Objective and design: A homozygous loss-of-function mutation in the gene RBM28 was recently reported to underlie alopecia, neurological defects, and endocrinopathy (ANE) syndrome. The aim of the present study was to characterize the endocrine phenotype of ANE syndrome and to delineate its pathogenesis. Methods: Detailed neuroendocrine assessment was performed in five affected male siblings harboring the homozygous p.L351P mutation in RBM28. Results: All five affected patients, aged 20-39 years, displayed absent puberty, hypogonadism, and variable degrees of short stature. Low IGF1 concentration and a lack of GH response to provocative tests in all siblings were consistent with GH deficiency. Low testosterone and gonadotropin levels with absence or low response to GnRH stimulation indicated hypogonadotropic hypogonadism. ACTH deficiency evolved over time, and glucocorticoid replacement therapy was initiated in four patients. Thyroid analysis showed variable abnormal TSH response to TRH stimulation, suggesting hypothalamic compensated hypothyroidism in four subjects and laboratory hypothyroidism (low free thyroxine) in one patient. Low prolactin levels were shown in one case. Conclusions: The endocrine defects characteristic of ANE syndrome are compatible with variable combined anterior pituitary hormone deficiency (CPHD), which evolves gradually over the years, indicating long-term hormonal monitoring. We propose that defects in the cellular Wnt/b-catenin signaling pathway underlie this endocrinopathy. RBM28 gene defects should be added to the growing list of gene defects associated with syndromic CPHD.

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