Summary
Background
Autosomal recessive congenital ichthyosis (ARCI) is a genetically heterogeneous group of rare Mendelian skin disorders characterized by cornification and differentiation defects of ...keratinocytes. Mutations in nine genes including PNPLA1 are known to cause nonsyndromic forms of ARCI. To date, only 10 distinct pathogenic mutations in PNPLA1 have been reported.
Objectives
To identify new causative PNPLA1 mutations.
Methods
We screened genetically unresolved cases, including our ARCI collection, comprising more than 700 families. Screening for mutations was performed either by direct Sanger sequencing or in combination with a multigene panel, followed by sequence and mutation analysis.
Results
Here we report on 16 novel mutations present in patients from 17 families. While all previously reported mutations and most of our novel mutations are located within the core patatin domain, we report five novel PNPLA1 mutations that are downstream of this domain. Thus, as recently described for PNPLA2, we hypothesize that a region larger than the core domain is required for full enzymatic activity of PNPLA1 in human skin barrier formation.
Conclusions
We estimate the frequency of PNPLA1 mutations among patients with ARCI to be around 3%. Most of our patients were born as collodion babies and showed a relatively mild ichthyosis phenotype. In four unrelated patients we observed a cyclic scaling course, which seems to be a potential phenotypic variation in a small percentage of patients with PNPLA1 mutations. The variability of the clinical manifestations and the lack of typical clinical features are specific for patients with PNPLA1 mutations, and emphasize the importance of DNA sequencing for differential diagnosis of ARCIs.
What's already known about this topic?
Only five reports with 10 distinct PNPLA1 mutations causing autosomal recessive congenital ichthyosis (ARCI) have been described.
Relatively little is known about the type and localization of mutations in PNPLA1 that cause ARCI.
What does this study add?
This is the first comprehensive series of PNPLA1 mutations, from 18 patients with autosomal recessive congenital ichthyosis.
The results of this study provide important conclusions about the localization of disease‐causing mutations in PNPLA1 and the resulting phenotype, including clinical variations.
What is the translational message?
Multigene panels and knowledge about causative PNPLA1 mutations will lead to progress in deciphering the function of PNPLA1.
This might facilitate diagnosis and provide a basis for novel therapeutic strategies in patients with PNPLA1 mutations.
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Linked Comment: Uitto et al. Br J Dermatol 2017; 177:342–343
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•CFTR-related disorders (RD) are a group of conditions caused by CFTR protein dysfunction, but to a level of dysfuncton not satisfying the diagnostic crtieria for cystic fibrosis (CF).•This paper ...discusses the individual disorders, including congenital absence of the vas deferens (CAVD), diffuse bronchiectasis, chronic or acute recurrent pancreatitis, allergic bronchopulmonary aspergillosis, chronic rhinosinusitis, primary sclerosing cholangitis and aquagenic wrinkling of the palms.•The CFTR functional and genetic evidence in support of each condition being a CFTR-RD are discussed and guidance for reaching the diagnosis is provided.•Gaps in our knowledge and future areas of research, including the role of CFTR modulators, are highlighted.
This is the third paper in the series providing updated information and recommendations for people with cystic fibrosis transmembrane conductance regulator (CFTR)-related disorder (CFTR-RD). This paper covers the individual disorders, including the established conditions - congenital absence of the vas deferens (CAVD), diffuse bronchiectasis and chronic or acute recurrent pancreatitis - and also other conditions which might be considered a CFTR-RD, including allergic bronchopulmonary aspergillosis, chronic rhinosinusitis, primary sclerosing cholangitis and aquagenic wrinkling. The CFTR functional and genetic evidence in support of the condition being a CFTR-RD are discussed and guidance for reaching the diagnosis, including alternative conditions to consider and management recommendations, is provided. Gaps in our knowledge, particularly of the emerging conditions, and future areas of research, including the role of CFTR modulators, are highlighted.
Summary
Background
Obesity is more common in adults with psoriasis than in the general population, but there is a lack of data available regarding this association in children.
Objectives
To evaluate ...whether obesity was more common in French children with psoriasis of any clinical type or severity.
Methods
A multicentre case–control study was performed in 23 French dermatology centres. Children without chronic or genetic inflammatory disease were selected as controls and matched for age, sex and dermatology centre. We used three weight cut‐off categories to compare the two groups: overweight, overweight with abdominal obesity and overweight with obesity according to the French Health Authority guidelines.
Results
A total of 261 children with psoriasis were included. The mean age was 9.8 years, 126 were boys and 135 were girls. Overall, 42.5% of these children had plaque psoriasis and 32.2% had severe psoriasis. There was no difference between the psoriasis and control groups when the frequency of children who were overweight was compared (20·7% in psoriasis group vs. 17·1% in control group; P = 0·18). Overweight with abdominal obesity including obesity (18·4% vs. 10·4%; P = 0·009) and obesity alone (10·0% vs. 3·1%; P = 0·001) were more common in the psoriasis group.
