The Endocrine System

  • Roger D. G. MalcomsonEmail author
  • Anita Nagy


In the developing fetus, the endocrine system progressively establishes feedback and regulatory mechanisms similar to those of the adult. However, the fetal system also has to accommodate additional endocrine tissues: the placenta, the steroidogenic zone (fetal zone, FZ) of the adrenal cortex, as well as a contribution from the central nervous system, which in the fetus is capable both of the production of certain tropic hormones and of being a target organ for certain steroid hormones produced by the gonads, adrenal gland, and placenta.

The cells of the target organs of the maturing fetal endocrine system are rapidly proliferating and differentiating under influences of tissue growth factors (paracrine hormones). Therefore, any fetal endocrine disorder can have particularly far-reaching effects. For example, fetal hyperadrenalism can cause gonadal intersex and may affect sexual preferences in adult life.

This chapter briefly outlines the development and function of the fetal endocrine system and provides an account of those abnormalities of the endocrine system that present in the neonatal period. Certain clinical conditions (e.g., neonatal hypocalcemia) that may mimic endocrine disease are also briefly discussed.


Hypothalamic pituitary axis Hormone Steroidogenesis Thyroid Parathyroid Adrenal Endocrine pancreas Infant of diabetic mother Congenital adrenal hyperplasia Congenital hyperinsulinism Goiter Congenital hypothyroidism Hypocalcemia Congenital hypoparathyroidism Developmental abnormality 


  1. 1.
    Petraglia F, Calza L, Garuh GC, Giardino L, De Ramundo BM, Angioni S. New aspects of placental endocrinology. J Endocrinol Invest. 1990;13:353–71.PubMedGoogle Scholar
  2. 2.
    Han VKM. The ontogeny of growth hormone, insulin-like growth factors and sex steroids: molecular aspects. Horm Res. 1996;45:61–6.PubMedGoogle Scholar
  3. 3.
    Efstratiadis A. Genetics of mouse growth. Int J Dev Biol. 1998;42:955–76.PubMedGoogle Scholar
  4. 4.
    Fowden AL. The insulin-like growth factors and feto-placental growth. Placenta. 2003;24:803–12.PubMedGoogle Scholar
  5. 5.
    Fowden A, Forhead AJ. Endocrine mechanisms of intrauterine programming. Reproduction. 2004;127:515–26.PubMedGoogle Scholar
  6. 6.
    Murphy VE, Smith R, Giles WB, et al. Endocrine regulation of human fetal growth: the role of the mother, placenta and fetus. Endocrine Rev. 2006;27:141–69.Google Scholar
  7. 7.
    Barker DJ, Bagby SP. Developmental antecedents of cardiovascular disease: a historical perspective. J Am Soc Nephrol. 2005;16:2537–44.PubMedGoogle Scholar
  8. 8.
    Phillips DW, Barker DJP, Hales CN, et al. Thinness at birth and insulin resistance in later life. Diabetologia. 1994;37:150–4.PubMedGoogle Scholar
  9. 9.
    Jones A, Godfrey KM, Wood P, Osmond C, Goulden P, Phillips DL. Fetal growth and the adrenocortical response to psychological stress. J Clin Endocrinol Metab. 2006;91:1868–71.PubMedGoogle Scholar
  10. 10.
    Karabulet AK, Layfield R, Pratten MK. Growth promoting effects of human placental lactogen during early organogenesis: a link to insulin-like growth factors. J Anat. 2001;198:651–62.Google Scholar
  11. 11.
    Gitau R, Cameron A, Fisk NM, Glover V. Fetal exposure to maternal cortisol. Lancet. 1998;352:707–8.PubMedGoogle Scholar
  12. 12.
    Brown RW, Chapman KE, Edwards CR, et al. Human placental 11 beta hydroxysteroid dehydrogenase: evidence for and partial purification of a distinct NAD-dependent isoform. Endocrinology. 1993;132:2614–21.PubMedGoogle Scholar
  13. 13.
    Sampath-Kumar R, Matthews SG, Yang K. 11 beta-hydroxysteroid dehydrogenase type 2 is the predominant isozyme in the guinea pig placenta: decreases in messenger ribonucleic acid and activity at term. Biol Reprod. 1998;59:1378–84.PubMedGoogle Scholar
  14. 14.
    Murphy VE, Clifton VL. Alterations in human placental 11 beta hydroxysteroid dehydrogenase type 1 and type 2 with gestational age and labour. Placenta. 2003;24:739–44.PubMedGoogle Scholar
  15. 15.
    Hardy DB, Yang K. The expression of 11 beta hydroxysteroid dehydrogenase type 2 is induced during trophoblast differentiation: effects of hypoxia. J Clin Endocrinol Metab. 2002;87:3696–701.PubMedGoogle Scholar
  16. 16.
