Monilethrix

A number sign (#) is used with this entry because of evidence that monilethrix is caused by heterozygous mutation in the hair cortex keratin genes KRTHB1 (KRT81; 602153), KRTHB6 (KRT86; 601928), and KRTHB3 (KRT83; 602765).

Description

Individuals with monilethrix have normal hair at birth, but within the first few months of life develop fragile, brittle hair that tends to fracture and produce varying degrees of dystrophic alopecia. In the mildest forms, only the occipital regions of the scalp are involved; however, in severe forms the eyebrows, eyelashes, and secondary sexual hair may also be involved. Follicular hyperkeratosis with predilection for the scalp, nape of neck, and extensor surfaces of the upper arm and thighs is also a characteristic finding in these patients. Light microscopic examination is diagnostic and reveals elliptical nodes of normal thickness and intermittent constrictions (internodes) at which the hair easily breaks. There may be spontaneous improvement with time, especially during puberty and pregnancy, but the condition never resolves completely (summary by Zlotogorski et al., 2006).

An autosomal recessive form of monilethrix-like congenital hypotrichosis (see 607903) is caused by mutation in the DSG4 gene (607892). The clinical picture of autosomal recessive monilethrix is more severe than the dominant form, with more extensive alopecia of the scalp, body, and limbs, and a papular rash involving the extremities and periumbilical region (Zlotogorski et al., 2006).

The term monilethrix derives from the Latin word for necklace and the Greek for hair (Schweizer, 2006).

Clinical Features

Salamon and Schnyder (1962) reviewed the clinical findings in 4 previously reported Swiss families segregating autosomal dominant monilethrix.

Hypotrichosis may be the presenting manifestation. The degree of hypotrichosis is variable from patient to patient and from time to time in the same individual. Perifollicular hyperkeratosis is a consistent feature. Microscopically, the hair is beaded. The beading is the result of a periodic narrowing of the shaft with nodes separated by about 0.7 mm (Ito et al., 1984).

Expression of monilethrix is variable; in mild cases, dystrophic hair may be confined to the occiput but more severely affected individuals have near total hair loss. In some cases, the hair loss persists throughout life; in others, regrowth of apparently normal hair may occur in adolescence or, temporarily, in pregnancy. Healy et al. (1995) reviewed the phenomenon of beading in this disorder. It had been shown that the periodicity is not diurnal and that it is not synchronous in independent follicles. In mild cases, close inspection is needed to confirm the presence of a few typical beaded hairs. Follicular keratosis and, in some families (Heydt, 1963), nail defects are associated. Electron microscopic studies of affected hair shafts showed defects in the microfibrillar structure of the cortex of the hair shaft and amorphous clumps of cysteine-rich material in both nodal and internodal regions. Hence, the genes for the structural proteins of the hair shaft were considered candidates for causative defects in monilethrix. The major structural proteins of hair are the relatively cysteine-rich 'hard' keratins, also found in nail.

Winter et al. (2000) reported a 3-generation French family with autosomal dominant inheritance of monilethrix. The proband showed diffuse hypotrichosis and onychodystrophy from 2 months of age. Microscopic examination of the hair showed typically beaded or short dystrophic hair. She also had keratosis pilaris. At age 11 years, she still had hypotrichosis with partial regrowth. Her affected father had moderate hypotrichosis with less beaded hair. Most affected family members had hypotrichosis following shedding of initial hair, and then developed individually varying hair growth. Genetic analysis identified a heterozygous mutation in the KRT86 gene (601928.0006).

Van Steensel et al. (2015) reported a Dutch brother and sister (patients 3 and 4) and a Belgian boy (patient 5) who had monilethrix and mutations in the KRT81 gene (see MOLECULAR GENETICS). The 27-year-old brother had fragile hair and alopecia, and complained of 'rough skin' on his upper arms and legs since childhood. Dermoscopic examination showed obvious beading of hair shafts, which was confirmed by light microscopy. He had follicular hyperkeratosis of the neck, upper arms, elbows, and upper thighs. His younger sister had a milder phenotype involving occipital balding with beading of her remaining hair, as well as slight follicular hyperkeratosis on the elbows. Their parents reportedly had normal hair but were not available for examination, and their maternal grandmother was said to have had quite short hair. The 2-year-old Belgian boy, whose mother and her twin sister were also affected, had occipital alopecia with short and brittle remaining hair, and he also exhibited follicular hyperkeratosis. Dermoscopic examination of the boy and his mother revealed beading consistent with the diagnosis of monilethrix.

Mapping

Spence et al. (1979) published a summary of linkage data from 30 tested members of 1 family. Most known cases are of European origin but an Indian pedigree (Bajaj et al., 1978) and an Arab pedigree (Schaap et al., 1982) have been described. The latter pedigree contained a sibship with both parents affected. Of the 8 affected sibs, some might well be homozygotes, but 'discrimination of 2 distinct phenotypic groups...is not obvious.'

Renwick and Izatt (1988) analyzed 2 unrelated Scottish kindreds. The only positive lod score was with the IGHG locus (0.42 at theta = 0.15). Spence et al. (1979) found weakly positive lod scores with PI (107400), which is closely linked to IGHG (147100) on 14q.

