Pseudohypoparathyroidism and Gsα–cAMP-linked disorders: current view and open issues (original) (raw)

• Bastepe, M. The GNAS locus and pseudohypoparathyroidism. Adv. Exp. Med. Biol. 626, 27–40 (2008).
  Article CAS PubMed Google Scholar
• Levine, M. A. An update on the clinical and molecular characteristics of pseudohypoparathyroidism. Curr. Opin. Endocrinol. Diabetes Obes. 19, 443–451 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Bastepe, M. Genetics and epigenetics of parathyroid hormone resistance. Endocr. Dev. 24, 11–24 (2013).
  Article CAS PubMed Google Scholar
• Silve, C., Clauser, E. & Linglart, A. Acrodysostosis. Horm. Metab. Res. 44, 749–758 (2012).
  Article CAS PubMed Google Scholar
• Falk, R. E. & Casas, K. A. Chromosome 2q37 deletion: clinical and molecular aspects. Am. J. Med. Genet. C Semin. Med. Genet. 145C, 357–371 (2007).
  Article PubMed Google Scholar
• Shore, E. M. et al. Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia. N. Engl. J. Med. 346, 99–106 (2002); erratum N. Engl. J. Med. 346, 1678 (2002).
  Article CAS PubMed Google Scholar
• Elli, F. M. et al. Screening for GNAS genetic and epigenetic alterations in progressive osseous heteroplasia: first Italian series. Bone 56, 276–280 (2013).
  Article CAS PubMed Google Scholar
• Mantovani, G. Clinical review: pseudohypoparathyroidism: diagnosis and treatment. J. Clin. Endocrinol. Metab. 96, 3020–3030 (2011).
  Article CAS PubMed Google Scholar
• Mantovani, G., Elli, F. M. & Spada, A. GNAS epigenetic defects and pseudohypoparathyroidism: time for a new classification? Horm. Metab. Res. 44, 716–723 (2012).
  Article CAS PubMed Google Scholar
• Albright, F. et al. Pseudohypoparathyroidism: an example of 'Seabright-Bantam syndrome'. Endocrinology 30, 922–932 (1942).
  CAS Google Scholar
• Albright, F., Forbes, A. P. & Henneman, P. H. Pseudopseudohypoparathyroidism. Trans. Assoc. Am. Physicians 65, 337–350 (1952).
  CAS PubMed Google Scholar
• Mann, J. B., Alterman, S. & Hills, A. G. Albright's hereditary osteodystrophy comprising pseudohypoparathyroidism and pseudo-pseudohypoparathyroidism: with a report of two cases representing the complete syndrome occurring in successive generations. Ann. Intern. Med. 56, 315–342 (1962).
  Article CAS PubMed Google Scholar
• Eyre, W. G. & Reed, W. B. Albright's hereditary osteodystrophy with cutaneous bone formation. Arch. Dermatol. 104, 634–642 (1971).
  Article CAS PubMed Google Scholar
• Farfel, Z. & Friedman, E. Mental deficiency in pseudohypoparathyroidism type I is associated with Ns-protein deficiency. Ann. Intern. Med. 105, 197–199 (1986).
  Article CAS PubMed Google Scholar
• Farfel, Z. et al. Pseudohypoparathyroidism: inheritance of deficient receptor-cyclase coupling activity. Proc. Natl Acad. Sci. USA 78, 3098–3102 (1981).
  Article CAS PubMed PubMed Central Google Scholar
• Fitch, N. Albright's hereditary osteodystrophy: a review. Am. J. Med. Genet. 11, 11–29 (1982).
  Article CAS PubMed Google Scholar
• Weinberg, A. G. & Stone, R. T. Autosomal dominant inheritance in Albright's hereditary osteodystrophy. J. Pediatr. 79, 996–999 (1971).
  Article CAS PubMed Google Scholar
• Tashjian, A. H. Jr, Frantz, A. G. & Lee, J. B. Pseudohypoparathyroidism: assays of parathyroid hormone and thyrocalcitonin. Proc. Natl Acad. Sci. USA 56, 1138–1142 (1966).
  Article CAS PubMed PubMed Central Google Scholar
• Chase, L. R., Melson, G. L. & Aurbach, G. D. Pseudohypoparathyroidism: defective excretion of 3′,5′-AMP in response to parathyroid hormone. J. Clin. Invest. 48, 1832–1844 (1969).
