Uncombable hair syndrome (UHS) is a rare structural anomaly of the hair with a variable degree of effect. It is characterized by hair that is silvery, dry, frizzy, wiry, and impossible to comb. It was first reported in the early 20th century. UHS has several names, including pili trianguli et canaliculi (Latin), cheveux incoiffables (French), and "spun-glass hair". This disorder is believed to be autosomal recessive in most instances, but there are a few documented cases where multiple family members display the trait in an autosomal dominant fashion. Based on the current scientific studies related to the disorder, the three genes that have been causally linked to UHS are PADI3, TGM3, and TCHH. These genes encode proteins important for hair shaft formation. Clinical symptoms of the disorder typically arise between 3 months and 12 years of age. The quantity of hair on the head does not change, but hair starts to grow more slowly and becomes increasingly "uncombable". To be clinically apparent, 50% of all scalp hair shafts must be affected by UHS. This syndrome only affects the hair shaft of the scalp and does not influence hair growth in terms of quantity, textural feel, or appearance on the rest of the body.
Presentation
The hair is normal in quantity and is usually silvery-blond or straw-colored. It is disorderly, stands out from the scalp, and cannot be combed flat, but it can be controlled by braiding methods. This is caused by mutations in one of three possible genes; PADI3, TGM, or TCHH. These genes code for proteins involved in hair shaft formation and improvement often occurs in later childhood. Uncombable hair syndrome is mainly autosomal recessive, but it can also be autosomal dominant because there are other involved genes that have yet to be identified. By early adulthood, phenotypic symptoms of UHS spontaneously improve or disappear. The hair of people with UHS may eventually lie flat and appear near normal in texture by adolescence or early adulthood for unknown reasons. Basmanav et al. have suggested that either different, non-mutated isoforms of the hair-forming enzymes are produced as we age, or that aging-related mechanistic changes in hair such as greater diameter and length help resolve UHS.
Symptoms Coarse hair Trichodysplasia White hair Woolly hair Patchy baldness
Cause As one would expect from the name, individuals affected by this disorder have difficulty managing and grooming their hair. Affected individuals usually possess blonde or silver hair that may be present at birth or develop over time. The hair is wiry, frizzy, and stands straight out from the scalp. It is often dry but not fragile or brittle. This is due to several structural abnormalities in the hair shaft. A cross-section of the hair shaft from affected individuals reveals a kidney bean, triangular, or oval diameter, unlike the circular shaft shape displayed in straight hair. This irregularity in the diameter of the hair shaft prevents the hair from lying neatly against adjacent hair fibers. Trichohyalin (TCHH) is a structural protein responsible for the proper cylindrical fiber topology of the hair shaft. TCHH binds other TCHH and keratin-intermediate filaments creating the proper cross-links and cylindrical shape of the hair shaft. PADI3 and TGM3 are two enzymes responsible for post-translational modification of TCHH important for cross-linking of TCHH within the hair. In Uncombable Hair Syndrome mutations in TCHH, PADI3, or TGM3 result in improper cross-linking and the resulting irregular shape of the hair shaft. The particular defect in TCHH as a structural component of hair may be a defect of deimination. Deimination converts the amino acid arginine to the amino acid citrulline. This conversion is done by calcium-dependent enzymes known as peptidylarginine deiminases (PADs). PADI3 is a member of this enzyme class. One study reported PAD involvement in skin and skin-related diseases, particularly at the hair follicle. Alterations to PAD activity resulted in the development of Uncombable Hair Syndrome. Another study examined the transglutaminase (TG) family of enzymes and their involvement in UHS. This family of enzymes includes TGM3, which is expressed in epidermal cells. Mutations in TGM3 may therefore reduce or alter the intermolecular cross-linking important for hair shaft formation, leading to Uncombable Hair Syndrome. Another molecular mechanism of UHS was proposed by Ralph Trueb in 2003. He suggested that premature keratinization of the inner hair root forms a rigid sheath that alters the shape of a hair strand as it grows out of the root.
TCHH Uncombable hair syndrome 1 is caused by a defect in the trichohyalin gene (TCHH) found in hair follicles and some parts of hair strands. It serves as a scaffold protein, with involucrin, in cell envelope organization. The trichohyalin gene is produced and changed by other proteins and to molecules such as keratin intermediate filaments to form organized cross-links. These networks provide the hair shaft with its cylindrical form. This, in turn, leads to frizzy hair, resulting in uncombable hair. The chromosomal location for this TCHH gene is located on chromosome 1. The condition usually improves over time, and will have better hair structure once it reaches adolescence. It is still being decided whether TCHH is autosomal dominant, or autosomal recessive. In an experiment, they identified the causative mutations of UHS in 3 genes; PADI3, TGM3, and TCHH in 11 children. These children carried homozygous/heterozygous mutations in those 3 genes, which resulted in autosomal recessive inheritance. Because it was identified as autosomal recessive inheritance, scanning electron microscopy was performed in order to rule out autosomal dominance since this type of gene can also be autosomal dominant to a certain extent.
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