Alopecia, Neurologic Defects, And Endocrinopathy Syndrome

A number sign (#) is used with this entry because of evidence that alopecia, neurologic defects, and endocrinopathy syndrome (ANES) is caused by homozygous mutation in the RBM28 gene (612074) on chromosome 7q32. One such family has been reported.

Clinical Features

Nousbeck et al. (2008) reported a consanguineous family of Arab Moslem descent in which 5 brothers had a complex phenotype characterized by alopecia, neurologic defects, and endocrinopathy (ANE syndrome). The patients had hair loss of variable severity, ranging from complete alopecia to near-normal scalp hair with absence of body hair. A scalp skin biopsy showed absence of mature hair follicles, rudimentary infundibula, and epithelial cysts. All patients had moderate to severe mental retardation and progressive motor deterioration during the second decade of life. Extensive endocrinologic studies showed central hypogonadotropic hypogonadism with delayed or absent puberty and central adrenal insufficiency. Brain MRI of 1 patient showed a hypoplastic pituitary. Additional features included short stature, microcephaly, gynecomastia, pigmentary anomalies, hypodontia, kyphoscoliosis, ulnar deviation of the hands, and loss of subcutaneous fat.

Spiegel et al. (2010) restudied the 5 affected brothers with ANES reported by Nousbeck et al. (2008). All 5, aged 20 to 39 years, displayed absent puberty, hypogonadism, and variable degrees of short stature. Low insulin-like growth factor-1 (IGF1; 147440) concentration and a lack of growth hormone (GH; 139250) response to provocative tests in all sibs were consistent with GH deficiency. Low testosterone and gonadotropin (see 118850) levels with absent or low response to gonadotropin-releasing hormone (GNRH1; 152760) stimulation indicated hypogonadotropic hypogonadism. Adrenocorticotropic hormone (ACTH) deficiency developed, and glucocorticoid replacement therapy was initiated in 4 patients. Thyroid analysis showed variable abnormal thyroid-stimulating hormone (TSH; see 188540) response to thyrotropin-releasing hormone (TRH; 613879) stimulation, suggesting hypothalamic compensated hypothyroidism in 4 patients and laboratory hypothyroidism (low free thyroxine) in 1 patient. Low prolactin (PRL; 176760) levels were shown in 1 case. Spiegel et al. (2010) concluded that ANES is characterized by variable anterior pituitary hormone deficiencies that develop over time, resulting in a syndromic form of combined anterior pituitary hormone deficiency (CPHD; see 613038).

Mapping

By genomewide linkage analysis of a consanguineous family with ANE syndrome, Nousbeck et al. (2008) identified a 6.45-Mb region of homozygosity on chromosome 7q31.32-7q32 that was shared by all patients (maximum multipoint lod score of 3.64 at marker D7S530). The critical region was between SNPs rs17147033 and rs205763.

Molecular Genetics

In affected members of a consanguineous family with ANE syndrome, Nousbeck et al. (2008) identified a homozygous mutation in the RBM28 gene (612074.0001).