  Article CAS PubMed PubMed Central Google Scholar
• Spiegel, A. M., Shenker, A. & Weinstein, L. S. Receptor-effector coupling by G proteins: implications for normal and abnormal signal transduction. Endocr. Rev. 13, 536–565 (1992).
  Article CAS PubMed Google Scholar
• Taskén, K. et al. Structure, function, and regulation of human cAMP-dependent protein kinases. Adv. Second Messenger Phosphoprotein Res. 31, 191–204 (1997).
  Article PubMed Google Scholar
• Taylor, S. S., Buechler, J. A. & Yonemoto, W. cAMP-dependent protein kinase: framework for a diverse family of regulatory enzymes. Annu. Rev. Biochem. 59, 971–1005 (1990).
  Article CAS PubMed Google Scholar
• Lania, A. G., Mantovani, G. & Spada, A. Mechanisms of disease: mutations of G proteins and G-protein-coupled receptors in endocrine diseases. Nat. Clin. Pract. Endocrinol. Metab. 2, 681–693 (2006).
  Article CAS PubMed Google Scholar
• Levine, M. A. et al. Deficient activity of guanine nucleotide regulatory protein in erythrocytes from patients with pseudohypoparathyroidism. Biochem. Biophys. Res. Commun. 94, 1319–1324 (1980).
  Article CAS PubMed Google Scholar
• Patten, J. L. et al. Mutation in the gene encoding the stimulatory G protein of adenylate cyclase in Albright's hereditary osteodystrophy. N. Engl. J. Med. 322, 1412–1419 (1990).
  Article CAS PubMed Google Scholar
• Weinstein, L. S. et al. Mutations of the Gs α-subunit gene in Albright hereditary osteodystrophy detected by denaturing gradient gel electrophoresis. Proc. Natl Acad. Sci. USA 87, 8287–8290 (1990).
  Article CAS PubMed PubMed Central Google Scholar
• Levine, M. A., Modi, W. S., O'Brien, S. J. Mapping of the gene encoding the α subunit of the stimulatory G protein of adenylyl cyclase (GNAS1) to 20q13.2→q13.3 in human by in situ hybridization. Genomics 11, 478–479 (1991).
  Article CAS PubMed Google Scholar
• Davies, S. J. & Hughes, H. E. Imprinting in Albright's hereditary osteodystrophy. J. Med. Genet. 30, 101–103 (1993).
  Article CAS PubMed PubMed Central Google Scholar
• Campbell, R., Gosden, C. M. & Bonthron, D. T. Parental origin of transcription from the human GNAS1 gene. J. Med. Genet. 31, 607–614 (1994).
  Article CAS PubMed PubMed Central Google Scholar
• Wilson, L. C., Oude Luttikhuis, M. E., Clayton, P. T., Fraser, W. D. & Trembath, R. C. Parental origin of Gsα gene mutations in Albright's hereditary osteodystrophy. J. Med. Genet. 31, 835–839 (1994).
  Article CAS PubMed PubMed Central Google Scholar
• Nakamoto, J. M., Sandstrom, A. T., Brickman, A. S., Christenson, R. A. & Van Dop, C. Pseudohypoparathyroidism type Ia from maternal but not paternal transmission of a Gsα gene mutation. Am. J. Med. Genet. 77, 261–267 (1998).
  Article CAS PubMed Google Scholar
• Yu, S. et al. Variable and tissue-specific hormone resistance in heterotrimeric Gs protein α-subunit (Gsα) knockout mice is due to tissue-specific imprinting of the Gsα gene. Proc. Natl Acad. Sci. USA 95, 8715–8720 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Hayward, B. E. et al. The human GNAS1 gene is imprinted and encodes distinct paternally and biallelically expressed G proteins. Proc. Natl Acad. Sci. USA 95, 10038–10043 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Hayward, B. E., Moran, V., Strain, L. & Bonthron, D. T. Bidirectional imprinting of a single gene: GNAS1 encodes maternally, paternally, and biallelically derived proteins. Proc. Natl Acad. Sci. USA 95, 15475–15480 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Liu, J. et al. GNAS1 imprinting defect in pseudohypoparathyroidism type IB. J. Clin. Invest. 106, 1167–1174 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Weinstein, L. S., Yu, S. & Ecelbarger, C. A. Variable imprinting of the heterotrimeric G protein Gsα-subunit within different segments of the nephron. Am. J. Physiol. Renal Physiol. 278, F507–F514 (2000).
