Isolated hyperchlorhidrosis

The condition was first discovered in 1979, when Greenburg et al. described 2 Puerto Rican brothers ages 7 and 15, respectively, who were found to have high amounts of chloride in their sweat. No disorder (including cystic fibrosis) that could be responsible for this symptom was identified in neither of the brothers, although one of them were found to have Klinefelter syndrome upon karyotyping.[8]

In 2010, Feldshtein et al. described 7 affected members belonging to a multigenerational Israeli Bedouin family. Alongside the hyperchlorhidrosis, said patients were found to have gastroenteritis. Personal testimonies from the patients told that high amounts of visible salt deposits could be spotted during sweating, particularly on areas of the body like the nape. A genome-wide linkage study done on the affected members mapped this condition's locus to a 11-cM region in chromosome 15. The disease-related haplotype was homozygous for those members of the family that were affected and either heterozygous or not present for unaffected members of the family. Sequencing of candidate genes within this genetic region found a homozygous missense mutation in exon 4 of the CA12 gene in affected members (heterozygous in some non-affected members).[6]

In 2011, Muhammad et al. described 3 patients from 3 consanguineous Bedouin families related through the same small clan with failure to thrive and, in 2 of the 3 patients, gastroenteritis. Laboratory tests found the associated bodily abnormalities of the disorder (hyponatremia, hyperkalemia, increased aldosterone, and increased sweat chloride, to be exact). Treatment with oral supplementation of sodium chloride proved successful, although the patients who accepted the treatment (2 out of the 3) developed benign salt cravings at ages 5.5 and 6. The patient who declined treatment continued having episodes of hyponatremic dehydration. All three of the patients showed "catch-up growth" as compensation for their previous failure at thriving. Sequencing of candidate genes following genome-wide linkage analysis found the exact same homozygous, missense mutation in the CA12 gene previously described in medical literature.[7]

In 2016, Lee et al. describes 3 patients from 2 un-related families of Euro-American and Omani descent, respectively.[9]

The first patient is a 25-year-old white woman from the United States who had the characteristic failure to thrive and episodic hyponatremia associated with this condition. In addition to these symptoms, she also had axillary hyperhidrosis (which was treated by a dermatologist) and symptoms suggestive of cystic fibrosis. To be more specific, she had childhood-onset airway obstruction and chronic cough associated with pseudomonas infections. She also had mild bronchiectasis and airway dilatation, both findings of which were found through high-resolution CT imaging. Testing of her CFTR (gene associated with cystic fibrosis), SCNN1A, SCNN1B, and SCNN1G genes came back normal. Sequencing of her CA12 gene found two pathogenic variants: a paternally-inherited c.908-1 G>A substitution and a maternally-inherited four-nucleotide insertion (c.859_860insACCT). On the Exome Aggregation Consortium variant browser, only 53 people were found to carry her c.908-1 G>A substitution mutation, while none were found to carry her four-nucleotide insertion. Saguer sequencing of the gene on the family members of the woman found the same mutations on their respective family sides.[9]

The second and third patients reported by Lee et al. were two siblings, born to consanguineous Omani parents. In addition to the two most common findings of isolated hyperchlorhidrosis, they were also found to have hyperkeratosis affecting their heels. Their lungs and their respective function were found to be healthy. Sequencing of the patients' CA12 gene found a c.363 C>A missense mutation in exon 4 of the gene that changed the His at codon 124 of the gene to Gln. Sequencing of the CA12 gene of the patients' three other unaffected siblings and two unaffected parents found the mutation in its heterozygous state on one of their siblings and both of their parents, while only two of their siblings carried both wild-type (healthy) variants of the gene.[9]