Conclusions
This study shows that being overweight with abdominal obesity and being obese is more common in children with psoriasis than in controls. The risk factors are the same as those that affect the French general population, i.e. female sex and having a parent who was overweight. The severity and clinical type of psoriasis do not affect overweight and obesity.
What's already known about this topic?
The frequency and severity of psoriasis are associated with a high prevalence of obesity in adults.
Obesity is associated with severe plaque psoriasis in children.
What does this study add?
Childhood psoriasis is associated with overweight with abdominal obesity, or obesity per se irrespective of the type of psoriasis and its severity.
There is no difference in the determinants for obesity in children with psoriasis and controls.
The main determinants for overweight in children with psoriasis are female sex and having a parent who is overweight.
Summary
Background Management of inherited ichthyoses is symptomatic. Despite treatment, skin symptoms have a major impact on patients’ quality of life (QoL).
Objectives To assess the short‐ and ...medium‐term efficacy of hydrotherapy on QoL and clinical symptoms of patients with inherited ichthyosis.
Methods In this 9‐month prospective, open‐label, multicentre study, 20 children and 24 adults with ichthyosis were enrolled in several French reference and competence centres, 2 months before undergoing a 3‐week treatment with specific hydrotherapeutic management at Avène Hydrotherapy Centre. At baseline (2 months before hydrotherapy), beginning (D0) and end of hydrotherapy (D18), and 3 and 6 months later at the reference and competence centres, patients self‐assessed QoL using the Dermatology Life Quality Index (DLQI) or its paediatric version (Children’s DLQI), and investigators evaluated ichthyosis severity using a specific clinical ichthyosis score.
Results The DLQI scores were significantly improved not only at the end of the hydrotherapy treatment (−56% vs. baseline; mean ± SD 3·59 ± 4·30 at D18 vs. 8·35 ± 5·71 at D0; P < 0·0001), but also at 3 months (−28% vs. baseline; P = 0·01) and 6 months after hydrotherapy (−26% vs. baseline; mean ± SD 5·21 ± 5·11 vs. 6·89 ± 5·38; P = 0·03) (primary criterion). Clinical symptoms were also significantly improved at all post‐treatment visits, with a decrease of the mean clinical ichthyosis score by −38% between D0 and D18, by −30% at 3 months and by −31% at 6 months vs. baseline.
Conclusions A 3‐week treatment at Avène Hydrotherapy Centre provided significant and persisting improvement of QoL and clinical symptoms in patients with inherited ichthyoses.
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
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Background
Our suggested ‘modern’ concepts of ‘neutrophilic dermatoses’ (ND) and ‘neutrophilic disease’ were based on observations in adult patients and have not been studied in paediatric patients. ...Only a minority of ND occurs in children, and little is known about age‐specific characteristics.
Objectives
To describe age‐specific characteristics of ND in children and to study whether our suggested ‘modern’ classification of ND may be applied to children.
Methods
We conducted a retrospective multicentre study in a French cohort of 27 paediatric patients diagnosed with pyoderma gangrenosum (PG) or Sweet's syndrome (SS).
Results
Demographics and distribution of typical/atypical forms were similar in patients diagnosed with PG and SS. Atypical ND were more frequent in infants (90%), when compared to young children (60%) and adolescents (33%). Neutrophilic disease was observed in 17/27 patients and was most frequent in infants. Neutrophilic disease of the upper respiratory tract, as well as cardiac neutrophilic disease, was only observed in infants, whereas other locations were similarly found in infants, young children and adolescents. In infants and young children, ND were associated with a large spectrum of general diseases, whereas in adolescents associations were limited to inflammatory bowel disease and Behçet's disease.
Conclusions
Our study describes the concept of ND in paediatric patients and shows that they have some characteristics different from ND occurring in adults. ND occurring in infants can be associated with a large spectrum of general diseases. Occurrence of neutrophilic disease is frequent in children. Thus, ND occurring in young paediatric patients should incite clinicians to schedule complementary explorations in order to search for involvement of other organs and to rule out monogenetic autoinflammatory syndromes.
Summary
Focal dermal hypoplasia (FDH, Goltz syndrome, MIM #305600) constitutes a rare multisystem genetic disorder of the skin, skeleton, teeth and eyes with considerable variation in the clinical ...features. FDH is transmitted as an X‐linked dominant trait and is caused by mutations in PORCN. In male children, hemizygous PORCN mutations are lethal in utero. Around 300 cases have been reported in the literature to date. About 10% of them are male patients presenting with either Klinefelter syndrome (karyotype 47, XXY) or mosaicism of a postzygotic mutation. Here we describe four cases of women with typical features of FDH, in whom a PORCN mutation was found in DNA from affected cutaneous tissue but not in DNA from peripheral blood. This study suggests that mosaicism caused by a postzygotic mutation occurs more often than assumed to date in female patients with FDH. A negative analysis performed on peripheral blood DNA does not exclude the diagnosis of FDH and it is therefore of practical importance to analyse DNA from the affected skin in order to identify low‐level mosaicism and thus to improve diagnostic precision. In total, we found two missense variants, one novel indel and one novel splice‐site variant. Individuals harbouring postzygotic mosaicism run a risk of transmitting the disorder to their daughters, because the maternal mosaic could also affect the gonads.
