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Classification of Pseudohypoparathyroidism and Differential Diagnosis

  • Giovanna MantovaniEmail author
  • Francesca M. Elli
Chapter

Abstract

Pseudohypoparathyroidism (PHP) exemplifies a quite unusual form of hormone resistance as the underlying molecular defect is a partial deficiency of the α subunit of the stimulatory G protein (Gsα), a key regulator of cAMP signaling pathway, rather than the hormone receptor itself. PHP, together with Albright hereditary osteodystrophy (AHO), is a rare disorder encompassing heterogeneous features, such as brachydactyly, ectopic ossifications, short stature, mental retardation, and endocrine deficiencies due to resistance to the action of different hormones, primarily PTH. The two main subtypes of PHP are caused by mutations and/or methylation defects within the imprinted GNAS cluster, whose main transcript is Gsα. Moreover, mutations in the PRKAR1A and PDE4D genes, both crucial as GNAS for cAMP-mediated signaling, have been demonstrated in patients with acrodysostosis, a disease of bone formation with characteristics similar to AHO, while small deletions of chromosome 2 may also lead to the AHO phenotype. The clinical and molecular overlap among these different but related disorders represents a challenge for endocrinologists as to differential diagnosis and genetic counseling.

Keywords

Pseudohypoparathyroidism Albright’s hereditary osteodystrophy Hormone resistance GNAS Imprinting 

References

  1. 1.
    Albright F, Burnett CH, Smith CH et al (1942) Pseudohypoparathyroidism: an example of “Seabright-Bantam syndrome”. Endocrinology 30:922–932Google Scholar
  2. 2.
    Eyre WG, Reed WB (1971) Albright’s hereditary osteodystrophy with cutaneous bone formation. Arch Dermatol 104:634–642CrossRefPubMedGoogle Scholar
  3. 3.
    Farfel Z, Friedman E (1986) Mental deficiency in pseudohypoparathyroidism type I is associated with Ns-protein deficiency. Ann Intern Med 105(2):197–199CrossRefPubMedGoogle Scholar
  4. 4.
    Tashjian AH Jr, Frantz AG, Lee JB (1966) Pseudohypoparathyroidism: assays of parathyroid hormone and thyrocalcitonin. Proc Natl Acad Sci U S A 56(4):1138–1142CrossRefPubMedCentralPubMedGoogle Scholar
  5. 5.
    Chase LR, Melson GL, Aurbach GD (1969) Pseudohypoparathyroidism: defective excretion of 3’,5’-AMP in response to parathyroid hormone. J Clin Invest 48(10):1832–1844CrossRefPubMedCentralPubMedGoogle Scholar
  6. 6.
    Albright F, Forbes AP, Henneman PH (1952) Pseudo-pseudohypoparathyroidism. Trans Assoc Am Physicians 65:337–350PubMedGoogle Scholar
  7. 7.
    Farfel Z, Brothers VM, Brickman AS et al (1981) Pseudohypoparathyroidism: inheritance of deficient receptor-cyclase coupling activity. Proc Natl Acad Sci U S A 78(5):3098–3102CrossRefPubMedCentralPubMedGoogle Scholar
  8. 8.
    Fitch N (1982) Albright’s hereditary osteodystrophy: a review. Am J Med Genet 11(1):11–29CrossRefPubMedGoogle Scholar
  9. 9.
    Weinberg AG, Stone RT (1971) Autosomal dominant inheritance in Albright’s hereditary osteodystrophy. J Pediatr 79(6):996–999CrossRefPubMedGoogle Scholar
  10. 10.
    Levine MA, Downs RW, Singer M et al (1980) Deficient activity of guanine nucleotide regulatory protein in erythrocytes from patients with pseudohypoparathyroidism. Biochem Biophys Res Commun 94:1319–1324CrossRefPubMedGoogle Scholar
  11. 11.
    Levine MA, Downs RW Jr, Moses AM et al (1983) Resistance to multiple hormones in patients with pseudohypoparathyroidism. Association with deficient activity of guanine nucleotide regulatory protein. Am J Med 74(4):545–556CrossRefPubMedGoogle Scholar
  12. 12.
    Weinstein LS, Gejman PV, Friedman E et al (1990) Mutations of the Gs alpha-subunit gene in Albright hereditary osteodystrophy detected by denaturing gradient gel electrophoresis. Proc Natl Acad Sci U S A 87(21):8287–8290CrossRefPubMedCentralPubMedGoogle Scholar
  13. 13.
