56. Dattani MT, Martinez-Barbera JP, Thomas PQ et al (1998) Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nat Genet 19:125–133. CrossRefPubMedGoogle Scholar
  57. Davis SW, Camper SA (2007) Noggin regulates Bmp4 activity during pituitary induction. Dev Biol 305:145–160. CrossRefPubMedPubMedCentralGoogle Scholar
  58. Davis EE, Frangakis S, Katsanis N (2014) Interpreting human genetic variation with in vivo zebrafish assays. Biochim Biophys Acta 1842:1960–1970. CrossRefPubMedPubMedCentralGoogle Scholar
  59. Davis SW, Keisler JL, Perez-Millan MI, Schade V, Camper SA (2016) All hormone-producing cell types of the pituitary intermediate and anterior lobes derive from Prop1-expressing progenitors. Endocrinology 157:1385–1396. CrossRefPubMedPubMedCentralGoogle Scholar
  60. Day RN, Koike S, Sakai M, Muramatsu M, Maurer RA (1990) Both Pit-1 and the estrogen receptor are required for estrogen responsiveness of the rat prolactin gene. Mol Endocrinol 4:1964–1971. CrossRefPubMedGoogle Scholar
  61. De Rienzo F, Mellone S, Bellone S et al (2015) Frequency of genetic defects in combined pituitary hormone deficiency: a systematic review and analysis of a multicentre Italian cohort. Clin Endocrinol 83:849–860. CrossRefGoogle Scholar
  62. Delahaye A, Bitoun P, Drunat S et al (2012) Genomic imbalances detected by array-CGH in patients with syndromal ocular developmental anomalies. Eur J Hum Genet 20:527–533. CrossRefPubMedPubMedCentralGoogle Scholar
  63. Demurger F, Ichkou A, Mougou-Zerelli S et al (2015) New insights into genotype-phenotype correlation for GLI3 mutations. Eur J Hum Genet 23:92–102. CrossRefPubMedGoogle Scholar
  64. Di Iorgi N, Morana G, Allegri AE et al (2016) Classical and non-classical causes of GH deficiency in the paediatric age. Best Pract Res Clin Endocrinol Metab 30:705–736. CrossRefPubMedGoogle Scholar
  65. Diaczok D, Romero C, Zunich J, Marshall I, Radovick S (2008) A novel dominant negative mutation of OTX2 associated with combined pituitary hormone deficiency. J Clin Endocrinol Metab 93:4351–4359. CrossRefPubMedPubMedCentralGoogle Scholar
  66. Drolet DW, Scully KM, Simmons DM, Wegner M, Chu KT, Swanson LW, Rosenfeld MG (1991) TEF, a transcription factor expressed specifically in the anterior pituitary during embryogenesis, defines a new class of leucine zipper proteins. Genes Dev 5:1739–1753. CrossRefPubMedGoogle Scholar
  67. Dubourg C, Lazaro L, Pasquier L et al (2004) Molecular screening of SHH, ZIC2, SIX3, and TGIF genes in patients with features of holoprosencephaly spectrum: mutation review and genotype-phenotype correlations. Hum Mutat 24:43–51. CrossRefPubMedGoogle Scholar
  68. Dusatkova P, Pfäffle R, Brown MR et al (2016) Genesis of two most prevalent PROP1 gene variants causing combined pituitary hormone deficiency in 21 populations. Eur J Hum Genet 24:415–420. CrossRefPubMedGoogle Scholar
  69. El-Jaick KB, Powers SE, Bartholin L et al (2007) Functional analysis of mutations in TGIF associated with holoprosencephaly. Mol Genet Metab 90:97–111. CrossRefPubMedGoogle Scholar
  70. Ergin AB, Kennedy AL, Gupta MK, Hamrahian AH (2015) The Cleveland Clinic manual of dynamic endocrine testing. Springer International, Cham. CrossRefGoogle Scholar
  71. Errichiello E, Gorgone C, Giuliano L et al (2018) 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 61:335–340. CrossRefPubMedGoogle Scholar
  72. Fang Q, Benedetti AF, Ma Q et al (2016a) HESX1 mutations in patients with congenital hypopituitarism: variable phenotypes with the same genotype. Clin Endocrinol 85:408–414. CrossRefGoogle Scholar
  73. Fang Q, George AS, Brinkmeier ML et al (2016b) Genetics of combined pituitary hormone deficiency: roadmap into the genome era. Endocr Rev 37:636–675. CrossRefPubMedPubMedCentralGoogle Scholar
  74. Fauquier T, Rizzoti K, Dattani M, Lovell-Badge R, Robinson IC (2008) SOX2-expressing progenitor cells generate all of the major cell types in the adult mouse pituitary gland. Proc Natl Acad Sci USA 105:2907–2912. CrossRefPubMedGoogle Scholar
  75. Flemming GM, Klammt J, Ambler G et al (2013) Functional characterization of a heterozygous GLI2 missense mutation in patients with multiple pituitary hormone deficiency. J Clin Endocrinol Metab 98:E567–E575. CrossRefPubMedPubMedCentralGoogle Scholar
  76. Franca MM, Jorge AA, Carvalho LR et al (2013) Relatively high frequency of non-synonymous GLI2 variants in patients with congenital hypopituitarism without holoprosencephaly. Clin Endocrinol 78:551–557. CrossRefGoogle Scholar
  77. Franco D, Sedmera D, Lozano-Velasco E (2017) Multiple roles of Pitx2 in cardiac development and disease. J Cardiovasc Dev Dis 4. CrossRefGoogle Scholar
  78. Fuxman Bass JI, Sahni N, Shrestha S et al (2015) Human gene-centered transcription factor networks for enhancers and disease variants. Cell 161:661–673. CrossRefPubMedGoogle Scholar
