Uncombable hair syndrome (UHS) is a rare disorder of the hair shaft of the scalp. It is usually characterized by silvery-blond or straw-colored hair that is disorderly; stands out from the scalp; and cannot be combed flat. It may first become apparent from 3 months of age to 12 years of age. Most cases are isolated, but in some cases it has been described in association with other diseases, such as ectodermal dysplasias, Bork syndrome and Angel-shaped phalangoepiphyseal dysplasia. The syndrome has been found to be caused by mutations in the genes PADI3, TGM3, and TCHH. These three genes code for proteins that are involved in hair shaft formation. The syndrome appears to be inherited in an autosomal recessive fashion; however, cases inherited in an autosomal dominant manner may also exist, as there are other genes involved in hair formation. The condition often spontaneously regresses in late childhood. Some published studies suggest that biotin may improve the condition.

Uncombable hair syndrome is a condition that is characterized by dry, frizzy hair that cannot be combed flat. This condition develops in childhood, often between infancy and age 3, but can appear as late as age 12. Affected children have light-colored hair, described as blond or silvery with a glistening sheen. The hair does not grow downward but out from the scalp in multiple directions. Despite its appearance, the hair is not fragile or brittle, and it grows at a normal or slightly slower rate. Only scalp hair is affected in uncombable hair syndrome.

For unknown reasons, this condition usually improves over time. By adolescence individuals with uncombable hair syndrome have hair that lies flat and has normal or nearly normal texture.

The prevalence of uncombable hair syndrome is unknown; at least 100 cases have been described in the scientific literature. There are likely more people who are undiagnosed because adults who seem unaffected may have had uncombable hair syndrome in childhood.

Uncombable hair syndrome is caused by mutations in the PADI3, TGM3, or TCHH gene. These genes provide instructions for making proteins that help give structure to the hair strand (shaft).

The proteins produced from the PADI3 and TGM3 genes modify the protein produced from the TCHH gene, known as trichohyalin. The modified trichohyalin can attach (bind) to other trichohyalin proteins and to molecules called keratin intermediate filaments to create organized cross-links. These links form dense networks that provide structure to the hair shaft and give it a cylindrical shape.

PADI3, TGM3, or TCHH gene mutations likely lead to the production of proteins with little or no activity. As a result, the shape of the hair shaft is altered. Instead of having a cylindrical shape, it has a triangular, heart-like, or flat cross-section. Sometimes all of these irregular shapes can occur along the length of a single strand of hair. Because of the angular shape of the hair shaft, the hair will not lie flat. In children with uncombable hair syndrome, 50 to 100 percent of their strands of hair have an irregular shape. Additionally, the abnormal hair reflects light differently than normal hair, accounting for its glistening sheen.

Some people with uncombable hair syndrome do not have an identified mutation in one of these three genes. The cause of the condition in these individuals is unknown.

Normal Function

The PADI3 gene provides instructions for making an enzyme called peptidylarginine deiminase type III. This enzyme modifies proteins by changing certain protein building blocks (amino acids). Specifically, it changes the positively charged amino acid arginine to the neutral amino acid citrulline when positively charged calcium atoms (ions) are present. This process is called deimination. In most cases, deimination alters the protein's interactions with other proteins.

Peptidylarginine deiminase type III is found in the skin's tough outer surface (the stratum corneum), within cells called keratinocytes. The protein also functions in hair follicles, which are specialized structures in the skin where hair growth occurs. In hair follicles, peptidylarginine deiminase type III modifies proteins involved in giving structure to the hair strand (shaft).

Health Conditions Related to Genetic Changes

Uncombable hair syndrome

At least nine mutations in the PADI3 gene have been found to cause uncombable hair syndrome. This condition is characterized by dry, frizzy, blond scalp hair that cannot be combed flat. This condition usually improves over time, and by adolescence individuals with uncombable hair syndrome have hair that lies flat and has normal or nearly normal texture.

