Clinical Characterization and Molecular Classification of 12 Korean Patients with Pseudohypoparathyroidism and Pseudopseudohypoparathyroidism

Abstract

Context:

Pseudohypoparathyroidism (PHP) is defined as resistance toward parathyroid hormones. PHP and pseudopseudohypoparathyroidism (PPHP) are rare disorders resulting from genetic and epigenetic aberrations within or upstream of the GNAS locus. This study investigated the clinical characteristics and performed a molecular analysis of PHP and PPHP.

Methods:

A total of 12 patients with (P)PHP from 11 unrelated families (4 with PHP-Ia, 6 with PHP-Ib, and 2 with PPHP) were characterized using both clinical and molecular methods. Clinical features included the presenting symptoms, Albright hereditary osteodystrophy features, and resistance to hormones. Comprehensive analysis of the GNAS and STX16 loci was undertaken to investigate the molecular defects underlying (P)PHP.

Results:

All PHP-Ib patients displayed hypocalcemic symptoms. All PHP-Ia patients showed resistance toward TSH, in addition to PTH. In most patients with PHP, when the diagnosis of PHP was first established, hypocalcemia and hyperphosphatemia were associated with a significant increase in serum PTH levels. One patient with PHP-Ia was diagnosed with growth hormone deficiency and showed a good response to human recombinant growth hormone therapy. 6 patients with PHP-Ia and PPHP showed 5 different mutations in the GNAS gene. 5 patients with PHP-Ib displayed a loss of differentially methylated region (DMR) imprints of the maternal GNAS. One PHP-Ib patient showed a de novo microdeletion in STX16 and a loss of methylation of exon A/B on the maternal allele. No patients revealed paternal disomy among 4 patients with PHP-Ib.

Conclusions:

Identification of the molecular causes of PHP and PPHP explains their distinctive clinical features and enables confirmation of the diagnosis and exact genetic counseling.

Key words

pseudohypoparathyroidism - pseudopseudohypoparathyroidism - GNAS - methylation

^* The first 2 authors contributed equally to this work.

• References

• 1 Mantovani G, Spada A. Mutations in the Gs alpha gene causing hormone resistance. Best Pract Res Clin Endocrinol Metab 2006; 20: 501-513
• 2 Mantovani G. Clinical review: Pseudohypoparathyroidism: diagnosis and treatment. J Clin Endocrinol Metab 2011; 96: 3020-3030
• 3 Weinstein LS, Yu S, Warner DR et al. Endocrine manifestations of stimulatory G protein alpha-subunit mutations and the role of genomic imprinting. Endocr Rev 2001; 22: 675-705
• 4 Tashjian Jr AH, Frantz AG, Lee JB. Pseudohypoparathyroidism: assays of parathyroid hormone and thyrocalcitonin. Proc Natl Acad Sci USA 1966; 56: 1138-1142
• 5 Mann JB, Alterman S, Hills AG. 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 1962; 56: 315-342
• 6 Fitch N. Albright’s hereditary osteodystrophy: a review. Am J Med Genet 1982; 11: 11-29
• 7 Bastepe M. The GNAS locus and pseudohypoparathyroidism. Adv Exp Med Biol 2008; 626: 27-40
• 8 Bastepe M, Juppner H. GNAS locus and pseudohypoparathyroidism. Horm Res 2005; 63: 65-74
• 9 Weinstein LS, Chen M, Liu J. Gs(alpha) mutations and imprinting defects in human disease. Ann N Y Acad Sci 2002; 968: 173-197
• 10 Wroe SF, Kelsey G, Skinner JA et al. An imprinted transcript, antisense to Nesp, adds complexity to the cluster of imprinted genes at the mouse Gnas locus. Proc Natl Acad Sci USA 2000; 97: 3342-3346
• 11 Bastepe M, Pincus JE, Sugimoto T et al. Positional dissociation between the genetic mutation responsible for pseudohypoparathyroidism type Ib and the associated methylation defect at exon A/B: evidence for a long-range regulatory element within the imprinted GNAS1 locus. Hum Mol Genet 2001; 10: 1231-1241
• 12 Juppner H, Linglart A, Frohlich LF et al. Autosomal-dominant pseudohypoparathyroidism type Ib is caused by different microdeletions within or upstream of the GNAS locus. Ann N Y Acad Sci 2006; 1068: 250-255
• 13 Juppner H, Schipani E, Bastepe M et al. The gene responsible for pseudohypoparathyroidism type Ib is paternally imprinted and maps in four unrelated kindreds to chromosome 20q13.3. Proc Natl Acad Sci USA 1998; 95: 11798-11803
• 14 Bastepe M, Frohlich LF, Hendy GN 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 2003; 112: 1255-1263
• 15 Linglart A, Gensure RC, Olney RC et al. 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 2005; 76: 804-814
• 16 Bastepe M, Frohlich LF, Linglart A et al. Deletion of the NESP55 differentially methylated region causes loss of maternal GNAS imprints and pseudohypoparathyroidism type Ib. Nat Genet 2005; 37: 25-27
• 17 Chillambhi S, Turan S, Hwang DY 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 2010; 95: 3993-4002
• 18 Weinstein LS. Albright hereditary Osteodystrophy, pseudohypoparathyroidism and Gs deficiency. Clifton, NJ: Humana Press; 1998
• 19 Alsum Z, Abu Safieh L, Nygren AO et al. Methylation-specific multiplex-ligation-dependent probe amplification as a rapid molecular diagnostic tool for pseudohypoparathyroidism type 1b. Genet Test Mol Biomarkers 2010; 14: 135-139
• 20 Jin HY, Lee BH, Choi JH et al Clinical characterization and identification of two novel mutations of the GNAS gene in patients with pseudohypoparathyroidism and pseudopseudohypoparathyroidism. Clin Endocrinol (Oxf) 2011; 75: 207-213
• 21 Mantovani G, Ferrante E, Giavoli C et al Recombinant human GH replacement therapy in children with pseudohypoparathyroidism type Ia: first study on the effect on growth. J Clin Endocrinol Metab 2010; 95: 5011-5017
• 22 Turan S, Ignatius J, Moilanen JS et al. De Novo STX16 Deletions: An Infrequent Cause of Pseudohypoparathyroidism Type Ib that Should Be Excluded in Sporadic Cases. J Clin Endocrinol Metab 2012; 97: E2314-E2319
• 23 Maupetit-Mehouas S, Mariot V, Reynes C et al. Quantification of the methylation at the GNAS locus identifies subtypes of sporadic pseudohypoparathyroidism type Ib. J Med Genet 2011; 48: 55-63