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Embryologic and Genetic Disorders of the Pituitary Gland

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Pituitary Disorders of Childhood

Part of the book series: Contemporary Endocrinology ((COE))

Abstract

Human embryonic hypothalamo-pituitary development is a complex process controlled by a spatio-temporal genetic cascade of transcription factors and signalling molecules within the hypothalamus and Rathke’s pouch, the primordium of the anterior pituitary (AP). The anterior and intermediate lobes of the pituitary derive from the oral ectoderm and the posterior lobe from the overlying neural ectoderm. The tightly regulated processes of cell proliferation and differentiation give rise to five different specialized AP cell types that secrete six hormones. Disordered embryogenesis can give rise to congenital hypopituitarism (CH), characterized by deficiencies in one or more of these six hormones in isolation or as combined pituitary hormone deficiency, with a wide variation in severity. CH may present early in the neonatal period or later in childhood, with midline and craniofacial structural abnormalities often accompanying the phenotype, giving rise to a range of highly variable disorders that will be discussed in this chapter.

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References

  1. Davis SW, Castinetti F, Carvalho LR, Ellsworth BS, Potok MA, Lyons RH, et al. Molecular mechanisms of pituitary organogenesis: in search of novel regulatory genes. Mol Cell Endocrinol. 2010;323(1):4–19.

    CAS  PubMed  Google Scholar 

  2. Cohen LE. Genetic disorders of the pituitary. Curr Opin Endocrinol Diabetes Obes. 2012;19(1):33–9.

    CAS  PubMed  Google Scholar 

  3. Bancalari RE, Gregory LC, McCabe MJ, Dattani MT. Pituitary gland development: an update. Endocr Dev. 2012;23:1–15.

    CAS  PubMed  Google Scholar 

  4. Kelberman D, Rizzoti K, Lovell-Badge R, Robinson IC, Dattani MT. Genetic regulation of pituitary gland development in human and mouse. Endocr Rev. 2009;30(7):790–829.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Alatzoglou KS, Dattani MT. Genetic forms of hypopituitarism and their manifestation in the neonatal period. Early Hum Dev. 2009;85(11):705–12.

    CAS  PubMed  Google Scholar 

  6. McCabe MJ, Gaston-Massuet C, Tziaferi V, Gregory LC, Alatzoglou KS, Signore M, et al. Novel FGF8 mutations associated with recessive holoprosencephaly, craniofacial defects, and hypothalamo-pituitary dysfunction. J Clin Endocrinol Metab. 2011;96(10):E1709–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Iguchi G, Okimura Y, Takahashi T, Mizuno I, Fumoto M, Takahashi Y, et al. Cloning and characterization of the 5′-flanking region of the human growth hormone-releasing hormone receptor gene. J Biol Chem. 1999;274(17):12108–14.

    CAS  PubMed  Google Scholar 

  8. Alatzoglou KS, Kular D, Dattani MT. Autosomal dominant growth hormone deficiency (Type II). Pediatr Endocrinol Rev. 2015;12(4):347–55.

    PubMed  Google Scholar 

  9. Alatzoglou KS, Webb EA, Le Tissier P, Dattani MT. Isolated growth hormone deficiency (GHD) in childhood and adolescence: recent advances. Endocr Rev. 2014;35(3):376–432.

    CAS  PubMed  Google Scholar 

  10. Cogan JD, Phillips JA 3rd. GH1 gene deletions and IGHD type 1A. Pediatr Endocrinol Rev. 2006;3(Suppl 3):480–8.

    PubMed  Google Scholar 

  11. Wagner JK, Eble A, Hindmarsh PC, Mullis PE. Prevalence of human GH-1 gene alterations in patients with isolated growth hormone deficiency. Pediatr Res. 1998;43(1):105–10.

    CAS  PubMed  Google Scholar 

  12. Baumann G, Maheshwari H. The dwarfs of Sindh: severe growth hormone (GH) deficiency caused by a mutation in the GH-releasing hormone receptor gene. Acta Paediatr Suppl. 1997;423:33–8.

    CAS  PubMed  Google Scholar 

  13. Leiberman E, Pesler D, Parvari R, Elbedour K, Abdul-Latif H, Brown MR, et al. Short stature in carriers of recessive mutation causing familial isolated growth hormone deficiency. Am J Med Genet. 2000;90(3):188–92.

    CAS  PubMed  Google Scholar 

  14. Phillips JA 3rd, Cogan JD. Genetic basis of endocrine disease. 6. Molecular basis of familial human growth hormone deficiency. J Clin Endocrinol Metab. 1994;78(1):11–6.

    CAS  PubMed  Google Scholar 

  15. Shohreh R, Sherafat-Kazemzadeh R, Jee YH, Blitz A, Salvatori R. A novel frame shift mutation in the GHRH receptor gene in familial isolated GH deficiency: early occurrence of anterior pituitary hypoplasia. J Clin Endocrinol Metab. 2011;96(10):2982–6.

    CAS  PubMed  Google Scholar 

  16. Baumann G. Mutations in the growth hormone releasing hormone receptor: a new form of dwarfism in humans. Growth Hormon IGF Res. 1999;9 Suppl B:24–9; discussion 9-30.

    CAS  Google Scholar 

  17. Carakushansky M, Whatmore AJ, Clayton PE, Shalet SM, Gleeson HK, Price DA, et al. A new missense mutation in the growth hormone-releasing hormone receptor gene in familial isolated GH deficiency. Eur J Endocrinol. 2003;148(1):25–30.