    Davies SJ, Hughes HE (1993) Imprinting in Albright’s hereditary osteodystrophy. J Med Genet 30(2):101–103CrossRefPubMedCentralPubMedGoogle Scholar
  14. 14.
    Levine MA, Modi WS, O’Brien SJ (1991) Mapping of the gene encoding the alpha subunit of the stimulatory G protein of adenylyl cyclase (GNAS1) to 20q13.2–q13.3 in human by in situ hybridization. Genomics 11(2):478–479CrossRefPubMedGoogle Scholar
  15. 15.
    Patten JL, Johns DR, Valle D et al (1990) Mutation in the gene encoding the stimulatory G protein of adenylate cyclase in Albright’s hereditary osteodystrophy. N Engl J Med 322(20):1412–1419CrossRefPubMedGoogle Scholar
  16. 16.
    Weinstein LS, Liu J, Sakamoto A et al (2004) Minireview: GNAS: normal and abnormal functions. Endocrinology 145(12):5459–5464CrossRefPubMedGoogle Scholar
  17. 17.
    Weinstein LS, Yu S, Warner DR et al (2001) Endocrine manifestations of stimulatory G protein α-subunit mutations and the role of genomic imprinting. Endocr Rev 22:675–705PubMedGoogle Scholar
  18. 18.
    Levine MA (2002) Pseudohypoparathyroidism. In: Bilezikian JP, Raisz LG, Rodan GA (eds) Principles of bone biology. Academic, New York, pp 1137–1163CrossRefGoogle Scholar
  19. 19.
    Shima M, Nose O, Shimizu K et al (1988) Multiple associated endocrine abnormalities in a patient with pseudohypoparathyroidism type 1a. Eur J Pediatr 147:536–538CrossRefPubMedGoogle Scholar
  20. 20.
    Liu J, Erlichman B, Weinstein LS (2003) The stimulatory G protein α-subunit Gsα is imprinted in human thyroid glands: implications for thyroid function in pseudohypoparathyroidism types 1A and 1B. J Clin Endocrinol Metab 88:4336–4341CrossRefPubMedGoogle Scholar
  21. 21.
    Kaji M, Umeda K, Ashida M et al (2001) A case of pseudohypoparathyroidism type la complicated with growth hormone deficiency: recovery of growth hormone secretion after vitamin D therapy. Eur J Pediatr 160:679–681CrossRefPubMedGoogle Scholar
  22. 22.
    Scott DC, Hung W (1995) Pseudohypoparathyroidism type Ia and growth hormone deficiency in two siblings. J Pediatr Endocrinol Metab 8(3):205–207CrossRefPubMedGoogle Scholar
  23. 23.
    Zwermann O, Piepkorn B, Engelbach M et al (2002) Abnormal pentagastrin response in a patient with pseudohypoparathyroidism. Exp Clin Endocrinol Diabetes 110:86–91CrossRefPubMedGoogle Scholar
  24. 24.
    Vlaeminck-Guillem V, D’Herbomez M, Pigny P et al (2001) Pseudohypoparathyroidism Ia and hypercalcitoninemia. J Clin Endocrinol Metab 86:3091–3096CrossRefPubMedGoogle Scholar
  25. 25.
    Bastepe M, Lane AH, Jüppner H (2001) Paternal uniparental isodisomy of chromosome 20q (patUPD20q)–and the resulting changes in GNAS1 methylation–as a plausible cause of pseudohypoparathyroidism. Am J Hum Genet 68:1283–1289CrossRefPubMedCentralPubMedGoogle Scholar
  26. 26.
    Bastepe M, Pincus JE, Sugimoto T et al (2001) Positional dissociation between the genetic mutation responsible for pseudohypoparathyroidism type Ib and the associated methylation defect at exon A/B: evidence for a long-range regulatory element within the imprinted GNAS1 locus. Hum Mol Genet 10:1231–1241CrossRefPubMedGoogle Scholar
  27. 27.
    Liu J, Litman D, Rosenberg MJ et al (2000) A GNAS imprinting defect in pseudohypoparathyroidism type Ib. J Clin Invest 106:1167–1174CrossRefPubMedCentralPubMedGoogle Scholar
  28. 28.