    Sarkar S, Tsai SW, Nguyen TT, et al. Inhibition of 11 beta-hydroxy dehydrogenase type 2 by catecholamines via alpha-adrenergic signaling. Am J Physiol Regul Integr Comp Physiol. 2001;281:1966–74.Google Scholar
  17. 17.
    Langdown ML, Sugden ML. Enhanced GLUT1 and GLUT3 expression in dexamethasone-induced fetal growth retardation. Mol Cell Endocrinol. 2001;185:109–17.PubMedGoogle Scholar
  18. 18.
    Haggstrom M, Richfield D. Diagram of the pathways of human steroidogenesis. Wiver J Med. 2014;1(1). doi: 10.15347/wjm/2014.005.
  19. 19.
    Stark R, Frantz AG. ACTH-β-endorphin in pregnancy. Clin Perinatol. 1983;10:653–7.PubMedGoogle Scholar
  20. 20.
    Goodyer GC, Guyda H, Giroud CJP. Development of the hypothalamic-pituitary axis in the human fetus. In: Tolis G, Labrie G, Martin JB, Naftolin F, editors. Clinical neuroendocrinology: a pathophysiological approach. New York: Raven; 1979. p. 199–214.Google Scholar
  21. 21.
    Smith YF, Mullon DK, Hamosh M, Scolon JW, Hamosh P. Serum prolactin and respiratory distress syndrome in the newborn. Pediatr Res. 1979;14:93–5.Google Scholar
  22. 22.
    Sclare G. The histological structure of the thyroid in the newborn. Scott Med J. 1956;1:251–8.Google Scholar
  23. 23.
    Gray ES, Abramovich DR. Morphologic features of the anencephalic adrenal gland in early pregnancy. Am J Obstet Gynecol. 1980;137:491–5.PubMedGoogle Scholar
  24. 24.
    Young MC, Laurence KM, Hughes IA. Relationship between fetal adrenal morphology and anterior pituitary function. Horm Res. 1989;32:130–5.PubMedGoogle Scholar
  25. 25.
    Facchinetti F, Lanzani A, Genazzani AR. Fetal intermediate lobe is stimulated by parturition. Am J Obstet Gynecol. 1989;161:1267–70.PubMedGoogle Scholar
  26. 26.
    Houghton DC, Walker DW, Young IR, McMillen IC. Melatonin and the light-dark cycle separately influence daily behaviour and hormonal rhythms in the pregnant ewe and sheep fetus. Endocrinology. 1993;133:90–8.PubMedGoogle Scholar
  27. 27.
    Moncrieff MW, Hill DS, Archer J, Arthur LJH. Congenital absence of the pituitary gland and adrenal hypoplasia. Arch Dis Child. 1972;47:136–7.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Kjaer I, Keeling JW, Reintoft I, et al. Pituitary gland and sella turcica in human trisomy 18 fetuses. Am J Med Genet. 1998;76:87–92.PubMedGoogle Scholar
  29. 29.
    Kjaer I, Keeling JW, Reintoft I, Nolting D, Fischer-Hansen B. Pituitary gland and sella turcica in human trisomy 21 fetuses related to axial skeletal development. Am J Med Genet. 1998;80:494–500.PubMedGoogle Scholar
  30. 30.
    Naeye RL, Blanc WA. Organ and body growth in anencephaly. A quantitative, morphological study. Arch Pathol. 1971;91:140–7.PubMedGoogle Scholar
  31. 31.
    Karalis K, Goodwin G, Majzoub JA. Cortisol blockade of progesterone: a possible molecular mechanism involved in the initiation of human labour. Nat Med. 1996;2(5):556–60.PubMedGoogle Scholar
  32. 32.
    Hayek A, Driscol SG, Warshaw JB. Endocrine studies in anencephaly. J Clin Invest. 1973;52:1636–41.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Jack PMB, Milner RDG. Effect of decapitation and ACTH on somatic development of the rabbit fetus. Biol Neonate. 1975;26:195–204.PubMedGoogle Scholar
  34. 34.
    Van Assche FA, Gepts W, De Gasparo M. The endocrine pancreas in anencephalics: a histological and biochemical study. Biol Neonate. 1969;14:374–88.Google Scholar
  35. 35.
    Salazar H, Macaulay MA, Charles D, Pardi M. The human hypophysis in anencephaly. Arch Pathol. 1969;87:201–11.PubMedGoogle Scholar
  36. 36.
    Preece MA, Kearney PJ, Marshall WC. Growth hormone deficiency in congenital rubella. Lancet. 1977;11:842–4.Google Scholar
  37. 37.
    Faggiano M, Minozzi M, Lombardi G, Carella C, Criscuolo T. Two cases of the chromatin positive variety of ovarian dysgenesis (XO/XX mosaicism) associated with HGH deficiency and marginal impairment of other hypothalamic pituitary functions. Clin Genet. 1975;8:324–9.PubMedGoogle Scholar
  38. 38.