  79. Gallardo ME, Lopez-Rios J, Fernaud-Espinosa I et al (1999) Genomic cloning and characterization of the human homeobox gene SIX6 reveals a cluster of SIX genes in chromosome 14 and associates SIX6 hemizygosity with bilateral anophthalmia and pituitary anomalies. Genomics 61:82–91. CrossRefPubMedGoogle Scholar
  80. Gangat M, Radovick S (2017) Pituitary hypoplasia. Endocrinol Metab Clin N Am 46:247–257. CrossRefGoogle Scholar
  81. Gaston-Massuet C, Andoniadou CL, Signore M, Sajedi E, Bird S, Turner JM, Martinez-Barbera JP (2008) Genetic interaction between the homeobox transcription factors HESX1 and SIX3 is required for normal pituitary development. Dev Biol 324:322–333. CrossRefPubMedPubMedCentralGoogle Scholar
  82. Gaston-Massuet C, McCabe MJ, Scagliotti V et al (2016) Transcription factor 7-like 1 is involved in hypothalamo-pituitary axis development in mice and humans. Proc Natl Acad Sci USA 113:E548–E557. CrossRefPubMedGoogle Scholar
  83. Gat-Yablonski G, Lazar L, Pertzelan A, Phillip M (2002) A novel mutation in PIT-1: phenotypic variability in familial combined pituitary hormone deficiencies. J Pediatr Endocrinol Metab 15:325–330. CrossRefPubMedGoogle Scholar
  84. Gergics P, Brinkmeier ML, Camper SA (2015) Lhx4 deficiency: increased cyclin-dependent kinase inhibitor expression and pituitary hypoplasia. Mol Endocrinol 29:597–612. CrossRefPubMedPubMedCentralGoogle Scholar
  85. Gerth-Kahlert C, Williamson K, Ansari M et al (2013) Clinical and mutation analysis of 51 probands with anophthalmia and/or severe microphthalmia from a single center. Mol Genet Genomic Med 1:15–31. CrossRefPubMedPubMedCentralGoogle Scholar
  86. Giri D, Vignola ML, Gualtieri A et al (2017) Novel FOXA2 mutation causes hyperinsulinism, hypopituitarism with craniofacial and endoderm-derived organ abnormalities. Hum Mol Genet 26:4315–4326. CrossRefPubMedGoogle Scholar
  87. Gorbenko Del Blanco D, Romero CJ, Diaczok D, de Graaff LC, Radovick S, Hokken-Koelega AC (2012) A novel OTX2 mutation in a patient with combined pituitary hormone deficiency, pituitary malformation, and an underdeveloped left optic nerve. Eur J Endocrinol 167:441–452. CrossRefPubMedGoogle Scholar
  88. Gordon DF, Haugen BR, Sarapura VD, Nelson AR, Wood WM, Ridgway EC (1993) Analysis of Pit-1 in regulating mouse TSH beta promoter activity in thyrotropes. Mol Cell Endocrinol 96:75–84. CrossRefPubMedGoogle Scholar
  89. Goto M, Hojo M, Ando M et al (2015) Hes1 and Hes5 are required for differentiation of pituicytes and formation of the neurohypophysis in pituitary development. Brain Res 1625:206–217. CrossRefPubMedGoogle Scholar
  90. Gregory LC, Gaston-Massuet C, Andoniadou CL et al (2015a) The role of the sonic hedgehog signalling pathway in patients with midline defects and congenital hypopituitarism. Clin Endocrinol 82:728–738. CrossRefGoogle Scholar
  91. Gregory LC, Humayun KN, Turton JP, McCabe MJ, Rhodes SJ, Dattani MT (2015b) Novel lethal form of congenital hypopituitarism associated with the first recessive LHX4 mutation. J Clin Endocrinol Metab 100:2158–2164. CrossRefPubMedPubMedCentralGoogle Scholar
  92. Grosse SD, Van Vliet G (2011) Prevention of intellectual disability through screening for congenital hypothyroidism: how much and at what level? Arch Dis Child 96:374–379. CrossRefPubMedGoogle Scholar
  93. Gucev Z, Tasic V, Plaseska-Karanfilska D et al (2016) LHX4 gene alterations: patient report and review of the literature. Pediatr Endocrinol Rev 13:749–755PubMedGoogle Scholar
  94. Haddad-Tovolli R, Paul FA, Zhang Y et al (2015) Differential requirements for Gli2 and Gli3 in the regional specification of the mouse hypothalamus. Front Neuroanat 9:34. CrossRefPubMedPubMedCentralGoogle Scholar
  95. Halasz Z, Toke J, Patócs A et al (2006) High prevalence of PROP1 gene mutations in Hungarian patients with childhood-onset combined anterior pituitary hormone deficiency. Endocrine 30:255–260. CrossRefPubMedGoogle Scholar
  96. Hayashizaki Y, Hiraoka Y, Endo Y, Miyai K, Matsubara K (1989) Thyroid-stimulating hormone (TSH) deficiency caused by a single base substitution in the CAGYC region of the beta-subunit. EMBO J 8:2291–2296. CrossRefPubMedPubMedCentralGoogle Scholar
  97. Hayes FJ, Seminara SB, Crowley WF Jr (1998) Hypogonadotropic hypogonadism. Endocrinol Metab Clin North Am 27:739–763, vii. CrossRefGoogle Scholar
  98. Heinen CA, Losekoot M, Sun Y et al (2016) Mutations in TBL1X are associated with central hypothyroidism. J Clin Endocrinol Metab 101:4564–4573. CrossRefPubMedPubMedCentralGoogle Scholar
  99. Henderson RH, Williamson KA, Kennedy JS et al (2009) A rare de novo nonsense mutation in OTX2 causes early onset retinal dystrophy and pituitary dysfunction. Mol Vis 15:2442–2447PubMedPubMedCentralGoogle Scholar
