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Keratitis-ichthyosis-deafness (KID) syndrome (MIM: #148210) is a rare form of syndromic ichthyosis associated with heterozygous mutations in I GJB2 i encoding connexin 26, a member of the connexin family of transmembrane proteins, involved in cell-cell communication.[1] I GJB2 i mutations are also associated with non-syndromic deafness.[2] Mosaic I GJB2 i mutations were previously identified in porokeratotic eccrine ostial and dermal duct nevus (PEODDN).[3] Here, we report two patients with mosaic I GJB2 i mutations thus expanding the clinical spectrum of I GJB2 i -related disorders. Extending the phenotypic spectrum of keratitis-ichthyosis-deafness syndrome: report of a patient with GJB2 (G12R) Connexin 26 mutation and unusual clinical findings. [Extracted from the article]

Albinism is a worldwide genetic disorder caused by mutations in at least 20 genes, identified to date, that affect melanin production or transport in the skin, hair and eyes. Patients present with variable degrees of diffuse muco‐cutaneous and adnexal hypopigmentation, as well as ocular features including nystagmus, misrouting of optic nerves and foveal hypoplasia. Less often, albinism is associated with blood, immunological, pulmonary, digestive and/or neurological anomalies. Clinical and molecular characterizations are essential in preventing potential complications. Disease‐causing mutations remain unknown for about 25% of patients with albinism. These guidelines have been developed for the diagnosis and management of syndromic and non‐syndromic forms of albinism, based on a systematic review of the scientific literature. These guidelines comprise clinical and molecular characterization, diagnosis, therapeutic approach and management. [ABSTRACT FROM AUTHOR]

Presence of "grain"-like superficial dyskeratotic keratinocytes (d). gl GLO:3NZ/01jun21:jdv17153-fig-0002.jpg PHOTO (COLOR): 2 Hyperkeratotic lesions in the patient (a) and in his mother (striate palmoplantar keratoderma) (b). gl After obtaining written informed consent, genomic DNA was extracted from the child peripheral blood leucocytes and linear trunk skin lesion. I Editor i Striate palmoplantar keratoderma (SPPK) is a rare autosomal-dominant form of PPK, characterized by linear hyperkeratosis of the volar aspects of the fingers extending onto the palm and focal to diffuse hyperkeratosis of the soles. [Extracted from the article]

Summary: Background: Data on dermatological manifestations of Noonan syndrome (NS) remain heterogeneous and are based on limited dermatological expertise. Objectives: To describe the dermatological manifestations of NS, compare them with the literature findings, and test for dermatological phenotype–genotype correlations with or without the presence of PTPN11 mutations. Methods: We performed a large 4‐year, prospective, multicentric, collaborative dermatological and genetic study. Results: Overall, 129 patients with NS were enrolled, including 65 patients with PTPN11‐NS, 34 patients with PTPN11‐NS with multiple lentigines (NSML), and 30 patients with NS who had a mutation other than PTPN11. Easy bruising was the most frequent dermatological finding in PTPN11‐NS, present in 53·8% of patients. Multiple lentigines and café‐au‐lait macules (n ≥ 3) were present in 94% and 80% of cases of NSML linked to specific mutations of PTPN11, respectively. Atypical forms of NSML could be associated with NS with RAF1 or NRAS mutations. In univariate analysis, patients without a PTPN11 mutation showed (i) a significantly higher frequency of keratinization disorders (P = 0·001), including keratosis pilaris (P = 0·005), ulerythema ophryogenes (P = 0·0001) and palmar and/or plantar hyperkeratosis (P = 0·06, trend association), and (ii) a significantly higher frequency of scarce scalp hair (P = 0·035) and scarce or absent eyelashes (P = 0·06, trend association) than those with PTPN11 mutations. Conclusions: The cutaneous phenotype of NS with a PTPN11 mutation is generally mild and nonspecific, whereas the absence of a PTPN11 mutation is associated with a high frequency of keratinization disorders and hair abnormalities. What's already known about this topic?Data on dermatological manifestations of Noonan syndrome (NS) remain heterogeneous and almost entirely without expert dermatological input.A broad spectrum of dermatological findings is present in NS and better knowledge might help to define phenotype–genotype correlations and differentiate forms of NS from other RASopathies, specifically cardiofaciocutaneous syndrome. What does this study add?NS with PTPN11 mutations is usually associated with a mild and nonspecific cutaneous phenotype.NS with multiple lentigines is typically associated with specific mutations of PTPN11 but atypical forms can be linked to RAF1 or NRAS mutations.Absence of PTPN11 mutation in NS is associated with a higher frequency of keratinization disorders and hair abnormalities, the latter being commonly observed in cardiofaciocutaneous syndrome. What is the translational message?Abnormalities of the genes of the Ras–MAPK signalling pathway that are involved in NS underlie a spectrum of cutaneous manifestations including hair abnormalities, keratinization, pigmentary and connective tissue disorders and multiple melanocytic naevi.This study adds new information to improve the definition of the cutaneous phenotype of NS and differentiate it phenotypically from RASopathies, specifically cardiofaciocutaneous syndrome and Costello syndrome. Linked Comment: Carcavilla. Br J Dermatol 2019; 180:1293. Plain language summary available online Respond to this article [ABSTRACT FROM AUTHOR]