    Ishimoto H, Jaffe RB. Development and function of the human fetal adrenal cortex: a key component in the feto-placental unit. Endocr Rev. 2011;32:317–55.PubMedGoogle Scholar
  39. 39.
    Hui XG, Akahira J, Suzuki T, Nio M, Nakamura Y, Suzuki H, et al. Development of the human adrenal zona reticularis: morphometric and immunohistochemical studies from birth to adolescence. Endocrinology. 2009;203:241–52.Google Scholar
  40. 40.
    Buster JE. Fetal adrenal cortex. Clin Obstet Gynecol. 1980;23:803–24.PubMedGoogle Scholar
  41. 41.
    Parker CR, Atkinson MW, Owen J, Andrews WW. Dynamics of fetal adrenal, cholesterol and apolipoprotein B responses to antenatal betamethasone therapy. Am J Obstet Gynecol. 1996;174:562–5.PubMedGoogle Scholar
  42. 42.
    Kaludjerovic J, Ward WE. The interplay between estrogen and fetal adrenal cortex. J Nutr Metab. 2012;2012:837901. doi:  10.1155/2012/837901. Epub 2012 Mar 28.Google Scholar
  43. 43.
    Strauss JF, Martinez F, Kirikidou M. Placental steroid hormone synthesis: unique features and unanswered questions. Biol Reprod. 1996;54:303–11.PubMedGoogle Scholar
  44. 44.
    Fujieda K, Farman C, Reyes FI, Winter JSD. The control of steroidogenesis by the human fetal adrenal cells in tissue culture, III. The effects of various hormonal peptides. J Clin Endocrinol Metab. 1981;53:690–3.PubMedGoogle Scholar
  45. 45.
    Fujieda K, Farman C, Reyes FI, Winter JSD. The control of steroidogenesis by the human fetal adrenal cells in tissue culture, IV. The effects of exposure to placental steroids. J Clin Endocrinol Metab. 1982;54:89–94.PubMedGoogle Scholar
  46. 46.
    Coulter CL, Goldsmith PC, Messiano S, et al. Functional maturation of the primate fetal adrenal in vivo: 1. Role of insulin-like growth factors (IGFs), IGF-1 receptor, and IGF binding proteins, in growth. Endocrinology. 1996;137:4487–98.PubMedGoogle Scholar
  47. 47.
    Coulter CL, Read LC, Carr BR, Tarantal AF, Barry S, Styne DM. A role for epidermal growth factor in the morphological and functional maturation of the adrenal gland in the rhesus monkey in vivo. J Clin Endocrinol Metab. 1996;81:1254–60.PubMedGoogle Scholar
  48. 48.
    Mesiano S, Jaffe RB. Developmental and functional biology of the primate fetal adrenal cortex. Endocr Rev. 1997;18:378–403.PubMedGoogle Scholar
  49. 49.
    Artal R. Fetal adrenal medulla. Clin Obstet Gynaecol. 1980;23:825–36.Google Scholar
  50. 50.
    Sekido R, Lovell-Badge R. Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer. Nature. 2008;453:930–4. Note: Erratum: Nature. 2008;456: 824.Google Scholar
  51. 51.
    Jameson JL. Of mice and men: the tale of steroidogenic factor-1. J Clin Endocrinol Metab. 2004;89:5927–9.PubMedGoogle Scholar
  52. 52.
    Vidal V, Schedl A. Requirement of WT1 for gonad and adrenal development: insights from transgenic animals. Endocr Res. 2000;26:1075–82.PubMedGoogle Scholar
  53. 53.
    Kerenyi N. Congenital adrenal hypoplasia. Report of a case of extreme adrenal hypoplasia and neurohypophyseal aplasia. Arch Pathol. 1961;71:336–43.PubMedGoogle Scholar
  54. 54.
    Guo W, Burris TP, McCabe ER. Expression of DAX-1, the gene responsible for X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism in the hypothalamic–pituitary–adrenal–gonadal axis. Biochem Mol Med. 1995;56:8–13.PubMedGoogle Scholar
  55. 55.
    Hossain A, Li C, Saunders GF. Generation of two distinct functional isoforms of dosage-sensitive sex reversal-adrenal hypoplasia congenita-critical region on the X chromosome gene 1 (DAX-1) by alternative splicing. Mol Endocrinol. 2004;18:1428–37.PubMedGoogle Scholar
  56. 56.
    Larroche JC. Developmental pathology of the neonate. Amsterdam: Excerpta Medica; 1977. p. 220.Google Scholar
  57. 57.
    Becker MJ, Becker AE. Fat distribution in the adrenal cortex as an indication of the mode of intrauterine death. Hum Pathol. 1976;7:495–504.Google Scholar
  58. 58.