    CAS  PubMed  Google Scholar 

  18. Salvatori R, Fan X, Mullis PE, Haile A, Levine MA. Decreased expression of the GHRH receptor gene due to a mutation in a Pit-1 binding site. Mol Endocrinol. 2002;16(3):450–8.

    CAS  PubMed  Google Scholar 

  19. Gregory LC, Alatzoglou KS, McCabe MJ, Hindmarsh PC, Saldanha JW, Romano N, et al. Partial loss of function of the GHRH receptor leads to mild growth hormone deficiency. J Clin Endocrinol Metab. 2016;101(10):3608–15.

    CAS  PubMed  Google Scholar 

  20. Lee MS, Wajnrajch MP, Kim SS, Plotnick LP, Wang J, Gertner JM, et al. Autosomal dominant growth hormone (GH) deficiency type II: the Del32-71-GH deletion mutant suppresses secretion of wild-type GH. Endocrinology. 2000;141(3):883–90.

    CAS  PubMed  Google Scholar 

  21. McGuinness L, Magoulas C, Sesay AK, Mathers K, Carmignac D, Manneville JB, et al. Autosomal dominant growth hormone deficiency disrupts secretory vesicles in vitro and in vivo in transgenic mice. Endocrinology. 2003;144(2):720–31.

    CAS  PubMed  Google Scholar 

  22. Ryther RC, McGuinness LM, Phillips JA 3rd, Moseley CT, Magoulas CB, Robinson IC, et al. Disruption of exon definition produces a dominant-negative growth hormone isoform that causes somatotroph death and IGHD II. Hum Genet. 2003;113(2):140–8.

    CAS  PubMed  Google Scholar 

  23. Zhao E, Li J, Xie Y, Jin W, Zhang Z, Chen J, et al. Cloning and identification of a novel human RNPC3 gene that encodes a protein with two RRM domains and is expressed in the cell nucleus. Biochem Genet. 2003;41(9–10):315–23.

    CAS  PubMed  Google Scholar 

  24. Argente J, Flores R, Gutierrez-Arumi A, Verma B, Martos-Moreno GA, Cusco I, et al. Defective minor spliceosome mRNA processing results in isolated familial growth hormone deficiency. EMBO Mol Med. 2014;6(3):299–306.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Yin X, Li Y, Xu G, An W, Zhang W. Ghrelin fluctuation, what determines its production? Acta Biochim Biophys Sin. 2009;41(3):188–97.

    CAS  PubMed  Google Scholar 

  26. Markmiller S, Cloonan N, Lardelli RM, Doggett K, Keightley MC, Boglev Y, et al. Minor class splicing shapes the zebrafish transcriptome during development. Proc Natl Acad Sci U S A. 2014;111(8):3062–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Ashkenazi-Hoffnung L, Lebenthal Y, Wyatt AW, Ragge NK, Dateki S, Fukami M, et al. A novel loss-of-function mutation in OTX2 in a patient with anophthalmia and isolated growth hormone deficiency. Hum Genet. 2010;127(6):721–9.

    PubMed  Google Scholar 

  28. Thomas PQ, Dattani MT, Brickman JM, McNay D, Warne G, Zacharin M, et al. Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. Hum Mol Genet. 2001;10(1):39–45.

    CAS  PubMed  Google Scholar 

  29. Douchi T, Nakae M, Yamamoto S, Iwamoto I, Oki T, Nagata Y. A woman with isolated prolactin deficiency. Acta Obstet Gynecol Scand. 2001;80(4):368–70.

    CAS  PubMed  Google Scholar 

  30. Kauppila A. Isolated prolactin deficiency. Curr Ther Endocrinol Metab. 1997;6:31–3.

    CAS  PubMed  Google Scholar 

  31. Zargar AH, Masoodi SR, Laway BA, Shah NA, Salahudin M. Familial puerperal alactogenesis: possibility of a genetically transmitted isolated prolactin deficiency. Br J Obstet Gynaecol. 1997;104(5):629–31.

    CAS  PubMed  Google Scholar 

  32. Iwama S, Welt CK, Romero CJ, Radovick S, Caturegli P. Isolated prolactin deficiency associated with serum autoantibodies against prolactin-secreting cells. J Clin Endocrinol Metab. 2013;98(10):3920–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Garcia M, Fernandez A, Moreno JC. Central hypothyroidism in children. Endocr Dev. 2014;26:79–107.

    CAS  PubMed  Google Scholar 

  34. Sun Y, Bak B, Schoenmakers N, van Trotsenburg AS, Oostdijk W, Voshol P, et al. Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement. Nat Genet. 2012;44(12):1375–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Wassner AJ, Cohen LE, Hechter E, Dauber A. Isolated central hypothyroidism in young siblings as a manifestation of PROP1 deficiency: clinical impact of whole exome sequencing. Horm Res Paediatr. 2013;79(6):379–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Hayashizaki Y, Hiraoka Y, Endo Y, Miyai K, Matsubara K. Thyroid-stimulating hormone (TSH) deficiency caused by a single base substitution in the CAGYC region of the beta-subunit. EMBO J. 1989;8(8):2291–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Medeiros-Neto G, Herodotou DT, Rajan S, Kommareddi S, de Lacerda L, Sandrini R, et al. A circulating, biologically inactive thyrotropin caused by a mutation in the beta subunit gene. J Clin Invest. 1996;97(5):1250–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. McDermott MT, Haugen BR, Black JN, Wood WM, Gordon DF, Ridgway EC. Congenital isolated central hypothyroidism caused by a “hot spot” mutation in the thyrotropin-beta gene. Thyroid. 2002;12(12):1141–6.