Summary: Background: Epidermolysis bullosa simplex generalized severe (EBS‐gen sev) is a genetic disorder caused by mutation in the KRT5 or KRT14 genes. Although it is usually considered a mechanical disease, recent data argue for additional inflammatory mechanisms. Objectives: To assess the inflammation in the skin of patients with EBS‐gen sev. Methods: A first immunohistochemical retrospective study was performed on frozen skin samples from 17 patients with EBS‐gen sev. A second multicentre prospective study was conducted on 10 patients with severe EBS‐gen sev. Blister fluid and epidermis were processed for immunochemical analysis and quantitative real‐time polymerase chain reaction. Cytokine expression was analysed in blister fluid and compared with that in controls. Results: Histological analysis showed a constant dermal perivascular CD4+ lymphocyte infiltrate in skin biopsies of both blister (n = 17) and rubbed skin (n = 5), an epidermal infiltration of neutrophils and eosinophils in 70% of cases, and increased immunostaining for CXCL9 and CXCL10 in blistering skin. High levels of T helper 17 cytokines were detected in lesional skin. Three adult patients with EBS‐gen sev were treated with apremilast, with a dramatic improvement of skin blistering and good tolerance. Conclusions: Our study demonstrates the importance of inflammation in patients with EBS‐gen sev and underlines the key role for T helper 17 cells in its pathogenesis. In addition, this study provides promising new therapeutic approaches for this disabling disorder. What's already known about this topic? Epidermolysis bullosa simplex generalized severe (EBS‐gen sev) is a rare disabling skin disorder related to skin fragility. What does this study add? We showed the presence of an immune infiltrate characterized by a T helper (Th)17 phenotype in the skin of patients with EBS‐gen sev.There was a marked improvement of the skin condition in patients with EBS after treatment with apremilast, an anti‐Th17 molecule. What is the translational message? Our results demonstrate the importance of inflammation in EBS‐gen sev and underline the key role of Th17 activation.Anti‐Th17 molecules such as apremilast provide a promising new therapeutic approach for this disabling disorder. Linked Comment:  Mellerio. Br J Dermatol 2019; 180:258–260. Plain language summary available online [ABSTRACT FROM AUTHOR]

Waardenburg syndrome (WS) is characterized by hypopigmentation of the hair and skin, congenital sensorineural hearing and various defects of neural crest-derived tissues. The patients with I PAX3 i mutations described here presented with café-au-lait macules and lentigines rather than large hypopigmented areas. In WS, café-au-lait macules have been reported only in patients with WS Type 2 associated with I KITLG i mutations, not in patients with I PAX3 i mutations.[5] I KITLG i mutations are also responsible for FPHH, which is mainly characterized by diffuse hyperpigmentation, including variable lentiginosis and café-au-lait macules.[6] The lesions increase in size and number with age. [Extracted from the article]

