ESPE Abstracts (2015) 84 P-3-672

Pseudohypoparathyroidism: Clinical Heterogeneity Illustrated by Three Different Cases

Annelies Lemaya, Marieke den Brinkera, Hilde Dotremonta, Berten Ceulemansb & Annick Francea

aDivision of Paediatric Endocrinology, Department of Paediatrics, University Hospital Antwerp, Antwerp, Belgium; bDivision of Paediatric Neurology, Department of Paediatrics, University Hospital Antwerp, Antwerp, Belgium

Background: Pseudohypoparathyroidism represents a group of clinical and molecular heterogeneous disorders, characterized by functional hypoparathyroidism, caused by end-organ resistance to the action of PTH. Pseudohypoparathyroidism manifests as hypocalcemia, hyperphosphatemia and elevated plasma levels of PTH. A combination of features, also known as Albright osteodystrophy including disproportionate short stature, obesity, dysmorphia, may co-exist.

Case presentation: We present three cases: The first case is a 13 years old boy who presented with fatigue and muscle cramps. During therapy he developed growth hormone deficiency and hypothyroidism. The second case is a 11 years old boy presenting with therapy-resistant absence epilepsy and intracerebral calcifications. The third case is a 5 years old girl with neonatal hypoglycemia and hypothyroidism. The girl’s development was retarded, with evolution towards growth failure, severe early-onset obesity, osteodystrophy. Loss-of-function mutations in GNAS or epigenetic aberrations leading to failure of expression cause different types of pseudohypoparathyroidism (PHP). GNAS encodes GS alpha, a protein that is required for normal transmembrane signal transduction by many hormones. This gene is imprinted in a tissue-specific manner, being primarily expressed from the maternal allele in renal proximal tubules, whereas both alleles are expressed in bone. Maternally inherited deletions lead to the severe type, PHP Ia. These patients present resistance to other hormones other than PTH that act via Gsalpha-coupled receptors, as resistance to TSH, gonadotropins and GHRH. Patients typically have features of Albright osteodystrophy. Our third case was genetically proven to have PHP-Ia. PHP type Ib is associated with a GNAS imprinting defect in which both alleles have a paternal imprinting pattern on both alleles. Patients manifest renal resistance to PTH, without features of Albright osteodystrophy. Case 1 and 2 are believed to belong to this group of PHP, but genetic analysis is pending.

Conclusion: Substantial clinical and molecular overlap occurs between PHP type 1a and type 1b, what makes it a challenging diagnosis.

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