  100. Hendriks-Stegeman BI, Augustijn KD, Bakker B, Holthuizen P, van der Vliet PC, Jansen M (2001) Combined pituitary hormone deficiency caused by compound heterozygosity for two novel mutations in the POU domain of the Pit1/POU1F1 gene. J Clin Endocrinol Metab 86:1545–1550. CrossRefPubMedGoogle Scholar
  101. Hergott-Faure L, Borot S, Kleinclauss C, Abitbol M, Penfornis A (2012) Pituitary function and glucose tolerance in a family with a PAX6 mutation. Ann Endocrinol (Paris) 73:510–514. CrossRefGoogle Scholar
  102. Hide T, Hatakeyama J, Kimura-Yoshida C et al (2002) Genetic modifiers of otocephalic phenotypes in Otx2 heterozygous mutant mice. Development 129:4347–4357PubMedGoogle Scholar
  103. Hu Y, Yu H, Shaw G, Renfree MB, Pask AJ (2011) Differential roles of TGIF family genes in mammalian reproduction. BMC Dev Biol 11:58. CrossRefPubMedPubMedCentralGoogle Scholar
  104. Hughes JN, Aubert M, Heatlie J et al (2016) Identification of an IGSF1-specific deletion in a five-generation pedigree with X-linked central hypothyroidism without macroorchidism. Clin Endocrinol 85:609–615. CrossRefGoogle Scholar
  105. Idrees F, Bloch-Zupan A, Free SL et al (2006) A novel homeobox mutation in the PITX2 gene in a family with Axenfeld-Rieger syndrome associated with brain, ocular, and dental phenotypes. Am J Med Genet B Neuropsychiatr Genet 141B:184–191. CrossRefPubMedGoogle Scholar
  106. Inoue H, Mukai T, Sakamoto Y et al (2012) 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. Clin Endocrinol 76:78–87. CrossRefGoogle Scholar
  107. Izumi Y, Suzuki E, Kanzaki S et al (2014) Genome-wide copy number analysis and systematic mutation screening in 58 patients with hypogonadotropic hypogonadism. Fertil Steril 102:1130–1136.e1133. CrossRefPubMedGoogle Scholar
  108. Johnston JJ, Olivos-Glander I, Killoran C et al (2005) Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations. Am J Hum Genet 76:609–622. CrossRefPubMedPubMedCentralGoogle Scholar
  109. Joustra SD, Roelfsema F, Endert E et al (2016) Pituitary hormone secretion profiles in IGSF1 deficiency syndrome. Neuroendocrinology 103:408–416. CrossRefPubMedGoogle Scholar
  110. Juanes M, Di Palma I, Ciaccio M et al (2016) Two novel heterozygous missense variations within the GLI2 gene in two unrelated Argentine patients. Medicina (B Aires) 76:213–218Google Scholar
  111. Jullien N, Romanet P, Philippon M et al (2018) Heterozygous LHX3 mutations may lead to a mild phenotype of combined pituitary hormone deficiency. Eur J Hum Genet. CrossRefGoogle Scholar
  112. Kang S, Graham JM Jr, Olney AH, Biesecker LG (1997) GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome. Nat Genet 15:266–268. CrossRefPubMedGoogle Scholar
  113. Kantaputra PN, Limwongse C, Tochareontanaphol C, Mutirangura A, Mevatee U, Praphanphoj V (2006) Contiguous gene syndrome of holoprosencephaly and hypotrichosis simplex: association with an 18p11.3 deletion. American J Med Genet A 140:2598–2602. CrossRefGoogle Scholar
  114. Kapali J, Kabat BE, Schmidt KL et al (2016) Foxo1 is required for normal somatotrope differentiation. Endocrinology 157:4351–4363. CrossRefPubMedPubMedCentralGoogle Scholar
  115. Kelberman D, Rizzoti K, Avilion A et al (2006) Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans. J Clin Invest 116:2442–2455. CrossRefPubMedPubMedCentralGoogle Scholar
  116. Kelberman D, Turton JP, Woods KS et al (2009) Molecular analysis of novel PROP1 mutations associated with combined pituitary hormone deficiency (CPHD). Clin Endocrinol 70:96–103. CrossRefGoogle Scholar
  117. Klee EW, Hoppman-Chaney NL, Ferber MJ (2011) Expanding DNA diagnostic panel testing: is more better? Expert Rev Mol Diagn 11:703–709. CrossRefPubMedGoogle Scholar
  118. Kristrom B, Zdunek AM, Rydh A, Jonsson H, Sehlin P, Escher SA (2009) 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 94:1154–1161. CrossRefPubMedGoogle Scholar
  119. Krude H, Biebermann H, Luck W, Horn R, Brabant G, Gruters A (1998) Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 19:155–157. CrossRefPubMedGoogle Scholar
  120. Kulig E, Camper SA, Kuecker S, Jin L, Lloyd RV (1998) Remodeling of hyperplastic pituitaries in hypothyroid alpha-subunit knockout mice after thyroxine and 17beta-estradiol treatment: role of apoptosis. Endocr Pathol 9:261–274. CrossRefPubMedGoogle Scholar
  121. Laumonnier F, Ronce N, Hamel BC et al (2002) Transcription factor SOX3 is involved in X-linked mental retardation with growth hormone deficiency. Am J Hum Genet 71:1450–1455. CrossRefPubMedPubMedCentralGoogle Scholar
  122. Leger J, Olivieri A, Donaldson M et al (2014) European Society for Paediatric Endocrinology consensus guidelines on screening, diagnosis, and management of congenital hypothyroidism. J Clin Endocrinol Metab 99:363–384. CrossRefPubMedPubMedCentralGoogle Scholar
