Jack Green

Loss-of-function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis

Marie Unna hereditary hypotrichosis (MUHH) is an autosomal dominant form of genetic hair loss. In a large Chinese family carrying MUHH, we identified a pathogenic initiation codon mutation in U2HR, an inhibitory upstream ORF in the 5′ UTR of the gene encoding the human hairless homolog (HR). U2HR is predicted to encode a 34–amino acid peptide that is highly conserved among mammals. In 18 more families from different ancestral groups, we identified a range of defects in U2HR, including loss of initiation, delayed termination codon and nonsense and missense mutations. Functional analysis showed that these classes of mutations all resulted in increased translation of the main HR physiological ORF. Our results establish the link between MUHH and U2HR, show that fine-tuning of HR protein levels is important in control of hair growth, and identify a potential mechanism for preventing hair loss or promoting hair removal.

Genetics of alopecia areata

Alopecia areata is a common disorder with a genetic predisposition where interaction with environmental factors leads to episodes of terminal hair loss. In this review article, we examine the evidence for a genetic basis to this disorder and discuss the prospects for future research into genetic susceptibility areas and the problems that are likely to be encountered in such research.

Global Allergy Forum and 3rd Davos Declaration 2015: Atopic dermatitis/Eczema: Challenges and opportunities toward precision medicine

Atopic dermatitis/eczema (AD) is a highly complex disease showing a clear increase in its incidence across all continents during the last decades 1, 2. It is the most common skin disease and has, almost other allergic diseases, a substantial socioeconomic impact 3. The complexity of the underlying mechanisms explains the wide spectrum of the clinical phenotype such as the age of onset, natural history, range of sensitization, provocation factors, clinical appearance, severity, and therapeutic response. Moreover, progress in the last years 4 has also highlighted the potential role of the skin microbiome, neuro‐immunological signals, and epigenetic regulation in the modulation of the disease, adding another level of complexity. This situation calls for a more differentiated approach in our efforts to understand the pathophysiology and to develop new preventative and therapeutic strategies better tailored for the subsets of this complex phenotype. This is particularly true when we consider the infantile and childhood onsets of AD, which are currently regarded as the first step of the feared atopic march including allergic rhinitis and/or asthma 5, 6. Thus, AD should more be considered as a systemic disease with a number of relevant comorbidities 7, 8, which will greatly benefit from new developments in the era of precision medicine 9. In July 2015, a group of 63 scientists and clinicians from 13 countries gathered under the auspices of the Christine Kuhne – Center for Allergy Research and Education (CK‐CARE) for the 3rd Global Allergy Forum in Davos, Switzerland. As in the past, the scientists intensely discussed key issues relevant in the field of allergy and AD 10, 11. The aim of the Think Tank meeting in 2015 was to define and discuss new strategies in research and education in AD, which will pave the way for the precision medicine pathways in AD. This document is not meant to be a comprehensive list of research areas but rather summarizes the main results of the working groups in charge of the six most important fields considered for this meeting.

Global Allergy Forum and 3rd Davos Declaration 2015: Atopic dermatitis/Eczema: Challenges and opportunities toward precision medicine Global Allergy Forum and 3rd Davos Declaration 2015: Atopic dermatitis/Eczema: Challenges and opportunities toward precision medicine

Atopic dermatitis/eczema (AD) is a highly complex disease showing a clear increase in its incidence across all continents during the last decades 1, 2. It is the most common skin disease and has, almost other allergic diseases, a substantial socioeconomic impact 3. The complexity of the underlying mechanisms explains the wide spectrum of the clinical phenotype such as the age of onset, natural history, range of sensitization, provocation factors, clinical appearance, severity, and therapeutic response. Moreover, progress in the last years 4 has also highlighted the potential role of the skin microbiome, neuro‐immunological signals, and epigenetic regulation in the modulation of the disease, adding another level of complexity. This situation calls for a more differentiated approach in our efforts to understand the pathophysiology and to develop new preventative and therapeutic strategies better tailored for the subsets of this complex phenotype. This is particularly true when we consider the infantile and childhood onsets of AD, which are currently regarded as the first step of the feared atopic march including allergic rhinitis and/or asthma 5, 6. Thus, AD should more be considered as a systemic disease with a number of relevant comorbidities 7, 8, which will greatly benefit from new developments in the era of precision medicine 9. In July 2015, a group of 63 scientists and clinicians from 13 countries gathered under the auspices of the Christine Kuhne – Center for Allergy Research and Education (CK‐CARE) for the 3rd Global Allergy Forum in Davos, Switzerland. As in the past, the scientists intensely discussed key issues relevant in the field of allergy and AD 10, 11. The aim of the Think Tank meeting in 2015 was to define and discuss new strategies in research and education in AD, which will pave the way for the precision medicine pathways in AD. This document is not meant to be a comprehensive list of research areas but rather summarizes the main results of the working groups in charge of the six most important fields considered for this meeting.