Like cytokeratins (see 139350), hair keratins have acidic and basic forms. (Paired keratins form heterodimers, which in turn condense to form intermediate filaments.) At least one acidic human hair keratin (601077) maps to the type I keratin gene cluster at 17q12-q21 and at least one basic hair keratin (148040) maps to the corresponding type II cluster at 12q13 (Rogers et al., 1995).

In 2 families with autosomal dominant monilethrix, Healy et al. (1995) excluded linkage to the type I keratin gene cluster on 17q but showed that the disorder is closely linked to the type II keratin cluster on 12q, where genes for basic trichocyte keratins are found. The combined maximum lod score for linkage to D12S96 was 12.27 at theta = 0.0. The authors noted that this was the first mapping of a primary human hair disorder and the first evidence implicating a defect of the 'hard' keratins of hair and nail in disease. One family studied by Healy et al. (1995) was a Scots family reported several times since 1910 (Cranston Low, 1910; Tomkinson, 1932; Alexander and Grant, 1958). The second family was apparently unrelated and of Irish origin. Follicular keratoses were present on the occiput and, in a few cases, on the limbs. In addition, 5 cases had dystrophic fingernails, including koilonychia, lamellar splitting, and brittleness.

Using microsatellite markers flanking the keratin gene clusters at 17q12-q21 and 12q11-q13, Stevens et al. (1996) demonstrated linkage in a monilethrix pedigree to the chromosome 12 region containing the type II keratin cluster. In 2 new families, Birch-Machin et al. (1997) likewise mapped monilethrix to the type II keratin gene cluster at 12q13. In one of the families, the disease was expressed in 4 of 12 cases only as a follicular keratosis of the neck, elbows, and knees, without clinical or historical evidence of hair anomalies; nonpenetrance in an obligate carrier was also observed in that kindred.

Molecular Genetics

Winter et al. (1997) identified a glu413-to-lys mutation (E413K; 601928.0001) in the type II hair cortex keratin gene they called HB6 in a 4-generation British family with monilethrix previously linked to 12q13, as well as in 3 unrelated isolated monilethrix patients. In a 3-generation French family with monilethrix of a milder and variable phenotype, they detected another heterozygous point mutation in the same glutamic acid codon of HB6 (E413D; 601928.0002). These mutations were the first direct evidence for involvement of hair keratins in hair disease.

Winter et al. (1998) stated that a survey of the 5 monilethrix families and 4 single patients investigated in their laboratory revealed that patients bearing the most prevalent HB6 mutation, E413K (601928.0001), invariably developed dystrophic hypotrichosis and follicular hyperkeratosis in the occipital region and the nape of the neck within the first year after birth. As a rule, these conditions persisted into adulthood, and an essential improvement of hair growth represented a unusual finding. In all cases, moniliform hair could easily be diagnosed by light microscopic examination. In contrast, pronounced intrafamilial phenotypic variation of the disease was observed in those pedigrees in which affected members exhibited the HB6 E413D mutation, the HB1 E413K mutation (602153.0001), or the HB1 E402K mutation (602153.0002) was observed.

Van Steensel et al. (2005) studied 3 patients with monilethrix, identifying a mutation in KRTHB3 in 1 (E407K; 602765.0001), a mutation in KRTHB6 in another (E402K; 601928.0003), and no mutations in KRTHB1, KRTHB3, or KRTHB6 in the third patient. The authors noted that the residue affected in KRTHB3, glu407, is equivalent to glu402 in the KRTHB1 and KRTHB6 genes (see 602153.0002 and 601928.0003, respectively), which is a hotspot for mutations causing monilethrix.

In a consanguineous Turkish family with monilethrix, including 11 affected members over 3 generations, Celep et al. (2009) performed linkage analysis and obtained a maximum lod score of only 1.7 (theta = 0.0) at marker D12S390, compared to the expected maximum calculated for simulated genotypes of 4.6. Screening of exon 7 of the KRTHB6 gene revealed heterozygosity for the E402K mutation (601928.0003) in all affected family members. The authors emphasized the difficulties of mapping a heterozygous disorder in a country with a high rate of consanguinity.

In a Dutch family (patients 3 and 4) and a Belgian family (patient 5) with monilethrix, van Steensel et al. (2015) analyzed the KRT81, KRT83, and KRT86 genes, and identified heterozygosity for the previously reported E407K mutation in KRT83 (602765.0001) in affected members of the Belgian family, as well as a different missense mutation in the KRT83 gene in the affected Dutch sibs (E418K; 602765.0002). Noting that the E418K change in KRT83 is equivalent to previously reported monilethrix-associated mutations in the KRT86 (E413K; 601928.0001) and KRT81 (E413K; 602153.0001) genes, the authors concluded that the E418K variant was likely pathogenic. Van Steensel et al. (2015) also analyzed the 3 genes in a large 4-generation Venezuelan family (patients 1 and 2) with monilethrix, and identified mutations in 2 of the genes: an L409P substitution in the KRT86 gene that segregated fully with disease, as well as an R408C variant of unclear significance in KRT81 that was found in 2 affected individuals as well as in 2 unaffected individuals. In addition, the authors identified a de novo L410P mutation in the KRT86 gene in an affected 5-year-old French boy (patient 6).