    Kelsey G (2010) Imprinting on chromosome 20: tissue-specific imprinting and imprinting mutations in the GNAS locus. Am J Med Genet C Semin Med Genet 154C:377–386CrossRefPubMedGoogle Scholar
  29. 29.
    Mantovani G, Bondioni S, Linglart A et al (2007) Genetic analysis and evaluation of resistance to thyrotropin and growth hormone-releasing hormone in pseudohypoparathyroidism type Ib. J Clin Endocrinol Metab 92:3738–3742CrossRefPubMedGoogle Scholar
  30. 30.
    de Nanclares GP, Fernández-Rebollo E, Santin I et al (2007) Epigenetic defects of GNAS in patients with pseudohypoparathyroidism and mild features of Albright hereditary osteodystrophy. J Clin Endocrinol Metab 92:2370–2373CrossRefPubMedGoogle Scholar
  31. 31.
    Mariot V, Maupetit-Méhouas S, Sinding C et al (2008) A maternal epimutation of GNAS leads to Albright osteodystrophy and parathyroid hormone resistance. J Clin Endocrinol Metab 93:661–665CrossRefPubMedGoogle Scholar
  32. 32.
    Unluturk U, Harmanci A, Babaoglu M et al (2008) Molecular diagnosis and clinical characterization of pseudohypoparathyroidism type-Ib in a patient with mild Albright hereditary osteodystrophy-like features, epileptic seizures, and defective renal handling of uric acid. Am J Med Sci 336:84–90CrossRefPubMedGoogle Scholar
  33. 33.
    Mantovani G, deSanctis L, Barbieri AM et al (2010) Pseudohypoparathyroidism and GNAS epigenetic defects: clinical evaluation of Albright hereditary osteodystrophy and molecular analysis in 40 patients. J Clin Endocrinol Metab 95:651–658CrossRefPubMedGoogle Scholar
  34. 34.
    Elli FM, DeSanctis L, Bollati V et al (2014) Quantitative analysis of methylation defects and correlation with clinical characteristics in patients with Pseudohypoparathyroidism type I and GNAS epigenetic alterations. J Clin Endocrinol Metab 99(33):E508–E517PubMedGoogle Scholar
  35. 35.
    Spiegel AM, Shenker A, Weinstein LS (1992) Receptor-effector coupling by G proteins: implications for normal and abnormal signal transduction. Endocr Rev 13(3):536–565CrossRefPubMedGoogle Scholar
  36. 36.
    Spiegel AM (1996) Mutations in G proteins and G protein-coupled receptors in endocrine disease. J Clin Endocrinol Metab 81(7):2434–2442PubMedGoogle Scholar
  37. 37.
    Farzel Z, Bourne HR, Iiri T (1999) The expanding spectrum of G protein diseases. N Engl J Med 340(13):1012–1020CrossRefGoogle Scholar
  38. 38.
    Lania A, Mantovani G, Spada A (2001) G protein mutations in endocrine diseases. Eur J Endocrinol 145(5):543–559CrossRefPubMedGoogle Scholar
  39. 39.
    Mantovani G, Spada A (2006) Mutations in the Gs alpha gene causing hormone resistance. Best Pract Res Clin Endocrinol Metab 20(4):501–513CrossRefPubMedGoogle Scholar
  40. 40.
    Wettschureck N, Offermanns S (2005) Mammalian G proteins and their cell type specific functions. Physiol Rev 85(4):1159–1204CrossRefPubMedGoogle Scholar
  41. 41.
    Potts JT (2005) Parathyroid hormone: past and present. J Endocrinol 187(3):311–325CrossRefPubMedGoogle Scholar
  42. 42.
    Gensure RC, Gardella TJ, Juppner H (2005) Parathyroid hormone and parathyroid hormone-related peptide and their receptors. Biochem Biophys Res Commun 328:666–678CrossRefPubMedGoogle Scholar
  43. 43.
    Gardner D, Shoback D (2011) Greenspan's basic & clinical endocrinology, 9th edn. McGraw Hill, New York, p 232Google Scholar
  44. 44.
    Poole K, Reeve J (2005) Parathyroid hormone – a bone anabolic and catabolic agent. Curr Opin Pharmacol 5(6):612–617CrossRefPubMedGoogle Scholar
  45. 45.
