Uncombable Hair Syndrome 1

A number sign (#) is used with this entry because of evidence that uncombable hair syndrome-1 (UHS1) is caused by homozygous or compound heterozygous mutation in the PADI3 gene (606755) on chromosome 1p36.

Description

Uncombable hair syndrome is characterized by silvery, blond, or straw-colored scalp hair that is dry, frizzy, and wiry, has a characteristic sheen, stands away from the scalp in multiple directions, and is impossible to comb. This hair shaft disorder occurs in children and improves with age. The hair growth rate can range from slow to normal (summary by U. Basmanav et al., 2016).

Genetic Heterogeneity of Uncombable Hair Syndrome

See UHS2 (617251), caused by mutation in the TGM3 gene (600238) on chromosome 20p12, and UHS3 (617252), caused by mutation in the TCHH gene (190370) on chromosome 1q21.

Clinical Features

This condition was described by French workers (Dupre et al., 1978) as 'le syndrome des cheveux incoiffables.' Scanning electron microscopy showed 2 specific alterations of the hair: a triangular cross-section and a longitudinal groove. Dupre et al. (1978) cited description of 3 infant sibs and affected father and son. The mother of the girl reported by Dupre et al. (1978) may have been mildly affected as a child. The manifestations seem to ameliorate with age. The same condition was probably described by Stroud and Mehregan (1973) under the designation 'spun glass hair.' Ferrando et al. (1980) stressed that the only characteristic morphologic finding is a longitudinal groove and favored the name 'pili canaliculi.'

Garty et al. (1982) described a striking example in a 2-year-old boy, born to unrelated Ashkenazi Jewish parents. The difficulty in combing the boy's hair met with little concern on the part of the parents because the father stated that during infancy he had had similar hair, which had gradually become normal by about age 5 years. The paternal grandfather and great-grandfather were said to have had the same hair peculiarity in infancy. Grupper et al. (1974) found uncombable hair in 3 of 8 sibs (with second-cousin parents). Laurent et al. (1978) reported father and son. According to Garty et al. (1982), the condition had been reported in 12 boys and 15 girls.

Zanca and Zanca (1993) stated that the earliest descriptions of this syndrome date back to the beginning of the 20th century, to the observations made by Le Double and Houssay (1912) in their book entitled 'Les Velus' (The Hirsute), regarding a syndrome they called 'chevelure en vadrouille' (mop hair), comparing the hair of affected individuals to a mop used in the navy to swab the decks. Le Double and Houssay (1912) recounted their personal observation of a 12-year-old girl with no history of albinism or hypertrichosis who had unusually fine, frizzy, almost white hair and did not tolerate combing; brushing her hair resulted in a 'kind of aureole' with a 'strange effect.' Examination over several months confirmed that her hair never varied in length. Her paternal grandfather reportedly had very thick, curly hair, but of normal length. A photograph of the girl included her 2-year-old brother, whose hair was normal. Zanca and Zanca (1993) suggested that the hair of these patients might have a silvery, shining appearance due to the way in which hair shafts of a different shape reflect light.

U. Basmanav et al. (2016) reported 9 patients with uncombable hair syndrome with a mutation in the PADI3 gene (see MOLECULAR GENETICS). The first patients studied were a brother and sister from the U.K. The sister was noted at a dermatology visit at age 11 years to have abnormal hair. Her parents stated that after 8 weeks of hair shedding in early childhood, her hair became very slow growing and came out easily and painlessly. Her hair was hard to brush or comb. Her teeth and nail development was normal. Her brother was examined at age 15 and had white brittle nails. His hair was described as 'spangly,' but had improved with age. Electron microscopy showed longitudinal running ridges along the hair shaft, with some twisting and triangular or heart-shaped cross-sections. The features in the other 7 patients, 2 of whom were previously reported by Nissen and Svendsen (2013) and Novoa et al. (2012), were consistent with UHS, including light-colored, dry, frizzy, unruly hair that had onset in infancy and ameliorated with age. None of the patients had any other abnormalities.

Diagnosis

The characteristic longitudinal grooves along the hair shaft, along with the triangular or kidney-shaped cross-section, allows UHS to be diagnosed microscopically (Calderon et al., 2009).

Inheritance

U. Basmanav et al. (2016) confirmed autosomal recessive inheritance of UHS in several families.

Hebert et al. (1987) a family in which a brother and sister had UHS. The father denied any history of hair abnormality, but characteristic hair morphology was observed on scanning electron microsopy in all 3 family members, documenting autosomal dominant transmission and complete penetrance in this family.

Calderon et al. (2009) stated that the majority of cases of uncombable hair syndrome are inherited in an autosomal dominant manner with either complete or incomplete penetrance

Molecular Genetics

In a family from the U.K. in which 2 of 4 sibs had uncombable hair syndrome, U. Basmanav et al. (2016) identified homozygosity for a missense mutation (A294V; 606755.0001) in the PADI3 gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Sequencing of PADI3 in 17 additional patients of various ethnic backgrounds identified homozygous or compound heterozygous mutations in 8 (see, e.g., 606755.0002-606755.0004). Two of the patients were previously reported (Nissen and Svendsen, 2013; Novoa et al., 2012). Immunofluoresence studies in HaCaT cells showed a diffuse homogeneous cytoplasmic distribution of wildtype PADI3, whereas all of the mutant proteins formed large aggregates throughout the cytoplasm. Additional studies suggested that the mutated forms were either not or only weakly active.

Animal Model

U. Basmanav et al. (2016) generated Padi3 knockout mice. Grossly, the skin of 7-week-old null mice appeared normal, but scanning electron microscopy revealed alterations in the morphology of hair coat and, less markedly, of whiskers. The surface of the lower (proximal) part of the vibrissae and the hairs on their entire length were irregular and rough and appeared as if hammered.

History

U. Basmanav et al. (2016) stated that the uncombable hair phenotype obtained notoriety as the famous literary character 'Struwwelpeter' ('Shockheaded Peter') from the children's story published by the German physician Heinrich Hoffmann in 1845. This story was later translated by Mark Twain into English.