Dear Editor, Xeroderma pigmentosum (XP) is a rare, autosomal, recessive disease caused by defective repair of UV-induced DNA lesions due to various genetic defects affecting genes involved in the nucleotide excision repair pathway. Ocular lesions were prominent, as mentioned in a well-documented clinical study of patients with XP from South Africa.[2] Neurological examination was unremarkable in all patients. Two families were diagnosed with XP-D ( I ERCC2 i gene) while the analysis was inconclusive in two young patients (aged 4 and 6 years), who could benefit from whole exome/genome analysis. [Extracted from the article]

Autosomal recessive hypotrichosis simplex (ARHS) presents with progressive hair loss mainly affecting the scalp area. In a small number of families, the condition has been associated with mutations in three distinct genes: DSG4, LIPH and LPAR6. To identify the molecular basis of ARHS in a consanguineous family of Turkish extraction. We used a combination of microsatellite marker screening and direct sequencing. We identified a novel missense mutation (c.C587T) in the human LPAR6 gene, resulting in the amino acid substitution p.P196L. The mutation affects a highly conserved amino acid residue, and is predicted to disrupt signalling through the P2Y5 receptor. This study provides further evidence supporting a role for the lysophosphatidyl signalling pathway in hair growth and differentiation. In addition, this paper reports, for the first time to our knowledge, the use of homozygosity mapping as a premutation screening tool in the diagnosis of a group of inherited hair disorders. [ABSTRACT FROM AUTHOR]

Ectodermal dysplasias are a large family of congenital disorders resulting in developmental defects of at least two structures derived from ectodermal embryologic structure (hair, nails, skin, sweat glands, teeth, eyes). A novel mutation in homeobox DNA binding domain of HOXC13 gene underlies pure hair and nail ectodermal dysplasia (ECTD9) in a Pakistani family. [Extracted from the article]

A letter to the editor is presented in response to the article concerning the severe linear form of granuloma annulare, along its classical form in a child.

The article presents a case study of a 4-year-old girl admitted with giant congenital melanocytic nevus (GCMN) and mosaic RASopathies, highlighting the risk of melanoma development. The article examines the development of focal cortical dysplasia through magnetic resonance imaging (MRI), the presence of a genetic postzygotic mutation, and epidermal hamartoma.

The article focuses on a study regarding the ineffective use of high-dose pulsed corticosteroid therapy (HDPCT) in the long term combined with methotrexate for severe alopecia areata of childhood. It mentions alopecia totalis (AAT) and universalis (AAU) who failed topical therapy underwent treatment and intravenous methylprednisolone. It also mentions methotrexate may exert its anti-inflammatory effect by increasing adenosine levels which reduce cytokine synthesis.

A letter to the editor is presented which describes the recognizable phenotype and hot-spot POMP mutation of KLICK syndrome in a young patient.

Copyright of British Journal of Dermatology is the property of Oxford University Press / USA and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Summary: Noonan syndrome (NS) is a genetic disorder affecting up to 1 in 1000 people. It is recognised by an unusual facial appearance, heart defects and small stature. Some people with features of NS also have lots of small dark brown flecks on their skin (lentigines), a condition formerly known as LEOPARD syndrome but now called NS with multiple lentigines (NSML). There are also some atypical (unusual) "Noonan‐like" syndromes: this overlapping group of "Rasopathies" also includes Costello syndrome and cardio‐facio‐cutaneous syndrome. About 10 genes responsible for these conditions are now known, but the dermatological (skin) features of the different genetic types have never been clearly defined. Therefore, these French doctors, based at 10 different hospitals, systematically recorded the skin abnormalities seen in patients with any kind of NS attending their clinics over a 4‐year period, and correlated them with NS subtype and gene. Of 129 patients, aged from 9 months to 77 years, three quarters had mutations (changes) in the PTPN11 gene and of these 65 were diagnosed as NS and 34 as NSML. Dermatological features in the NS patients were mild and non‐specific such as easy bruising, raised hair follicles (keratosis pilaris), lax skin or wavy hair. NSML patients additionally had dozens of lentigines, larger brown patches and usually had particular PTPN11 mutations. NS patients with mutations in a different gene were more likely to have striking skin features including unusually curly hair, sparse eyebrows, marked keratosis pilaris or multiple moles. This research highlights the value of careful dermatological documentation in patients with genetic syndromes. Linked Article: Bessis et al. Br J Dermatol 2019; 180:1438–1448 [ABSTRACT FROM AUTHOR]