  123. Lek M, Karczewski KJ, Minikel EV et al (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536:285. CrossRefPubMedPubMedCentralGoogle Scholar
  124. Li S, Crenshaw EB 3rd, Rawson EJ, Simmons DM, Swanson LW, Rosenfeld MG (1990) Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene pit-1. Nature 347:528–533. CrossRefPubMedGoogle Scholar
  125. Li MH, Eberhard M, Mudd P et al (2015) Total colonic aganglionosis and imperforate anus in a severely affected infant with Pallister-Hall syndrome. Am J Med Genet A 167A:617–620. CrossRefPubMedGoogle Scholar
  126. Lim HT, Kim DH, Kim H (2017) PAX6 aniridia syndrome: clinics, genetics, and therapeutics. Curr Opin Ophthalmol 28:436–447. CrossRefPubMedGoogle Scholar
  127. Lin SC, Li S, Drolet DW, Rosenfeld MG (1994) Pituitary ontogeny of the Snell dwarf mouse reveals Pit-1-independent and Pit-1-dependent origins of the thyrotrope. Development 120:515–522PubMedGoogle Scholar
  128. Lonero A, Delvecchio M, Primignani P et al (2016) A novel OTX2 gene frameshift mutation in a child with microphthalmia, ectopic pituitary and growth hormone deficiency. J Pediatr Endocrinol Metab 29:603–605. CrossRefPubMedGoogle Scholar
  129. Lougaris V, Tabellini G, Vitali M et al (2015) Defective natural killer-cell cytotoxic activity in NFKB2-mutated CVID-like disease. J Allergy Clin Immunol 135:1641–1643. CrossRefPubMedGoogle Scholar
  130. Lowry RB, Gould DB, Walter MA, Savage PR (2007) Absence of PITX2, BARX1, and FOXC1 mutations in De Hauwere syndrome (Axenfeld-Rieger anomaly, hydrocephaly, hearing loss): a 25-year follow up. Am J Med Genet A 143A:1227–1230. CrossRefPubMedGoogle Scholar
  131. Ma Y, Qi X, Du J et al (2009) Identification of candidate genes for human pituitary development by EST analysis. BMC Genomics 10:109. CrossRefPubMedPubMedCentralGoogle Scholar
  132. Macchiaroli A, Kelberman D, Auriemma RS et al (2014) A novel heterozygous SOX2 mutation causing congenital bilateral anophthalmia, hypogonadotropic hypogonadism and growth hormone deficiency. Gene 534:282–285. CrossRefPubMedGoogle Scholar
  133. Machinis K, Pantel J, Netchine I et al (2001) Syndromic short stature in patients with a germline mutation in the LIM homeobox LHX4. Am J Hum Genet 69:961–968. CrossRefPubMedPubMedCentralGoogle Scholar
  134. Madeira JL, Nishi MY, Nakaguma M et al (2017) Molecular analysis of brazilian patients with combined pituitary hormone deficiency and orthotopic posterior pituitary lobe reveals eight different PROP1 alterations with three novel mutations. Clin Endocrinol 87:725–732. CrossRefGoogle Scholar
  135. Maione L, Dwyer AA, Francou B, Guiochon-Mantel A, Binart N, Bouligand J, Young J (2018) GENETICS IN ENDOCRINOLOGY: genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing. Eur J Endocrinol 178:R55–R80. CrossRefPubMedGoogle Scholar
  136. Man PS, Wells T, Carter DA (2014) Cellular distribution of Egr1 transcription in the male rat pituitary gland. J Mol Endocrinol 53:271–280. CrossRefPubMedGoogle Scholar
  137. Marcinkiewicz M, Day R, Seidah NG, Chretien M (1993) Ontogeny of the prohormone convertases PC1 and PC2 in the mouse hypophysis and their colocalization with corticotropin and alpha-melanotropin. Proc Natl Acad Sci USA 90:4922–4926. CrossRefPubMedGoogle Scholar
  138. Martinez-Frias ML, Ocejo-Vinyals JG, Arteaga R et al (2014) Interstitial deletion 14q22.3-q23.2: genotype-phenotype correlation. Am J Med Genet A 164A:639–647. CrossRefPubMedGoogle Scholar
  139. Matzuk MM, Kornmeier CM, Whitfield GK, Kourides IA, Boime I (1988) The glycoprotein alpha-subunit is critical for secretion and stability of the human thyrotropin beta-subunit. Mol Endocrinol 2:95–100. CrossRefPubMedGoogle Scholar
  140. McCabe MJ, Dattani MT (2014) Genetic aspects of hypothalamic and pituitary gland development. Handb Clin Neurol 124:3–15. CrossRefPubMedGoogle Scholar
  141. McNay DE, Turton JP, Kelberman D et al (2007) HESX1 mutations are an uncommon cause of septooptic dysplasia and hypopituitarism. J Clin Endocrinol Metab 92:691–697. CrossRefPubMedGoogle Scholar
  142. Metherell LA, Savage MO, Dattani M, Walker J, Clayton PE, Farooqi IS, Clark AJ (2004) TPIT mutations are associated with early-onset, but not late-onset isolated ACTH deficiency. Eur J Endocrinol 151:463–465CrossRefGoogle Scholar
  143. Mishra R, Gorlov IP, Chao LY, Singh S, Saunders GF (2002) PAX6, paired domain influences sequence recognition by the homeodomain. J Biol Chem 277:49488–49494. CrossRefPubMedGoogle Scholar
  144. Molitch ME, Clemmons DR, Malozowski S, Merriam GR, Vance ML, Endocrine Society (2011) Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 96:1587–1609. CrossRefPubMedGoogle Scholar
