Anhidrosis, Isolated, With Normal Sweat Glands

A number sign (#) is used with this entry because of evidence that isolated anhidrosis with normal sweat glands (ANHD) is caused by homozygous mutation in the ITPR2 gene (600144) on chromosome 12p11. One such family has been reported.

Clinical Features

Dann et al. (1990) reported the case of a young man with generalized anhidrosis rendering him heat intolerant. His reaction to muscarinic stimulation of sweat glands was 10% of normal. On biopsy, the sweat glands were morphologically intact and cardiovascular autonomic responses were normal. The patient's mother reported reduced sweating and her response to muscarinic stimulation was 50% of normal, but the father and 2 sisters sweated normally. A postganglionic defect was postulated. The sketchy information on the family is consistent with autosomal dominant inheritance but also with X-linked inheritance since the deficiency in the mother appears to have been less severe than that in the son. Ingber (1990) suggested that the disorder described by Dann et al. (1990) be named Dann-Epstein-Sohar syndrome.

Klar et al. (2014) described a consanguineous Pakistani family in which 5 members had anhidrosis and severe heat intolerance, confirmed by starch-iodine sweat test. Body growth, teeth, hair, nails, and skin were normal. Affected family members did not report dry mouth, reduced saliva production, and malabsorption. Biochemical analysis of serum and urine in 2 affected individuals showed electrolyte levels within normal ranges; S-amylase levels were also normal. Skin biopsy from the forearm of 1 affected family member showed normal morphology and a normal number of eccrine sweat glands.

Classification

Ingber (1990) commented that there are 3 types of generalized anhidrosis: (1) ectodermal dysplasia with generalized anhidrosis, and hair, sweat gland and dental anomalies with or without additional congenital defects (see 305100); (2) ectodermal dysplasia with generalized anhidrosis, with no other defects but with morphologic and functional abnormalities of sweat glands (see 206600); and (3) ectodermal dysplasia with generalized anhidrosis, with no other defects and with no morphologic sweat gland anomalies.

Inheritance

The inheritance pattern of isolated anhidrosis in the family reported by Klar et al. (2014) was consistent with autosomal recessive inheritance.

Mapping

By autozygosity mapping of a consanguineous Pakistani family with isolated anhidrosis, Klar et al. (2014) identified a single homozygous region on chromosome 12p12.1-p11.22 of the ITPR2 gene in all 5 affected individuals. The authors confirmed segregation of this candidate region by polymorphic microsatellite markers and linkage analysis (lod score of 3.08).

Molecular Genetics

By whole-genome sequencing in a consanguineous Pakistani family with isolated anhidrosis and morphologically normal eccrine sweat glands, Klar et al. (2014) identified a homozygous missense mutation in the ITPR2 gene (G2498S; 600144.0001). The mutation, which occurred in a highly conserved residue of the protein, was not found in 200 Swedish and 200 Pakistani control chromosomes, in 850 in-house exomes, or in the Exome Variant Server database. Functional studies showed that the mutation abrogates Ca(2+) release from the endoplasmic reticulum, suggesting that intracellular Ca(2+) release by ITPR2 in clear cells of the sweat glands is important for eccrine sweat production.

Animal Model

By analyzing eccrine glands in the paws of Itpr2-null mice, Klar et al. (2014) observed a 3-fold reduction in the number of pilocarpine-responsive sweat glands. The sweat glands of these mice showed a significant reduction in Ca(2+) response following acetylcholine stimulation compared with those of wildtype mice. The Itpr2-null mice retained some residual sweat production, in contrast to the human phenotype of anhidrosis. Klar et al. (2014) suggested that this phenotypic discrepancy may be due to differences between humans and mice in the expression of the 3 ITPR isoforms, as well as to the different stimuli used to provoke sweat production in Itpr2-null mice.