Erythrokeratodermia variabilis (EKV) is a rare genodermatosis characterized by well-demarcated erythematous patches and hyperkeratotic plaques. EKV is most often transmitted in an autosomal dominant ...manner. Until recently, only mutations in connexins such as
(connexin 31),
(connexin 30.3), and occasionally
(connexin 43) were known to cause EKV. In recent years, mutations in other genes have been described as rare causes of EKV, including the genes
,
, and
. Features of the EKV phenotype can also appear with other genodermatoses: for example, in Netherton syndrome, which hampers correct diagnosis. However, in autosomal recessive congenital ichthyosis (ARCI), an EKV phenotype has rarely been described. Here, we report on seven patients who clinically show a clear EKV phenotype, but in whom molecular genetic analysis revealed biallelic mutations in
, which is why the patients are classified in the ARCI group. Our study indicates that ARCI should be considered as a differential diagnosis in EKV.
Autosomal recessive Chanarin-Dorfman syndrome (CDS, MIM #275630) is defined as a neutral lipid storage disease with ichthyosis (NLSDI) due to an accumulation of lipid droplets in a variety of ...different tissues including liver and muscle cells, leucocytes, fibroblasts and nerve cells It is caused by biallelic mutations in the abhydrolase domain containing 5 gene (
, MIM *604780) which is localized on the short arm of chromosome 3. Here we report an 18 month-old girl in whom we have identified the homozygous
mutation c.700C > T, p.(Arg234*). Since none of the parents carried this point mutation, parentage was confirmed by microsatellite marker analysis. Suspected uniparental disomy (UPD) was confirmed by microsatellite genotyping over the entire chromosome 3 and indicated a maternal origin. UPD is an extremely rare event that is not necessarily pathogenic, but may cause disease if the affected chromosome contains genes that are imprinted. Here we report the first case of Chanarin-Dorfman syndrome due to a
mutation in the maternal germ cell, combined with a maternal uniparental isodisomy of chromosome 3. This case demonstrates that genetic analysis of the patient and both parents is crucial to provide correct genetic counseling.
Key Clinical Message
Keratosis palmoplantaris striata type I (SPPK‐I) is a rare autosomal‐dominant type of hereditary epidermolytic palmoplantar keratoderma, which can be caused by mutations in ...desmoglein‐1 (DSG‐1). Patients suffer from hyperkeratotic plaques and painful palmoplantar fissures. Unfortunately, treatment options including salicylic vaseline, topical corticosteroids, phototherapy, and retinoids are inefficient.
Hereditary palmoplantar keratodermas (PPKs) represent a heterogeneous group of rare skin disorders with epidermal palmoplantar hyperkeratosis. Mutations in the desmoglein 1 gene (DSG1), a transmembrane glycoprotein, have been reported primarily in striate PPKs. We report a patient with keratosis palmoplantaris striata type I (SPPK‐I) with a specific pathogenic variant c.349C>T, p.(Arg117*) in DSG1. Despite increased understanding, effective treatment options for PPK, including SPPK‐I, remain limited.
The autosomal recessive congenital ichthyoses (ARCI) are a nonsyndromic group of cornification disorders that includes lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ...ichthyosis. To date mutations in ten genes have been identified to cause ARCI:
,
,
,
,
,
,
,
,
, and
. The main focus of this report is the mutational spectrum of the genes
and
, which encode the epidermal lipoxygenases arachidonate 12-lipoxygenase, i.e., 12R type (12R-LOX), and the epidermis-type lipoxygenase-3 (eLOX3), respectively. Deficiency of 12R-LOX and eLOX3 disrupts the epidermal barrier function and leads to an abnormal epidermal differentiation. The type and the position of the mutations may influence the ARCI phenotype; most patients present with a mild erythrodermic ichthyosis, and only few individuals show severe erythroderma. To date, 88 pathogenic mutations in
and 27 pathogenic mutations in
have been reported in the literature. Here, we presented a large cohort of 224 genetically characterized ARCI patients who carried mutations in these genes. We added 74 novel mutations in
and 25 novel mutations in
. We investigated the spectrum of mutations in
and
in our cohort and additionally in the published mutations, the distribution of these mutations within the gene and gene domains, and potential hotspots and recurrent mutations.
Autosomal recessive congenital ichthyosis (ARCI) is a non-syndromic congenital disorder of cornification characterized by abnormal scaling of the skin. The three major phenotypes are lamellar ...ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis. ARCI is caused by biallelic mutations in
,
,
,
,
,
,
,
,
, and
. The most severe form of ARCI, harlequin ichthyosis, is caused by mutations in
. Mutations in this gene can also lead to congenital ichthyosiform erythroderma or lamellar ichthyosis. We present a large cohort of 64 patients affected with ARCI carrying biallelic mutations in
. Our study comprises 34 novel mutations in
, expanding the mutational spectrum of
-associated ARCI up to 217 mutations. Within these we found the possible mutational hotspots c.4541G>A, p.(Arg1514His) and c.4139A>G, p.(Asn1380Ser). A correlation of the phenotype with the effect of the genetic mutation on protein function is demonstrated. Loss-of-function mutations on both alleles generally result in harlequin ichthyosis, whereas biallelic missense mutations mainly lead to CIE or LI.