  Article CAS PubMed Google Scholar
• Zheng, H., Radeva, G., McCann, J. A., Hendy, G. N. & Goodyer, C. G. Gαs transcripts are biallelically expressed in the human kidney cortex: implications for pseudohypoparathyroidism type 1b. J. Clin. Endocrinol. Metab. 86, 4627–4629 (2001).
  CAS PubMed Google Scholar
• Mantovani, G., Ballare, E., Giammona, E., Beck-Peccoz, P. & Spada, A. The Gsα gene: predominant maternal origin of transcription in human thyroid gland and gonads. J. Clin. Endocrinol. Metab. 87, 4736–4740 (2002).
  Article CAS PubMed Google Scholar
• Mantovani, G. et al. Biallelic expression of the Gsα gene in human bone and adipose tissue. J. Clin. Endocrinol. Metab. 89, 6316–6319 (2004).
  Article CAS PubMed Google Scholar
• Klenke, S., Siffert, W. & Frey, U. H. A novel aspect of GNAS imprinting: higher maternal expression of Gαs in human lymphoblasts, peripheral blood mononuclear cells, mammary adipose tissue, and heart. Mol. Cell. Endocrinol. 341, 63–70 (2011).
  Article CAS PubMed Google Scholar
• Liu, J., Erlichman, B. & Weinstein, L. S. 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, 4336–4341 (2003).
  Article CAS PubMed Google Scholar
• Bastepe, M. et al. 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, 1255–1263 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Bastepe, M. et al. Deletion of the NESP55 differentially methylated region causes loss of maternal GNAS imprints and pseudohypoparathyroidism type Ib. Nat. Genet. 37, 25–27 (2005).
  Article CAS PubMed Google Scholar
• Linglart, A., Gensure, R. C., Olney, R. C., Juppner, H. & Bastepe, M. 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, 804–814 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Chillambhi, S. et al. Deletion of the noncoding GNAS antisense transcript causes pseudohypoparathyroidism type Ib and biparental defects of GNAS methylation in cis. J. Clin. Endocrinol. Metab. 95, 3993–4002 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Richard, N. et al. 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, E863–E867 (2012).
  Article CAS PubMed Google Scholar
• Elli, F. M. et al. Autosomal dominant pseudohypoparathyroidism type Ib: a novel inherited deletion ablating STX16 causes loss of imprinting at the A/B DMR. J. Clin. Endocrinol. Metab. 99, E724–E728 (2014).
  Article CAS PubMed Google Scholar
• Bastepe, M., Lane, A. H. & Jüppner, H. Paternal uniparental isodisomy of chromosome 20q — and the resulting changes in GNAS1 methylation — as a plausible cause of pseudohypoparathyroidism. Am. J. Hum. Genet. 68, 1283–1289 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Lecumberri, B. et al. Coexistence of two different pseudohypoparathyroidism subtypes (Ia and Ib) in the same kindred with independent Gsα coding mutations and GNAS imprinting defects. J. Med. Genet. 47, 276–280 (2010).
  Article CAS PubMed Google Scholar
• Fernández-Rebollo, E. et al. New mechanisms involved in paternal 20q disomy associated with pseudohypoparathyroidism. Eur. J. Endocrinol. 163, 953–962 (2010).
  Article CAS PubMed Google Scholar
• Dixit, A. et al. Pseudohypoparathyroidism type 1b due to paternal uniparental disomy of chromosome 20q. J. Clin. Endocrinol. Metab. 98, E103–E108 (2013).
  Article CAS PubMed Google Scholar
• Takatani, R. et al. Similar frequency of paternal uniparental disomy involving chromosome 20q (patUPD20q) in Japanese and Caucasian patients affected by sporadic pseudohypoparathyroidism type Ib (sporPHP1B). Bone 79, 15–20 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• de Nanclares, G. P. et al. Epigenetic defects of GNAS in patients with pseudohypoparathyroidism and mild features of Albright hereditary osteodystrophy. J. Clin. Endocrinol. Metab. 92, 2370–2373 (2007).
  Article CAS PubMed Google Scholar
• Mariot, V., Maupetit-Méhouas, S., Sinding, C., Kottler, M. L. & Linglart, A. A maternal epimutation of GNAS leads to Albright osteodystrophy and parathyroid hormone resistance. J. Clin. Endocrinol. Metab. 93, 661–665 (2008).