    Ikeda Y, Lister J, Boulton JM, Buyukpamkcu M. Congenital neuroblastoma, neuroblastoma in situ, and the normal fetal development of the adrenal gland. J Pediatr Surg. 1981;16:636–44.PubMedGoogle Scholar
  59. 59.
    Van Hale HM, Turkel SB. Neuroblastoma and adrenal morphologic features in anencephalic infants. Arch Pathol Lab Med. 1979;103:119–21.PubMedGoogle Scholar
  60. 60.
    Taweevisit M, Shuangshoti S, Thorner PS. Adrenal cytomegaly is a frequent pathologic finding in hemoglobin Bart hydrops fetalis. Pediatr Dev Pathol. 2012;15:187–91.Google Scholar
  61. 61.
    Fasano M, Greco MA. Proliferative activity of adrenal glands with adrenocortical cytomegaly measured by MIB-1 labelling index. Pediatr Pathol Lab Med. 1996;16:765–76.PubMedGoogle Scholar
  62. 62.
    DeSa DJ. Stress response and its relationship to cystic (pseudofollicular) change in the definitive cortex of the adrenal gland in stillborn infants. Arch Dis Child. 1978;53:769–76.Google Scholar
  63. 63.
    Gaillard DA, Lallemand AV, Moirot HH, Visseaux-Coletto BJ, Paradis PH. Fetal adrenal development during the second trimester of gestation. Pediatr Pathol. 1990;10:335–50.PubMedGoogle Scholar
  64. 64.
    Sandison AT. A form of lipoidosis of the adrenal cortex in an infant. Arch Dis Child. 1955;30:538–41.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Prader A, Gurtner HP. Das syndrome des Pseudohermaphroditismus masculinus bei kongenitaler Nebennierenrindenhyperplasie ohne Androgenuberproduktion (adrenaler Pseudohermaphroditismus masculinus). Helv Paediatr Acta. 1955;10:397–412.PubMedGoogle Scholar
  66. 66.
    Baker BY, Lin L, Kim CJ, Raza J, Smith CP, Miller WL, Achermann JC. Nonclassic congenital lipoid adrenal hyperplasia: a new disorder of the steroidogenic acute regulatory protein with very late presentation and normal male genitalia. J Clin Endocrinol Metab. 2006;91:4781–5.PubMedPubMedCentralGoogle Scholar
  67. 67.
    Kim CJ, Lin L, Huang N, Quigley CA, AvRuskin TW, Achermann JC, Miller WL. Severe combined adrenal and gonadal deficiency caused by novel mutations in the cholesterol side chain cleavage enzyme, P450scc. J Clin Endocrinol Metab. 2008;93:696–702.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Cagle PT, Hough AJ, Pysher J, et al. Comparison of adrenal cortical tumours in children and adults. Cancer. 1986;57(11):2235–37.PubMedGoogle Scholar
  69. 69.
    van Wassenaer AG, Kok JH. Hypothyroxinaemia and thyroid function after preterm birth. Semin Neonatol. 2004;9:3–11.PubMedGoogle Scholar
  70. 70.
    Thorpe-Beeston JG, Nicolaides KH, Felton CV, Butler J, McGregor AM. Maturation of the secretion of thyroid hormone and thyroid-stimulating hormone in the fetus. N Engl J Med. 1991;21:532–6.Google Scholar
  71. 71.
    Hobel CJ. Fetal thyroid. Clin Obstet Gynecol. 1980;23:779–90.PubMedGoogle Scholar
  72. 72.
    Fisher DA, Odell WD. Acute release of thyrotropin in the newborn. J Clin Invest. 1969;48:1670–7.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Bocian-Sobkowska J, Wozniak W, Malendowicz LK. Morphometric studies on the development of the human thyroid gland II. The late fetal life. Histol Histopathol. 1997;12L:79–84.Google Scholar
  74. 74.
    Ernst LM. Thyroid gland. In: Ernst LM, Ruchelli ED, Huff DS, editors. Color atlas of fetal and neonatal histology. 1st ed. Springer-Verlag New York; 2011. p. 214.Google Scholar
  75. 75.
    Potter EL, Craig JM. Pathology of the fetus and infant. 3rd ed. Chicago: Book Medical Publishers; 1976. p. 326.Google Scholar
  76. 76.
    Carpenter GR, Emery JL. Inclusion in the human thyroid. J Anat. 1976;122:77–89.PubMedPubMedCentralGoogle Scholar
  77. 77.
    Iancu T, Boyanower Y, Laurian N. Congenital goiter due to maternal ingestion of iodide. Am J Dis Child. 1974;128:528–30.PubMedGoogle Scholar
  78. 78.
    Perelman AH, Johnson RL, Clemens RD, Finberg HJ, Clewell WH, Trujillo L. Intrauterine diagnosis and treatment of fetal goitrous hypothyroidism. J Clin Endocrinol Metab. 1990;71:618–21.PubMedGoogle Scholar
  79. 79.