    CAS  PubMed  Google Scholar 

  39. Karges B, LeHeup B, Schoenle E, Castro-Correia C, Fontoura M, Pfaffle R, et al. Compound heterozygous and homozygous mutations of the TSHbeta gene as a cause of congenital central hypothyroidism in Europe. Horm Res. 2004;62(3):149–55.

    CAS  PubMed  Google Scholar 

  40. Nicholas AK, Jaleel S, Lyons G, Schoenmakers E, Dattani MT, Crowne E, et al. Molecular spectrum of TSHbeta subunit gene defects in central hypothyroidism in the UK and Ireland. Clin Endocrinol (Oxf). 2017;86(3):410–8.

    CAS  Google Scholar 

  41. Buyukgebiz A. Newborn screening for congenital hypothyroidism. J Clin Res Pediatr Endocrinol. 2013;5(Suppl 1):8–12.

    PubMed  PubMed Central  Google Scholar 

  42. Collu R, Tang J, Castagne J, Lagace G, Masson N, Huot C, et al. A novel mechanism for isolated central hypothyroidism: inactivating mutations in the thyrotropin-releasing hormone receptor gene. J Clin Endocrinol Metab. 1997;82(5):1561–5.

    CAS  PubMed  Google Scholar 

  43. Bonomi M, Busnelli M, Beck-Peccoz P, Costanzo D, Antonica F, Dolci C, et al. A family with complete resistance to thyrotropin-releasing hormone. N Engl J Med. 2009;360(7):731–4.

    CAS  PubMed  Google Scholar 

  44. Koulouri O, Nicholas AK, Schoenmakers E, Mokrosinski J, Lane F, Cole T, et al. A novel thyrotropin-releasing hormone receptor missense mutation (P81R) in central congenital hypothyroidism. J Clin Endocrinol Metab. 2016;101(3):847–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Tenenbaum-Rakover Y, Turgeon MO, London S, Hermanns P, Pohlenz J, Bernard DJ, et al. Familial central hypothyroidism caused by a novel IGSF1 gene mutation. Thyroid. 2016;26(12):1693–700.

    CAS  PubMed  Google Scholar 

  46. Garcia M, Barrio R, Garcia-Lavandeira M, Garcia-Rendueles AR, Escudero A, Diaz-Rodriguez E, et al. The syndrome of central hypothyroidism and macroorchidism: IGSF1 controls TRHR and FSHB expression by differential modulation of pituitary TGFbeta and Activin pathways. Sci Rep. 2017;7:42937.

    PubMed  PubMed Central  Google Scholar 

  47. Hughes JN, Aubert M, Heatlie J, Gardner A, Gecz J, Morgan T, et al. Identification of an IGSF1-specific deletion in a five-generation pedigree with X-linked Central Hypothyroidism without macroorchidism. Clin Endocrinol. 2016;85(4):609–15.

    CAS  Google Scholar 

  48. Joustra SD, Schoenmakers N, Persani L, Campi I, Bonomi M, Radetti G, et al. The IGSF1 deficiency syndrome: characteristics of male and female patients. J Clin Endocrinol Metab. 2013;98(12):4942–52.

    CAS  PubMed  Google Scholar 

  49. Turgeon MO, Silander TL, Doycheva D, Liao XH, Rigden M, Ongaro L, et al. TRH action is impaired in pituitaries of male IGSF1-deficient mice. Endocrinology. 2017;158(4):815–30.

    PubMed  PubMed Central  Google Scholar 

  50. Bassi MT, Ramesar RS, Caciotti B, Winship IM, De Grandi A, Riboni M, et al. X-linked late-onset sensorineural deafness caused by a deletion involving OA1 and a novel gene containing WD-40 repeats. Am J Hum Genet. 1999;64(6):1604–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Heinen CA, Losekoot M, Sun Y, Watson PJ, Fairall L, Joustra SD, et al. Mutations in TBL1X are associated with central hypothyroidism. J Clin Endocrinol Metab. 2016;101(12):4564–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Ahn SW, Kim TY, Lee S, Jeong JY, Shim H, Han YM, et al. Adrenal insufficiency presenting as hypercalcemia and acute kidney injury. Int Med Case Rep J. 2016;9:223–6.

    PubMed  PubMed Central  Google Scholar 

  53. Alsaleem M, Saadeh L, Misra A, Madani S. Neonatal isolated ACTH deficiency (IAD): a potentially life-threatening but treatable cause of neonatal cholestasis. BMJ Case Rep. 2016;2016. pii: bcr2016215032. https://doi.org/10.1136/bcr-2016-215032.

  54. Bigos ST, Carnes TD. Isolated ACTH deficiency presenting as severe hypercalcemia. Am J Med Sci. 1982;284(1):24–30.

    CAS  PubMed  Google Scholar 

  55. Doroftei NA, de Rudder C, de Visscher N, Hanon F. Isolated ACTH deficiency in a patient with empty sella as revealed by severe hyponatremia. Acta Clin Belg. 2016;71(6):451–4.