  Article CAS PubMed Google Scholar
• Unluturk, U. et al. 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, 84–90 (2008).
  Article PubMed Google Scholar
• Mantovani, G. et al. Pseudohypoparathyroidism and GNAS epigenetic defects: clinical evaluation of Albright hereditary osteodystrophy and molecular analysis in 40 patients. J. Clin. Endocrinol. Metab. 95, 651–658 (2010).
  Article CAS PubMed Google Scholar
• Brix, B. et al. Different pattern of epigenetic changes of the GNAS gene locus in patients with pseudohypoparathyroidism type Ic confirm the heterogeneity of underlying pathomechanisms in this subgroup of pseudohypoparathyroidism and the demand for a new classification of _GNAS_-related disorders. J. Clin. Endocrinol. Metab. 99, E1564–E1570 (2014).
  Article CAS PubMed Google Scholar
• Elli, F. M. et al. 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, E508–E517 (2014).
  Article CAS PubMed Google Scholar
• Turan, S. et al. Evidence of hormone resistance in a pseudo-pseudohypoparathyroidism patient with a novel paternal mutation in GNAS. Bone 71, 53–57 (2015).
  Article CAS PubMed Google Scholar
• Genevieve, D. et al. Paternal deletion of the GNAS imprinted locus (including Gnasxl) in two girls presenting with severe pre- and post-natal growth retardation and intractable feeding difficulties. Eur. J. Hum. Genet. 13, 1033–1039 (2005).
  Article CAS PubMed Google Scholar
• Fernandez-Rebollo, E. et al. Deletion involving exon A/B in pseudohypoparathyroidism type 1a resulting in an apparent loss of exon A/B methylation: potential for misdiagnosis of pseudohypoparathyroidism type 1B. J. Clin. Endocrinol. Metab. 95, 765–771 (2010).
  Article CAS PubMed Google Scholar
• Fernandez-Rebollo, E. et al. New mutation type in pseudohypoparathyroidism type Ia. Clin. Endocrinol. (Oxf.) 69, 705–712 (2008).
  Article CAS Google Scholar
• Mitsui, T. et al. A family of pseudohypoparathyroidism type Ia with an 850-kb submicroscopic deletion encompassing the whole GNAS locus. Am. J. Med. Genet. A 158A, 261–264 (2012).
  Article CAS PubMed Google Scholar
• Garin, I. et al. Novel microdeletions affecting the GNAS locus in pseudohypoparathyroidism: characterization of the underlying mechanisms. J. Clin. Endocrinol. Metab. 100, E681–E687 (2015).
  Article CAS PubMed Google Scholar
• Linglart, A. et al. Recurrent PRKAR1A mutation in acrodysostosis with hormone resistance. N. Engl. J. Med. 364, 2218–2226 (2011).
  Article CAS PubMed Google Scholar
• Michot, C. et al. Exome sequencing identifies PDE4D mutations as another cause of acrodysostosis. Am. J. Hum. Genet. 90, 740–745 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Lee, H. et al. Exome sequencing identifies PDE4D mutations in acrodysostosis. Am. J. Hum. Genet. 90, 746–751 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Nagasaki, K. et al. PRKAR1A mutation affecting cAMP-mediated G protein-coupled receptor signaling in a patient with acrodysostosis and hormone resistance. Clin. Endocrinol. Metab. 97, E1808–E1813 (2012).
  Article CAS Google Scholar
• Linglart, A. et al. PRKAR1A and PDE4D mutations cause acrodysostosis but two distinct syndromes with or without GPCR-signaling hormone resistance. J. Clin. Endocrinol. Metab. 97, E2328–E2338 (2012).
  Article CAS PubMed Google Scholar
• Lynch, D. C. et al. Identification of novel mutations confirms PDE4D as a major gene causing acrodysostosis. Hum. Mutat. 34, 97–102 (2013).
  Article CAS PubMed Google Scholar
• Muhn, F. et al. Novel mutations of the PRKAR1A gene in patients with acrodysostosis. Clin. Genet. 84, 531–538 (2013).
  Article CAS PubMed Google Scholar
• Lindstrand, A. et al. Different mutations in PDE4D associated with developmental disorders with mirror phenotypes. J. Med. Genet. 51, 45–54 (2014).
  Article CAS PubMed Google Scholar
• Kaname, T. et al. Heterozygous mutations in cyclic AMP phosphodiesterase-4D (PDE4D) and protein kinase A (PKA) provide new insights into the molecular pathology of acrodysostosis. Cell. Signal. 26, 2446–2459 (2014).
