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

Alessandro Brancatella, Giovanna Mantovani, Francesca M. Elli, Simona Borsari, Claudio Marcocci, Filomena Cetani

Research output: Contribution to journalArticle

Abstract

Purpose: 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. Methods: 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. Results: 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. Conclusions: 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.

Original languageEnglish
Pages (from-to)466-472
Number of pages7
JournalEndocrine
Volume67
Issue number2
DOIs
Publication statusPublished - Feb 1 2020

Keywords

  • PDE3A
  • PDE4D
  • PHP
  • PRKAR1A
  • Pseudohypoparathyroidism
  • Pseudopseudohypoparathyroidism

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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