    Uhrmann S, Marks KH, Maisels MJ, et al. Thyroid function in the preterm infant: a longitudinal assessment. J Pediatr. 1978;92:968–73.PubMedGoogle Scholar
  80. 80.
    Bliddal S, Rasmussen AK, Sundberg K, Brocks V, Feldt-Rasmussen U. Antithyroid drug-induced fetal goitrous hypothyroidism. Nat Rev Endocrinol. 2011;7:396–406.PubMedGoogle Scholar
  81. 81.
    Danziger Y, Pertzelan A, Mimouni M. Transient congenital hypothyroidism after topical iodine in pregnancy. Arch Dis Child. 1987;62:295–6.PubMedPubMedCentralGoogle Scholar
  82. 82.
    Pemberton HN, Franklyn JA, Kilby MD. Thyroid hormones and fetal brain development. Minerva Ginecol. 2005;57:367–78.PubMedGoogle Scholar
  83. 83.
    Fisher DA. Fetal thyroid function: diagnosis and management of fetal thyroid disorders. Clin Obstet Gynecol. 1997;40:16–31.PubMedGoogle Scholar
  84. 84.
    Polak M. Hyperthyroidism in early infancy: pathogenesis, clinical features and diagnosis with a focus on neonatal hyperthyroidism. Thyroid. 1998;8:1171–7.PubMedGoogle Scholar
  85. 85.
    Volumenie JL, Polak M, Guibourdenche J, Oury JF, Vuillard E, Sibony O, et al. Management of fetal thyroid goitres: a report of 11 cases in a single perinatal unit. Prenat Diagn. 2000;20:799–806.PubMedGoogle Scholar
  86. 86.
    Carvalheiras G, Faria R, Braga J, Vasconcelos C. Fetal outcome in autoimmune diseases. Autoimmun Rev. 2012;11:A520–30.PubMedGoogle Scholar
  87. 87.
    Polak M. Thyroid disorders during pregnancy: impact on the fetus. Horm Res Paediatr. 2011;76:97–101.PubMedGoogle Scholar
  88. 88.
    Zakarija M, McKenzie JM. Pregnancy-associated changes in the thyroid-stimulating antibody of Graves’ disease and the relationship to neonatal hyperthyroidism. J Clin Endocrinol Metab. 1983;57:1036–40.PubMedGoogle Scholar
  89. 89.
    Polak M, Legac I, Vuillard E, Guibourdenche J, Castanet M, Luton D. Congenital hyperthyroidism: the fetus as a patient. Horm Res. 2006;65:235–42.PubMedGoogle Scholar
  90. 90.
    Davies TF, Ando T, Lin RY, Tomer Y, Latif R. Thyrotropin receptor-associated diseases: from adenoma to Grave disease. J Clin Invest. 2005;115:1972–83.PubMedPubMedCentralGoogle Scholar
  91. 91.
    Huel C, Guibourdenche J, Vuillard E, Ouahba J, Piketty M, Oury JF, Luton D. Use of ultrasound to distinguish between fetal hyperthyroidism and hypothyroidism on discovery of a goiter. Ultrasound Obstet Gynecol. 2009;33:412–20.PubMedGoogle Scholar
  92. 92.
    Heckel S, Favre R, Schlienger JL, Soskin P. Diagnosis and successful treatment of fetal goitrous hyperthyroidism caused by maternal Graves disease. A case report. Fetal Diagn Ther. 1997;12:54–8.PubMedGoogle Scholar
  93. 93.
    Mills SE, Allen MS. Occult papillary carcinoma of thyroid gland. Hum Pathol. 1986;17:1179–81.PubMedGoogle Scholar
  94. 94.
    Fleischman AR. Fetal parathyroid gland and calcium homeostasis. Clin Obstet Gynecol. 1980;23:791–802.PubMedGoogle Scholar
  95. 95.
    Kovacs CS, Kronenberg HM. Maternal-fetal calcium and bone metabolism during pregnancy, puerperium, and lactation. Endocr Rev. 1997;18:832–72.PubMedGoogle Scholar
  96. 96.
    Simmonds CS, Karsenty G, Karaplis AC, Kovacs CS. Parathyroid hormone regulates fetal-placental mineral homeostasis. J Bone Miner Res. 2010;24:594–605.Google Scholar
  97. 97.
    Maclsaac RJ, Heath JA, Rodda CP. Role of fetal parathyroid glands and parathyroid hormon-related protein in the regulation of placental transport of calcium, magnesium and inorganic phosphate. Reprod Fertil Dev. 1991;3:447–57.Google Scholar
  98. 98.
    Harach HR, Vujanic GM. Intrathyroid parathyroid. Pediatr Pathol. 1993;13:71–4.PubMedGoogle Scholar
  99. 99.
