Gene detection in a family with monilethrix and treatment with 5% topical minoxidil.

OBJECTIVE: To determine the causative gene mutation in a family with monilethrix and observe the therapeutic effect of 5% topical minoxidil. METHOD: Clinical data from a family with monilethrix were collected. Peripheral blood samples were taken from the proband, the parents, and 100 unrelated healthy controls. Genomic DNA was extracted. The genetic variation sites were screened with exome sequencing and verified by Sanger sequencing. The proband was treated with 5% topical minoxidil (1 mL twice daily). Hair quality was examined by dermoscopy before and after treatment. RESULTS: The proband and her father have the heterozygous missense variant c.1204G > A (p.E402K) in exon 7 of the KRT86 gene. However, the mutation was not found in the mother and healthy controls. The proband was treated with 5% topical minoxidil. Hair density and hair shaft quality improved significantly after 6 months of treatment. No adverse events occurred during treatment. CONCLUSION: This study shows that p.E402K is a mutation "hot spot" in patients with autosomal dominant monilethrix in China. Treatment with 5% topical minoxidil, is safe and effective.

Autosomal recessive monilethrix: Novel variants of the DSG4 gene in three Chinese families.

BACKGROUND: Monilethrix is a rare hereditary hair loss disorder characterized by hair fragility and beaded hair shaft alterations. Monilethrix is classically inherited in an autosomal dominant (AD) fashion caused by variants in the hair keratin genes KRT81, KRT83, or KRT86. Interestingly, an autosomal recessive (AR) form of monilethrix with variants in DSG4 gene has also been reported in recent years. OBJECTIVE: To identify causative variants in Chinese patients with autosomal recessive (AR) form of monilethrix. METHODS: Three families with AR form of monilethrix were observed and sequence variant analysis of DSG4 was performed by polymerase chain reaction (PCR), quantitative real-time PCR, and DNA sequencing. RESULTS: All the patients had sparse, fragile hair involving the scalp, eyebrows, and eyelashes with keratotic follicular papules and pruritus since birth. Atypical-beaded hairs and broken hair shaft fragments were identified in all the patients under dermoscopy. Heterozygous variants c.837del and c. 2389C > T, a homozygous splice site variant c.2355 + 1G > A, and a homozygous 48,644 bp large deletion variant g.31381440_31430084del in the DSG4 gene were identified and verified in the families. CONCLUSION: This report provided further evidence for the phenotypic spectrum and clinical features of, and the expanded variant database of AR form of monilethrix.

[Monilethrix is a hereditary hair shaft disorder].

Monilethrix is a rare genodermatosis with high penetrance and variable expressivity. This is a case report of a Danish family with varying phenotypical presentations. The family members were diagnosed using dermatoscopy and microscopy, which were subsequently supported by gene sequence analysis. No cure of monilethrix exists, but a single case report shows promising results using low dosage of oral minoxidil. Reducing hair dressing trauma to diminish weathering remains the best prophylaxis.

Recessive progressive symmetric erythrokeratoderma results from a homozygous loss-of-function mutation of KRT83 and is allelic with dominant monilethrix.

BACKGROUND: Progressive symmetric erythrokeratoderma (PSEK) is a rare skin disorder characterised by symmetrically distributed demarcated hyperkeratotic plaques, often with associated palmoplantar hyperkeratosis, with new plaques appearing over time. Most cases are inherited in an autosomal dominant manner, although a few cases exhibit apparent autosomal recessive inheritance. OBJECTIVE: To identify the gene underlying autosomal recessive PSEK in a large Pakistani kindred. METHODS: We first carried out autozygosity mapping using microsatellite markers in candidate regions of the genome. We then carried out exome sequencing of five family members, autozygosity mapping and mutation analysis using the exome data and verification by Sanger sequencing. RESULTS: Autozygosity mapping and exome sequencing identified a homozygous frameshift deletion (c.811delA; p.Ser271fs) in KRT83, which co-segregated with the PSEK phenotype in the family and which is expected to abolish keratin 83, a type II keratin of hair and skin. CONCLUSIONS: At least some cases of PSEK result from loss-of-function mutations in KRT83. Heterozygous missense substitutions in KRT83 have been implicated in autosomal dominant monilethrix, a rare hair disorder. Our findings indicate that at least some cases of autosomal recessive PSEK and autosomal dominant monilethrix are allelic, respectively resulting from loss-of-function and missense mutations in the KRT83 gene. Together, these findings indicate that different types of mutations in KRT83 can result in quite different skin and hair phenotypes.