    Breslau NA, Weinstock RS (1988) Regulation of 1,25 (OH)2D synthesis in hypoparathyroidism and pseudohypoparathyroidism. Am J Physiol 255:E730–E736PubMedGoogle Scholar
  46. 46.
    Drezner MK, Neelon FA, Haussler M et al (1976) 1,25-Dihydroxycholecalciferol deficiency: the probable cause of hypocalcemia and metabolic bone disease in pseudohypoparathyroidism. J Clin Endocrinol Metab 42(4):621–628CrossRefPubMedGoogle Scholar
  47. 47.
    Stone MD, Hosking DJ, Garcia-Himmelstine C et al (1993) The renal response to exogenous parathyroid hormone in treated pseudohypoparathyroidism. Bone 14(5):727–735CrossRefPubMedGoogle Scholar
  48. 48.
    Kidd GS, Schaaf M, Adler RA et al (1980) Skeletal responsiveness in pseudohypoparathyroidism: a spectrum of clinical disease. Am J Med 68:772–781CrossRefPubMedGoogle Scholar
  49. 49.
    Murray TM, Rao LG, Wong MM et al (1993) Pseudohypoparathyroidism with osteitis fibrosa cystica: direct demonstration of skeletal responsiveness to parathyroid hormone in cells cultured from bone. J Bone Miner Res 8:83–91CrossRefPubMedGoogle Scholar
  50. 50.
    Eubanks PJ, Stabile BE (1998) Osteitis fibrosa cystica with renal parathyroid hormone resistance: a review of pseudohypoparathyroidism with insight into calcium homeostasis. Arch Surg 133:673–676CrossRefPubMedGoogle Scholar
  51. 51.
    Cohen RD, Vince FP (1969) Pseudohypoparathyroidism with raised plasma alkaline phosphatase. Arch Dis Child 44:96–101CrossRefPubMedCentralPubMedGoogle Scholar
  52. 52.
    Kolb FO, Steinbach HL (1962) Pseudohypoparathyroidism with secondary hyperparathyroidism and osteitis fibrosa. J Clin Endocrinol Metab 22:59–70CrossRefPubMedGoogle Scholar
  53. 53.
    Tollin SR, Perlmutter S, Aloia JF (2000) Serial changes in bone mineral density and bone turnover after correction of secondary hyperparathyroidism in a patient with pseudohypoparathyroidism type Ib. J Bone Miner Res 15:1412–1416CrossRefPubMedGoogle Scholar
  54. 54.
    Ish-Shalom S, Rao LG, Levine MA et al (1996) Normal parathyroid hormone responsiveness of bone-derived cells from a patient with pseudohypoparathyroidism. J Bone Miner Res 11:8–14CrossRefPubMedGoogle Scholar
  55. 55.
    Drezner M, Neelon FA, Lebovitz HE (1973) Pseudohypoparathyroidism type II: a possible defect in the reception of the cyclic AMP signal. N Engl J Med 289:1056–1060CrossRefPubMedGoogle Scholar
  56. 56.
    Wemeau JL, Balavoine AS, Ladsous M et al (2006) Multihormonal resistance to parathyroid hormone, thyroid stimulating hormone, and other hormonal and neurosensory stimuli in patients with pseudohypoparathyroidism. J Pediatr Endocrinol Metab 19(Suppl 2):653–661PubMedGoogle Scholar
  57. 57.
    Germain-Lee EL (2006) Short stature, obesity, and growth hormone deficiency in pseudohypoparathyroidism type Ia. Pediatr Endocrinol Rev 3:318–327PubMedGoogle Scholar
  58. 58.
    Levine MA, Jap TS, Hung W (1985) Infantile hypothyroidism in two sibs: an unusual presentation of pseudohypoparathyroidism type Ia. J Pediatr 107:919–922CrossRefPubMedGoogle Scholar
  59. 59.
    Pohlenz J, Ahrens W, Hiort O (2003) A new heterozygous mutation (L338N) in the human Gsα (GNAS1) gene as a cause for congenital hypothyroidism in Albright’s hereditary osteodystrophy. Eur J Endocrinol 148:463–468CrossRefPubMedGoogle Scholar
  60. 60.
    Riepe FG, Ahrens W, Krone N et al (2005) Early manifestation of calcinosis cutis in pseudohypoparathyroidism type Ia associated with a novel mutation in the GNAS gene. Eur J Endocrinol 152:515–519CrossRefPubMedGoogle Scholar
  61. 61.
