A Novel GNAS Mutation Causing Isolated Infantile Cushing's Syndrome.

Infantile Cushing's syndrome is potentially found as part of McCune-Albright syndrome (MAS) which is caused by postzygotic somatic mutations of the GNAS gene. MAS is typically characterized by a triad of polyostotic fibrous dysplasia, café-au-lait skin pigmentation, and precocious puberty or other endocrine hyperfunction. Here, we describe a 2-month-old female infant with features of Cushing's syndrome without café au lait spots, polyostotic fibrous dysplasia, and clinical evidence of other endocrine hyperfunction. Investigations demonstrated adrenocorticotropic hormone-independent Cushing's syndrome with bilateral adrenal gland enlargement. Whole-exome sequencing of leukocytes identified a de novo heterozygous novel missense mutation (c.521G>A, p.Cys174Tyr) in the GNAS gene. The patient experienced clinical improvement of Cushing's syndrome during ketoconazole treatment. Her clinical course was complicated by Pneumocystis jiroveci pneumonia. She also had shortened activated partial thromboplastin time indicating a hypercoagulable state and resulting in pulmonary embolism. She eventually manifested gonadotropin-independent precocious puberty at the age of 13 months after ketoco-nazole was discontinued. This patient demonstrated that Cushing syndrome can be the presenting sign of MAS in infancy. A high index of suspicion followed by genetic analysis is essential in order to establish a diagnosis.

Under-recognized Hypoparathyroidism in Thalassemia

Objective: Symptomatic hypoparathyroidism [symptomatic hypocalcemia without elevated serum parathyroid hormone (PTH)] in patients with thalassemia is relatively rare. Asymptomatic mild hypocalcemia without elevated PTH, which is considered hypoparathyroidism, may be more common but under-recognized. Methods: Sixty-six transfusion-dependent thalassemic patients and 28 healthy controls were enrolled. Serum calcium (Ca), phosphate (P), creatinine (Cr), albumin, intact PTH, 25-hydroxyvitamin D (25-OHD), plasma intact fibroblast growth factor-23 (FGF-23), urinary Ca, P and Cr were measured. Tubular reabsorption of P was calculated. Results: Thalassemic patients had significantly lower median serum Ca levels than the controls [8.7 (7.8-9.7) vs 9.6 (8.7-10.1) mg/dL, p<0.001]. Hypoparathyroidism was found in 25 of 66 (38%) patients. Symptomatic hypoparathyroidism was not encountered. Thalassemic patients also had significantly lower median plasma FGF-23 levels than the controls [35.7 (2.1-242.8) vs 53.2 (13.3-218.6) pg/mL, p=0.01]. In patients with hypoparathyroidism, median plasma FGF-23 level was significantly lower than that of normoparathyroid patients [34.8 (2.1-120.0) vs 43.1 (3.2-242.8) pg/mL, p=0.048]. However, serum P, Cr, intact PTH and 25-OHD levels were not significantly different in the two groups. Conclusion: Hypoparathyroidism was not uncommon in patients with transfusion-dependent thalassemia treated with suboptimal iron chelation. Plasma intact FGF-23 level in hypoparathyroid patients was lower than that of normoparathyroid patients.