A severe inactivating PTH/PTHrP signaling disorder type 2 in a patient carrying a novel large deletion of the GNAS gene: a case report and review of the literature

  • 34 Accesses



Pseudohypoparathyroidism (PHP), characterized by multihormone resistance and Albright’s hereditary osteodystrophy (AHO), is caused by GNAS mutations. Whole or partial gene deletions are rare. All disorders due to inactivating mutations of the GNAS gene are now classified as “inactivating PTH/PTHrP signaling disorder type 2” (iPPSD2). This study reports a family harboring a large GNAS gene deletion in order to improve the knowledge of genotype–phenotype correlation of this disease.


An 18-year-old man with severe diffuse soft ossifications and multihormone resistance underwent to clinical, biochemical, radiological, and genetic studies. A review of the literature of other cases of iPPSD2 due to GNAS large deletions was performed focusing on clinical and biochemical features.


The proband presented signs of hypocalcemia and marked AHO features. Laboratory tests revealed hypocalcemia, high levels of serum phosphate, PTH, TSH, and calcitonin despite therapy with calcium carbonate, calcitriol, and levothyroxine. Diffuse soft tissue ossifications and brain calcifications were shown by radiological exams. Family history was remarkable for hypocalcemia, neurocognitive impairment, and cerebral calcifications in his brother and AHO features in the maternal grandfather. The proband’s mother showed short stature, whereas physical examination of the father was unremarkable. Genetic analysis of the GNAS gene revealed an unreported large deletion encompassing exons 1–7 in the proband, brother, and mother. By reviewing the literature, only six other cases were described.


We report a kindred harboring a large GNAS deletion. A genotype–phenotype correlation was observed in term of severity of tissue ossifications in the siblings but not in the mother.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 199

This is the net price. Taxes to be calculated in checkout.

Fig. 1
Fig. 2
Fig. 3


  1. 1.

    M.C. Lemos, R.V. Thakker, GNAS mutations in pseudohypoparathyroidism type 1a and related disorders. Hum. Mutat. 36, 11–19 (2015)

  2. 2.

    S. Thiele, G. Mantovani, A. Barlier, V. Boldrin, P. Bordogna, L. De Sanctis, F.M. Elli, K. Freson, I. Garin, V. Grybek, P. Hanna, B. Izzi, O. Hiort, B. Lecumberri, A. Pereda, V. Saraff, C. Silve, S. Turan, A. Usardi, R. Werner, G.P. de Nanclares, A. Linglart, From pseudohypoparathyroidism to inactivating PTH/PTHrP signalling disorder (iPPSD), a novel classification proposed by the EuroPHP network. Eur. J. Endocrinol. 175, P1–P17 (2016)

  3. 3.

    G. Mantovani, F.M. Elli, Inactivating PTH/PTHrP signaling disorders. Front. Horm. Res. 51, 147–159 (2019).

  4. 4.

    I. Garin, F.M. Elli, A. Linglart, C. Silve, L. de Sanctis, P. Bordogna, A. Pereda, J.T.R. Clarke, C. Kannengiesser, R. Coutant, Y. Tenebaum-Rakover, O. Admoni, G.P. de Nanclares, G. Mantovani, Novel microdeletions affecting the GNAS locus in pseudohypoparathyroidism: characterization of the underlying mechanisms. J. Clin. Endocrinol. Metab. 100, E681–E687 (2015)

  5. 5.

    L.S. Weinstein, P.V. Gejman, E. Friedman, T. Kadowaki, R.M. Collins, E.S. Gershon, A.M. Spiegel, Mutations of the Gs alpha-subunit gene in Albright hereditary osteodystrophy detected by denaturing gradient gel electrophoresis. Proc. Natl Acad. Sci. USA 87, 8287–8290 (1990)

  6. 6.

    F.M. Elli, L. deSanctis, B. Ceoloni, A.M. Barbieri, P. Bordogna, P. Beck-Peccoz, A. Spada, G. Mantovani, Pseudohypoparathyroidism type Ia and pseudo-pseudohypoparathyroidism: the growing spectrum of GNAS inactivating mutations. Hum. Mutat. (2013).

  7. 7.