De novo mutations in monilethrix

Abstract: Mutations in the hair keratins hHb1 and hHb6 have been recently reported to cause monilethrix, an autosomal dominant hair shaft disorder, characterized by variable degrees of hair fragility and follicular hyperkeratosis. We found 10 families with monilethrix in which the parents were not clinically affected, and sequenced the hair keratin hHb1, hHb3 and hHb6 genes in seven patients. In five patients no mutations were found, while in two patients we identified de novo germline missense mutations at the helix termination motif: E402K (hHb6) and E413K (hHb1).

Successful treatment of female-pattern hair loss with spironolactone in a 9-year-old girl.

A 9‐year‐old prepubertal girl with female pattern hair loss treated with spironolactone 100 mg orally per day had objective improvement demonstrated by regrowth observed clinically and on comparison of pre‐ and post‐treatment stereotactic scalp photographs taken 6 months apart.

Successful treatment of Behçet’s disease with lenalidomide

tological examination revealed a disparity of fibre diameters, corresponding to scattered atrophic fibres and inflammatory infiltrates in septa. A massive mononuclear inflammatory cell infiltrate was seen in the endomysium, surrounding a capillary. Major histocompatibility complex (MHC) class I was positive in damaged and in intact areas. Pulmonary and digestive investigations did not reveal any anomaly. Carbimazole was stopped as the patient was euthyroid and there was a suspicion of drug-related dermatitis. Without any treatment, within a few weeks the asthenia and arthralgia disappeared. After 3 months, strength testing and muscle-derived enzymes had returned to normal levels and erythema had regressed. Nine months after carbimazole was stopped, the patient was still healthy and neuromuscular examination was normal. The papules on her hand started to decrease. She remains euthyroid. This observation was reported to the pharmacovigilance department and the case was entered in the national drug reactions database. Intrinsic imputability has been assessed as possible (I2), according to the method of Begaud et al. The patient was diagnosed as having JD because she had at least three criteria according to Bohan et al.: symmetrical proximal muscle involvement, elevated muscle-derived enzymes, electromyography changes of inflammatory myopathy. She also had characteristic skin lesions (facial erythema in association with Gottron’s papules). Apart from atrophy and inflammation, histological findings were not entirely specific of dermatomyositis as atrophic fibres were not focused on perifascicular areas, inflammatory infiltrates were seen in septa but also in endomysium, and class I MHC was positive in intact areas of the biopsy. The onset of the symptoms 3 months after the introduction of carbimazole and the rapid resolution after discontinuation of the drug were very suggestive of a causal association. To our knowledge, drug-induced JD has not been reported previously. In contrast, drug-induced dermatomyositis has been reported in adults. The reported drugs were as follows: statins, omeprazole, nonsteroidal anti-inflammatory drugs and D-penicillamine. Several cases of dermatomyositis-like eruption or Gottron’s papules were reported under hydroxyurea. The differential diagnosis of muscle involvement due to hyperthyroidism was excluded in our case as the patient was euthyroid when the symptoms appeared. Dermatomyositis is not a reported side-effect of carbimazole, but related diseases have been described. Shabtai et al. described a case of antithyroid arthritis syndrome due to carbimazole, including myalgia, arthralgia, arthritis, fever and rash. Four adults suffering from myositis associated with carbimazole have also been reported, with only one biopsy-proven case. One patient suffering from carbimazole-induced leukocytoclastic vasculitis has been described. The pathogenesis of carbimazole-related JD is unclear.

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.

Disappearance of pili annulati following an episode of alopecia areata.

Summary Pili annulati is a distinctive autosomal dominant hair shaft disorder that produces alternating light and dark bands that can give a spangled appearance to the hair. The literature contains three case reports of patients in whom the condition has disappeared following recovery from alopecia totalis. None of these reports contain a direct microscopic comparison of pre‐ and post‐regrowth hairs. We report a 6‐year‐old girl who was first noted to have pili annulati at the age of 2 years and who developed alopecia totalis at the age of 3 years. When the hair regrew spontaneously, 18 months later, the pili annulati was no longer visible. Hair samples obtained before and after the episode of alopecia areata were compared by normal and cross‐polarized light microscopy. While not apparent on careful clinical examination, banding was present on light microscopy in 20% of the hairs. Eighty per cent of the affected hairs displayed banding throughout their entire length. In contrast, prior to the episode of alopecia totalis, when the pili annulati was clearly visible, 50% of the hair obtained was banded on microscopy and 90% of the affected hairs showed banding throughout their microscopic length.

Omeprazole‐induced dermatomyositis

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