ANE syndrome caused by mutated RBM28 gene: a novel etiology of combined pituitary hormone deficiency

Abstract

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.

Wnt signalling in pituitary development and tumorigenesis

“…Skin biopsies taken from one patient with ANE demonstrated a loss of mature follicles and the presence of dermal cysts, mirroring the findings in the skin of mice with b-catenin deficiency. A reduction in b-catenin expression in this skin biopsy was also observed, indicating that canonical signalling may play a role in the pituitary failure of these patients (Nousbeck et al 2008, Spiegel et al 2010). …”

“…In the alopecia, neurological defects and endocrinopathy (ANE) syndrome, patients developed combined anterior hormone deficiency including gonadotrophs and corticotrophs (Spiegel et al 2010). Skin biopsies taken from one patient with ANE demonstrated a loss of mature follicles and the presence of dermal cysts, mirroring the findings in the skin of mice with b-catenin deficiency.…”

RBM28, a protein deficient in ANE syndrome, regulates hair follicle growth via miR‐203 and p63

“…Although decreased expression of RBM28 has been shown to be associated with alopecia in patients with ANE syndrome, it is not known whether RBM28 deficiency is directly responsible for abnormal hair growth in the patients, or whether it leads to hair loss indirectly, possibly through its deleterious effect on the development of the pituitary gland . To obtain direct evidence for a role of RBM28 in hair growth and development, we utilized an ex vivo human hair follicle (HF) organ culture model .…”

“…In the current study, we aimed to delineate the molecular pathways affected by abnormal RBM28 expression in ANE syndrome. We predicted these regulatory mechanisms to be multifaceted, due to the pleiotropic and complex nature of ANE syndrome clinical phenotype .…”

MicroRNAs and developmental timing

“…RMB-28 is homologous to the human RBM28, a nucleolar protein which has been implicated in diseases associated with defects in spliceosomal and/or ribosome biogenesis [29] [30] [31], suggesting a possible intersection of nucleolar RNP function and the regulation of lin-4 accumulation.…”