Journey toward unraveling the molecular basis of hereditary hair disorders.

Recent advances in molecular genetics have led to the identification of many genes expressed in hair follicle (HF), while the precise roles of these genes in the HF have not completely been disclosed. Using the methods of forward genetics, we and others have recently identified a series of genes responsible for hereditary hair disorders in humans, including monilethrix, woolly hair, and various ectodermal dysplasia syndromes. Furthermore, expression and functional analyzes have gradually revealed that these genes are directly or indirectly related with each other. As such, the journey toward unraveling the molecular basis of hereditary hair disorders will contribute to better understanding of the complex mechanisms for HF morphogenesis and development in humans.

Molecular genetics of alopecias.

Recent developments in research methods and techniques, such as whole-exome and -genome sequencing, have substantially improved our understanding of genetic conditions. Special progress has been made in the field of genotrichoses, or hereditary hair diseases, a field that has been obscure for many years. The underlying genes for many of the monogenic hair diseases are now known. Additionally, complex analyses of large cohorts of patients have given us the first clues to the genes associated with polygenic hair disorders, such as androgenetic alopecia and alopecia areata. Thanks to these major findings, the sophisticated regulation of the morphogenesis, development and growth of hair follicles has begun to be revealed, and new players in this delicate molecular interplay have been exposed.

Novel D323G mutation of DSG4 gene in a girl with localized autosomal recessive hypotrichosis clinically overlapped with monilethrix.

BACKGROUND: Localized autosomal recessive hypotrichosis (LAH) is an inherited rare disease caused by DSG4 mutations, characterized by short, sparse, brittle hair affecting restricted areas such as the scalp, trunk, and extremities. To date, DSG4 mutations have been reported in 14 pedigrees of LAH overlapping with monilethrix. METHODS: To clarify the etiology of hair defects for a 2-year-old Chinese girl, peripheral blood, skin, and hair samples were collected, and skin immunohistochemistry, electron microscopy (scanning and transmission types), Vivascope confocal microscopy, and DSG4 sequencing were investigated. RESULTS: The patient presented sparse hairs of various length and follicular hyperkeratotic papules. Eyebrows and lashes were also involved (broke or shed). The biopsy specimen revealed curled ingrown hair shafts within the hair follicle and keratin-filled hair follicles. Scanning electron microscopy revealed hair cuticle loosely and irregularly arranged, as well as a marked warping, curling, cracking, and detachment of hair cuticle. Transmission electron microscopy indicated notable dysadhesion between cells of the outer root sheath. A homozygous mutation A1103G in exon 8 of DSG4 was identified in the patient, resulting in the substitution of an aspartic acid by glycine (D323G) and reduced DSG4 expression in the affected scalp epidermis. CONCLUSIONS: The homozygous A1103G mutation in DSG4 was responsible for the disease development.

A novel KRT86 mutation in a Turkish family with monilethrix, and identification of maternal mosaicism.