The PADI3 gene mutations likely result in a peptidylarginine deiminase type III enzyme with little or no activity. As a result, the enzyme cannot deiminate other proteins. In particular, peptidylarginine deiminase type III cannot deiminate a protein within the hair shaft called trichohyalin. Trichohyalin needs this modification so that it can attach (bind) to other proteins, giving the hair shaft its cylindrical shape. Without deimination of trichohyalin, the cross-section of the hair shaft becomes triangular, heart-like, or flat. These angular hair shafts result in frizzy hair that will not lie flat, which is typical of uncombable hair syndrome.

Other Names for This Gene

• PAD3
• PDI3
• peptidyl arginine deiminase, type III
• peptidylarginine deiminase III
• protein-arginine deiminase type III
• protein-arginine deiminase type-3

Genomic Location

Normal Function

The TGM3 gene provides instructions for making an enzyme called transglutaminase 3. This enzyme is found in certain skin cells called keratinocytes and corneocytes, as well as in various structures that make up scalp hair, including the root and strand (shaft).

Transglutaminase 3 helps proteins attach (bind) to each other at specific protein building blocks (amino acids). Specifically, transglutaminase 3 helps bind proteins together at their glutamine and lysine amino acids. This binding forms stabilizing cross-links between proteins. These protein cross-links provide strength and structure to cells, particularly skin and hair cells.

Health Conditions Related to Genetic Changes

Uncombable hair syndrome

At least one mutation in the TGM3 gene has been found to cause uncombable hair syndrome. This condition is characterized by dry, frizzy, blond scalp hair that cannot be combed flat. This condition usually improves over time, and by adolescence individuals with uncombable hair syndrome have hair that lies flat and has normal or nearly normal texture.

The TGM3 gene mutation that has been identified leads to a premature stop signal in the instructions used to make transglutaminase 3, resulting in an abnormally short enzyme with severely reduced activity. A shortage (deficiency) of functional enzyme impairs cross-linking between certain proteins. Particularly, the hair shaft protein trichohyalin cannot bind to other trichohyalin proteins or to molecules called keratin intermediate filaments. These proteins and molecules need to bind to each other to form the cross-links that give the hair shaft its cylindrical shape. Because transglutaminase 3 cannot facilitate these cross-links, the cross-section of the hair shaft becomes triangular, heart-shaped, or flat. These angular hair shafts result in frizzy hair that will not lie flat, which is typical of uncombable hair syndrome.

Other Names for This Gene

• E polypeptide, protein-glutamine-gamma-glutamyltransferase
• protein-glutamine gamma-glutamyltransferase E
• TG(E)
• TGase E
• TGase-3
• TGE
• transglutaminase E

Genomic Location

Normal Function

The TCHH gene provides instructions for making a protein called trichohyalin. This protein is primarily found in hair follicles, which are specialized structures in the skin where hair growth occurs. Trichohyalin can also be found in the hair strand (shaft). Once trichohyalin is produced, it is modified by other proteins so that it can attach (bind) to other trichohyalin proteins and to molecules called keratin intermediate filaments to create organized cross-links. These links form dense networks that give the hair shaft its cylindrical shape.

Health Conditions Related to Genetic Changes

Uncombable hair syndrome

At least one mutation in the TCHH gene has been found to cause uncombable hair syndrome. This condition is characterized by dry, frizzy, blond scalp hair that cannot be combed flat. This condition usually improves over time, and by adolescence individuals with uncombable hair syndrome have hair that lies flat and has normal or nearly normal texture.

The TCHH gene mutation that has been identified leads to a premature stop signal in the instructions used to make trichohyalin, resulting in an abnormally short protein with severely reduced activity. A shortage (deficiency) of functional protein reduces the cross-links that are formed between trichohyalin proteins and keratin intermediate filaments. As a result, the cross-section of the hair shaft becomes triangular, heart-shaped, or flat. These angular hair shafts result in frizzy hair that will not lie flat, which is typical of uncombable hair syndrome.

Other Names for This Gene

• AHF
• THH
• THL
• TRHY

Genomic Location