Hypotrichosis simplex refers to a group of hereditary isolated alopecias characterized by diffuse and progressive hair loss, usually beginning in early childhood (Pasternack et al., 2008). Localized autosomal recessive hypotrichosis (LAH) is characterized by fragile hairs that break ... Hypotrichosis simplex refers to a group of hereditary isolated alopecias characterized by diffuse and progressive hair loss, usually beginning in early childhood (Pasternack et al., 2008). Localized autosomal recessive hypotrichosis (LAH) is characterized by fragile hairs that break easily, leaving short, sparse scalp hairs. The disorder affects the trunk and extremities as well as the scalp, and the eyebrows and eyelashes may also be involved, whereas beard, pubic, and axillary hairs are largely spared. In addition, patients can develop hyperkeratotic follicular papules, erythema, and pruritus in affected areas (summary by Schaffer et al., 2006). Woolly hair (WH) refers to a group of hair shaft disorders that are characterized by fine and tightly curled hair. Compared to normal curly hair that is observed in some populations, WH grows slowly and stops growing after a few inches. Under light microscopy, WH shows some structural anomalies, including trichorrhexis nodosa and tapered ends (summary by Petukhova et al., 2009). Several families have been reported in which some affected individuals exhibit features of hypotrichosis while others have woolly scalp hair (Khan et al., 2011). Woolly hair is also a feature of several syndromes, such as Naxos disease (601214) and cardiofaciocutaneous syndrome (115150) (Petukhova et al., 2009), or the palmoplantar keratoderma and cardiomyopathy syndrome (601214) (Carvajal-Huerta, 1998). - Genetic Heterogeneity of Hypotrichosis and Woolly Hair For a discussion of genetic heterogeneity of nonsyndromic hypotrichosis, see HYPT1 (605389). For a discussion of genetic heterogeneity of localized hypotrichosis, see LAH1 (HYPT6; 607903). Another form of autosomal recessive woolly hair with or without hypotrichosis (ARWH2; 604379) is caused by mutation in the LIPH gene (607365) and is allelic to autosomal recessive localized hypotrichosis (LAH2). An autosomal dominant form of woolly hair (ADWH; 194300) is caused by mutation in the KRT74 gene (608248).
In addition to the better known autosomal dominant form (194300), Hutchinson et al. (1974) suggested the existence of a recessive form. The hair is blond and the diameter of the hair shaft is reduced. All the cases to ... In addition to the better known autosomal dominant form (194300), Hutchinson et al. (1974) suggested the existence of a recessive form. The hair is blond and the diameter of the hair shaft is reduced. All the cases to that time had, it seemed, been sporadic, and the recessive hypothesis was suggested by the parents of 1 patient being second cousins. Wali et al. (2007) described 2 related consanguineous Pakistani families in which 10 men and 6 women demonstrated typical features of hereditary hypotrichosis, including absent to sparse scalp hair, eyebrows, eyelashes, axillary hair, and body hair. At birth, scalp hair was present but regrew sparsely following ritual shaving, which occurred at 1 week of age. Affected males had sparse beards. Teeth, nails, sweating, and hearing were normal in all affected family members. Shimomura et al. (2008) identified several Pakistani families that included consanguineous marriages and had multiple individuals showing features consistent with recessively inherited woolly hair that was present at birth. The hair over the entire scalp region was coarse, lusterless, dry, and tightly curled, leading to a diffuse woolly hair phenotype with varying degrees of hypotrichosis or sparse hair. Most of the plucked hairs showed dystrophic features without root sheath components in the bulb portion. Eyebrow, eyelash, and beard hairs appeared normal. Affected individuals in all families showed normal teeth, nails, and sweating and did not show palmoplantar hyperkeratosis or keratosis pilaris. Shimomura et al. (2008) identified several consanguineous Pakistani families segregating autosomal recessive woolly hair with variable hypotrichosis. In affected individuals, woolly hair was present at birth, and the hair over the entire scalp region was coarse, lusterless, dry, and tightly curled, leading to a diffuse woolly hair phenotype with varying degrees of hypotrichosis or sparse hair. Most of the plucked hairs showed dystrophic features without root sheath components in the bulb portion. Eyebrow, eyelash, and beard hairs appeared normal. Affected individuals in all families showed normal teeth, nails, and sweating and did not show palmoplantar hyperkeratosis or keratosis pilaris. Pasternack et al. (2008) studied a consanguineous Saudi Arabian family in which 4 of 10 sibs presented with progressive hair loss, thinning of scalp hair since early childhood (3 to 6 years), and sparse body hair. The oldest and the youngest of the affected individuals were almost completely bald. Eyebrows, eyelashes, and pubic and axillary hair were normal in all but 1 individual; the oldest affected sib showed a mild thinning of the eyebrows. This family had been described in detail by Al Aboud et al. (2002). Azeem et al. (2008) reported 14 Pakistani families with LAH3. Affected individuals had sparse or absent scalp hair, sparse