    Pinsker JE, Rogers W, McLean S et al (2006) Pseudohypoparathyroidism type 1a with congenital hypothyroidism. J Pediatr Endocrinol Metab 19:1049–1052CrossRefPubMedGoogle Scholar
  62. 62.
    Mantovani G, Spada A (2006) Resistance to growth hormone releasing hormone and gonadotropins in Albright’s hereditary osteodystrophy. J Pediatr Endocrinol Metab 19:663–670CrossRefPubMedGoogle Scholar
  63. 63.
    Mantovani G, Maghnie M, Weber G et al (2003) Growth hormone-releasing hormone resistance in pseudohypoparathyroidism type Ia: new evidence for imprinting of the Gsα gene. J Clin Endocrinol Metab 88:4070–4074CrossRefPubMedGoogle Scholar
  64. 64.
    Germain-Lee EL, Groman J, Crane JL et al (2003) Growth hormone deficiency in pseudohypoparathyroidism type 1a: another manifestation of multihormone resistance. J Clin Endocrinol Metab 88:4059–4069CrossRefPubMedGoogle Scholar
  65. 65.
    de Sanctis L, Bellone J, Salerno M et al (2007) GH secretion in a cohort of children with pseudohypoparathyroidism type Ia. J Endocrinol Invest 30:97–103CrossRefPubMedGoogle Scholar
  66. 66.
    Moses AM, Weinstock RS, Levine MA et al (1986) Evidence for normal antidiuretic responses to endogenous and exogenous arginine vasopressin in patients with guanine nucleotide-binding stimulatory protein-deficient pseudohypoparathyroidism. J Clin Endocrinol Metab 62:221–224CrossRefPubMedGoogle Scholar
  67. 67.
    Faull CM, Welbury RR, Paul B et al (1991) Pseudohypoparathyroidism: its phenotypic variability and associated disorders in a large family. Q J Med 78:251–264PubMedGoogle Scholar
  68. 68.
    Tsai KS, Chang CC, Wu DJ et al (1989) Deficient erythrocyte membrane Gsα activity and resistance to trophic hormones of multiple endocrine organs in two cases of pseudohypoparathyroidism. Taiwan Yi Xue Hui Za Zhi 88:450–455PubMedGoogle Scholar
  69. 69.
    Long DN, Levine MA, Germain-Lee EL (2010) Bone mineral density in pseudohypoparathyroidism type 1a. J Clin Endocrinol Metab 95:4465–4475CrossRefPubMedCentralPubMedGoogle Scholar
  70. 70.
    Mann JB, Alterman S, Hills AG (1962) Albright’s hereditary osteodystrophy comprising pseudohypoparathyroidism and pseudopseudohypoparathyroidism with a report of two cases representing the complete syndrome occurring in successive generations. Ann Intern Med 56:315–342CrossRefPubMedGoogle Scholar
  71. 71.
    Levine MA, Jap TS, Mauseth RS et al (1986) Activity of the stimulatory guanine nucleotide-binding protein is reduced in erythrocytes from patients with pseudohypoparathyroidism and pseudopseudohypoparathyroidism: biochemical, endocrine, and genetic analysis of Albright’s hereditary osteodystrophy in six kindreds. J Clin Endocrinol Metab 62:497–502CrossRefPubMedGoogle Scholar
  72. 72.
    Wilson LC, Leverton K, Oude Luttikhuis ME et al (1995) Brachydactyly and mental retardation: an Albright’s hereditary osteodystrophy-like syndrome localized to 2q37. Am J Hum Genet 56:400–407PubMedCentralPubMedGoogle Scholar
  73. 73.
    Phelan MC, Rogers RC, Clarkson KB et al (1995) Albright’s hereditary osteodystrophy and del(2)(q37.3) in four unrelated individuals. Am J Med Genet 58:1–7CrossRefPubMedGoogle Scholar
  74. 74.
    Elli FM, deSanctis L, Ceoloni B (2013) Pseudohypoparathyroidism type Ia and pseudo-pseudohypoparathyroidism: the growing spectrum of GNAS inactivating mutations. Hum Mutat 34(3):411–416CrossRefPubMedGoogle Scholar
  75. 75.
    Aldred MA (2006) Genetics of pseudohypoparathyroidism types Ia and Ic. J Pediatr Endocrinol Metab 19(2):635–640PubMedGoogle Scholar
  76. 76.
