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Bone. 2015 Feb;71:53-7. doi: 10.1016/j.bone.2014.10.006. Epub 2014 Oct 18.

Evidence of hormone resistance in a pseudo-pseudohypoparathyroidism patient with a novel paternal mutation in GNAS.

Author information

1
Marmara University, Department of Pediatric Endocrinology, Istanbul, Turkey. Electronic address: serap.turan@marmara.edu.tr.
2
Division of Experimental Paediatric Endocrinology and Diabetes, University of Luebeck, Germany.
3
Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
4
Marmara University, Department of Pediatric Endocrinology, Istanbul, Turkey.
5
Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, USA. Electronic address: bastepe@helix.mgh.harvard.edu.

Abstract

CONTEXT:

Loss-of-function GNAS mutations lead to hormone resistance and Albright's hereditary osteodystrophy (AHO) when maternally inherited, i.e. pseudohypoparathyroidism-Ia (PHPIa), but cause AHO alone when located on the paternal allele, i.e. pseudoPHP (PPHP).

OBJECTIVE:

We aimed to establish the molecular diagnosis in a patient with AHO and evidence of hormone resistance.

CASE:

The patient is a female who presented at the age of 13.5years with short stature and multiple AHO features. No evidence for TSH or gonadotropin-resistance was present. Serum calcium and vitamin D levels were normal. However, serum PTH was elevated on multiple occasions (64-178pg/mL, normal: 9-52) and growth hormone response to clonidine or L-DOPA was blunted, suggesting hormone resistance and PHP-Ia. The patient had diminished erythrocyte Gsα activity and a novel heterozygous GNAS mutation (c.328 G>C; p.A109P). The mother lacked the mutation, and the father's DNA was not available. Hence, a diagnosis of PPHP also appeared possible, supported by low birth weight and a lack of AHO features associated predominantly with PHP-Ia, i.e. obesity and cognitive impairment. To determine the parental origin of the mutation, we amplified the paternally expressed A/B and biallelically expressed Gsα transcripts from the patient's peripheral blood RNA. While both wild-type and mutant nucleotides were detected in the Gsα amplicon, only the mutant nucleotide was present in the A/B amplicon, indicating that the mutation was paternal.

CONCLUSION:

These findings suggest that PTH and other hormone resistance may not be an exclusive feature of PHP-Ia and could also be observed in patients with PPHP.

KEYWORDS:

GNAS; Hormone resistance; Pseudohypoparathyroidism; Pseudopseudohypoparathyroidism

PMID:
25464124
PMCID:
PMC4273232
DOI:
10.1016/j.bone.2014.10.006
[Indexed for MEDLINE]
Free PMC Article

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