  145. Mukhopadhyay S, Dermawan JK, Lanigan CP, Farver CF (2019) Insulinoma-associated protein 1 (INSM1) is a sensitive and highly specific marker of neuroendocrine differentiation in primary lung neoplasms: an immunohistochemical study of 345 cases, including 292 whole-tissue sections. Mod Pathol 32:100–109. CrossRefPubMedGoogle Scholar
  146. Nakamura A, Bak B, Silander TL et al (2013) Three novel IGSF1 mutations in four Japanese patients with X-linked congenital central hypothyroidism. J Clin Endocrinol Metab 98:E1682–E1691. CrossRefPubMedGoogle Scholar
  147. Narumi Y, Kosho T, Tsuruta G et al (2010) Genital abnormalities in Pallister-Hall syndrome: report of two patients and review of the literature. Am J Med Genet A 152A:3143–3147. CrossRefPubMedGoogle Scholar
  148. Navardauskaite R, Dusatkova P, Obermannova B et al (2014) High prevalence of PROP1 defects in Lithuania: phenotypic findings in an ethnically homogenous cohort of patients with multiple pituitary hormone deficiency. J Clin Endocrinol Metab 99:299–306. CrossRefPubMedGoogle Scholar
  149. Nicholas AK, Jaleel S, Lyons G et al (2017) Molecular spectrum of TSHbeta subunit gene defects in central hypothyroidism in the UK and Ireland. Clin Endocrinol 86:410–418. CrossRefGoogle Scholar
  150. Norppa AJ, Kauppala TM, Heikkinen HA, Verma B, Iwai H, Frilander MJ (2018) Mutations in the U11/U12-65K protein associated with isolated growth hormone deficiency lead to structural destabilization and impaired binding of U12 snRNA. RNA 24:396–409. CrossRefPubMedPubMedCentralGoogle Scholar
  151. Obermannova B, Pfaeffle R, Zygmunt-Gorska A et al (2011) Mutations and pituitary morphology in a series of 82 patients with PROP1 gene defects. Horm Res Paediatr 76:348–354. CrossRefPubMedGoogle Scholar
  152. Osmundsen AM, Keisler JL, Taketo MM, Davis SW (2017) Canonical WNT signaling regulates the pituitary organizer and pituitary gland formation. Endocrinology 158:3339–3353. CrossRefPubMedGoogle Scholar
  153. Patti G, Guzzeti C, Di Iorgi N, Maria Allegri AE, Napoli F, Loche S, Maghnie M (2018) Central adrenal insufficiency in children and adolescents. Best Pract Res Clin Endocrinol Metab 32:425–444. CrossRefPubMedGoogle Scholar
  154. Pekic S, Doknic M, Miljic D et al (2011) Case seminar: a young female with acute hyponatremia and a sellar mass. Endocrine 40:325–331. CrossRefPubMedGoogle Scholar
  155. Pellegrini I, Roche C, Quentien MH et al (2006) Involvement of the pituitary-specific transcription factor pit-1 in somatolactotrope cell growth and death: an approach using dominant-negative pit-1 mutants. Mol Endocrinol 20:3212–3227. CrossRefPubMedGoogle Scholar
  156. Perez Millan MI, Vishnopolska SA, Daly AZ et al (2018) Next generation sequencing panel based on single molecule molecular inversion probes for detecting genetic variants in children with hypopituitarism. Mol Genet Genomic Med. CrossRefGoogle Scholar
  157. Pfaeffle RW, Hunter CS, Savage JJ et al (2008) Three novel missense mutations within the LHX4 gene are associated with variable pituitary hormone deficiencies. J Clin Endocrinol Metab 93:1062–1071. CrossRefPubMedGoogle Scholar
  158. Pfäffle R (2006) Genetics of growth in the normal child. Eur J Endocrinol 155:S27–S33. CrossRefGoogle Scholar
  159. Prasov L, Masud T, Khaliq S et al (2012) ATOH7 mutations cause autosomal recessive persistent hyperplasia of the primary vitreous. Hum Mol Genet 21:3681–3694. CrossRefPubMedPubMedCentralGoogle Scholar
  160. Pulichino AM, Vallette-Kasic S, Couture C et al (2003) Human and mouse TPIT gene mutations cause early onset pituitary ACTH deficiency. Genes Dev 17:711–716. CrossRefPubMedPubMedCentralGoogle Scholar
  161. Quentien MH, Vieira V, Menasche M et al (2011) Truncation of PITX2 differentially affects its activity on physiological targets. J Mol Endocrinol 46:9–19. CrossRefPubMedGoogle Scholar
  162. Raitila A, Lehtonen HJ, Arola J et al (2010) Mice with inactivation of aryl hydrocarbon receptor-interacting protein (Aip) display complete penetrance of pituitary adenomas with aberrant ARNT expression. Am J Pathol 177:1969–1976. CrossRefPubMedPubMedCentralGoogle Scholar
  163. Rajab A, Kelberman D, de Castro SC et al (2008) Novel mutations in LHX3 are associated with hypopituitarism and sensorineural hearing loss. Hum Mol Genet 17:2150–2159. CrossRefPubMedGoogle Scholar
  164. Ramzan K, Bin-Abbas B, Al-Jomaa L, Allam R, Al-Owain M, Imtiaz F (2017) Two novel LHX3 mutations in patients with combined pituitary hormone deficiency including cervical rigidity and sensorineural hearing loss. BMC Endocr Disord 17:17. CrossRefPubMedPubMedCentralGoogle Scholar
  165. Rauchman M, Hoffman WH, Hanna JD, Kulharya AS, Figueroa RE, Yang J, Tuck-Miller CM (2001) Exclusion of SIX6 hemizygosity in a child with anophthalmia, panhypopituitarism and renal failure. Am J Med Genet 104:31–36. CrossRefPubMedGoogle Scholar
