Mendelian Disorders Of Cornification Research Articles

Syndromic ichthyoses.

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.

Variants in KLK11, affecting signal peptide cleavage of kallikrein-related peptidase 11, cause an autosomal-dominant cornification disorder.

Mendelian disorders of cornification (MeDOC) are a group of heterogeneous genodermatoses with different genetic bases. The pathogenesis of a substantial group of MeDOC remains to be elucidated. To identify a new causative gene and the pathogenesis of a previously undescribed autosomal-dominant cornification disorder. Whole-exome sequencing was performed in three families with the novel cornification disorder to identify the disease-causing variants. As the variants were located around the signal peptide (SP) cleavage site of a kallikrein-related peptidase, SP cleavage, subcellular localization and extracellular secretion of the variants were evaluated in eukaryotic overexpression systems by Western blotting or immunocytochemistry. Then the trypsin-like and chymotrypsin-like proteolytic activity of the peptidase and degradation of its catalytic substrate were assayed using the patients' stratum corneum (SC) samples. The morphology of the lamellar bodies and corneodesmosomes (CDs) in the patients' SC was ultrastructurally examined. A mouse model harbouring the equivalent variant was constructed and evaluated histologically. We identified two heterozygous variants affecting Gly50 in kallikrein-related peptidase (KLK)11 in a familial case and two sporadic cases with the new disorder, which is characterized by early-onset ichthyosiform erythroderma or erythrokeratoderma. KLK11 belongs to the family of kallikrein-related peptidases participating in skin desquamation by decomposing CDs, a process essential for shedding of the SC. In vitro experiments demonstrated that the variants perturbed the SP cleavage of KLK11, leading to subcellular mislocalization and impaired extracellular secretion of the KLK11 Gly50Glu variant. Both trypsin-like and chymotrypsin-like proteolytic activities were significantly decreased in the patients' SC samples. Reduced proteolysis of desmoglein 1 and delayed degeneration of CDs were detected in patients' SC, indicating delayed skin desquamation. Consistently, the patients showed a thickened, dense SC, indicating abnormal skin desquamation. Mice harbouring the homozygous c.131G>A (p.Gly44Glu) Klk11 variant, which is equivalent to KLK11 c.149G>A (p.Gly50Glu) in humans, exhibited hyperkeratosis and abnormal desquamation, partially recapitulating the phenotype. We provide evidence that variants at Gly50 affecting the SP cleavage of KLK11 cause a new autosomal-dominant cornification disorder with abnormal desquamation. Our findings highlight the essential role of KLKs in maintaining homeostasis of skin keratinization and desquamation.

185 GJB2 mutations in patients with ichthyosis follicularis and histopathology of porokeratotic adnexal ostial nevus

Ichthyosis follicularis (IF) is a distinct cutaneous entity reported in combination with atrichia and photophobia. Mutations in SREBF1 and MBTPS2 have been associated with IF. We sought the genetic cause of IF in two distinct families from a cohort of 180 patients with clinical manifestation of Mendelian disorders of cornification (MeDOC) or ichthyosis. In Family 1, the proband presented with IF, bilateral sensorineural hearing loss (SNHL), and keratitis was found to have a de novo heterozygous GJB2: c.148G>A, p.Asp50Asn in genomic DNA extracted from the peripheral blood lymphocytes. In Family 2, manifested by IF, bilateral SNHL, and punctate palmoplantar keratoderma, compound heterozygous mutations in the GJB2 were discovered: a pathogenic c.526A>G; p.Asn176Asp, and a common frameshift mutation, c.35delG; p.Gly12Valfs*2. Histopathology from both patients was compatible with porokeratotic adnexal ostial nevus (PAON). Interestingly previously, somatic mutations in the GJB2 were shown in association with PAON. Due to shared histopathology between segmental and mosaic PAON and the PAON in association with ichthyosis syndromes such as Keratitis-ichthyosis-deafness (KID) syndrome, it was suggested that KID syndrome is the constitutional form of PAON. Accordingly, our finding supports this hypothesis by finding GJB2 mutations in the DNA of lymphocytes in MeDOC patients with PAON histopathology. These findings attest to the complexity of the clinical consequences of different mutations in GJB2.

Genetics of Inherited Ichthyoses and Related Diseases.

Inherited ichthyoses are classified as Mendelian disorders of cornification (MEDOC), which are defined on the basis of clinical and genetic features and are mainly divided into non-syndromic and syndromic ichthyoses. Numerous genes, which encode for corresponding proteins, are involved in the normal differentiation of keratinocytes (cornification) and participate in the formation of a functional epidermal barrier. To date, mutations in more than 50 genes are known to result in various types of ichthyoses. Thanks to modern genetic diagnostic methods based on targeted next generation sequencing (NGS), approximately 80–90% of cases can be resolved at present. Further sequencing methods covering the whole exome (WES) or whole genome (WGS) will obviously elucidate another portion of the remaining unknown ichthyoses in the future.

Genodermatoses - pathogenesis and molecular diagnostics

Genetically determined skin diseases, genodermatoses, are a group of rare disorders characterized by heterogeneous clinical course, prognosis and complex molecular pathology. In Epidermolysis Bullosa (EB) and Mendelian disorders of cornification (MeDOC) epidermal dysfunction occurs. Mutations in several dozen genes have been identified to be responsible for clinical symptoms of EB and MeDOC, which, in general, include: tendency to blister formation with skin fragility and abnormal keratinization, respectively. However, clinical symptoms of these diseases can be variable and genotype-phenotype correlations are only partially determined. Molecular diagnostics aimed at identification of mutations in affected individuals enables verification of clinical diagnosis, calculation of disease recurrence risk in other family members and, gradually, is also the basis for new therapies development. Nevertheless, even modern molecular technologies allow mutation detection in 80% of patients only. Hence, further, interdisciplinary scientific research are needed in order to increase detection rate and develop effective therapies.

