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Summary: Background: Hypotrichosis simplex of the scalp (HSS) is characterized by progressive loss of scalp hair that results in almost complete baldness at a young age. HSS is often caused by dominant nonsense mutations in CDSN encoding corneodesmosin, leading to the formation of an amyloid‐like material, which interferes with normal hair follicle cycle. Objectives: As gentamicin has been shown to mediate ribosomal read‐through, we aimed to ascertain its therapeutic efficacy in a small series of patients carrying a recurrent mutation in CDSN. Methods: We used a green fluorescence reporter assay system, confocal microscopy and Western blot analysis to ascertain in vitro the ability of gentamicin to induce translational read‐through across a causative CDSN mutation. Results: Using a reporter assay, we initially showed that gentamicin induces read‐through activity across an HSS‐causing nonsense mutation. Gentamicin was further shown to rescue corneodesmosin translation in primary keratinocytes obtained from a patient with HSS. To validate the in vitro data, we conducted a pilot clinical trial where the scalp of four patients was treated topically with gentamicin for 6 months, demonstrating significant improvement as ascertained by the Severity of Alopecia Tool score. Conclusions: Our findings indicate that topical gentamicin should be considered as a potential therapeutic modality in HSS. What's already known about this topic? Hypotrichosis simplex of the scalp (HSS) is caused by nonsense mutations in CDSN encoding corneodesmosin.The mutant corneodesmosin has been hypothesized to be toxic to the hair follicles, leading to hypotrichosis.Disorders caused by nonsense mutations are amenable to ribosomal read‐through using gentamicin. What does this study add? Gentamicin enhanced read‐through activity and promoted full‐length corneodesmosin synthesis in primary keratinocytes derived from patients carrying a nonsense mutation in CDSN.Topical treatment with gentamicin was found to rescue the hypotrichosis phenotype partially in four patients with HSS. What is the translational message? Topical gentamicin should be considered as a potential treatment for HSS. Linked Comment: Kibbi and Rajan. Br J Dermatol 2020; 183:11. Plain language summary available online [ABSTRACT FROM AUTHOR]

Summary: Background: Severely debilitating plantar keratoderma pain is the most distressing clinical feature of pachyonychia congenita (PC). Several earlier publications have reported therapeutic success with plantar injections of botulinum toxin (Btx). Objectives: To describe our 4‐year experience during which we administered a total of 30 plantar Btx injections to five patients with PC following an optimized protocol. Methods: Five patients with PC (age 21–54 years) who were treated at our medical centre from April 2015 to June 2018 were included in the study. After an ultrasound‐guided nerve block performed by an anaesthesiologist, the patients received plantar intradermal injections of Btx A. To ascertain the effect of the treatment, we used a dedicated quality‐of‐life questionnaire for patients with PC (PCQoL) and asked the patients to evaluate the intensity of eight parameters pertaining to their symptoms at baseline and before every treatment session. At study closure, patients were asked to evaluate the maximal improvement in the same eight parameters throughout the study period. Results: All patients demonstrated a decrease in PCQoL scores during the follow‐up period. All patients showed a significant improvement in PCQoL after the first treatment session and at the last evaluation (P = 0·043). The scores with the best improvement concerned morning feet burning and long‐distance walking (> 500 m). The scores were significantly lower if the intervals between Btx injections were <100 days. Conclusions: Btx treatment of PC‐associated keratoderma following an optimized protocol leads to a major change in patients' quality of life. What's already known about this topic? Plantar pain is considered by patients to be the most severe and debilitating manifestation of pachyonychia congenita (PC).Over the past few years, a number of reports have shown that plantar injections of botulinum toxin (Btx) reduce or even eliminate pain, blistering and callosities in patients with PC.However, the injection technique, doses of Btx and methods of anaesthesia varied between reports and patients. What does this study add? Here we report our 4‐year experience in providing 30 treatments to five patients following an optimized protocol.Btx was found to provide a quantifiable improvement in all patients treated. What is the translational message? Btx treatment of PC‐associated keratoderma using a structured approach, which includes the use of a sufficient dose of Btx (200–400 U of onabotulinumtoxinA or 500–1000 U of abobotulinumtoxinA), and regular intervals between treatment sessions (of < 100 days), leads to a major change in patients' quality of life. Linked Editorial:Steele and O'Toole. Br J Dermatol 2020; 182:521–522. Linked Comment:Thomas and Sahota. Br J Dermatol 2020; 182:531–532. Plain language summary available online [ABSTRACT FROM AUTHOR]