  166. Regal M, Paramo C, Sierra SM, Garcia-Mayor RV (2001) Prevalence and incidence of hypopituitarism in an adult Caucasian population in northwestern Spain. Clin Endocrinol 55:735–740. CrossRefGoogle Scholar
  167. Rentzsch P, Witten D, Cooper GM, Shendure J, Kircher M (2019) CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res 47:D886–D894. CrossRefPubMedGoogle Scholar
  168. Reynaud R, Albarel F, Saveanu A et al (2011) Pituitary stalk interruption syndrome in 83 patients: novel HESX1 mutation and severe hormonal prognosis in malformative forms. Eur J Endocrinol 164:457–465. CrossRefPubMedGoogle Scholar
  169. Reynaud R, Jayakody SA, Monnier C et al (2012) PROKR2 variants in multiple hypopituitarism with pituitary stalk interruption. J Clin Endocrinol Metab 97:E1068–E1073. CrossRefPubMedGoogle Scholar
  170. Richards S, Aziz N, Bale S et al (2015) 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. Genet Med 17:405–424. CrossRefPubMedPubMedCentralGoogle Scholar
  171. Richter T, Nestler-Parr S, Babela R et al (2015) Rare disease terminology and definitions-a systematic global review: report of the ISPOR rare disease special interest group. Value Health 18:906–914. CrossRefPubMedGoogle Scholar
  172. Rizzoti K, Brunelli S, Carmignac D, Thomas PQ, Robinson IC, Lovell-Badge R (2004) SOX3 is required during the formation of the hypothalamo-pituitary axis. Nat Genet 36:247–255. CrossRefPubMedGoogle Scholar
  173. Rizzoti K, Akiyama H, Lovell-Badge R (2013) Mobilized adult pituitary stem cells contribute to endocrine regeneration in response to physiological demand. Cell Stem Cell 13:419–432. CrossRefPubMedPubMedCentralGoogle Scholar
  174. Rochette C, Jullien N, Saveanu A et al (2015) Identifying the deleterious effect of rare LHX4 allelic variants, a challenging issue. PLoS One 10:e0126648. CrossRefPubMedPubMedCentralGoogle Scholar
  175. Roessler E, Ermilov AN, Grange DK, Wang A, Grachtchouk M, Dlugosz AA, Muenke M (2005) A previously unidentified amino-terminal domain regulates transcriptional activity of wild-type and disease-associated human GLI2. Hum Mol Genet 14:2181–2188. CrossRefPubMedGoogle Scholar
  176. Rostomyan L, Potorac I, Beckers P, Daly AF, Beckers A (2017) AIP mutations and gigantism. Ann Endocrinol (Paris) 78:123–130. CrossRefGoogle Scholar
  177. Sato N, Kamachi Y, Kondoh H, Shima Y, Morohashi K, Horikawa R, Ogata T (2007) Hypogonadotropic hypogonadism in an adult female with a heterozygous hypomorphic mutation of SOX2. Eur J Endocrinol 156:167–171. CrossRefPubMedGoogle Scholar
  178. Schaum N, Karkanias J, Neff NF et al (2018) Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris. Nature 562:367–372. CrossRefPubMedCentralGoogle Scholar
  179. Schilter KF, Schneider A, Bardakjian T, Soucy JF, Tyler RC, Reis LM, Semina EV (2011) OTX2 microphthalmia syndrome: four novel mutations and delineation of a phenotype. Clin Genet 79:158–168. CrossRefPubMedPubMedCentralGoogle Scholar
  180. Schilter KF, Reis LM, Schneider A et al (2013) Whole-genome copy number variation analysis in anophthalmia and microphthalmia. Clin Genet 84:473–481. CrossRefPubMedPubMedCentralGoogle Scholar
  181. Schneider A, Bardakjian T, Reis LM, Tyler RC, Semina EV (2009) Novel SOX2 mutations and genotype-phenotype correlation in anophthalmia and microphthalmia. Am J Med Genet A 149A:2706–2715. CrossRefPubMedPubMedCentralGoogle Scholar
  182. Seifi M, Walter MA (2018) Axenfeld-Rieger syndrome. Clin Genet 93:1123–1130. CrossRefPubMedGoogle Scholar
  183. Semina EV, Reiter R, Leysens NJ et al (1996) Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Nat Genet 14:392–399. CrossRefPubMedGoogle Scholar
  184. Seminara SB, Oliveira LM, Beranova M, Hayes FJ, Crowley WF Jr (2000) Genetics of hypogonadotropic hypogonadism. J Endocrinol Investig 23:560–565. CrossRefGoogle Scholar
  185. Shimada A, Takagi M, Nagashima Y, Miyai K, Hasegawa Y (2016) A novel mutation in OTX2 causes combined pituitary hormone deficiency, bilateral microphthalmia, and agenesis of the left internal carotid artery. Horm Res Paediatr 86:62–69. CrossRefPubMedGoogle Scholar
  186. Shimo N, Yasuda T, Kitamura T et al (2014) Aniridia with a heterozygous PAX6 mutation in which the pituitary function was partially impaired. Intern Med 53:39–42. CrossRefPubMedGoogle Scholar
  187. Shirakawa T, Nakashima Y, Watanabe S et al (2018) A novel heterozygous GLI2 mutation in a patient with congenital urethral stricture and renal hypoplasia/dysplasia leading to end-stage renal failure. CEN Case Rep 7:94–97. CrossRefPubMedPubMedCentralGoogle Scholar
  188. Simm F, Griesbeck A, Choukair D et al (2018) Identification of SLC20A1 and SLC15A4 among other genes as potential risk factors for combined pituitary hormone deficiency. Genet Med 20:728–736. CrossRefPubMedGoogle Scholar