    Peden VH. True idiopathic hypoparathyroidism as a sex linked recessive trait. Am J Hum Genet. 1960;12:323–7.PubMedPubMedCentralGoogle Scholar
  100. 100.
    Thakker RV. Genetics of endocrine and metabolic disorders: parathyroid. Rev Endocr Metab Disord. 2004;5:37–51.PubMedGoogle Scholar
  101. 101.
    Baron J, Winer KK, Yanovski JA, Cunningham AW, Laue L, Zimmerman R, Cutler GB. Mutations in the Ca2+-sensing receptor gene cause autosomal dominant and sporadic hypoparathyroidism. Hum Mol Genet. 1996;5:601–6.PubMedGoogle Scholar
  102. 102.
    Mannstadt M, Bertrand G, Muresan M, Weryha G, Leheup B, Pulusani SR, et al. Dominant-negative GCMB mutations cause an autosomal dominant form of hypoparathyroidism. J Clin Endocrinol Metab. 2008;93:3568–76.PubMedPubMedCentralGoogle Scholar
  103. 103.
    Bowl MR, Nesbit A, Harding B, Levy E, Jefferson A, Volpi E, et al. An interstitial deletion-insertion involving chromosomes 2p25.3 and Xq27.1, near SOX3, causes X-linked recessive hypoparathyroidism. J Clin Invest. 2005;115:2822–31.PubMedPubMedCentralGoogle Scholar
  104. 104.
    Parvari R, Hershkovitz E, Grossman N, Gorodischer R, Loeys B, Zecic A, et al. Mutation of TBCE causes hypoparathyroidism – retardation – dysmorphism and autosomal recessive Kenny-Caffey syndrome. Nat Genet. 2002;32:448–52.PubMedGoogle Scholar
  105. 105.
    Gray MJ, van Kogelenberg M, Beddow R, Morgan T, Wordsworth P, Shears DJ, et al. A new acro-osteolysis syndrome caused by duplications including PTHLH. J Hum Genet. 2014;59:484–7.PubMedGoogle Scholar
  106. 106.
    Hsu SC, Levine MA. Perinatal calcium metabolism: physiology and pathophysiology. Semin Neonatal. 2004;9:23–36.Google Scholar
  107. 107.
    Nako Y, Fukushima N, Tomomasa T, Nagashima K, Kuroume T. Hypervitaminosis D after prolonged feeding with a premature formula. Pediatrics. 1993;92:862–4.PubMedGoogle Scholar
  108. 108.
    Pollak MR, Brown EM, Chou YH, Hebert SC, Marx SJ, Steinmann B, et al. Mutations in the human Ca2+ sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell. 1993;75:1297–303.PubMedGoogle Scholar
  109. 109.
    Schipani E, Langman CB, Parfitt AM, Jensen GS, Kikuchi S, Kooh SW, et al. Constitutively activated receptors for parathyroid hormone and parathyroid hormone-related peptide in Jansen’s metaphyseal chondrodysplasia. N Engl J Med. 1996;335:708–14.PubMedGoogle Scholar
  110. 110.
    Meng X, Lu X, Li Z, Green ED, Massa H, Trask BJ, et al. Complete physical map of the common deletion region in Williams syndrome and identification and characterization of three novel genes. Hum Genet. 1998;103:590–9.PubMedGoogle Scholar
  111. 111.
    Kruse K, Pankau R, Gosch A, Wohlfahrt K. Calcium metabolism in Williams-Beuren syndrome. J Pediatr. 1992;121:902–7.PubMedGoogle Scholar
  112. 112.
    Kruse K, Irle U, Uhlig R. Elevated 1,25 dihydroxyvitamin D serum concentrations in infants with subcutaneous fat necrosis. J Pediatr. 1993;122:460–3.PubMedGoogle Scholar
  113. 113.
    Lakhir F, Lawson D, Schatz D. Fatal parathyroid hormone-related protein humoral hypercalcaemia of malignancy in a 3-month old infant. Eur J Pediatr. 1994;153:718–20.Google Scholar
  114. 114.
    Michigami T, Yamato H, Mushiake S, Nakayama M, Yoneda A, Satomura K, et al. Hypercalcaemia associated with infantile fibrosarcoma producing parathyroid hormone-related protein. J Clin Endocrinol Metab. 1996;81:1090–5.PubMedGoogle Scholar
  115. 115.
    Liu HM, Potter EL. Development of the human pancreas. Arch Pathol. 1962;74:439–52.PubMedGoogle Scholar
  116. 116.
    Jaffe R, Hashida Y, Yunis EJ. Pancreatic pathology in hyperinsulinemic hypoglycemia of infancy. Lab Invest. 1980;42:356–65.PubMedGoogle Scholar
  117. 117.
