Isolated hyperchlorhidrosis is characterized by the excessive loss of salt (sodium chloride or NaCl) in sweat. In particular, "hyperchlorhidrosis" refers to the high levels of chloride found in sweat, although both sodium and chloride are released. Because the salt is abnormally released from the body in sweat, there are lower than normal levels of sodium in fluids inside the body (hyponatremia). Most infants with isolated hyperchlorhidrosis experience one or more episodes of dehydration with low levels of sodium in the blood (hyponatremic dehydration), which can require hospitalization. These episodes typically follow a mild illness that causes vomiting or diarrhea. Affected infants also have poor feeding and an inability to grow and gain weight at the expected rate (failure to thrive). By early childhood, though, weight and height usually catch up to normal, although the abnormal loss of salt still remains. These individuals may still experience dangerous hyponatremia when they sweat excessively, for example in warm temperatures or when exercising.

While hyperchlorhidrosis can occur as one of several features of other conditions, such as cystic fibrosis, people with isolated hyperchlorhidrosis do not have the additional signs and symptoms of these other conditions.

Isolated hyperchlorhidrosis is caused by a mutation in the CA12 gene. This gene provides instructions for making a protein called carbonic anhydrase 12 (CA 12), which belongs to a family of related proteins known as carbonic anhydrases. These proteins carry out a chemical reaction that involves the molecules carbon dioxide and water and produces a negatively charged bicarbonate molecule (bicarbonate ion) and a positively charged hydrogen atom (known as a proton). The presence of protons and bicarbonate affect the relative acidity (pH) of cells, which is important for several cellular processes, including the transport of salt into and out of cells. Researchers suggest that by regulating cellular pH in the sweat glands, CA 12 is able to control the amount of salt released in sweat.

The CA12 gene mutation involved in isolated hyperchlorhidrosis leads to reduction of CA 12 protein function. Researchers speculate that the altered CA 12 is less able to regulate pH, and it loses its ability to control how much salt is released in sweat, leading to hyperchlorhidrosis.

Normal Function

The CA12 gene provides instructions for making a protein called carbonic anhydrase 12 (CA 12), which belongs to a family of proteins known as carbonic anhydrases. These proteins carry out a chemical reaction that involves the molecules carbon dioxide and water and produces a negatively charged bicarbonate molecule (bicarbonate ion) and a positively charged hydrogen atom (known as a proton). Carbonic anhydrases can also carry out the reverse reaction, forming carbon dioxide and water from bicarbonate. Carbon dioxide, bicarbonate, and protons are involved in many functions in the body; by regulating the levels of these substances, carbonic anhydrases play roles in several important processes. The presence of protons and bicarbonate affect the relative acidity (pH) of cells; one function of some carbonic anhydrases is to help maintain the correct cellular pH.

CA 12 is found in several tissues, including the sweat glands, kidneys, and large intestine. The protein likely helps regulate the transport of salt (sodium chloride or NaCl) in these tissues. Researchers suggest that channels that move salt in and out of cells are controlled in part by the pH of the cells. By regulating cellular pH, CA 12 may be able to control salt transport. In sweat glands, CA 12 is thought to play a role in determining how much salt is released from the body in sweat.

Health Conditions Related to Genetic Changes

Isolated hyperchlorhidrosis

At least one mutation in the CA12 gene causes isolated hyperchlorhidrosis, a condition characterized by abnormally high levels of salt in sweat that can lead to dehydration associated with low levels of sodium in the blood (hyponatremic dehydration). The gene mutation that causes this condition changes a single protein building block (amino acid) in the CA 12 protein, replacing the amino acid glutamate at position 143 with the amino acid lysine (written as Glu143Lys or E143K). The function of the altered protein is reduced to about 70 percent of normal. In addition, the altered protein is more easily turned off (inhibited) than normal, which further reduces protein function. It is thought that the altered CA 12 is less able to regulate pH, and it loses its ability to control how much salt is released in sweat, leading to hyperchlorhidrosis.

Researchers suggest that other tissues are seemingly unaffected by CA12 gene mutations because these tissues contain other carbonic anhydrases that compensate for the loss of CA 12 function.

Other Names for This Gene

• CA XII
• CA-XII
• carbonate dehydratase XII
• carbonic anhydrase XII
• carbonic dehydratase
• CAXII
• tumor antigen HOM-RCC-3.1.3

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Isolated hyperchlorhidrosis is a rare condition, although its prevalence is unknown. The condition has been found mostly in the Bedouin population of southern Israel.