    PubMed  Google Scholar 

  56. Metherell LA, Savage MO, Dattani M, Walker J, Clayton PE, Farooqi IS, et al. TPIT mutations are associated with early-onset, but not late-onset isolated ACTH deficiency. Eur J Endocrinol. 2004;151(4):463–5.

    CAS  PubMed  Google Scholar 

  57. Lamolet B, Pulichino AM, Lamonerie T, Gauthier Y, Brue T, Enjalbert A, et al. A pituitary cell-restricted T box factor, Tpit, activates POMC transcription in cooperation with Pitx homeoproteins. Cell. 2001;104(6):849–59.

    CAS  PubMed  Google Scholar 

  58. Couture C, Saveanu A, Barlier A, Carel JC, Fassnacht M, Fluck CE, et al. Phenotypic homogeneity and genotypic variability in a large series of congenital isolated ACTH-deficiency patients with TPIT gene mutations. J Clin Endocrinol Metab. 2012;97(3):E486–95.

    CAS  PubMed  Google Scholar 

  59. Akcan N, Serakinci N, Turkgenc B, Bundak R, Bahceciler N, Temel SG. A novel TBX19 gene mutation in a case of congenital isolated adrenocorticotropic hormone deficiency presenting with recurrent respiratory tract infections. Front Endocrinol. 2017;8:64.

    Google Scholar 

  60. Seidah NG, Chretien M. Proprotein and prohormone convertases: a family of subtilases generating diverse bioactive polypeptides. Brain Res. 1999;848(1–2):45–62.

    CAS  PubMed  Google Scholar 

  61. Slominski A, Wortsman J, Luger T, Paus R, Solomon S. Corticotropin releasing hormone and proopiomelanocortin involvement in the cutaneous response to stress. Physiol Rev. 2000;80(3):979–1020.

    CAS  PubMed  Google Scholar 

  62. Rousseau K, Kauser S, Pritchard LE, Warhurst A, Oliver RL, Slominski A, et al. Proopiomelanocortin (POMC), the ACTH/melanocortin precursor, is secreted by human epidermal keratinocytes and melanocytes and stimulates melanogenesis. FASEB J. 2007;21(8):1844–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Valverde P, Healy E, Jackson I, Rees JL, Thody AJ. Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans. Nat Genet. 1995;11(3):328–30.

    CAS  PubMed  Google Scholar 

  64. Gorrigan RJ, Guasti L, King P, Clark AJ, Chan LF. Localisation of the melanocortin-2-receptor and its accessory proteins in the developing and adult adrenal gland. J Mol Endocrinol. 2011;46(3):227–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Lu D, Willard D, Patel IR, Kadwell S, Overton L, Kost T, et al. Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor. Nature. 1994;371(6500):799–802.

    CAS  PubMed  Google Scholar 

  66. Krude H, Biebermann H, Luck W, Horn R, Brabant G, Gruters A. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet. 1998;19(2):155–7.

    CAS  PubMed  Google Scholar 

  67. Jackson RS, Creemers JW, Ohagi S, Raffin-Sanson ML, Sanders L, Montague CT, et al. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet. 1997;16(3):303–6.

    CAS  PubMed  Google Scholar 

  68. Jackson RS, Creemers JW, Farooqi IS, Raffin-Sanson ML, Varro A, Dockray GJ, et al. Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency. J Clin Invest. 2003;112(10):1550–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Zhu X, Zhou A, Dey A, Norrbom C, Carroll R, Zhang C, et al. Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects. Proc Natl Acad Sci U S A. 2002;99(16):10293–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Philippe J, Stijnen P, Meyre D, De Graeve F, Thuillier D, Delplanque J, et al. A nonsense loss-of-function mutation in PCSK1 contributes to dominantly inherited human obesity. Int J Obes (2005). 2015;39(2):295–302.

    CAS  Google Scholar 

  71. Wang L, Sui L, Panigrahi SK, Meece K, Xin Y, Kim J, et al. PC1/3 deficiency impacts pro-opiomelanocortin processing in human embryonic stem cell-derived hypothalamic neurons. Stem Cell Rep. 2017;8(2):264–77.

    CAS  Google Scholar 

  72. Stijnen P, Ramos-Molina B, O’Rahilly S, Creemers JW. PCSK1 mutations and human endocrinopathies: from obesity to gastrointestinal disorders. Endocr Rev. 2016;37(4):347–71.

    CAS  PubMed  Google Scholar 

  73. Martin MG, Lindberg I, Solorzano-Vargas RS, Wang J, Avitzur Y, Bandsma R, et al. Congenital proprotein convertase 1/3 deficiency causes malabsorptive diarrhea and other endocrinopathies in a pediatric cohort. Gastroenterology. 2013;145(1):138–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. De Morsier G. Studies on malformation of cranio-encephalic sutures. III. Agenesis of the septum lucidum with malformation of the optic tract. Schweizer Archiv fur Neurologie und Psychiatrie Archives suisses de neurologie et de psychiatrie Archivio svizzero di neurologia e psichiatria. 1956;77(1–2):267–92.

    Google Scholar 

  75. Brodsky MC, Glasier CM. Optic nerve hypoplasia. Clinical significance of associated central nervous system abnormalities on magnetic resonance imaging. Arch Ophthalmol (Chicago, Ill: 1960). 1993;111(1):66–74.

