ESPE Abstracts

Case Description: We report a case of a 7-month old Vietnamese boy who presented with failure to thrive and a Cushingoid appearance from 1 month old. There was no history of exogenous steroid use. On examination, height and weight were <3^rd centile. He was Cushingoid with motor development delay. There were multiple large café-au-lait lesions over the sacral region but no limb asymmetry to suggest fibrous dysplasia.

Endocrine investigations were consistent with adrenal Cushing's syndrome: 8am serum cortisol 852nmol/L (normal range, NR 123.0-626.0), ACTH 2.1pg/mL (NR 7.2-63.3), failure of cortisol suppression with the overnight dexamethasone suppression and low dose dexamethasone suppression tests. In addition, serum testosterone was elevated at 3.85nmol/L (NR 0.42-0.72) as was DHEA-S at 26umol/L (NR 0-1.2). Adrenal CT did not reveal any gross masses. There were no liver or cardiac comorbids. DNA extraction from peripheral blood and skin swab returned negative, but repeat testing on buccal swab revealed a pathogenic GNAS mutation: c.601C>T(p.Arg201Cys), confirming the diagnosis of McCune Albright syndrome (MAS). Both parents were negative for the mutation.

Our patient was given a test dose of oral ketoconazole (4mg/kg/day) but developed hepatotoxicity after 1 week, making this unsuitable for therapy. Despite that, the patient improved clinically with good weight gain and linear growth, with decreasing cortisol levels to 478nmol/L within 3 months even without therapy. He was commenced on oral metyrapone 10mg/kg/day for further cortisol suppression. Within 1 week of treatment, 8am serum cortisol had normalized. Metyrapone dose was weaned step-wise until a low dose of 2mg/kg/dose, where serum cortisol remained normal throughout. He tolerated the metyrapone well with no side effects.

Discussion: Infantile Cushing's syndrome (ICS) is a rare but early manifestation of MAS, and may precede the appearance of its skin and bone manifestation. ICS is unique among MAS-related endocrinopathies in its tendency to spontaneously resolve in some cases, due to foetal adrenal regression. In our case, the spontaneous improvement seen before treatment initiation was likely explained by this phenomenon. Despite complete resolution of Cushing's syndrome, patients will require monitoring for neurocognitive development and development of fibrous dysplasia or other endocrinopathies associated with MAS.

This case reinforces the genetic pathogenesis of MAS, which is a mosaic disease arising from post-zygotic somatic mutations of the GNAS gene and may have low mutation abundance. As such, DNA sampling from multiple sites, particularly from affected tissues, is recommended to increase the genetic diagnostic yield.