  Article CAS PubMed Google Scholar
• Li, N. et al. The first mutation identified in a Chinese acrodysostosis patient confirms a p.G289E variation of PRKAR1A causes acrodysostosis. Int. J. Mol. Sci. 15, 13267–13274 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Mitsui, T. et al. Acroscyphodysplasia as a phenotypic variation of pseudohypoparathyroidism and acrodysostosis type 2. Am. J. Med. Genet. A 164A, 2529–2534 (2014).
  Article CAS PubMed Google Scholar
• Potts, J. T. Parathyroid hormone: past and present. J. Endocrinol. 187, 311–325 (2005).
  Article CAS PubMed Google Scholar
• Gensure, R. C., Gardella, T. J. & Jüppner, H. Parathyroid hormone and parathyroid hormone-related peptide, and their receptors. Biochem. Biophys. Res. Commun. 328, 666–678 (2005).
  Article CAS PubMed Google Scholar
• Stone, M. D. et al. The renal response to exogenous parathyroid hormone in treated pseudohypoparathyroidism. Bone 14, 727–735 (1993).
  Article CAS PubMed Google Scholar
• Gardner, D. & Shoback, D. Greenspan's Basic & Clinical Endocrinology 9th edn (McGraw Hill, 2011).
  Google Scholar
• Poole, K. & Reeve, J. Parathyroid hormone — a bone anabolic and catabolic agent. Curr. Opin. Pharmacol. 5, 612–617 (2005).
  Article CAS PubMed Google Scholar
• Murray, T. M. et al. Pseudohypoparathyroidism with osteitis fibrosa cystica: direct demonstration of skeletal responsiveness to parathyroid hormone in cells cultured from bone. J. Bone Miner. Res. 8, 83–91 (1993).
  Article CAS PubMed Google Scholar
• Ish-Shalom, S. et al. Normal parathyroid hormone responsiveness of bone-derived cells from a patient with pseudohypoparathyroidism. J. Bone Miner. Res. 11, 8–14 (1996).
  Article CAS PubMed Google Scholar
• Kidd, G. S. et al. Skeletal responsiveness in pseudohypoparathyroidism: a spectrum of clinical disease. Am. J. Med. 68, 772–781 (1980).
  Article CAS PubMed Google Scholar
• Eubanks, P. J. & Stabile, B. E. Osteitis fi brosa cystica with renal parathyroid hormone resistance: a review of pseudohypoparathyroidism with insight into calcium homeostasis. Arch. Surg. 133, 673–676 (1998).
  Article CAS PubMed Google Scholar
• Cohen, R. D. & Vince, F. P. Pseudohypoparathyroidism with raised plasma alkaline phosphatase. Arch. Dis. Child. 44, 96–101 (1969).
  Article CAS PubMed PubMed Central Google Scholar
• Kolb, F. O. & Steinbach, H. L. Pseudohypoparathyroidism with secondary hyperparathyroidism and osteitis fibrosa. J. Clin. Endocrinol. Metab. 22, 59–70 (1962).
  Article CAS PubMed Google Scholar
• Tollin, S. R., Perlmutter, S. & Aloia, J. F. 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, 1412–1416 (2000).
  Article CAS PubMed Google Scholar
• de Sanctis, L. et al. Brachydactyly in 14 genetically characterized pseudohypoparathyroidism type Ia patients. J. Clin. Endocrinol. Metab. 89, 1650–1655 (2004).
  Article CAS PubMed Google Scholar
• Roberts, T. T. et al. Spinal cord compression in pseudohypoparathyroidism. Spine J. 13, e15–e19 (2013).
  Article PubMed Google Scholar
• Joseph, A. W., Shoemaker, A. H. & Germain-Lee, E. L. Increased prevalence of carpal tunnel syndrome in Albright hereditary osteodystrophy. J. Clin. Endocrinol. Metab. 96, 2065–2073 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Eddy, M. C. et al. Deficiency of the α-subunit of the stimulatory G protein and severe extraskeletal ossification. J. Bone Miner. Res. 15, 2074–2083 (2000).
