Monilethrix: A New Family with the Novel Mutation in KRT81 Gene.

Sir,

Monilethrix is an autosomal dominant transmitted disease with very few cases of autosomal recessive inheritance. It is caused by mutations in the type II trichocyte keratin genes hHb1, hHb3, and hHb6.[1] It has been suggested that mutation in hHb1 produces a less severe phenotype. Affected individuals have normal hair at birth, but within the first months of life develop the characteristic moniliform aspect of the hair shaft. In the mildest forms, only the occipital regions of the scalp are involved; however, in severe forms, the secondary sexual hair, the eyebrows, and the eyelashes may be involved. In addition, nail defects have been reported. We report a 2-year-old girl with the clinical manifestations, dermoscopy and light microscopy examination characteristics of monilethrix, with a novel mutation.

A healthy 2-year-old girl presented at our department with a diffuse hypotrichosis of the scalp and follicular hyperkeratosis in the occipital area since birth [Figure 1a]. There was no relevant familial background. Her parents and her brother and sister were examined with no findings of hair abnormalities. Dermoscopy and light microscopy examination of the patient's hair showed periodic constriction of the hair shaft with a beading appearance [Figure 1b] in keeping with the diagnosis of monilethrix. Chromosomal analysis of the patient showed a heterozygotic nucleotidic change in the position 154 of the exon-1 of KRT81 gene (c.154G>C) [Figure 2]. The same mutation was seen in her mother and sister. No changes have been reported in her father and brother. Genetic analysis of KRT86 gene revealed no changes in the patient.

Figure 1

(a) Patient with diffuse hypotrichosis of the scalp; b) Dermoscopy showing periodic constriction of the hair shaft

Figure 2

Electropherogram of the proband showing G to C substitution in the position 154 of the exon 1 of KRT81 gene

Monilethrix is an autosomal dominant hair disorder that can cause scarring alopecia in affected individuals,[2] nail changes and keratosis pilaris of the skin of neck and arms. The hallmark is a beading of the hair shaft caused by periodic narrowing with the nodes separated by about 0.7 mm.[3] The expression of monilethrix is variable.[4] Most cases are associated with mutations in the type II keratin genes hHb1, hHb3, and hHb6.[1] Recently, autosomal dominant mutations in exon-7 of KRT86 gene were identified in large families from Turkey and India as well as in the KRT81 gene in a family of Indian origin.[5]

These genes have a mutational hotspot in the region coding for the helix termination motif, and most mutations seem to affect the same residues–glutamic acids at positions 413 and 402.[6] Mutations affecting the helix initiation motif have also been found.[7] Recently, mutations in desmoglein 4 have been associated with monilethrix with localized autosomal recessive hypotrichosis.[8]

Dermoscopy and light microscopy of the hair shaft of our patient showed elliptical nodes of normal thickness that were regularly separated by dystrophic constrictions, features typical of monilethrix.

The molecular study showed a mutation in the position 154 of the exon-1 of KRT81 gene (c.154G>C) in the affected girl, her mother, and her sister. In the DNA sequence, this substitution means a substitution of glycine by arginine in the position 52 of the protein (p.Gly52Arg). Glycine is a small amino-acid that enables keratin and other proteins to adopt different conformations. The change of glycine by arginine, a bigger amino-acid, alters the function of the protein with severe structural consequences, lacking flexibility of the hair shaft. In silico studies of p.Gly52Arg, change with the Alamut Mutation Interpretation Software (http://www.interactive-biosoftware.com) predicted a deleterious effect of the change of glycine by arginine in the protein by two of the three algorithm implemented in this software. The codon p.Gly52 is located on the head domain of KRT81 gene, which is far upstream from the most known keratin mutation hot spot: helix initiation motif; nevertheless, this domain has been demonstrated to be essential of intermediate filament formation in type II keratin. These data point to a possible pathogenic effect of the identified change p.Gly52Arg in KRT81 gene.

The p.Gly52Arg substitution of the exon 1 of KRT81 associated with monilethrix in this family has not been previously described in the literature as a monilethrix-associated mutation. Due to the fact that the girl, and her mother and sister had the same mutation, but only our patient had diffuse hypotrichosis of the scalp and follicular hyperkeratosis, we believe that this condition could be explained by two different hypothesis: the monilethrix could have an incomplete penetrance, or the monilethrix could be a multifactorial disease and would require other mutations besides the p.Gly52Arg substitution for the development of clinical manifestations.

In conclusion, we report a novel mutation in hHb1 gene associated with monilethrix. This finding, as well as those from other studies, indicates genetic heterogeneity in monilethrix and incomplete penetrance of the disease.