    CAS  Google Scholar 

  76. McNay DE, Turton JP, Kelberman D, Woods KS, Brauner R, Papadimitriou A, et al. HESX1 mutations are an uncommon cause of septooptic dysplasia and hypopituitarism. J Clin Endocrinol Metab. 2007;92(2):691–7.

    CAS  PubMed  Google Scholar 

  77. Webb EA, Dattani MT. Septo-optic dysplasia. Eur J Hum Genet. 2010;18(4):393–7.

    PubMed  Google Scholar 

  78. Lippe B, Kaplan SA, LaFranchi S. Septo-optic dysplasia and maternal age. Lancet (London, England). 1979;2(8133):92–3.

    CAS  Google Scholar 

  79. Kelberman D, Dattani MT. Genetics of septo-optic dysplasia. Pituitary. 2007;10(4):393–407.

    CAS  PubMed  Google Scholar 

  80. Kelberman D, Dattani MT. Septo-optic dysplasia - novel insights into the aetiology. Horm Res. 2008;69(5):257–65.

    CAS  PubMed  Google Scholar 

  81. Mehta A, Hindmarsh PC, Mehta H, Turton JP, Russell-Eggitt I, Taylor D, et al. Congenital hypopituitarism: clinical, molecular and neuroradiological correlates. Clin Endocrinol (Oxf). 2009;71(3):376–82.

    Google Scholar 

  82. McCabe MJ, Alatzoglou KS, Dattani MT. Septo-optic dysplasia and other midline defects: the role of transcription factors: HESX1 and beyond. Best Pract Res Clin Endocrinol Metab. 2011;25(1):115–24.

    CAS  PubMed  Google Scholar 

  83. Dattani MT, Martinez-Barbera JP, Thomas PQ, Brickman JM, Gupta R, Martensson IL, et al. Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nat Genet. 1998;19(2):125–33.

    CAS  PubMed  Google Scholar 

  84. Sajedi E, Gaston-Massuet C, Signore M, Andoniadou CL, Kelberman D, Castro S, et al. Analysis of mouse models carrying the I26T and R160C substitutions in the transcriptional repressor HESX1 as models for septo-optic dysplasia and hypopituitarism. Dis Model Mech. 2008;1(4–5):241–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Woods KS, Cundall M, Turton J, Rizotti K, Mehta A, Palmer R, et al. Over- and underdosage of SOX3 is associated with infundibular hypoplasia and hypopituitarism. Am J Hum Genet. 2005;76(5):833–49.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. McCabe MJ, Hu Y, Gregory LC, Gaston-Massuet C, Alatzoglou KS, Saldanha JW, et al. Novel application of luciferase assay for the in vitro functional assessment of KAL1 variants in three females with septo-optic dysplasia (SOD). Mol Cell Endocrinol. 2015;417:63–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Raivio T, Avbelj M, McCabe MJ, Romero CJ, Dwyer AA, Tommiska J, et al. Genetic overlap in Kallmann syndrome, combined pituitary hormone deficiency, and septo-optic dysplasia. J Clin Endocrinol Metab. 2012;97(4):E694–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Gaston-Massuet C, McCabe MJ, Scagliotti V, Young RM, Carreno G, Gregory LC, et al. Transcription factor 7-like 1 is involved in hypothalamo-pituitary axis development in mice and humans. Proc Natl Acad Sci U S A. 2016;113(5):E548–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Polizzi A, Pavone P, Iannetti P, Manfre L, Ruggieri M. Septo-optic dysplasia complex: a heterogeneous malformation syndrome. Pediatr Neurol. 2006;34(1):66–71.

    PubMed  Google Scholar 

  90. Dasen JS, Martinez Barbera JP, Herman TS, Connell SO, Olson L, Ju B, et al. Temporal regulation of a paired-like homeodomain repressor/TLE corepressor complex and a related activator is required for pituitary organogenesis. Genes Dev. 2001;15(23):3193–207.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Sajedi E, Gaston-Massuet C, Andoniadou CL, Signore M, Hurd PJ, Dattani M, et al. DNMT1 interacts with the developmental transcriptional repressor HESX1. Biochim Biophys Acta. 2008;1783(1):131–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Thomas P, Beddington R. Anterior primitive endoderm may be responsible for patterning the anterior neural plate in the mouse embryo. Curr Biol. 1996;6(11):1487–96.

    CAS  PubMed  Google Scholar 

  93. Hermesz E, Mackem S, Mahon KA. Rpx: a novel anterior-restricted homeobox gene progressively activated in the prechordal plate, anterior neural plate and Rathke’s pouch of the mouse embryo. Development. 1996;122(1):41–52.

    CAS  PubMed  Google Scholar 

  94. Sobrier ML, Netchine I, Heinrichs C, Thibaud N, Vie-Luton MP, Van Vliet G, et al. Alu-element insertion in the homeodomain of HESX1 and aplasia of the anterior pituitary. Hum Mutat. 2005;25(5):503.

    PubMed  Google Scholar 

  95. Kelberman D, Dattani MT. Hypothalamic and pituitary development: novel insights into the aetiology. Eur J Endocrinol. 2007;157(Suppl 1):S3–14.

    CAS  PubMed  Google Scholar 

  96. Newbern K, Natrajan N, Kim HG, Chorich LP, Halvorson LM, Cameron RS, et al. Identification of HESX1 mutations in Kallmann syndrome. Fertil Steril. 2013;99(7):1831–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Stevanovic M, Lovell-Badge R, Collignon J, Goodfellow PN. SOX3 is an X-linked gene related to SRY. Hum Mol Genet. 1993;2(12):2013–8.