Copyright of British Journal of Dermatology is the property of Oxford University Press / USA and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Summary: Epidermolysis bullosa (EB) is a group of genetic disorders in which the skin is abnormally fragile. In EB simplex, the skin cells tend to fall apart because their internal scaffolding of keratin fibres is defective, due to mutations in the genes encoding keratins type 5 or 14 (KRT5 and KRT14). But people with the generalised, severe type of EB simplex (EBS‐GS) are sometimes more ill than would be expected just from a mechanical problem with the skin; some even die in infancy, usually from infection. This group from France and Scotland explored the possibility that EBS‐GS patients also have a faulty immune system. They re‐examined skin specimens taken previously for diagnostic purposes from 17 patients with EBS‐GS and also tested fresh skin biopsies and blister fluid from a further 10 patients. They consistently found more inflammatory cells and higher levels of chemicals which promote inflammation (cytokines) than normal. The findings were the same regardless of whether the sample was from blistered or normal‐looking skin and whether the fault was in KRT5 or KRT14. Markers for the cytokine Th17 were particularly high, encouraging them to treat three EBS‐GS patients with the anti‐Th17 drug Apremilast as used in psoriasis. All three reported a dramatic reduction in blisters within the first month, which lasted throughout treatment for up to 10 months, with minimal side‐effects. One patient stopped the Apremilast after 7 months because of nausea and the blistering came back 2 days later. This appears to be a promising new approach to treating EBS‐GS. Linked Article: Castela et al. Br J Dermatol 2019; 180:357–364 [ABSTRACT FROM AUTHOR]

Copyright of British Journal of Dermatology is the property of Oxford University Press / USA and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Summary: Cardiofaciocutaneous syndrome (CFC) is one of a group of rare genetic disorders called the RASopathies because they are caused by mutations in the genes related to HRAS, KRAS or NRAS. The other RASopathies are Noonan (NS) and Costello (CS) syndromes. These conditions can affect the heart, nervous system, bony skeleton and muscles; there is sometimes an unusual facial appearance and occasionally a tendency to develop tumours. CFC patients often have skin problems but dermatologists have difficulty recognising the syndrome because it is very rare and the skin symptoms are not particularly unusual. Also there is a lot of overlap between the different RASopathies. In this study from France, geneticists and dermatologists reviewed 45 patients with CFC caused by mutations in the genes BRAF, MAP2K1 or MAP2K2 and compared the findings with published data. They noted a lack of precise dermatological descriptions in the RASopathy literature. They observed certain skin conditions more frequently in CFC patients than is reported in the general population. These included common disorders such as prominent follicles (keratosis pilaris), multiple moles, and curly hair, and unusual but rather non‐specific features such as lax skin, thickened palms and soles, sparse eyebrows and excessive sweating. The thickened palms and soles responded well to treatment with a drug called acitretin in two patients. As the accompanying commentary points out, most people with these skin features do not have a RASopathy, but that diagnosis is worth considering if the skin condition is unusually marked, is absent in close family members, or associated with other abnormalities. Linked Article: Bessis et al. Br J Dermatol 2019; 180:172–180 [ABSTRACT FROM AUTHOR]

ORIGINAL ARTICLE, p 615 [ABSTRACT FROM AUTHOR]