Summary
Autosomal recessive epidermolytic ichthyosis is a rare skin condition associated with KRT10 loss‐of‐function mutations. It presents with severe life‐threatening clinical manifestations. Here ...we describe a case of autosomal recessive epidermolytic ichthyosis with an unusually mild, spontaneously improving phenotype. Erythroderma and superficial blistering were present at birth, but the skin recovered and remained almost intact at the age of 1 year. Mild scaling on the neck and skin fragility manifesting as superficial erosions after scratching were the only clinical features as the child grew. As a cause, previously unreported compound heterozygous KRT10 pathogenic variants were found: a nonsense mutation leads to mRNA decay, while the other synonymous variant induces a leaky splice site, explaining the residual keratin 10 expression and mild clinical phenotype.
What's already known about this topic?
Autosomal recessive epidermolytic ichthyosis is a rare skin condition caused by loss‐of‐function KRT10 mutations.
The clinical phenotype is severe with superficial skin blistering, scaling and hyperkeratosis.
What does this study add?
Here we extend the mutational and phenotypic spectrum of autosomal recessive epidermolytic ichthyosis.
Our case presented with erythroderma and superficial blistering at birth, but the skin recovered and was almost intact at the age of 1 year. The only disease manifestations were mild scaling on the neck and skin fragility appearing as superficial erosions after scratching.
The causative factors were found to be one nonsense mutation in KRT10 that leads to mRNA decay, and one synonymous variant that affects the donor splice site of exon 3.
We hypothesize that this leaky splice site explains the residual keratin 10 expression and self‐improving clinical phenotype.
Alitretinoin in punctate palmoplantar keratoderma Yilmaz, P.; Medvecz, M.; Kohlhase, J. ...
British journal of dermatology (1951),
April 2019, 2019-04-00, 20190401, Letnik:
180, Številka:
4
Journal Article
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
Plain language summary available online
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
Mosaicism in women with focal dermal hypoplasia Heinz, L.; Bourrat, E.; Vabres, P. ...
British journal of dermatology (1951),
March 2019, 2019-03-00, 20190301, Letnik:
180, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Summary
This report from Germany and France describes four women with focal dermal hypoplasia (FDH), a genetic condition affecting the skin, skeleton, teeth and eyes. FDH is caused by a mutant ...(abnormal) gene called PORCN, found on the X chromosome. Male embryos with the mutant gene do not usually survive. Females are more complicated. Firstly, they have two X chromosomes, but for FDH to show up it only needs the mutant gene to be present on one of them. Secondly, soon after conception one of the two X chromosomes in each cell of the embryo is randomly deactivated. Cell lines (daughter cells) from cells where the normal X chromosome remains active develop normally; cell lines where the abnormal X chromosome remains active develop abnormally owing to the mutant gene. This phenomenon, where cell lines in an individual represent different genetic populations, is called mosaicism (and, incidentally, explains why tortoiseshell cats are always female). The FDH mutation also frequently happens spontaneously after fertilisation, in the earliest stages of development, but before X chromosome deactivation. The main message from this report is that one cannot exclude FDH simply by using standard genetic tests on blood alone. In affected women, in whom the clinical signs may be subtle and a blood test negative, because of mosaicism the abnormal gene may still be found in those skin cells where the X chromosome carrying it remains active. Importantly, the ovaries may also contain such cells, in which case the condition could be passed on to children.
Linked Article: Heinz et al. Br J Dermatol 2019; 180:657–661
The precise classification of epidermolysis bullosa (EB) into 4 main types and more than 30 subtypes is based on the level of skin cleavage, as well as clinical and molecular features, and is crucial ...for early prognostication, case management, genetic counselling and prenatal or pre-implantation diagnosis. We report here the molecular pathology of 40 consecutive cases of suspected EB, which were investigated by immunofluorescence mapping (IFM) and/or by a targeted next-generation sequencing (NGS) multi-gene panel. IFM correctly established the EB subtype in 76% of cases, while the molecular pathology was completely elucidated in 90% of cases by the targeted NGS multi-gene panel. Thirteen previously unreported mutations in EB genes were identified. In cases with unclear clinical and IFM findings, mutations were found by NGS in previously unexpected genes. IFM was useful in delivering fast results in newborns, and in indicating the consequences of the variants of uncertain significance on protein level. This study underscores the efficacy of the strategy of combining targeted NGS with IFM in resolving unusual EB phenotypes. It also suggests that, despite technological advances, careful clinical evaluation and deep phenotyping remains a crucial factor that dictates successful diagnosis of EB.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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