    CAS  PubMed  Google Scholar 

  98. Hutton SR. Sox gene expression. In: Lemke G, editor. Developmental biology, vol. 2009: Elseveir. p. 165.

    Google Scholar 

  99. Bylund M, Andersson E, Novitch BG, Muhr J. Vertebrate neurogenesis is counteracted by Sox1-3 activity. Nat Neurosci. 2003;6(11):1162–8.

    CAS  PubMed  Google Scholar 

  100. Solomon NM, Ross SA, Morgan T, Belsky JL, Hol FA, Karnes PS, et al. Array comparative genomic hybridisation analysis of boys with X linked hypopituitarism identifies a 3.9 Mb duplicated critical region at Xq27 containing SOX3. J Med Genet. 2004;41(9):669–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Rizzoti K, Brunelli S, Carmignac D, Thomas PQ, Robinson IC, Lovell-Badge R. SOX3 is required during the formation of the hypothalamo-pituitary axis. Nat Genet. 2004;36(3):247–55.

    CAS  PubMed  Google Scholar 

  102. Potok MA, Cha KB, Hunt A, Brinkmeier ML, Leitges M, Kispert A, et al. WNT signaling affects gene expression in the ventral diencephalon and pituitary gland growth. Dev Dyn. 2008;237(4):1006–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Wong J, Farlie P, Holbert S, Lockhart P, Thomas PQ. Polyalanine expansion mutations in the X-linked hypopituitarism gene SOX3 result in aggresome formation and impaired transactivation. Front Biosci: J Virtual Libr. 2007;12:2085–95.

    CAS  Google Scholar 

  104. Hamel BC, Smits AP, Otten BJ, van den Helm B, Ropers HH, Mariman EC. Familial X-linked mental retardation and isolated growth hormone deficiency: clinical and molecular findings. Am J Med Genet. 1996;64(1):35–41.

    CAS  PubMed  Google Scholar 

  105. Laumonnier F, Ronce N, Hamel BC, Thomas P, Lespinasse J, Raynaud M, et al. Transcription factor SOX3 is involved in X-linked mental retardation with growth hormone deficiency. Am J Hum Genet. 2002;71(6):1450–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Alatzoglou KS, Azriyanti A, Rogers N, Ryan F, Curry N, Noakes C, et al. SOX3 deletion in mouse and human is associated with persistence of the craniopharyngeal canal. J Clin Endocrinol Metab. 2014;99(12):E2702–8.

    CAS  PubMed  Google Scholar 

  107. Alatzoglou KS, Kelberman D, Cowell CT, Palmer R, Arnhold IJ, Melo ME, et al. Increased transactivation associated with SOX3 polyalanine tract deletion in a patient with hypopituitarism. J Clin Endocrinol Metab. 2011;96(4):E685–90.

    CAS  PubMed  Google Scholar 

  108. Hutton SR, Pevny LH. SOX2 expression levels distinguish between neural progenitor populations of the developing dorsal telencephalon. Dev Biol. 2011;352(1):40–7.

    CAS  PubMed  Google Scholar 

  109. Avilion AA, Nicolis SK, Pevny LH, Perez L, Vivian N, Lovell-Badge R. Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev. 2003;17(1):126–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Kelberman D, Rizzoti K, Avilion A, Bitner-Glindzicz M, Cianfarani S, Collins J, 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(9):2442–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Taranova OV, Magness ST, Fagan BM, Wu Y, Surzenko N, Hutton SR, et al. SOX2 is a dose-dependent regulator of retinal neural progenitor competence. Genes Dev. 2006;20(9):1187–202.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Williamson KA, Hever AM, Rainger J, Rogers RC, Magee A, Fiedler Z, et al. Mutations in SOX2 cause anophthalmia-esophageal-genital (AEG) syndrome. Hum Mol Genet. 2006;15(9):1413–22.

    CAS  PubMed  Google Scholar 

  113. Jayakody SA, Andoniadou CL, Gaston-Massuet C, Signore M, Cariboni A, Bouloux PM, et al. SOX2 regulates the hypothalamic-pituitary axis at multiple levels. J Clin Invest. 2012;122(10):3635–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Alatzoglou KS, Andoniadou CL, Kelberman D, Buchanan CR, Crolla J, Arriazu MC, et al. SOX2 haploinsufficiency is associated with slow progressing hypothalamo-pituitary tumours. Hum Mutat. 2011;32(12):1376–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Goldsmith S, Lovell-Badge R, Rizzoti K. SOX2 is sequentially required for progenitor proliferation and lineage specification in the developing pituitary. Development. 2016;143(13):2376–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Li H, Collado M, Villasante A, Matheu A, Lynch CJ, Canamero M, et al. p27(Kip1) directly represses Sox2 during embryonic stem cell differentiation. Cell Stem Cell. 2012;11(6):845–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Fauquier T, Rizzoti K, Dattani M, Lovell-Badge R, Robinson IC. SOX2-expressing progenitor cells generate all of the major cell types in the adult mouse pituitary gland. Proc Natl Acad Sci U S A. 2008;105(8):2907–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Andoniadou CL, Matsushima D, Mousavy Gharavy SN, Signore M, Mackintosh AI, Schaeffer M, et al. Sox2(+) stem/progenitor cells in the adult mouse pituitary support organ homeostasis and have tumor-inducing potential. Cell Stem Cell. 2013;13(4):433–45.