Summary: Background: Pachyonychia congenita (PC) is a rare autosomal dominant genodermatosis caused by a mutation in any one of five keratin genes (KRT6A,KRT6B,KRT6C,KRT16 or KRT17). Characteristic features of PC are painful palmoplantar keratoderma, variable nail dystrophy, cysts, follicular hyperkeratosis and often oral leukokeratosis. Although oral leukokeratosis can go unnoticed, mucosal involvement of the oral cavity and upper airways can manifest with pain during feeding, hoarseness, stridor and, occasionally, life‐threatening obstruction. Objectives: To characterize patients with PC with symptomatic mucosal involvement. Methods: We present a case series of nine children with PC with symptomatic mucosal involvement, all with heterozygous mutations in KRT6A. Seven patients complained of painful feeding problems. Four patients were diagnosed with failure to thrive, three of whom required a feeding tube. Simple feeding solutions were beneficial in most cases. Seven patients had laryngeal involvement and one patient died at 4 years of age from acute laryngeal obstruction. Conclusions: It is important for dermatologists and otolaryngologists to be aware that symptomatic mucosal involvement, and very rarely laryngeal obstruction, can occur in patients with PC. Usually simple feeding solutions may prevent complications and failure to thrive. What's already known about this topic? Pachyonychia congenita (PC) is a rare autosomal dominant genodermatosis due to a mutation in any one of five keratin genes.Symptomatic mucosal involvement is an important clinical feature of PC and appears to be more pronounced in KRT6A mutation carriers.Only leukokeratosis is frequently seen in PC and can be one of the earliest signs of disease.Laryngeal involvement is a less common feature. It might be symptomatic but usually presents as hoarseness, stridor and, occasionally, as a life‐threatening respiratory distress. What does this study add? In most cases of laryngeal involvement, there is no need for any intervention.Although pain and feeding difficulties are usually attributed to the oral leukokeratosis, they can be related to a phenomenon called 'first bite syndrome' (FBS).Symptomatic mucosal involvement with feeding difficulty is important but can be managed in most cases with simple feeding solutions (e.g. softer nipple with a larger hole, thicker formula and feeding with a syringe). Linked Comment:Youssefian and Vahidnezhad. Br J Dermatol 2020; 182:536–537. [ABSTRACT FROM AUTHOR]

Summary: Background: Dowling–Degos disease (DDD), featuring reticulate pigmentation, and familial hidradenitis suppurativa (HS) share many clinical features including autosomal dominant inheritance, flexural location and follicular defects. The coexistence of the two disorders was recently found to result from mutations in PSENEN, encoding the γ‐secretase subunit protein presenilin enhancer. Objectives: To investigate PSENEN mutations in a series of four unrelated patients who presented with combined DDD and HS. Methods: Mutation and haplotype analysis of PSENEN by polymerase chain reaction, and cellular assays investigating the Notch signalling pathway. Results: Here we report four families of Jewish Ashkenazi origin who presented with clinical features characteristic of both disorders. All patients were found to carry the same, heterozygous mutation in PSENEN (c.168T>G, p.Y56X). Haplotype analysis revealed that the mutation originated from a common ancestor. Genes associated with DDD, as well as HS, have been shown to encode important regulators of Notch signalling. Accordingly, using a reporter assay, we demonstrated decreased Notch activity in a patient's keratinocytes. Conclusions: The present data confirm the genetic basis of the combined DDD‐HS phenotype and suggest that Notch signalling may play a central role in the pathogenesis of this rare condition. [ABSTRACT FROM AUTHOR]