eyebrows and eyelashes, and sparse axillary and body hair. Affected adult males had normal beard hair. Teeth, nails, and sweating were normal in all affected individuals. Scalp skin biopsy from 1 affected individual revealed the complete absence of normal hair follicle structures and comedo-like remnants of the hair follicle. The remnants of the hair follicle infundibulum showed hyperkeratinization. Sebaceous glands appeared morphologically normal but had lost connections to the remnants of the hair follicle infundibulum. Nahum et al. (2010) identified a consanguineous family of Turkish extraction with autosomal recessive hypotrichosis. The proband was born with normal hair that, over the first year of life, progressively became thin, sparse, short, and fair. Sparse eyebrows and eyelashes and nail pitting and longitudinal ridging were also present. Under light microscopy, dystrophic hair shafts with irregular cuticles and banding were seen. Teeth and sweating were normal, hyperkeratosis was absent, and there were no other skin, neurologic, skeletal, or cardiac abnormalities. His younger brother and sister had similar symptoms. An older sister and both parents had normal hair. The family history included hypotrichosis in a maternal cousin. Khan et al. (2011) studied 17 families with the hypotrichosis/woolly hair phenotype belonging to different ethnic groups living in Pakistan. At birth, affected individuals had sparse scalp hair. Affected members of 8 of the families had features of hypotrichosis, with sparse fragile hair on the scalp and sparse to absent eyebrows, eyelashes, and axillary, pubic, and body hair. Affected members of 6 other families exhibited features of woolly hair on the scalp and sparse to absent hair on the rest of the body. In the remaining 3 families, some affected individuals had features of hypotrichosis whereas others had woolly scalp hair. All male members in all 17 families had normal hair in the beard and moustache area.
Shimomura et al. (2008) sequenced genes in the critical mapping region related to autosomal recessive woolly hair and found pathogenic mutations in P2RY5 (609239), which encodes a G protein-coupled receptor and is a nested gene residing within intron ... Shimomura et al. (2008) sequenced genes in the critical mapping region related to autosomal recessive woolly hair and found pathogenic mutations in P2RY5 (609239), which encodes a G protein-coupled receptor and is a nested gene residing within intron 17 of the RB1 gene (614041). P2RY5 is expressed in both the Henle and the Huxley layers of the inner root sheath of the hair follicle. In 2 of 6 families different mutations predicted to result in frameshift and premature termination were found. In the remaining 4 families, 3 missense mutations were found. In a consanguineous Saudi Arabian family with hypotrichosis simplex, Pasternack et al. (2008) identified a homozygous truncating mutation in the P2RY5 (LPAR6) gene (609239.0001), which encodes a G protein-coupled receptor. They detected an additional homozygous truncating mutation in P2RY5 (609239.0002) in 2 other affected families. In 6 Pakistani families with woolly hair and hair density that varied from normal to sparse, Shimomura et al. (2008) sequenced genes in the critical mapping region related to autosomal recessive woolly hair and found homozygosity for pathogenic mutations in the P2RY5 gene in all 6 families (see, e.g., 609239.0003; 609239.0004; 609239.0006). Immunofluorescence analysis of human hair follicles showed that P2RY5 is expressed in both the Henle and the Huxley layers of the inner root sheath of the hair follicle. In 2 of 6 families different mutations predicted to result in frameshift and premature termination were found; in the remaining 4 families, 3 missense mutations were found. In affected individuals from 14 Pakistani families with LAH3, Azeem et al. (2008) identified 7 different homozygous mutations in the P2RY5 gene (see, e.g., 609239.0003; 609239.0005; 609239.0006). Three of the mutations had been reported by Shimomura et al. (2008) in individuals with woolly hair. However, none of the individuals reported by Azeem et al. (2008) had the woolly hair phenotype. In affected members of a consanguineous Turkish family segregating localized hypotrichosis, Nahum et al. (2010) identified homozygosity for a missense mutation in the LPAR6 (P2RY5) gene (P196L; 609239.0007). The mutation segregated with the disease in the family and was absent from 100 population-matched controls. Nahum et al. (2010) noted that mutations in LIPH (607365) result in impaired signaling through LPAR6 and in a phenotype (LAH2; 604379) indistinguishable from that displayed by individuals carrying mutations in LPAR6. Khan et al. (2011) performed microsatellite genotyping in 17 Pakistani families with the hypotrichosis/woolly hair phenotype and found linkage to the LIPH gene in 9 families (see HYPT7, 604379) and to the LPAR6 gene in 8 families. Sequence analysis of LPAR6 in the 8 linked families revealed 4 recurrent homozygous mutations (see, e.g., 609239.0003-609239.0005), in families with hypotrichosis, woolly hair with or without hypotrichosis, or a mixed phenotype. Khan et al. (2011) observed no difference in severity of hair loss in patients carrying different mutations in either LIPH or LPAR6, and there were no clear genotype/phenotype correlations.