    CAS  PubMed  Google Scholar 

  119. Frantz GD, Weimann JM, Levin ME, McConnell SK. Otx1 and Otx2 define layers and regions in developing cerebral cortex and cerebellum. J Neurosci. 1994;14(10):5725–40.

    CAS  PubMed  Google Scholar 

  120. Ang SL, Jin O, Rhinn M, Daigle N, Stevenson L, Rossant J. A targeted mouse Otx2 mutation leads to severe defects in gastrulation and formation of axial mesoderm and to deletion of rostral brain. Development. 1996;122(1):243–52.

    CAS  PubMed  Google Scholar 

  121. Housset M, Samuel A, Ettaiche M, Bemelmans A, Beby F, Billon N, et al. Loss of Otx2 in the adult retina disrupts retinal pigment epithelium function, causing photoreceptor degeneration. J Neurosci. 2013;33(24):9890–904.

    CAS  PubMed  Google Scholar 

  122. Mortensen AH, MacDonald JW, Ghosh D, Camper SA. Candidate genes for panhypopituitarism identified by gene expression profiling. Physiol Genomics. 2011;43(19):1105–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Diaczok D, DiVall S, Matsuo I, Wondisford FE, Wolfe AM, Radovick S. Deletion of Otx2 in GnRH neurons results in a mouse model of hypogonadotropic hypogonadism. Mol Endocrinol (Baltimore, Md). 2011;25(5):833–46.

    CAS  Google Scholar 

  124. Gorbenko Del Blanco D, Romero CJ, Diaczok D, de Graaff LC, Radovick S, Hokken-Koelega AC. 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(3):441–52.

    PubMed  Google Scholar 

  125. Tajima T, Ohtake A, Hoshino M, Amemiya S, Sasaki N, Ishizu K, et al. OTX2 loss of function mutation causes anophthalmia and combined pituitary hormone deficiency with a small anterior and ectopic posterior pituitary. J Clin Endocrinol Metab. 2009;94(1):314–9.

    CAS  PubMed  Google Scholar 

  126. Chassaing N, Sorrentino S, Davis EE, Martin-Coignard D, Iacovelli A, Paznekas W, et al. OTX2 mutations contribute to the otocephaly-dysgnathia complex. J Med Genet. 2012;49(6):373–9.

    CAS  PubMed  Google Scholar 

  127. Roessler E, Du YZ, Mullor JL, Casas E, Allen WP, Gillessen-Kaesbach G, et al. Loss-of-function mutations in the human GLI2 gene are associated with pituitary anomalies and holoprosencephaly-like features. Proc Natl Acad Sci U S A. 2003;100(23):13424–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Roessler E, Ermilov AN, Grange DK, Wang A, Grachtchouk M, Dlugosz AA, et al. A previously unidentified amino-terminal domain regulates transcriptional activity of wild-type and disease-associated human GLI2. Hum Mol Genet. 2005;14(15):2181–8.

    CAS  PubMed  Google Scholar 

  129. Gregory LC, Gaston-Massuet C, Andoniadou CL, Carreno G, Webb EA, Kelberman D, et al. The role of the sonic hedgehog signalling pathway in patients with midline defects and congenital hypopituitarism. Clin Endocrinol (Oxf). 2015;82(5):728–38.

    CAS  Google Scholar 

  130. Franca MM, Jorge AA, Carvalho LR, Costalonga EF, Vasques GA, Leite CC, et al. Novel heterozygous nonsense GLI2 mutations in patients with hypopituitarism and ectopic posterior pituitary lobe without holoprosencephaly. J Clin Endocrinol Metab. 2010;95(11):E384–91.

    PubMed  Google Scholar 

  131. Franca MM, Jorge AA, Carvalho LR, Costalonga EF, Otto AP, Correa FA, et al. Relatively high frequency of non-synonymous GLI2 variants in patients with congenital hypopituitarism without holoprosencephaly. Clin Endocrinol (Oxf). 2013;78(4):551–7.

    CAS  Google Scholar 

  132. Bear KA, Solomon BD, Antonini S, Arnhold IJ, Franca MM, Gerkes EH, et al. Pathogenic mutations in GLI2 cause a specific phenotype that is distinct from holoprosencephaly. J Med Genet. 2014;51(6):413–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Flemming GM, Klammt J, Ambler G, Bao Y, Blum WF, Cowell C, et al. Functional characterization of a heterozygous GLI2 missense mutation in patients with multiple pituitary hormone deficiency. J Clin Endocrinol Metab. 2013;98(3):E567–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Bashamboo A, Bignon-Topalovic J, Rouba H, McElreavey K, Brauner R. A nonsense mutation in the hedgehog receptor CDON associated with pituitary stalk interruption syndrome. J Clin Endocrinol Metab. 2016;101(1):12–5.

    CAS  PubMed  Google Scholar 

  135. Karaca E, Buyukkaya R, Pehlivan D, Charng WL, Yaykasli KO, Bayram Y, et al. Whole-exome sequencing identifies homozygous GPR161 mutation in a family with pituitary stalk interruption syndrome. J Clin Endocrinol Metab. 2015;100(1):E140–7.

    CAS  PubMed  Google Scholar 

  136. Blockus H, Chedotal A. The multifaceted roles of Slits and Robos in cortical circuits: from proliferation to axon guidance and neurological diseases. Curr Opin Neurobiol. 2014;27:82–8.

