Polyendocrine-Polyneuropathy Syndrome

A number sign (#) is used with this entry because of evidence that the polyendocrine-polyneuropathy syndrome (PEPNS) is caused by homozygous mutation in the DMXL2 gene (612186) on chromosome 15q21.2. One such family has been reported.

Clinical Features

Tata et al. (2014) described a consanguineous Senegalese family in which 3 of 5 children had a progressive endocrine and neurodevelopmental disorder. The 3 affected brothers displayed growth retardation and had recurrent episodes of asymptomatic profound hypoglycemia with incomplete suppression of insulin concentration that appeared between 2 and 5 years of age. At 14 to 16 years of age, all 3 gradually developed nonautoimmune insulin-dependent diabetes mellitus. Their puberty was incomplete and they had low testicular volumes; all had a normal sense of smell. During adolescence, the brothers exhibited dysarthria and ataxia, and neurologic examination revealed polyneuropathy, with a motor deficit predominantly affecting the proximal lower limbs, as well as pes cavus, claw toes, and cerebellar and pyramidal signs. Electrophysiologic analysis was consistent with demyelinating polyneuropathy, with a diffuse homogeneous pattern of slowing motor conduction in peripheral nerves, and greater preservation of sensory conduction in the legs than in the arms. Brain MRI showed moderate subcortical temporal white matter disease, and 1 brother also showed mild hypoplasia of the cerebellum and a small anterior pituitary gland. Hormone assessment in adulthood showed an increase in HbA1c levels, with low insulin levels in an intravenous glucose tolerance test and subnormal basal C-peptide levels. In addition, the patients had low serum-free T4 with normal thyroid-stimulating hormone (TSH; see 188540) levels; the effects of thyrotropin-releasing hormone (TRH; 613879) administration were consistent with central hypothyroidism of hypothalamic origin. All 3 brothers had low plasma testosterone levels for their age, as well as low luteinizing hormone (LH; see 152780) and follicle-stimulating hormone (FSH; see 136530) concentrations. The gonadotropin-releasing hormone (GnRH; see 152760) stimulation test showed a large increase in LH with a normal rise in FSH levels. Other features in the 3 brothers included moderate intellectual disability and progressive hearing loss. Their parents were of normal height and experienced normal pubertal development, with a spontaneous pregnancy in the mother at age 20 years; their father developed glucose intolerance at 46 years of age.

Mapping

In a consanguineous Senegalese family in which 3 of 5 children had a progressive endocrine and neurodevelopmental disorder, under the assumption of a fully penetrant recessive transmission model with a disease allele frequency of 0.0001, Tata et al. (2014) identified 2 candidate regions on chromosomes 13 and 15, with a lod score of 2.5.

Molecular Genetics

In a consanguineous Senegalese family in which 3 of 5 children had a progressive endocrine and neurodevelopmental disorder mapping to either chromosome 13 or 15, Tata et al. (2014) performed high-throughput sequencing of all exons of both candidate regions and identified a 15-bp in-frame deletion in the DMXL2 gene (612186.0001) on chromosome 15q21 that segregated with the disorder. Analysis of DMXL2 in 10 patients with hypogonadotropic hypogonadism and a similar phenotype did not reveal any additional mutations. Tata et al. (2014) noted overlap between the features exhibited by affected individuals in the Senegalese family and the phenotypes of the Warburg Micro (see 600118) and Martsolf (212720) syndromes, which are caused by mutations in genes (RAB3GAP1, 602536 and RAB3GAP2, 609275, respectively) encoding components of the protein complex containing DMXL2.

Animal Model

Tata et al. (2014) performed conditional heterozygous deletion of Dmxl2 in mouse neurons and observed delayed puberty as well as very low fertility; the reproductive phenotype was associated with a reduced number of GnRH neurons in the hypothalamus of adult mice. Mice with a homozygous deletion of Dmxl2 died during embryonic development. Tata et al. (2014) proposed that the severity of the phenotype is highly associated with neuronal expression levels of DMXL2, and also suggested that the phenotypic discrepancy between mice and humans might result from interactions of different partners with DMXL2.