In about 20-30% of all women with breast cancer, an increased number of cases of breast cancer can be observed in their family history. However, currently, only 5-10% of all breast cancer cases can ...be attributed to a pathogenic gene alteration. Molecular genetic diagnostics underwent enormous development within the last 10 years. Next-generation sequencing approaches allow increasingly extensive analyses resulting in the identification of additional candidate genes. In the present work, the germline molecular diagnostic analysis of a cohort of 228 patients with suspected hereditary breast and ovarian cancer syndrome (HBOC) was evaluated. The 27 pathogenic gene variants initially detected are listed, and their distribution in the high-risk
and
genes is presented in this study. In ten high-risk patients, in whom, to date, no pathogenic variant could be detected, an extended genetic analysis of previously not considered risk genes was performed. Three variants of uncertain significance and one pathogenic variant could be described. This proves the importance of extended analysis using current molecular genetic methods.
Many of the genetic childhood disorders leading to death in the perinatal period follow autosomal recessive inheritance and bear specific challenges for genetic counseling and prenatal diagnostics. ...Often, affected children die before a genetic diagnosis can be established, thereby precluding targeted carrier testing in parents and prenatal or preimplantation genetic diagnosis in further pregnancies. The clinical phenotype of congenital disorders of glycosylation (CDG) is very heterogeneous and ranges from relatively mild symptoms to severe multisystem dysfunction and even a fatal course. A very rare subtype, COG6‐CDG, is caused by deficiency of subunit 6 of the conserved oligomeric Golgi complex and is usually characterized by growth retardation, developmental delay, microcephaly, liver and gastrointestinal disease, joint contractures and episodic fever. It has been proposed that a distinctive feature of COG6‐CDG can be ectodermal signs such as hypohidrosis/hyperthermia, hyperkeratosis and tooth anomalies. In a Greek family, who had lost two children in the neonatal period, with prominent skin features initially resembling restrictive dermopathy, severe arthrogryposis, respiratory insufficiency and a rapid fatal course trio whole‐exome sequencing revealed the homozygous nonsense mutation c.511C>T, p.(Arg171*) in the COG6 gene. Skin manifestations such as dry skin and hyperkeratosis have been reported in only five out of the 21 reported COG6‐CDG cases so far, including two patients with the c.511C>T variant in COG6 but with milder ectodermal symptoms. Our case adds to the phenotypic spectrum of COG6‐CDG with prominent ectodermal manifestations at birth and underlines the importance of considering CDG among the possible causes for congenital syndromic genodermatoses.
Recurrent blister formation in children may be a sign of hereditary epidermolysis bullosa even if no salient family history can be elicited. In a case of a 5-year-old boy with recurrent occasional ...skin blistering, we diagnosed epidermolysis bullosa simplex and found a causative rare homozygous mutation in EXPH5. Precise molecular genetic analysis is a prerequisite for the accurate diagnosis and adequate counselling of affected families.
Integrin α6β4, encoded by ITGA6 and ITGB4, is a transmembrane component of hemidesmosomes and plays an important role in connecting keratinocytes with extracellular matrix proteins. ITGB4 or ITGA6 ...biallelic pathogenic variants cause junctional epidermolysis bullosa (JEB) with pyloric atresia, which is associated with high lethality. Patients who survive usually develop JEB of intermediate severity and urorenal manifestations. In this study, we report a very rare subtype of late-onset, nonsyndromic JEB associated with a recurrent amino acid substitution in the highly conserved cysteine-rich tandem repeats of the integrin β4 subunit. Literature review shows that among the patients diagnosed with ITGB4 mutations, only two had no extracutaneous manifestations, and only two patients with JEB with pyloric atresia carried missense mutations located in cysteine-rich tandem repeats. We analyzed the consequences of the novel ITGB4 variant c.1642G>A, p.Gly548Arg, on the clinical phenotype, the predicted protein structure, cellular phenotype, and gene expression pattern to show its pathogenicity. The results indicated that the p.Gly548Arg amino acid substitution affected the protein structure of integrin β4 subunits and disrupted the stability of hemidesmosomes and in turn impaired the adhesion of keratinocytes. RNA-sequencing results indicated similar changes in extracellular matrix structure organization and differentiation in keratinocytes completely devoid of integrin β4 and with the amino acid substitution p.Gly548Arg, which further supports the dysregulation of the function of the integrin β4 subunit caused by p.Gly548Arg. Our results provided evidence for a late-onset, mild JEB subtype without extracutaneous manifestations and extend the ITGB4-related genotype−phenotype correlations.
Inherited ichthyoses are classified as Mendelian disorders of cornification (MEDOC), which are further defined on the basis of clinical and genetic features and can be divided into non-syndromic and ...syndromic forms. To date, mutations in more than 30 genes are known to result in various types of syndromic ichthyoses, which, in addition to mostly generalised scaling and hyperkeratosis of the skin, also show additional organ involvement. The syndromic ichthyoses are generally very rare and are classified based on the mode of inheritance, and can be further subdivided according to the predominant symptoms.
In our review we provide a concise overview of the most prevalent syndromic forms of ichthyosis within each subgroup. We emphasize the importance of the clinical assessment of complex syndromes even in the era of genetic testing as a first-tier diagnostic and specifically the need to actively assess potential organ involvement in patients with ichthyosis, thereby enabling efficient diagnostic and therapeutic approaches and timely access to specialized centers for rare disorders of cornifications. As part of the Freiburg Center for Rare Diseases a Center for Cornification Disorders was recently established with collaboration of the Institute of Human Genetics and the Department of Dermatology.
An early diagnosis of syndromes will be of direct benefit to the patient regarding interventional and therapeutic measures e. g. in syndromes with cardiac or metabolic involvement and allows informed reproductive options and access to prenatal and preimplantation genetic diagnosis in the family.
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