Helix Syndrome

A number sign (#) is used with this entry because of evidence that HELIX syndrome (HELIX) is caused by homozygous mutation in the CLDN10 gene (617579) on chromosome 13q32.

Clinical Features

Klar et al. (2017) studied 13 patients from 2 distantly related consanguineous Pakistani families segregating congenital heat intolerance and generalized anhidrosis. In all patients, the anhidrosis was associated with the inability to produce tears (alacrima) and dry mouth (xerostomia). Several affected individuals developed nephrolithiasis in adolescence, with recurrent bouts of pain. Serum electrolyte analysis revealed increased Mg(2+) levels, and abnormal renal reabsorption of cations was reflected in urine spot samples that showed low concentrations of Mg(2+) and Ca(2+). Parathyroid hormone (PTH; 168450) levels were increased 2- to 3-fold above normal in 2 patients, who also had reduced 25-hydroxy vitamin D levels. These observations suggested secondary hyperparathyroidism and renal damage, further supported by an estimated glomerular filtration rate (eGFR) in the low normal range. Serum creatinine, urea, and bicarbonate were normal, as were CT scans of the kidneys. Pancreatic and lung function were normal. Histologic analysis of patient sweat glands showed normal morphology and number.

Hadj-Rabia et al. (2018) reported 6 patients from 2 unrelated consanguineous families with hypohidrosis, electrolyte imbalance, lacrimal gland dysfunction, ichthyosis, and xerostomia, which the authors designated 'HELIX syndrome.' Dental examination showed severe enamel wear; panoramic dental x-rays of patients from both families showed that enamel formed but eroded quickly after tooth eruption. In both families, affected individuals had dry skin with fine white scaling, predominantly on the arms and knees. Histologic examination of patient skin specimens showed epidermal changes consistent with ichthyosis, including a slightly thickened stratum corneum with follicular ostial dilation and basket-weave keratin, and an increased number of dilated eccrine sweat glands, the epithelial cells of which showed an acantholytic appearance. All 6 patients had high plasma renin levels with normal to high plasma aldosterone and normal to low blood pressure. Plasma potassium was low in adults but normal in children, and 5 of the 6 patients had elevated plasma magnesium levels. All had normal eGFR at first visit, but eGFR decreased in the oldest patient (age 46 years) to less than half the normal value; percutaneous kidney biopsy in that patient showed extensive fibrosis but no specific damage. None of the adult patients had nephrocalcinosis. Analysis of the renal response to furosemide in 3 adult patients showed higher baseline fractional excretion (FE) of sodium and chloride than found in controls, with the FEs increasing to similar values in patients and controls during furosemide infusion. The FE of calcium increased significantly with furosemide, but less in patients than in controls, whereas the FE of magnesium increased more in patients than in controls. Hadj-Rabia et al. (2018) suggested that the renal NaCl wasting syndrome observed in these patients was primarily due to electrolyte transport disturbances in the thick ascending limb of the loop of Henle.

Mapping

In 2 distantly related consanguineous Pakistani families with generalized anhidrosis, severe heat intolerance, and mild renal failure, Klar et al. (2017) performed autozygosity mapping and identified a homozygous region of 235 consecutive SNPs spanning a 2-Mb interval on chromosome 13q32. Fine mapping with microsatellite markers confirmed homozygosity, and linkage analysis yielded a 2-point lod score of 4.25.

Molecular Genetics

In 13 affected members of 2 distantly related consanguineous Pakistani families with generalized anhidrosis, severe heat intolerance, and mild renal failure mapping to chromosome 13q32, Klar et al. (2017) identified homozygosity for a missense mutation in the CLDN10 gene (N48K; 617579.0001). The mutation segregated fully with disease in both families and was not found in 600 Pakistani control chromosomes or in the ExAC database.