    Mantovani G (2011) Pseudohypoparathyroidism: diagnosis and treatment. J Clin Endocrinol Metab 96(10):3020–3030CrossRefPubMedGoogle Scholar
  77. 77.
    Barret D, Breslau NA, Wax MB et al (1989) New form of pseudohypoparathyroidism with abnormal catalytic adenylate cyclase. Am J Physiol 257:E277–E283Google Scholar
  78. 78.
    Winter JS, Hughes IA (1986) Familial pseudohypoparathyroidism without somatic anomalies. Can Med Assoc J 123:26–31Google Scholar
  79. 79.
    Nusynowitz ML, Frame B, Kolb FO (1976) The spectrum of the hypoparathyroid states: a classification based on physiologic principles. Medicine 55:105–119CrossRefPubMedGoogle Scholar
  80. 80.
    Zazo C, Thiele S, Martín C et al (2011) Gsα activity is reduced in erythrocyte membranes of patients with pseudohypoparathyroidism due to epigenetic alterations at the GNAS locus. J Bone Miner Res 26(8):1864–1870CrossRefPubMedGoogle Scholar
  81. 81.
    Schipani E, Weinstein LS, Bergwitz C et al (1995) Pseudohypoparathyroidism type Ib is not caused by mutations in the coding exons of the human parathyroid hormone (PTH)/PTH-related peptide receptor gene. J Clin Endocrinol Metab 80(5):1611–1621PubMedGoogle Scholar
  82. 82.
    Juppner H, Bastepe M (2006) Different mutations within or upstream of the GNAS locus cause distinct forms of pseudohypoparathyroidism. J Pediatr Endocrinol Metab 19(Suppl 2):641–646PubMedGoogle Scholar
  83. 83.
    Bastepe M, Frohlich LF, Hendy GN et al (2003) Autosomal dominant pseudohypoparathyroidism type Ib is associated with a heterozygous microdeletion that likely disrupts a putative imprinting control element of GNAS. J Clin Invest 112(8):1255–1263CrossRefPubMedCentralPubMedGoogle Scholar
  84. 84.
    Bastepe M, Frohlich LF, Linglart A et al (2005) Deletion of the NESP55 differentially methylated region causes loss of maternal GNAS imprints and pseudohypoparathyroidism type Ib. Nat Genet 37(1):25–27PubMedGoogle Scholar
  85. 85.
    Linglart A, Gensure RC, Olney RC et al (2005) A novel STX16 deletion in autosomal dominant pseudohypoparathyroidism type Ib redefines the boundaries of a cis-acting imprinting control element of GNAS. Am J Hum Genet 76:804–814CrossRefPubMedCentralPubMedGoogle Scholar
  86. 86.
    Chillambhi S, Turan S, Hwang D et al (2010) Deletion of the noncoding GNAS antisense transcript causes pseudohypoparathyroidism type Ib and biparental defects of GNAS methylation in cis. J Clin Endocrinol Metab 95(8):3993–4002CrossRefPubMedCentralPubMedGoogle Scholar
  87. 87.
    Richard N, Abeguilè G, Coudray N et al (2012) A new deletion ablating NESP55 causes loss of maternal imprint of A/B GNAS and autosomal dominant pseudohypoparathyroidism type Ib. J Clin Endocrinol Metab 97(5):E863–E867CrossRefPubMedGoogle Scholar
  88. 88.
    Linglart A, Bastepe M, Jüppner H (2007) Similar clinical and laboratory findings in patients with symptomatic autosomal dominant and sporadic pseudohypoparathyroidism type Ib despite different epigenetic changes at the GNAS locus. Clin Endocrinol (Oxf) 67:822–831CrossRefGoogle Scholar
  89. 89.
    Linglart A, Menguy C, Couvineau A et al (2011) Recurrent PRKAR1A mutation in acrodysostosis with hormone resistance. N Engl J Med 364(23):2218–2226CrossRefPubMedGoogle Scholar
  90. 90.
    Lee H, Graham JM Jr, Rimoin DL et al (2012) Exome sequencing identifies PDE4D mutations in acrodysostosis. Am J Hum Genet 90:746–751CrossRefPubMedCentralPubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Endocrinology and Diabetology Unit, Department of Clinical Sciences and Community HealthUniversity of Milan, Fondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoMilanItaly

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