One gene and pathogenic missense variants in that gene account for most cases of uncombable hair syndrome (UHS), a rare hair shaft anomaly that manifests during infancy, investigators have reported.

The findings are from a cohort study published in JAMA Dermatology that involved 107 unrelated children and adults suspected of having UHS, as well as family members, all of whom were recruited from January 2013 to December 2021. Genetic analyses were conducted in Germany from January 2014 to December 2021 with exome sequencing.

Senior author Regina C. Betz, MD, professor of dermatogenetics at the Institute of Human Genetics, University Hospital Bonn, Bonn, Germany, told Medscape that in 2016, she and her co-investigators authored a study on the molecular genetics of UHS. That study, which involved 18 people with UHS, identified variants in three genes PADI3, TCHH, and TGM3 that encode proteins that play a role in the formation of the hair shaft. The investigators described how a deficiency in the shaping and mechanical strengthening of the hair shaft that occurs in the UHS phenotype, which is characterized by dry, frizzy, and wiry hair that cannot be combed flat.

Dr Regina Betz

As a result of that previous work, "we base the assignment or confirmation of a clinical diagnosis of UHS on molecular genetic diagnostics," the authors write in the new study, rather than on the clinical appearance of the hair and the physical examination of the patient, with confirmation on microscopical examination of the hair shaft.

Following the 2016 study, Betz and colleagues were contacted by many clinicians and by the public through Facebook and other social media platforms with details about possible cases of UHS, an autosomal recessive disorder. Through these contacts, blood samples, saliva, or DNA was sent to the investigators' laboratory from 89 unrelated index patients (69 female patients, and 20 male patients) suspected of having UHS. This resulted in the identification of pathogenic variants in 69 cases, the investigators write.

"In the first study, we had 18 patients, and then we tried to collect as many as possible" to determine the main mechanism behind UHC, Betz said. One question is whether there are additional genes responsible for UHS, she noted. "Even now, we are not sure, because in 25% [of cases in the new study], we didn't find any mutation in the three known genes."

The current study resulted in the discovery of eight novel pathogenic variants in PADI3, which are responsible for 71.0% (76) of the 107 cases. Of those, "6 were single observations and 2 were observed in 3 and 2 individuals, respectively," the investigators write.

Children can grow out of this disorder, but it can persist into adulthood, Betz noted. Communication that investigators had with parents of the children with UHS revealed that these children are often the targets of bullying by other children, she added.

She and her and colleagues will continue this research and are currently studying adults who have UHS.

Jeff Donovan, MD, FRCPC, FAAD, a dermatologist and medical director of the Donovan Hair Clinic in Whistler, British Columbia, described these findings as fundamental to understanding UHS and creating pathways to possible treatments.

Dr Jeff Donovan

The study "identifies more about the genetic basis of this challenging condition," said Donovan, who is also clinical instructor in the Department of Dermatology at the University of British Columbia, Vancouver, and president of the Canadian Hair Loss Foundation. "We really need this type of information in order to have any sort of clue in terms of how to treat it," he told Medscape.

"In the hair loss world, it's pretty clear that if you can understand the genetic basis of things, or the basic science of a condition, whether it's the basic genetics or the basic immunology, you give yourself the best chance to develop good treatments," said Donovan.

The article provides advanced genetic information of the condition, such that geneticists can test for at least three markers if they are suspecting UHS, Donovan observed.

Donovan also commented that UHS can have a detrimental impact on children with regard to socializing with their peers. "Having hair that sticks out and is very full like this is challenging because kids do get teased," he said.

"It is often the parents who are the most affected" when a child aged 2 to 5 years has a hair condition such as UHS. But at age 5 to 9, "children are developing self-identity and an understanding of various aspects of self-esteem and what they look like and what others look like. And that's where the teasing really starts. And that's where it does become troublesome."

Betz and Donovan have disclosed no relevant financial relationships.

JAMA Dermatol. Published online August 31, 2022. Abstract

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One Gene, Variants Linked to Many Cases of Rare Hair Condition - Medscape

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