    CAS  PubMed  Google Scholar 

  137. Bashamboo A, Bignon-Topalovic J, Moussi N, McElreavey K, Brauner R. Mutations in the human ROBO1 gene in pituitary stalk interruption syndrome. J Clin Endocrinol Metab. 2017;102(7):2401–6.

    PubMed  Google Scholar 

  138. Diaczok D, Romero C, Zunich J, Marshall I, Radovick S. A novel dominant negative mutation of OTX2 associated with combined pituitary hormone deficiency. J Clin Endocrinol Metab. 2008;93(11):4351–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Reynaud R, Jayakody SA, Monnier C, Saveanu A, Bouligand J, Guedj AM, et al. PROKR2 variants in multiple hypopituitarism with pituitary stalk interruption. J Clin Endocrinol Metab. 2012;97(6):E1068–73.

    CAS  PubMed  Google Scholar 

  140. Keith B, Adelman DM, Simon MC. Targeted mutation of the murine arylhydrocarbon receptor nuclear translocator 2 (Arnt2) gene reveals partial redundancy with Arnt. Proc Natl Acad Sci U S A. 2001;98(12):6692–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Webb EA, AlMutair A, Kelberman D, Bacchelli C, Chanudet E, Lescai F, et al. ARNT2 mutation causes hypopituitarism, post-natal microcephaly, visual and renal anomalies. Brain: J Neurol. 2013;136(Pt 10):3096–105.

    Google Scholar 

  142. Rainier S, Bui M, Mark E, Thomas D, Tokarz D, Ming L, et al. Neuropathy target esterase gene mutations cause motor neuron disease. Am J Hum Genet. 2008;82(3):780–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Topaloglu AK, Lomniczi A, Kretzschmar D, Dissen GA, Kotan LD, McArdle CA, et al. Loss-of-function mutations in PNPLA6 encoding neuropathy target esterase underlie pubertal failure and neurological deficits in Gordon Holmes syndrome. J Clin Endocrinol Metab. 2014;99(10):E2067–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Hufnagel RB, Arno G, Hein ND, Hersheson J, Prasad M, Anderson Y, et al. Neuropathy target esterase impairments cause Oliver-McFarlane and Laurence-Moon syndromes. J Med Genet. 2015;52(2):85–94.

    CAS  PubMed  Google Scholar 

  145. Wang Q, Curran ME, Splawski I, Burn TC, Millholland JM, VanRaay TJ, et al. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet. 1996;12(1):17–23.

    PubMed  Google Scholar 

  146. Tommiska J, Kansakoski J, Skibsbye L, Vaaralahti K, Liu X, Lodge EJ, et al. Two missense mutations in KCNQ1 cause pituitary hormone deficiency and maternally inherited gingival fibromatosis. Nat Commun. 2017;8(1):1289.

    PubMed  PubMed Central  Google Scholar 

  147. Stojilkovic SS, Tabak J, Bertram R. Ion channels and signaling in the pituitary gland. Endocr Rev. 2010;31(6):845–915.

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Stojilkovic SS, Bjelobaba I, Zemkova H. Ion channels of pituitary gonadotrophs and their roles in signaling and secretion. Front Endocrinol. 2017;8:126.

    Google Scholar 

  149. Xu R, Roh SG, Loneragan K, Pullar M, Chen C. Human GHRH reduces voltage-gated K+ currents via a non-cAMP-dependent but PKC-mediated pathway in human GH adenoma cells. J Physiol. 1999;520(Pt 3):697–707.

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Beales PL, Bland E, Tobin JL, Bacchelli C, Tuysuz B, Hill J, et al. IFT80, which encodes a conserved intraflagellar transport protein, is mutated in Jeune asphyxiating thoracic dystrophy. Nat Genet. 2007;39(6):727–9.

    CAS  PubMed  Google Scholar 

  151. Bredrup C, Saunier S, Oud MM, Fiskerstrand T, Hoischen A, Brackman D, et al. Ciliopathies with skeletal anomalies and renal insufficiency due to mutations in the IFT-A gene WDR19. Am J Hum Genet. 2011;89(5):634–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Waters AM, Beales PL. Ciliopathies: an expanding disease spectrum. Pediatr Nephrol (Berlin, Germany). 2011;26(7):1039–56.

    Google Scholar 

  153. Lucas-Herald AK, Kinning E, Iida A, Wang Z, Miyake N, Ikegawa S, et al. A case of functional growth hormone deficiency and early growth retardation in a child with IFT172 mutations. J Clin Endocrinol Metab. 2015;100(4):1221–4.

    CAS  PubMed  Google Scholar 

  154. Romano S, Maffei P, Bettini V, Milan G, Favaretto F, Gardiman M, et al. Alstrom syndrome is associated with short stature and reduced GH reserve. Clin Endocrinol (Oxf). 2013;79(4):529–36.

    CAS  Google Scholar 

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  1. Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, UK

    Louise C. Gregory & Mehul T. Dattani

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    Brenda Kohn

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Gregory, L.C., Dattani, M.T. (2019). Embryologic and Genetic Disorders of the Pituitary Gland. In: Kohn, B. (eds) Pituitary Disorders of Childhood. Contemporary Endocrinology. Humana Press, Cham. https://doi.org/10.1007/978-3-030-11339-1_1

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