    E. Fernandez-Rebollo, B. Garcia-Cuartero, I. Garin, C. Largo, F. Martinez, C. Garcia-Lacalle, L. Castano, M. Bastepe, G.P. de Nanclares, Intragenic GNAS 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)

  8. 8.

    T. Mitsui, K. Nagasaki, M. Takagi, S. Narumi, T. Ishii, T. Hasegawa, 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)

  9. 9.

    S.Y. Cho, Y.A. Yoon, C.-S. Ki, H.J. Huh, H.-W. Yoo, B.H. Lee, G.-H. Kim, J.-H. Yoo, S.-Y. Kim, S.J. Kim, Y.B. Sohn, S.W. Park, R. Huh, M.S. Chang, J. Lee, Y. Kwun, S.H. Maeng, D.-K. Jin, Clinical characterization and molecular classification of 12 Korean patients with pseudohypoparathyroidism and pseudopseudohypoparathyroidism. Exp. Clin. Endocrinol. Diabetes 121, 539–545 (2013)

  10. 10.

    R. Takatani, A. Molinaro, G. Grigelioniene, O. Tafaj, T. Watanabe, M. Reyes, A. Sharma, V. Singhal, F.L. Raymond, A. Linglart, H. Juppner, Analysis of multiple families with single individuals affected by pseudohypoparathyroidism type Ib (PHP1B) reveals only one novel maternally inherited GNAS deletion. J. Bone Miner. Res. 31, 796–805 (2016)

  11. 11.

    M. Reyes, A. Karaca, M. Bastepe, N.E. Gulcelik, H. Juppner, A novel deletion involving GNAS exon 1 causes PHP1A and further refines the region required for normal methylation at exon A/B. Bone 103, 281–286 (2017)

  12. 12.

    A. Plagge, G. Kelsey, E.I. Germain-Lee, Physiological functions of the imprinted Gnas locus and its protein variants Gαs and XLαs in human and mouse. J. Endocrinol. (2008).

  13. 13.

    G. Mantovani, S. Bondioni, M. Locatelli, C. Pedroni, A.G. Lania, E. Ferrante, M. Filopanti, P. Beck-Peccoz, A. Spada, Biallelic expression of the Gsα gene in human bone and adipose tissue. J. Clin. Endocrinol. Metab. (2004).

  14. 14.

    F.M. Elli, A. Pereda, A. Linglart, G. Perez de Nanclares, G. Mantovani, Parathyroid hormone resistance syndromes—inactivating PTH/PTHrP signaling disorders (iPPSDs). Best Pract. Res. Clin. Endocrinol. Metab. 32, 941–954 (2018)

  15. 15.

    S. Thiele, R. Werner, W. Ahrens, A. Hbner, K.G. Hinkel, W. Hppner, B. Igl, O. Hiort, Selective deficiency of gs and the possible role of alternative gene products of GNAS in albright hereditary osteodystrophy and pseudohypoparathyroidism type Ia. Exp. Clin. Endocrinol. Diabetes (2010).

  16. 16.

    S. Thiele, R. Werner, J. Grötzinger, B. Brix, P. Staedt, D. Struve, B. Reiz, J. Farida, O. Hiort, 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. Genom. Med. 3, 111–120 (2015)

  17. 17.

    M. Bastepe, Relative functions of Gαs and its extra-large variant XLαs in the endocrine system. Horm. Metab. Res. (2012).

  18. 18.

    A.W. Morrison, The genetic background of anticipation. J. R. Soc. Med. 88, 483 (1995)

Download references


We wish to thank the members of the family who graciously agree to collaborate in the study. We also thank Mrs Laura Macrì for her technical help in drawing the figures.

Author contributions

A.B. and F.C. planned the study. G.M. and F.M.E performed the genetic analyses. A.B. and F.C. wrote the manuscript. All authors discussed the results

Author information

Correspondence to Filomena Cetani.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent

Written informed consent was obtained from the patient and his parents for publication of this case report and any accompanying images.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Brancatella, A., Mantovani, G., Elli, F.M. et al. A severe inactivating PTH/PTHrP signaling disorder type 2 in a patient carrying a novel large deletion of the GNAS gene: a case report and review of the literature. Endocrine (2020).

Download citation


  • Pseudohypoparathyroidism
  • Pseudopseudohypoparathyroidism
  • PHP
  • PDE4D
  • PDE3A