BACKGROUND: Monilethrix is a rare monogenic dystrophic hair loss disorder with high levels of intrafamilial and interfamilial variability. It is characterized by diffuse occipital or temporal alopecia, hair fragility and follicular hyperkeratosis of the occipital region. Mutations in the keratin genes KRT81, KRT83 and KRT86 lead to autosomal dominant monilethrix, whereas mutations in the desmoglein 4 gene (DSG4) cause an autosomal recessive form. AIM: To identify the mutation in a consanguineous Turkish family with three affected children and apparently unaffected parents. METHODS: Sequencing analysis of the genes DSG4 and KRT86 was performed. SNaPshot analysis was conducted to quantify the proportion of cells carrying the KRT86 mutation and to confirm maternal mosaicism of KRT86. RESULTS: No pathogenic mutation was found by sequencing analysis of DSG4; however, analysis of KRT86 revealed a novel mutation, c.1231G>T;p.Glu411*, in exon 7 in the three affected children and their mother. The mutation signal was weaker in the mother than in the three siblings, and SNaPshot analysis revealed substantial mutation-level variation between the children and their mother. CONCLUSIONS: Our results extend the spectrum of KRT86 mutations and indicate KRT86 mosaicism in the family examined. This study is the first, to our knowledge, to describe mosaicism for a monogenic hair loss disorder, and suggests that mosaicism leads to a mild manifestation of monilethrix.

Novel KRT83 and KRT86 mutations associated with monilethrix.

Monilethrix is an autosomal dominant hair disorder caused by mutations in the hard keratins KRT81, KRT83 and KRT86. The affected hairs are fragile and break easily, leading to scarring alopecia. Follicular hyperkeratosis in the neck and on extensor sides of extremities is a frequently associated finding. The disorder is rare, but probably underreported because its manifestations may be mild. Mutations in KRT81 and KRT86 are the most common. Here, we report new cases from Venezuela, the Netherlands, Belgium and France. The Venezuelan kindred is special for having patients with digenic novel nucleotide changes, a KRT86 mutation associated with monilethrix and a KRT81 variant of unknown clinical significance. In the French and Dutch patients, we found novel KRT86 and KRT83 mutations. Our findings expand the mutational spectrum associated with monilethrix.

An autosomal recessive mutation of DSG4 causes monilethrix through the ER stress response.

Monilethrix is a hair shaft anomaly characterized by beaded hair with periodic changes in hair thickness. Mutations in the desmoglein 4 (DSG4) gene reportedly underlie the autosomal recessive form of the disease. However, the pathogenesis and cellular basis for the DSG4 mutation-induced monilethrix remained largely unknown. We report a Japanese female patient with monilethrix. Observation of her hair shaft by means of transmission electron microscopy showed fewer desmosomes and abnormal keratinization. Genetic analysis revealed a homozygous mutation, c.2119delG (p.Asp707Ilefs*109), in the DSG4 gene, which was predicted to cause a frameshift and premature termination in the intracellular region of the DSG4 protein. The mutation has not been reported previously. In the patient's hair shaft, we detected reduced but partial expression of the mutant DSG4 protein. Cellular analyses demonstrated that the mutant DSG4 lost its affinity to plakoglobin and accumulated in the endoplasmic reticulum (ER). The amounts of mutant DSG4 were increased by proteasome inhibitor treatment, and the expression of an ER chaperone, GRP78/BiP, was elevated in the patient's skin. Collectively, these results suggest that the dysfunctional mutated DSG4, tethered in the ER, undergoes ER-associated degradation, leading to unfolded protein response induction, and thus ER stress may have a role in the pathogenesis of monilethrix.

Mutation detection of type II hair cortex keratin gene KRT86 in a Chinese Han family with congenital monilethrix.

BACKGROUND: Monilethrix is an autosomal dominant hair disorder characterized clinically by alopecia and follicular papules. In this study, we collected a Han monilethrix family to detect the mutations in patients and investigated the correlation between the genotype and phenotype of monilethrix. METHODS: In this study, we identified a Chinese family with monilethrix through light microscopic and scanning electron microscopic (SEM) examination. Genomic DNA from peripheral blood samples was prepared. DNA samples from controls and monilethrix patients were subject to polymerase chain reaction (PCR) amplification. Two pairs of primers were used to amplify the seventh exon of KRT86. Mutation screening of the PCR products was detected using direct sequencing. RESULTS: Light microscopic examination showed a regular alternate enlargement and narrow area. SEM examination showed that part of the cuticle of the nodules shed and disappeared gradually in the narrow area with granular protrusions on the surface similar to the erosion-like structure. Parallel longitudinal ridge and groovepattern appeared, and the ridges varied in width, like dead wood. A heterozygous transversion mutation c.1204G > A (p.E402K) in the seventh exon of KRT86 was identified in both patients. CONCLUSIONS: The mutation of extron 7 of KRT86 identified plays a major role in the pathogenesis of this pedigree with monilethrix, and is a mutation hot spot of KRT86. Further research is needed to explore the relationship between the phenotype and the mutation of the type II hair keratin gene KRT86 of monilethrix.

