Lab Med Online.  2017 Apr;7(2):83-87. 10.3343/lmo.2017.7.2.83.

A Case of Pseudohypoparathyroidism Type Ib Caused by Aberrant Methylation in the GNAS Complex Locus

• Jo SJ
• Han E
• Jang W
• Chae H
• Kim Y
• Lee GD
• Cho WK
• Suh BK
• Kim M

• KMID: 2373857
• DOI: http://doi.org/10.3343/lmo.2017.7.2.83

Abstract

Pseudohypoparathyroidism (PHP) is a rare disorder caused by genetic and epigenetic aberrations in the GNAS complex locus resulting in impaired expression of stimulatory G protein (Gsα). PHP type Ib (PHP-Ib) is characterized by hypocalcemia and hyperphosphatemia due to renal resistance to the parathyroid hormone, and is distinguished from PHP-Ia by the absence of osteodystrophic features. An 11-yr-old boy presented with poor oral intake and cramping lower limb pain after physical activity. Laboratory studies revealed hypocalcemia, hyperphosphatemia, and increased parathyroid hormone levels. The GNAS complex locus was evaluated using the methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) assay. Gain of methylation in the NESP55 domain and loss of methylation in the antisense (AS) transcript, XL, and A/B domains in the maternal allele were observed. Consequently, we present a case of PHP-Ib diagnosed using MS-MLPA.

Keyword

Pseudohypoparathyroidism; Methylation; GNAS complex locus; MLPA

MeSH Terms

Alleles
Epigenomics
GTP-Binding Proteins
Humans
Hyperphosphatemia
Hypocalcemia
Lower Extremity
Male
Methylation*
Motor Activity
Multiplex Polymerase Chain Reaction
Muscle Cramp
Parathyroid Hormone
Pseudohypoparathyroidism*
GTP-Binding Proteins
Parathyroid Hormone

Figure

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  Fig. 1 Multiple methylated regions and GNAS gene of the GNAS complex locus. The general organization and imprinting patterns of GNAS alleles are shown. NESP55 is imprinted in the paternal allele and AS, XL and A/B are imprinted in the maternal allele (grey colored box ).

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  Fig. 2 The brain CT scan. Multiple high density nodular lesions in the bilateral basal ganglia and subcortical white matter of the frontal lobe.

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  Fig. 3 MS-MLPA analysis of GNAS and STX16. (A) MS-MLPA peak ratio of patient treated after HhaI enzyme. Peaks for NESP55 (black colored box ■) and AS, XL, A/B (grey colored box ) are expressed. (B) Relative copy numbers of DMRs (NESP55, AS, XL, and A/B) after HhaI restriction enzyme treated to the each allele compared to healthy control. NESP55 conserved about a pair of alleles, suggesting gain of methylation in the paternal allele. AS, XL and AS showed a 100% reduction of relative peaks, suggesting that loss of methylations in the maternal allele.

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