Case Report of GNAS Epigenetic Defect Revealed by a Congenital Hypothyroidism

Abstract

Pseudohypoparathyroidism (PHP) is a group of disorders characterized by end-organ resistance to the parathyroid hormone (PTH). PHP type 1A includes multihormone resistance syndrome, Albright's hereditary osteodystrophy, and obesity and is caused by mutations in GNAS exon 1 through 13. PHP type 1B (PHP1B), caused by epigenetic changes in the GNAS locus, was initially described as an isolated resistance to PTH. Epigenetic changes in GNAS have also been reported in patients who display mild Albright's hereditary osteodystrophy or mild thyroid-stimulating hormone (TSH) resistance without mutation of GNAS. Here we report a case of PHP caused by epigenetic changes in GNAS in a patient with congenital hypothyroidism. The patient was referred for a positive newborn screening for hypothyroidism (TSH 50 mIU/L). She exhibited severe clinical features of congenital hypothyroidism. The thyroid was in place, and etiologic explorations were negative. TSH was normalized under L-thyroxin, and the symptoms disappeared, except for a macroglossia. In childhood, PHP was suspected in addition to elevated PTH, obesity, brachydactyly, and a rounded face. Sequencing, methylation analysis, and large deletion research were performed in GNAS. No genetic mutations were found. Methylation analysis revealed a broad epigenetic defect without deletion in GNAS consistent with sporadic PHP1B. The multilocus methylation analysis were negative. This finding expands the known onsets of PHP1B and emphasizes the need for a new PHP classification system. This case report has important consequences for the etiologic diagnosis of congenital hypothyroidism because it adds a new cause of the disease.

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international consensus statement

“…Subsequent analyses have demonstrated that some patients with PHP1B display additional features that overlap with PHP1A. As in PHP1A, PTH resistance might not be present at birth and develops only over time [44][45][46][47][48][49][50] . TSH resistance and patterns of excessive intrauterine growth or weight gain at birth or during early infancy and childhood have been described 44,51,52 .…”

“…Brachydactyly develops over time and might not be evident in early life, except in patients with acrodysostosis 6,35,86 . The frequency and severity of brachydactyly vary among the different disorders: 70-80% in PHP1A 51 , 15-33% in PHP1B 46,51,70,[87][88][89][90][91][92][93] and all patients with acrodysostosis 5,6,14,15,20,[62][63][64][94][95][96] (Table 1). However, brachydactyly is not specific to PHP and related disorders and can be found in patients with, for example, tricho-rhino-phalangeal syndrome, brachydactyly mental retardation syndrome or Turner syndrome (Table 2).…”

“…Early-onset obesity Beckwith-Wiedemann syndrome 104,210 Hemihypertrophy and macroglossia Genetic, cytogenetic or syndromic anomalies associated with early-onset obesity , including Prader-Willi syndrome and monogenic obesity (mutations in POMC, MC4R, leptin and the leptin receptor) 46,275 Progression of obesity through childhood; possible associated features, such as red hair and hypoadrenalism…”

“…Early-onset hypothyroidism Congenital hypothyroidism of any cause 46,47 Small thyroid and TSH moderately elevated; no other associated features TSH resistance due to mutations in the TSH receptor 276 Small thyroid and TSH moderately elevated; no other associated features…”

“…The average level of TSH is 5.3 ± 4.7 mUI/l (4.8 ± 3.4 mUI/l and 5.4 ± 5.2 mUI/l in autosomal dominant PHP1B and sporadic PHP1B, respectively), ranging from 0.8 mUI/l to 50.0 mUI/l (reFs 36,44,[46][47][48][49]51,53,54,87,89,91,102,105,131,143,153,164,166,169,178,200,[206][207][208][209][210] ).…”