What's already known about this topic?
Mutations in PORCN cause focal dermal hypoplasia (FDH).
In male children, hemizygous PORCN mutations are lethal in utero.
To date, only around 300 patients with mutations in PORCN have been reported.
What does this study add?
In four women affected by FDH, PORCN mutations were found to be present in affected cutaneous tissue but not in peripheral blood.
Negative mutation analysis of blood samples does not exclude the diagnosis of FDH, as a mosaic constellation due to postzygotic mutations has been repeatedly observed in female patients with FDH as shown in this study.
Linked Comment: Traupe. Br J Dermatol 2019; 180:461–462.
Plain language summary available online
KLICK syndrome: an unusual phenotype Onnis, G.; Bourrat, E.; Jonca, N. ...
British journal of dermatology (1951),
June 2018, 2018-06-00, 20180601, 2018-06, Letnik:
178, Številka:
6
Journal Article
Recenzirano
Erythrokeratoderma refers to a group of rareinherited disorders with both clinical and genetic hetero-geneities. Lesions usually start in infancy and are characterized by localized and ...well-demarcated erythematous andhyperkeratotic plaques, sometimes with a migratory nature. Erythrokeratoderma is often inherited as an autosomal dominant trait caused by mutations in the genesGJB3,GJB4orGJA1, encoding connexins 31, 303, and 43, respectively. Ery-throkeratoderma may be associated with neurological anomalies and can be caused by mutations inELOVL4. Recently,mutations inKDSR(3-ketodihydrosphingosine reductase), encoding an enzyme in the ceramide pathway, were also demonstrated to lead to erythrokeratoderma. Erythrokeratoderma should be distinguished from other skindiseases with erythematous and hyperkeratotic lesions in localized and well-demarcated patterns, such as KID (keratitis–ichthyosis–deafness) syndrome, MEDNIK syndrome, psoriasis,pityriasis rubra pilaris and some localized forms of keratinopathicichthyosis. Erythrokeratoderma should also not be confused with hereditary palmoplantar keratodermas (PPKs), especially when the lesions spread to adjacent areas. Loricrin keratoderma, causedby mutations inLOR, is another important differential diagnosis,the most distinctive but inconstant feature of which is the presence of a honeycomb PPK with digital constrictions.
Background
Three biotherapies – etanercept, adalimumab and ustekinumab – are licensed in childhood psoriasis. The few data available on their efficacy and tolerance are mainly derived from industry ...trials. However, biological drug survival impacts long‐term performance in real‐life settings.
Objective
The objective of this study was to evaluate the survival rates of biological therapies in children with psoriasis in real‐life conditions. Secondary objectives were to evaluate the factors associated with the choice of the biological therapy and to report severe adverse events.
Materials and methods
This study was an observational retrospective study. Data were extracted from the clinical records of 134 children. Kaplan–Meier estimates were used to analyse drug survival overall and in subgroups of plaque psoriasis, bio‐naïve and non‐naïve patients.
Results
We analysed 184 treatment courses: 70 with etanercept, 68 with adalimumab and 46 with ustekinumab. Factors associated with the choice of first‐line biological agent were age at initiation (younger for adalimumab, P < 0.0001), age at onset of psoriasis (younger for adalimumab and etanercept, P = 0.03) and baseline Psoriasis Assessment Severity Index and Physician global assessment (both higher for adalimumab, P < 0.001). Drug survival rates were higher for ustekinumab than for adalimumab and etanercept (P < 0.0001) for all treatment and all psoriasis types, plaque‐type psoriasis (P = 0.0003), patients naïve for biological agents (P = 0.0007) and non‐naïve patients (P = 0.007). We reported eight serious adverse events (SAEs): severe infections (n = 3), significant weight gain (n = 2), psoriasis flare (n = 1) and malaise (n = 1). Biological therapy was discontinued in three children (one with psoriasis flare and two with weight gain). Only the two cases of weight gain resulted in an unfavourable outcome.
Conclusions
Our real‐life comparative study found that ustekinumab had the best drug survival outcome. The profile of SAEs in children was comparable to that in adults. These results will assist dermatologists in the decision‐making process when choosing treatment options for children with psoriasis in daily practice.
Linked Commentary: A. Torrelo. J Eur Acad Dermatol Venereol 2019; 33: 1816. https://doi.org/10.1111/jdv.15855.