    Ruchelli ED. Pancreas. In: Ernst LM, Ruchelli ED, Huff DS, editors. Color atlas of fetal and neonatal histology. 1st ed. Springer-Verlag New York; 2011. p. 82–5.Google Scholar
  118. 118.
    Hay Jr WW. Placental-fetal glucose exchange and fetal glucose metabolism. Trans Am Clin Climatol Assoc. 2006;117:321–39.PubMedPubMedCentralGoogle Scholar
  119. 119.
    Suman Rao PN, Shashidhar A, Ashok C. In utero fuel homeostasis: lesson for a clinician. Indian J Endocrinol Metab. 2013;17:60–8.Google Scholar
  120. 120.
    Kalhan S, Parimi P. Gluconeogenesis in the fetus and neonate. Semin Perinatol. 2000;24:94–106.PubMedGoogle Scholar
  121. 121.
    Hill DE. Fetal endocrine pancreas. Clin Obstet Gynecol. 1980;23:837–47.PubMedGoogle Scholar
  122. 122.
    Staffers DA, Zinkin NT, Stanojevic V, Clarke WL, Habener JF. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet. 1997;15:106–10.Google Scholar
  123. 123.
    Arnoux JB, Verkarre V, Saint-Martin C, Montravers F, Brassier A, Valayannopoulos V, et al. Congenital hyperinsulinism: current trends in diagnosis and therapy. Orphanet J Rare Dis. 2011;6:63.PubMedPubMedCentralGoogle Scholar
  124. 124.
    Dunne MJ, Cosgrove KE, Stephen RM, Aynsley-Green A, Lindley KJ. Hyperinsulinism in infancy: from basic science to clinical disease. Physiol Rev. 2004;84:239–75.PubMedGoogle Scholar
  125. 125.
    Kapoor RR, Locke J, Colclough K, Wales J, Conn JJ, Hattersley AT, et al. Persistent hyperinsulinemic hypoglycemia and maturity-onset diabetes of the young due to heterozygous HNF4A mutations. Diabetes. 2008;57:1659–63.PubMedGoogle Scholar
  126. 126.
    Arya VB, Mohammed Z, Blankenstein O, De Lonlay P, Hussain K. Hyperinsulinaemic hypoglycaemia. Horm Metab Res. 2014;46:157–70.PubMedGoogle Scholar
  127. 127.
    Bell R, Glinianaia SV, Tennant PW, Bilous RW, Rankin J. Peri-conception hyperglycaemia and nephropathy are associated with risk of congenital anomaly in women with pre-existing diabetes: a population-based cohort study. Diabetologia. 2012;55:936–47.Google Scholar
  128. 128.
    Wilmot EG, Mansell P. Diabetes and pregnancy. Clin Med. 2014;6:677–80.Google Scholar
  129. 129.
    Gutgesell HP, Spear M, Rosenberg HS. Characterisation of the cardiomyopathy of infants of diabetic mothers. Circulation. 1980;61:441–50.PubMedGoogle Scholar
  130. 130.
    Silverman JL. Eosinophil infiltration in the pancreas of infants of diabetic mothers. Diabetes. 1963;12:528–37.PubMedGoogle Scholar
  131. 131.
    Nelson L, Turkel S, Shulman I, Gabbe S. Pancreatic islet fibrosis in young infants of diabetic mothers. Lancet. 1977;11:362–3.Google Scholar
  132. 132.
    Bloodworth JMB, editor. Endocrine pathology. Baltimore: Williams and Wilkins; 1982. p. 625.Google Scholar
  133. 133.
    Milner RDG, Barson AJ, Ashworth MA. Human fetal pancreatic insulin secretion in response to ionic and other stimuli. J Endocrinol. 1971;51:323–32.PubMedGoogle Scholar
  134. 134.
    Milner RDG. Amino acids and beta cell growth. In: Merkatz IR, Adam PAJ, editors. The diabetic pregnancy. New York: Grune and Stratton; 1979. p. 145–53.Google Scholar
  135. 135.
    Hiden U, Glitzner E, Hartmann M, Desoye G. Insulin and the IGF system in the human placenta of normal and diabetic pregnancies. J Anat. 2009;215:60–8.PubMedPubMedCentralGoogle Scholar
  136. 136.
    Hiden U, Froehlich J, Desoye G. Diabetes and placenta. In: Kay HH, Nelson DM, Wang Y, editors. The placenta: from development to disease. 1st ed. Wiley-Blackwell, Oxford, UK. 2011. p. 228–35.Google Scholar
  137. 137.
    Cvitic S, Desoye G, Ursula H. Glucose, insulin and oxygen interplay in placental hypervascularisation in diabetes mellitus. Biomed Res Int. 2014:145846. doi:  10.1155/2014/145846. Epub 2014 Sep 2.Google Scholar
  138. 138.