  189. Skowronska-Krawczyk D, Ma Q, Schwartz M et al (2014) Required enhancer-matrin-3 network interactions for a homeodomain transcription program. Nature 514:257–261. CrossRefPubMedPubMedCentralGoogle Scholar
  190. Sobrier ML, Maghnie M, Vie-Luton MP, Secco A, di Iorgi N, Lorini R, Amselem S (2006) Novel HESX1 mutations associated with a life-threatening neonatal phenotype, pituitary aplasia, but normally located posterior pituitary and no optic nerve abnormalities. J Clin Endocrinol Metab 91:4528–4536. CrossRefPubMedGoogle Scholar
  191. Sobrier ML, Brachet C, Vié-Luton MP et al (2012) 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 97:E503–E509. CrossRefPubMedGoogle Scholar
  192. Sobrier ML, Tsai YC, Pérez C et al (2015) Functional characterization of a human POU1F1 mutation associated with isolated growth hormone deficiency (IGHD): a novel etiology for IGHD. Hum Mol Genet. CrossRefGoogle Scholar
  193. Sobrier ML, Tsai YC, Pérez C et al (2016) Functional characterization of a human POU1F1 mutation associated with isolated growth hormone deficiency: a novel etiology for IGHD. Hum Mol Genet 25:472–483. CrossRefPubMedGoogle Scholar
  194. Solomon BD et al (2009) Compound heterozygosity for mutations in PAX6 in a patient with complex brain anomaly, neonatal diabetes mellitus, and microophthalmia. Am J Med Genet A 149A:2543–2546. CrossRefPubMedPubMedCentralGoogle Scholar
  195. Sornson MW, Pineda-Alvarez DE, Balog JZ et al (1996) Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism. Nature 384:327–333. CrossRefPubMedGoogle Scholar
  196. Strande NT, Riggs ER, Buchanan AH et al (2017) Evaluating the clinical validity of gene-disease associations: an evidence-based framework developed by the clinical genome resource. Am J Hum Genet 100:895–906. CrossRefPubMedPubMedCentralGoogle Scholar
  197. Sun Y, Bak B, Schoenmakers N et al (2012) Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement. Nat Genet 44:1375–1381. CrossRefPubMedPubMedCentralGoogle Scholar
  198. Sutton E, Hughes J, White S et al (2011) Identification of SOX3 as an XX male sex reversal gene in mice and humans. J Clin Invest 121:328–341. CrossRefPubMedGoogle Scholar
  199. Tajima T, Hattorri T, Nakajima T et al (2003) Sporadic heterozygous frameshift mutation of HESX1 causing pituitary and optic nerve hypoplasia and combined pituitary hormone deficiency in a Japanese patient. J Clin Endocrinol Metab 88:45–50. CrossRefPubMedGoogle Scholar
  200. Tajima T, Ohtake A, Hoshino M, Amemiya S, Sasaki N, Ishizu K, Fujieda K (2009) OTX2 loss of function mutation causes anophthalmia and combined pituitary hormone deficiency with a small anterior and ectopic posterior pituitary. J Clin Endocrinol Metab 94:314–319. CrossRefPubMedGoogle Scholar
  201. Tajima T, Nakamura A, Ishizu K (2013) A novel mutation of IGSF1 in a Japanese patient of congenital central hypothyroidism without macroorchidism. Endocr J 60:245–249. CrossRefPubMedGoogle Scholar
  202. Takagi M, Ishii T, Torii C, Kosaki K, Hasegawa T (2014a) 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 17:569–574. CrossRefPubMedGoogle Scholar
  203. Takagi M, Narumi S, Asakura Y, Muroya K, Hasegawa Y, Adachi M, Hasegawa T (2014b) A novel mutation in SOX2 causes hypogonadotropic hypogonadism with mild ocular malformation. Horm Res Paediatr 81:133–138. CrossRefPubMedGoogle Scholar
  204. Takagi M, Nagasaki K, Fujiwara I et al (2015) Heterozygous defects in PAX6 gene and congenital hypopituitarism. Eur J Endocrinol 172:37–45. CrossRefPubMedGoogle Scholar
  205. Takagi M, Takahashi M, Ohtsu Y, Sato T, Narumi S, Arakawa H, Hasegawa T (2016) A novel mutation in HESX1 causes combined pituitary hormone deficiency without septo optic dysplasia phenotypes. Endocr J 63:405–410. CrossRefPubMedGoogle Scholar
  206. Takagi M, Kamasaki H, Yagi H, Fukuzawa R, Narumi S, Hasegawa T (2017) A novel heterozygous intronic mutation in POU1F1 is associated with combined pituitary hormone deficiency. Endocr J 64:229–234. CrossRefPubMedGoogle Scholar
  207. Tasdemir S, Sahin I, Cayır A et al (2014) Holoprosencephaly: ZIC2 mutation in a case with panhypopituitarism. J Pediatr Endocrinol Metab 27:777–781. CrossRefPubMedGoogle Scholar
  208. Tatsi C, Sertedaki A, Voutetakis A et al (2013) Pituitary stalk interruption syndrome and isolated pituitary hypoplasia may be caused by mutations in holoprosencephaly-related genes. J Clin Endocrinol Metab 98:E779–E784. CrossRefPubMedGoogle Scholar
  209. Tenenbaum-Rakover Y, Turgeon MO, London S, Hermanns P, Pohlenz J, Bernard DJ, Bercovich D (2016) Familial central hypothyroidism caused by a novel IGSF1 gene mutation. Thyroid 26:1693–1700. CrossRefPubMedGoogle Scholar
  210. Thomas PQ, Dattani MT, Brickman JM et al (2001) Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. Hum Mol Genet 10:39–45. CrossRefPubMedGoogle Scholar
