Metyrapone as treatment in the neonatal McCune-Albright syndrome.

Objectives To present a case report of succesfully metyrapone treatment of a neonatal patient with McCune-Albrigth syndrome (MAS), a rare disease caused by a genetically mosaic disorder and is characterized by variable hyperfunctional endocrinopathies, bone dysplasia, and café-au-lait spots. Case presentation A preterm newborn was admitted to hospital and she presented difficulty controlling hypertension, café-au-lait spots, and failure to thrive. An abdominal ultrasound and a magnetic resonance showed a high volume of both suprarenal glands. Therefore, MAS was suspected. Laboratory data confirmed adrenocorticotropic hormone-independent Cushing's syndrome with hepatic dysfunction and metyrapone treatment was initiated. A progressive normalization of cortisol levels was achieved despite poor oral tolerance. Conclusion Our case shows that metyrapone is useful in the management of neonatal Cushing's syndrome due to McCune-Albright syndrome.

Familial hyperaldosteronism type III a novel case and review of literature.

Less than 15% of hypertension cases in children are secondary to a primary hyperaldosteronism. This is idiopathic in 60% of the cases, secondary to a unilateral adenoma in 30% and 10% remaining by primary adrenal hyperplasia, familial hyperaldosteronism, ectopic aldosterone production or adrenocortical carcinoma.To date, four types of familial hyperaldosteronism (FH I to FH IV) have been reported. FH III is caused by germline mutations in KCNJ5, encoding the potassium channel Kir3.4. The mutations cause the channel to lose its selectivity for potassium, allowing large quantities of sodium to enter the cell. As a consequence, the membrane depolarizes, voltage-gated calcium channels open, calcium enters the cell, initiating the cascade that leads to aldosterone synthesis. Somatic mutations in KCNJ5 has also been described in aldosterone-producing adenomas. The most frequent presentation of FH III is with severe hyperaldosteronism symptoms and resistance to pharmacological therapy which leads to bilateral adrenalectomy. We will review current literature and describe a child with FH III due to a novel de novo deletion in KCNJ5 with wild phenotype as a sign of clinical variability of this disease.

GATA4 Variants in Individuals With a 46,XY Disorder of Sex Development (DSD) May or May Not Be Associated With Cardiac Defects Depending on Second Hits in Other DSD Genes.

Disorders of sex development (DSD) consist of a wide range of conditions involving numerous genes. Nevertheless, about half of 46,XY individuals remain genetically unsolved. GATA4 gene variants, mainly related to congenital heart defects (CHD), have also been recently associated with 46,XY DSD. In this study, we characterized three individuals presenting with 46,XY DSD with or without CHD and GATA4 variants in order to understand the phenotypical variability. We studied one patient presenting CHD and 46,XY gonadal dysgenesis, and two patients with a history of genetically unsolved 46,XY DSD, also known as male primary hypogonadism. Mutation analysis was carried out by candidate gene approach or targeted gene panel sequencing. Functional activity of GATA4 variants was tested in vitro on the CYP17 promoter involved in sex development using JEG3 cells. We found two novel and one previously described GATA4 variants located in the N-terminal zinc finger domain of the protein. Cys238Arg variant lost transcriptional activity on the CYP17 promoter reporter, while Trp228Cys and Pro226Leu behaved similar to wild type. These results were in line with bioinformatics simulation studies. Additional DSD variations, in the LRP4 and LHCGR genes, respectively, were identified in the two 46,XY individuals without CHD. Overall, our study shows that human GATA4 mutations identified in patients with 46,XY DSD may or may not be associated with CHD. Possible explanations for phenotypical variability may comprise incomplete penetrance, variable sensitivity of partner genes, and oligogenic mechanisms.