  Article CAS PubMed Google Scholar
• Adegbite, N. S., Xu, M., Kaplan, F. S., Shore, E. M. & Pignolo, R. J. Diagnostic and mutational spectrum of progressive osseous heteroplasia (POH) and other forms of _GNAS_-based heterotopic ossification. Am. J. Med. Genet. A 146A, 1788–1796 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Barret, D. et al. New form of pseudohypoparathyroidism with abnormal catalytic adenylate cyclase. Am. J. Physiol. 257, E277–E283 (1989).
  Article Google Scholar
• Weinstein, L. S. et al. Endocrine manifestations of stimulatory G protein α-subunit mutations and the role of genomic imprinting. Endocr. Rev. 22, 675–705 (2001).
  CAS PubMed Google Scholar
• Turan, S. et al. Postnatal establishment of allelic Gαs silencing as a plausible explanation for delayed onset of parathyroid hormone resistance owing to heterozygous Gαs disruption. J. Bone Miner. Res. 29, 749–760 (2014).
  Article CAS PubMed Google Scholar
• Levine, M. A. et al. Resistance to multiple hormones in patients with pseudohypoparathyroidism. Association with deficient activity of guanine nucleotide regulatory protein. Am. J. Med. 74, 545–556 (1983).
  Article CAS PubMed Google Scholar
• Wemeau, J. L. et al. 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), 653–661 (2006).
  CAS PubMed Google Scholar
• Germain-Lee, E. L. Short stature, obesity, and growth hormone deficiency in pseudohypoparathyroidism type Ia. Pediatr. Endocrinol. Rev. 3, 318–327 (2006).
  PubMed Google Scholar
• Levine, M. A., Jap, T. S. & Hung, W. Infantile hypothyroidism in two sibs: an unusual presentation of pseudohypoparathyroidism type Ia. J. Pediatr. 107, 919–922 (1985).
  Article CAS PubMed Google Scholar
• Pohlenz, J., Ahrens, W. & Hiort, O. 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, 463–468 (2003).
  Article CAS PubMed Google Scholar
• Pinsker, J. E. et al. Pseudohypoparathyroidism type 1a with congenital hypothyroidism. J. Pediatr. Endocrinol. Metab. 19, 1049–1052 (2006).
  Article PubMed Google Scholar
• Mantovani, G. & Spada, A. Resistance to growth hormone releasing hormone and gonadotropins in Albright's hereditary osteodystrophy. J. Pediatr. Endocrinol. Metab. 19, 663–670 (2006).
  Article CAS PubMed Google Scholar
• Mantovani, G. et al. Growth hormone-releasing hormone resistance in pseudohypoparathyroidism type Ia: new evidence for imprinting of the Gsα gene. J. Clin. Endocrinol. Metab. 88, 4070–4074 (2003).
  Article CAS PubMed Google Scholar
• Germain-Lee, E. L. et al. Growth hormone deficiency in pseudohypoparathyroidism type 1a: another manifestation of multihormone resistance. J. Clin. Endocrinol. Metab. 88, 4059–4069 (2003).
  Article CAS PubMed Google Scholar
• de Sanctis, L. et al. GH secretion in a cohort of children with pseudohypoparathyroidism type Ia. J. Endocrinol. Invest. 30, 97–103 (2007).
  Article CAS PubMed Google Scholar
• Vlaeminck-Guillem, V. et al. Pseudohypoparathyroidism Ia and hypercalcitoninemia. J. Clin. Endocrinol. Metab. 86, 3091–3096 (2001).
  Article CAS PubMed Google Scholar
• Moses, A. M. et al. 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, 221–224 (1986).
  Article CAS PubMed Google Scholar
• Faull, C. M. et al. Pseudohypoparathyroidism: its phenotypic variability and associated disorders in a large family. Q. J. Med. 78, 251–264 (1991).
  CAS PubMed Google Scholar
• Tsai, K. S. et al. 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, 450–455 (1989).
  CAS PubMed Google Scholar
• Muniyappa, R. et al. Reduced insulin sensitivity in adults with pseudohypoparathyroidism type 1a. J. Clin. Endocrinol. Metab. 98, E1796–E1801 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Long, D. N., McGuire, S., Levine, M. A., Weinstein, L. S. & Germain-Lee, E. L. Body mass index differences in pseudohypoparathyroidism type 1a versus pseudopseudohypoparathyroidism may implicate paternal imprinting of Gαs in the development of human obesity. J. Clin. Endocrinol. Metab. 92, 1073–1079 (2007).