  211. Tommiska J, Känsäkoski J, Skibsbye L et al (2017) Two missense mutations in KCNQ1 cause pituitary hormone deficiency and maternally inherited gingival fibromatosis. Nat Commun 8:1289. CrossRefPubMedPubMedCentralGoogle Scholar
  212. Treier M, O’Connell S, Gleiberman A et al (2001) Hedgehog signaling is required for pituitary gland development. Development 128:377–386PubMedGoogle Scholar
  213. Trujillano D, Bertoli-Avella AM, Kumar Kandaswamy K et al (2017) Clinical exome sequencing: results from 2819 samples reflecting 1000 families. Eur J Hum Genet 25:176–182. CrossRefPubMedGoogle Scholar
  214. Tsai EA, Grochowski CM, Falsey AM et al (2015) Heterozygous deletion of FOXA2 segregates with disease in a family with heterotaxy, panhypopituitarism, and biliary atresia. Hum Mutat 36:631–637. CrossRefPubMedPubMedCentralGoogle Scholar
  215. Turton JP, Mehta A, Raza J et al (2005a) Mutations within the transcription factor PROP1 are rare in a cohort of patients with sporadic combined pituitary hormone deficiency (CPHD). Clin Endocrinol 63:10–18. CrossRefGoogle Scholar
  216. Turton JP, Reynaud R, Mehta A et al (2005b) Novel mutations within the POU1F1 gene associated with variable combined pituitary hormone deficiency. J Clin Endocrinol Metab 90:4762–4770. CrossRefPubMedGoogle Scholar
  217. Turton JP, Strom M, Langham S, Dattani MT, Le Tissier P (2012) Two novel mutations in the POU1F1 gene generate null alleles through different mechanisms leading to combined pituitary hormone deficiency. Clin Endocrinol 76:387–393. CrossRefGoogle Scholar
  218. Vajravelu ME, Chai J, Krock B, Baker S, Langdon D, Alter C, De Leon DD (2018) Congenital hyperinsulinism and hypopituitarism attributable to a mutation in FOXA2. J Clin Endocrinol Metab 103:1042–1047. CrossRefPubMedPubMedCentralGoogle Scholar
  219. Vallette-Kasic S, Pellegrini-Bouiller I, Sampieri F et al (2001) Combined pituitary hormone deficiency due to the F135C human Pit-1 (pituitary-specific factor 1) gene mutation: functional and structural correlates. Mol Endocrinol 15:411–420. CrossRefPubMedGoogle Scholar
  220. Vallette-Kasic S, Brue T, Pulichino AM et al (2005) Congenital isolated adrenocorticotropin deficiency: an underestimated cause of neonatal death, explained by TPIT gene mutations. J Clin Endocrinol Metab 90:1323–1331. CrossRefPubMedGoogle Scholar
  221. van Tijn DA, de Vijlder JJ, Verbeeten B Jr, Verkerk PH, Vulsma T (2005) Neonatal detection of congenital hypothyroidism of central origin. J Clin Endocrinol Metab 90:3350–3359. CrossRefPubMedGoogle Scholar
  222. Vaquerizas JM, Kummerfeld SK, Teichmann SA, Luscombe NM (2009) A census of human transcription factors: function, expression and evolution. Nat Rev Genet 10:252–263. CrossRefPubMedGoogle Scholar
  223. Vincent A, Forster N, Maynes JT et al (2014) OTX2 mutations cause autosomal dominant pattern dystrophy of the retinal pigment epithelium. J Med Genet 51:797–805. CrossRefPubMedGoogle Scholar
  224. Vivenza D, Godi M, Faienza MF et al (2011) A novel HESX1 splice mutation causes isolated GH deficiency by interfering with mRNA processing. Eur J Endocrinol 164:705–713. CrossRefPubMedGoogle Scholar
  225. Warr A, Robert C, Hume D, Archibald A, Deeb N, Watson M (2015) Exome sequencing: current and future perspectives. G3 (Bethesda) 5:1543–1550. CrossRefGoogle Scholar
  226. Webb EA, AlMutair A, Kelberman D et al (2013) ARNT2 mutation causes hypopituitarism, post-natal microcephaly, visual and renal anomalies. Brain 136:3096–3105. CrossRefPubMedPubMedCentralGoogle Scholar
  227. Welcker JE, Hernandez-Miranda LR, Paul FE, Jia S, Ivanov A, Selbach M, Birchmeier C (2013) Insm1 controls development of pituitary endocrine cells and requires a SNAG domain for function and for recruitment of histone-modifying factors. Development 140:4947–4958. CrossRefPubMedGoogle Scholar
  228. Wingender E, Schoeps T, Haubrock M, Donitz J (2015) TFClass: a classification of human transcription factors and their rodent orthologs. Nucleic Acids Res 43:D97–102 CrossRefGoogle Scholar
  229. Woods KS, Cundall M, Turton J et al (2005) Over- and underdosage of SOX3 is associated with infundibular hypoplasia and hypopituitarism. Am J Hum Genet 76:833–849. CrossRefPubMedPubMedCentralGoogle Scholar
  230. Zhao L, Bakke M, Krimkevich Y, Cushman LJ, Parlow AF, Camper SA, Parker KL (2001) Steroidogenic factor 1 (SF1) is essential for pituitary gonadotrope function. Development 128:147–154PubMedGoogle Scholar
  231. Zwaveling-Soonawala N, Alders M, Jongejan A et al (2018) Clues for polygenic inheritance of pituitary stalk interruption syndrome from exome sequencing in 20 patients. J Clin Endocrinol Metab 103:415–428. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Human Genetics, University of MichiganAnn ArborUSA

Personalised recommendations