ESPE Abstracts (2016) 86 P-P1-688

Thyrotoxicosis, Nephrogenic Syndrome of Inappropriate Antidiuresis, Tall Stature and Mental Retardation Caused by a Novel GNAS Gain of Function Mutation

Muriel Houanga,b, Marie-Laure Kottlerc, Albert Bensmand,e, Jean-Philippe Haymanne,f, Nicolas Richardc, Olivier Dunandd, Murate Bastepeg, Caroline Silveh, Nathalie Coudrayi, Irène Netchinea,e & Agnès Linglarti


aExplorations Fonctionnelles Endocriniennes, Hôpital Trousseau-APHP, Paris, France; bINSERM U938, Paris, France; cUniversity hospital and CMR Calcium-Phosphore, Normandy University, Caen, France; dService de Néphrologie Pédiatrique, Hôpital Trousseau APHP, Paris, France; eUniversity UMPC Paris VI, Paris, France; fExplorations Fonctionnelles, Hôpital Tenon APHP, Paris; France; gEndocrine Unit, Massachussetts General Hospital, Boston, MA, USA; hService de Biologie Moléculaire Hormonale, Hôpital Cochin APHP, Paris, France; iINSERM and APHP, CMR Calcium-Phosphore, Bicêtre Paris sud, Paris, France


Background: Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a very rare clinical condition. Patients suffer from hyponatremia, hypo-osmolality with inappropriately elevated urinary osmolality and undetectable AVP levels. Activating mutations of AVPR2, the vasopressin receptor type 2 (V2R), induce a prolonged signaling of the intracellular cAMP/PKA pathway and cause NSIAD in patients.

Objective and hypotheses: To describe a new phenotype in a patient with symptoms suggestive of the concomitant and inappropriate activity of several GPCRs, a pattern reminiscent of Mc Cune Albright syndrome (MAS), yet with a different phenotype including the phenocopy of the V2R constitutive activation.

Patient: A 4-years old tall girl had persistent hyponatremia (118–128 mmol/l) and antidiuresis. Her plasmatic osmolarity was low (260 mOsm/lkg) while the urinary osmolarity was inadequately elevated (1020 mOsm/kg). The AVP level was undetectable. No variant was identified in the AVPR2 gene. She also had symptoms of androgen secretion (mild clitoral enlargement, pubic hair and advanced bone age, slightly elevated testosterone and sDHA levels). Adrenals were of normal size and shape on the CT-scan. At the age of 5 years, she developed a non-immune thyrotoxicosis. At the age of 6, a café au lait spot appeared on the tight. We hypothesized that she could have a constitutional activation of the cAMP/PKA pathway and we searched for mutations in candidate genes downstream of AVRPR2 and the TSH receptor.

Results: We found a de novo S250I mutation in GNAS, encoding the alpha-subunit of the stimulatory G protein (Gsα). Transfection of the mutated S250I-Gsα in Gnas null cells demonstrated a greater accumulation in cAMP compared to the wild-type Gsa (P=0.0004). But a lesser cAMP production than that we observed upon R201-Gsα transfection (the activating mutation responsible for MAS) (P<0.0001).

Conclusion: We describe a novel form of constitutive Gsα activation responsible for NSIAD and thyrotoxicosis.