  Article CAS PubMed Google Scholar
• Bréhin, A. C. et al. Loss of methylation at GNAS exon A/B is associated with increased intrauterine growth. J. Clin. Endocrinol. Metab. 100, E623–E631 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Richard, N. et al. Paternal GNAS mutations lead to severe intrauterine growth retardation (IUGR) and provide evidence for a role of XLas in fetal development. J. Clin. Endocrinol. Metab. 98, E1549–E1556 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Kaplan, F. S. et al. Progressive osseous heteroplasia: a distinct developmmental disorder of heterotopic ossification two new case reports and follow-up of three previously reported cases. J. Bone Joint Surg. 76, 425–436 (1994).
  Article CAS PubMed Google Scholar
• Cairns, D. M. et al. Somitic disruption of GNAS in chick embryos mimics progressive osseous heteroplasia. J. Clin. Invest. 123, 3624–3633 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Tresserra, L., Tresserra, F., Grases, P. J., Badosa, J. & Tresserra, M. Congenital plate-like osteoma cutis of the forehead: an atypical presentation form. J. Craniomaxillofac. Surg. 26, 102–106 (1998).
  Article CAS PubMed Google Scholar
• Lebrun, M. et al. Progressive osseous heteroplasia: a model for the imprinting effects of GNAS inactivating mutations in humans. J. Clin. Endocrinol. Metab. 95, 3028–3038 (2010).
  Article CAS PubMed Google Scholar
• Winter, J. S. & Hughes, I. A. Familial pseudohypoparathyroidism without somatic anomalies. Can. Med. Assoc. J. 123, 26–31 (1986).
  Google Scholar
• Nusynowitz, M. L., Frame, B. & Kolb, F. O. The spectrum of the hypoparathyroid states: a classification based on physiologic principles. Medicine (Baltimore) 55, 105–119 (1976).
  Article CAS Google Scholar
• Mantovani, G. et al. Genetic analysis and evaluation of resistance to thyrotropin and growth hormone-releasing hormone in pseudohypoparathyroidism type Ib. J. Clin. Endocrinol. Metab. 92, 3738–3742 (2007).
  Article CAS PubMed Google Scholar
• Sano, S. et al. Growth hormone deficiency in monozygotic twins with autosomal dominant pseudohypoparathyroidism type Ib. Endocr. J. 62, 523–529 (2015).
  Article CAS PubMed Google Scholar
• Kidd, G. S., Schaaf, M., Adler, R. A., Lassman, M. N. & Wray, H. L. Skeletal responsiveness in pseudohypoparathyroidism: a spectrum of clinical disease. Am. J. Med. 68, 772–781 (1980).
  Article CAS PubMed Google Scholar
• Burnstein, M. I. et al. Metabolic bone disease in pseudohypoparathyroidism: radiologic features. Radiology 155, 351–356 (1985).
  Article CAS PubMed Google Scholar
• Jacobson, H. G. Dense bone — too much bone: radiological considerations and differential diagnosis. Skeletal Radiol. 13, 1–20 (1985).
  Article CAS PubMed Google Scholar
• Balkissoon, A. R. & Hayes, C. W. Case 14: intramedullary osteosclerosis. Radiology 212, 708–710 (1999).
  Article CAS PubMed Google Scholar
• Sbrocchi, A. M. et al. Osteosclerosis in two brothers with autosomal dominant pseudohypoparathyroidism type 1b: bone histomorphometric analysis. Eur. J. Endocrinol. 164, 295–301 (2011).
  Article CAS PubMed Google Scholar
• Brailsford, J. F. Radiology of Bones and Joints 4th edn (Williams & Wilkins, 1948).
  Google Scholar
• Maroteaux, P. & Malamut, G. Acrodysostosis. Presse Med. 76, 2189–2192 (1968).
  CAS PubMed Google Scholar
• Robinow, M. et al. Acrodysostosis. A syndrome of peripheral dysostosis, nasal hypoplasia, and mental retardation. Am. J. Dis. Child. 121, 195–203 (1971).
  Article CAS PubMed Google Scholar
• Reiter, S. Acrodysostosis. A case of peripheral dysostosis, nasal hypoplasia, mental retardation and impaired hearing. Pediatr. Radiol. 7, 53–55 (1978).
  Article CAS PubMed Google Scholar
• Davies, S. J. & Hughes, H. E. Familial acrodysostosis: can it be distinguished from Albright's hereditary osteodystrophy? Clin. Dysmorphol. 1, 207–215 (1992).