    Warren S, Le Compte PM, Legg MA. The pathology of diabetes mellitus. 4th ed. Philadelphia: Lea & Febiger; 1966. p. 406–33.Google Scholar
  139. 139.
    Hubbell JP, Muirhead DM, Drorbaugh JE. The new-born infant of the diabetic mother. Med Clin North Am. 1965;49:1035–52.PubMedGoogle Scholar
  140. 140.
    Cunningham MD, Desai NS, Thompson SA, Greene JM. Amniotic fluid phosphatidyl glycerol in diabetic pregnancies. Am J Obstet Gynecol. 1978;131:719–24.PubMedGoogle Scholar
  141. 141.
    Mathew PM, Young JM, Abu-Osba YK, et al. Persistent neonatal hyperinsulinism. Clin Pediatr Phila. 1988;27:148–51.PubMedGoogle Scholar
  142. 142.
    Kawakita R, Sugimine H, Nagai S, Kawai M, Kusuda S, Yorifuji T. Clinical characteristics of congenital hyperinsulinemic hypoglycemia in infant: a nationwide epidemiological survey in Japan. Nihon Shonika Gakkai Zasshi. 2011;115:563–9 (in Japanese).Google Scholar
  143. 143.
    Yorifuji T, Masue M, Nishibori H. Congenital hyperinsulinism: global and Japanese perspectives. Pediatr Int. 2014;56:467–76.PubMedGoogle Scholar
  144. 144.
    Goossens A, Gepts W, Saudubray JM, et al. Diffuse and focal nesidioblastosis. A clinicopathological study of 24 patients with persistent neonatal hyperinsulinemic hypoglycemia. Am J Surg Pathol. 1989;13:766–75.PubMedGoogle Scholar
  145. 145.
    de Lonlay P, Fournet JC, Rahier J, Gross-Morand MS, Poggi-Travert F, Foussier V, et al. Somatic deletion of the imprinted 11p15 region in sporadic persistent hyperinsulinemic hypoglycemia of infancy is specific of focal adenomatous hyperplasia and endorses partial pancreatectomy. J Clin Invest. 1997;100:802–7.PubMedPubMedCentralGoogle Scholar
  146. 146.
    Verkarre V, Fournet JC, de Lonlay P, Gross-Morand MS, Devillers M, Rahier J, et al. Paternal mutation of the sulfonylurea receptor (SUR1) gene and maternal loss of 11p15 imprinted genes lead to persistent hyperinsulinism in focal adenomatous hyperplasia. J Clin Invest. 1998;102:1286–91.PubMedPubMedCentralGoogle Scholar
  147. 147.
    Cohen MM. Beckwith-Wiedemann syndrome: historical, clinicopathological, and etiopathogenic perspectives. Pediatr Dev Pathol. 2005;8:287–304.PubMedGoogle Scholar
  148. 148.
    Ashton IK, Aynsley-Green A. Somatomedin in an infant with Beckwith’s syndrome. Early Hum Dev. 1978;1:357–66.PubMedGoogle Scholar
  149. 149.
    Aynsley-Green A. Hypoglycemia in infants and children. Clin Endocrinol Metab. 1982;11:159–94.PubMedGoogle Scholar
  150. 150.
    Sun F-L, Dean WL, Kelsey G, Allen ND, Reik W. Transactivation of Igf-2 in a mouse model of Beckwith-Wiedemann syndrome. Nature. 1997;389:809–15.PubMedGoogle Scholar
  151. 151.
    Catchpoole D, Lamm WWK, Valler D, Temple IK, Joyce JA, Reik W, et al. Epigenetic modification and uniparental inheritance of H19 in Beckwith-Wiedemann syndrome. J Med Genet. 1997;34:353–9.PubMedPubMedCentralGoogle Scholar
  152. 152.
    Greco MA, Finegold MJ. Familial giant cell hepatitis. Report of two cases and a review of the literature. Arch Pathol. 1973;95:240–4.PubMedGoogle Scholar
  153. 153.
    Yoon JW, Austin M, Onodera R, Notkins AL. Virus induced diabetes mellitus. Isolation of a virus from a pancreas of a child with diabetic ketoacidosis. N Engl J Med. 1979;300:1173–9.PubMedGoogle Scholar
  154. 154.
    Kloppel G. Islet histopathology in diabetes mellitus. In: Kloppel G, Heitz PU, editors. Pancreatic pathology. Edinburgh: Churchill Livingstone; 1984. p. 173–4.Google Scholar

Copyright information

© Springer International Publishing 2015

Authors and Affiliations

  1. 1.Department of HistopathologyUniversity Hospitals of Leicester NHS Trust, Leicester Royal InfirmaryLeicesterUK
  2. 2.Department of HistopathologyCambridge University Hospitals NHS Foundation Trust, Addenbrooke’s HospitalCambridgeUK

Personalised recommendations