A novel monilethrix mutation in coil 2A of KRT86 causing autosomal dominant monilethrix with incomplete penetrance.

BACKGROUND: Monilethrix is a genetic hair shaft disorder that causes a dystrophic alopecia. Mutations causing autosomal dominant monilethrix have been found in the helix initiation and helix termination motifs of the type II hair keratins KRT81, KRT83 and KRT86. Mutations in DSG4 are linked to recessive transmission. OBJECTIVES: We investigated a large Tasmanian family demonstrating autosomal dominant monilethrix with incomplete penetrance in order to identify the responsible genetic mutation. As only some affected hairs were moniliform, analysis was undertaken to demonstrate a deficit in the tensile strength of nonmoniliform hairs. METHODS: One hundred and twenty family members were examined. Light microscopy of hair samples was used to support clinical diagnoses. Linkage and gene sequencing studies were then undertaken. Nonbeaded fibres were analysed using the Single Fibre Analyser 3 (SIFAN 3). RESULTS: We identified a novel A280V (c.839C > T substitution) mutation in the coil 2A region of KRT86. This is the first mutation located in a region other than the helix initiation or termination motifs. The A280V mutation was identified in both affected and clinically unaffected family members. Nonmoniliform hairs demonstrated reduced elasticity among both affected and unaffected individuals carrying the A280V mutation. CONCLUSIONS: This is the first mutation located in a region other than the helix initiation or termination motifs, thus expanding the spectrum of mutations and highlighting the importance of molecular diagnosis in monilethrix.

The proteomic profile of hair damage.

BACKGROUND: Monilethrix is a congenital hair shaft disorder with associated fragility. Many of the changes seen in monilethrix hair on light microscopy and scanning electron microscopy are also seen in hair weathering and cosmetic damage to hair. OBJECTIVES: We used monilethrix as a model to investigate the relationship between hair protein structure and hair strength and resistance to cosmetic insult. METHODS: We applied proteomic techniques to identify novel peptide damage markers for chemical oxidative damage to hair. RESULTS: The findings suggest that specific sites in the protein structure of hair are targeted during oxidative damage from bleaching, a unique insight into how chemical damage compromises the structural integrity of the hair shaft at the molecular level. CONCLUSIONS: Applying proteomics to the study of congenital and acquired hair shaft disorders can deliver new insights into hair damage and novel strategies to strengthen hair.

A case of monilethrix caused by novel compound heterozygous mutations in the desmoglein 4 (DSG4) gene.

Monilethrix is a rare condition characterized by a hair shaft anomaly known as beaded hair. It can show either an autosomal dominant or an autosomal recessive inheritance pattern. The autosomal dominant form of monilethrix is caused by mutations in the basic hair keratin genes KRT81, KRT83 or KRT86, while the autosomal recessive form results from mutations in the desmoglein 4 (DSG4) gene. We define the molecular basis of monilethrix in a Japanese patient who has had sparse and fragile scalp hairs since birth. We performed mutation analysis of candidate genes. In addition, we performed co-immunoprecipitation assays and immunofluorescence studies in cultured cells to investigate the functional consequences caused by a mutation. Mutation analysis resulted in the identification of novel compound heterozygous mutations, c.624delG (p.M208IfsX4) and c.2468G>A (p.W823X), in the DSG4 gene of the patient. Furthermore, we show that the mutant DSG4 protein with the mutation p.W823X severely affects the affinity to plakoglobin protein, which may contribute to disruption of desmosomes in the patient's hair shaft. Our results further underscore the crucial role of the DSG4 gene in differentiation of the hair shaft in humans.