  Article CAS PubMed Google Scholar
• Silve, C. et al. Acrodysostosis syndromes. BoneKEy Rep. 225, 1–7 (2012).
  Google Scholar
• Ablow, R. C., Hsia, Y. E. & Brandt, I. K. Acrodysostosis coinciding with pseudohypoparathyroidism and pseudo-pseudohypoparathyroidism. AJR Am. J. Roentgenol. 128, 95–99 (1977).
  Article CAS PubMed Google Scholar
• Elli, F. M. et al. Screening of PRKAR1A and PDE4D in a large Italian series of patients clinically diagnosed with Albright hereditary osteodystrophy and/or pseudohypoparathyroidism. J. Bone Miner. Res. http://dx.doi.org/10.1002/jbmr.2785 (2016).
• Phelan, M. C. et al. Albright's hereditary osteodystrophy and del(2)(q37.3) in four unrelated individuals. Am. J. Med. Genet. 58, 1–7 (1995).
  Article CAS PubMed Google Scholar
• Wilson, L. C. et al. Brachydactyly and mental retardation: an Albright hereditary osteodystrophy-like syndrome localized to 2q37. Am. J. Hum. Genet. 56, 400–407 (1995).
  CAS PubMed PubMed Central Google Scholar
• Chassaing, N. et al. Molecular characterization of a cryptic 2q37 deletion in a patient with Albright hereditary osteodystrophy-like phenotype. Am. J. Med. Genet. A 128A, 410–413 (2004).
  Article CAS PubMed Google Scholar
• Aldred, M. A. et al. Molecular analysis of 20 patients with 2q37.3 monosomy: definition of minimum deletion intervals for key phenotypes. J. Med. Genet. 41, 433–439 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Williams, S. R. et al. Haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral problems. Am. J. Hum. Genet. 87, 219–228 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Leroy, C. et al. The 2q37-deletion syndrome: an update of the clinical spectrum including overweight, brachydactyly and behavioural features in 14 new patients. Eur. J. Hum. Genet. 21, 602–612 (2013).
  Article CAS PubMed Google Scholar
• Villavicencio-Lorini, P. et al. Phenotypic variant of Brachydactyly-mental retardation syndrome in a family with an inherited interstitial 2q37.3 microdeletion including HDAC4. Eur. J. Hum. Genet. 21, 743–748 (2013).
  Article CAS PubMed Google Scholar
• Williamson, C. M. et al. A _cis_-acting control region is required exclusively for the tissue-specific imprinting of Gnas. Nat. Genet. 36, 894–899 (2004).
  Article CAS PubMed Google Scholar
• Elli, F. M. et al. Pseudohypoparathyroidism type Ia and pseudo-pseudohypoparathyroidism: the growing spectrum of GNAS inactivating mutations. Hum. Mutat. 34, 411–416 (2013).
  Article CAS PubMed Google Scholar
• Thiele, S. et al. A positive genotype–phenotype correlation in a large cohort of patients with pseudohypoparathyroidism type Ia and pseudo-pseudohypoparathyroidism and 33 newly identified mutations in the GNAS gene. Mol. Genet. Genomic Med. 3, 111–120 (2015).
  Article CAS PubMed Google Scholar
• Lemos, M. C. & Thakker, R. V. GNAS mutations in pseudohypoparathyroidism type 1a and related disorders. Hum. Mutat. 36, 11–19 (2015).
  Article CAS PubMed Google Scholar
• Todorova-Koteva, K., Wood, K., Imam, S. & Jaume, J. C. Screening for parathyroid hormone resistance in patients with non-phenotypically evident pseudohypoparathyroidism. Endocr. Pract. 18, 864–869 (2012).
  Article PubMed Google Scholar
• Neary, N. M. et al. Development and treatment of tertiary hyperparathyroidism in patients with pseudohypoparathyroidism type 1B. J. Clin. Endocrinol. Metab. 97, 3025–3030 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Mantovani, G. et al. Recombinant human GH replacement therapy in children with pseudohypoparathyroidism type Ia: first study on the effect on growth. J. Clin. Endocrinol. Metab. 95, 5011–5017 (2010).
  Article CAS PubMed Google Scholar
• Underbjerg, L., Sikjaer, T., Mosekilde, L. & Rejnmark, L. Pseudohypoparathyroidism — epidemiology, mortality and risk of complications. Clin. Endocrinol. (Oxf.) http://dx.doi.org/10.1111/cen.12948 (2015).