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Early manifestation of calcinosis cutis in pseudohypoparathyroidism type Ia associated with a novel mutation in the GNAS gene

Department of Pediatrics, Division of Pediatric Endocrinology, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Christian-Albrechts-Universität, 24105 Kiel, Germany, ¹ Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Universität zu Läbeck, 23538 Lübeck, Germany, ² Department of Dermatology, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Christian-Albrechts-Universität, 24105 Kiel, Germany and ³ Children’s Hospital, Städtische Kliniken Esslingen, 73730 Esslingen a.N., Germany

(Correspondence should be addressed to W G Sippell; Email: sippell{at}pediatrics.uni-kiel.de)

Abstract

Objective: To clarify the molecular defect for the clinical finding of congenital hypothyroidism combined with the manifestation of calcinosis cutis in infancy.

Case report: The male patient presented with moderately elevated blood thyrotropin levels at neonatal screening combined with slightly decreased plasma thyroxine and tri-iodothyronine concentrations, necessitating thyroid hormone substitution 2 weeks after birth. At the age of 7 months calcinosis cutis was seen and the patient underwent further investigation. Typical features of Albright’s hereditary osteodystrophy (AHO), including round face, obesity and delayed psychomotor development, were found.

Methods and results: Laboratory investigation revealed a resistance to parathyroid hormone (PTH) with highly elevated PTH levels and a reduction in adenylyl cyclase-stimulating protein (Gs) activity leading to the diagnosis of pseudohypoparathyroidism type Ia (PHP Ia). A novel heterozygous mutation (c364T > G in exon 5, leading to the amino acid substitution Ile-106 Ser) was detected in the GNAS gene of the patient. This mutation was not found in the patient’s parents, both of whom showed normal Gs protein activity in erythrocytes and no features of AHO. A de novo mutation is therefore likely.

Conclusions: Subcutaneous calcifications in infancy should prompt the clinician to a thorough search for an underlying disease. The possibility of AHO and PHP Ia should be considered in children with hypothyroidism and calcinosis cutis. Systematic reviews regarding the frequency of calcinosis in AHO are warranted.

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