Mendelian Disorders of Cornification Caused by Defects in Intracellular Calcium Pumps: Mutation Update and Database for Variants in ATP2A2 and ATP2C1 Associated with Darier Disease and Hailey-Hailey Disease.

The two disorders of cornification associated with mutations in genes coding for intracellular calcium pumps are Darier disease (DD) and Hailey-Hailey disease (HHD). DD is caused by mutations in the ATP2A2 gene, whereas the ATP2C1 gene is associated with HHD. Both are inherited as autosomal-dominant traits. DD is mainly defined by warty papules in seborrheic and flexural areas, whereas the major symptoms of HHD are vesicles and erosions in flexural skin. Both phenotypes are highly variable. In 12%-40% of DD patients and 12%-55% of HHD patients, no mutations in ATP2A2 or ATP2C1 are found. We provide a comprehensive review of clinical variability in DD and HHD and a review of all reported mutations in ATP2A2 and ATP2C1. Having the entire spectrum of ATP2A2 and ATP2C1 variants allows us to address the question of a genotype-phenotype correlation, which has not been settled unequivocally in DD and HHD. We created a database for all mutations in ATP2A2 and ATP2C1 using the Leiden Open Variation Database (LOVD v3.0), for variants reported in the literature and future inclusions. This data may be of use as a reference tool in further research on treatment of DD and HHD.

Interdisciplinary care of newborns with epidermolysis bullosa and severe congenital ichthyoses

Severe genodermatoses such as hereditary blistering diseases or Mendelian disorders of cornification may present as neonatal emergencies requiring interdisciplinary care. In particular, epidermolysis bullosa hereditaria, the collodion baby phenotype and harlequin ichthyosis represent serious clinical challenges with neonatal onset. This review summarizes dermatologically relevant aspects regarding pathogenesis, clinical presentation, diagnosis and therapy of these illnesses.

Targeting epidermal lipids for treatment of Mendelian disorders of cornification

BackgroundInherited ichthyoses or Mendelian disorders of cornification (MeDOC) are clinically heterogeneous disorders with high unmet therapeutic needs, which are characterized by skin hyperkeratosis and scaling. Some MeDOC types are associated with defects of the epidermal lipid metabolism, resulting in perturbed barrier permeability and subsequent epidermal hyperplasia, hyperkeratosis and inflammation. An example is the CHILD (congenital hemidysplasia with ichthyosiform nevus and limb defects) syndrome, an X-linked dominant multisystem MeDOC caused by mutations in the NSDHL (NAD(P)H steroid dehydrogenase-like protein) gene, which is involved in the distal cholesterol biosynthetic pathway. The skin manifestations of the CHILD syndrome have been attributed to two major mechanisms: deficiency of cholesterol, probably influencing the proper corneocyte membrane formation, and toxic accumulation of aberrant steroid precursors.MethodsHere we addressed the efficacy of an ointment containing cholesterol and simvastatin, an agent inhibiting endogenous cholesterol synthesis in a compassionate-use treatment of three patients with CHILD syndrome. To test the specificity of this therapeutic approach, we applied the same topical treatment to two patients with other types of MeDOC with disturbed skin lipid metabolism.ResultsThe therapy with simvastatin and cholesterol was highly effective and well-tolerated by the CHILD syndrome patients; only lesions in the body folds represented a therapeutic challenge. No improvement was noted in the patients with other types of MeDOC.ConclusionsThis therapy is inexpensive and accessible to every patient with CHILD syndrome, because both simvastatin and cholesterol are available worldwide. Our data provide initial evidence of the specificity of the therapeutic effect of the simvastatin-cholesterol ointment in CHILD syndrome in comparison to other types of MeDOC.

Nonsyndromic types of ichthyoses – an update

Ichthyoses are genetically determined Mendelian disorders of cornification (MEDOC) that are characterized by universal scaling. Today we distinguish between non-syndromic and syndromic forms. Ichthyosis vulgaris is the most frequent type (prevalence 1:100) and is caused by autosomal semi-dominant filaggrin mutations. It is associated with a higher risk for the development of atopic diseases, such as atopic eczema and allergic rhinitis. Recessive X-linked ichthyosis (RXLI) occurs almost exclusively in boys; in Germany it has a prevalence of around 1:4,000. It is caused by steroid sulfatase deficiency and is often associated with further clinical problems, such as cryptorchidism (∼20%) or social communication deficits, such as attention deficit hyperactivity syndrome (40%) or autism (25%). Autosomal recessive congenital ichthyosis (ARCI) is genetically very heterogeneous and 8 different genes have been identified so far. The most frequent cause of ARCI is a transglutaminase 1 deficiency (prevalence 1:200, 000). Mutations in keratin genes are the cause of the keratinopathic ichthyoses, such as epidermolytic ichthyosis. They manifest at birth and often feature episodes of blistering. Most of these types are inherited as autosomal dominant traits, but autosomal recessive forms have also been described on occasion.

Congenital disorders of glycosylation: other causes of ichthyosis

We read with interest the comprehensive review by Schmuth et al1 on inherited ichthyoses/generalized Mendelian disorders of cornification. We would like to point out that some congenital disorders of glycosylation (CDG) present ichthyosis. Associations have been described for MPDU1-CDG (formerly CDG-If), DOLK-CDG (CDG-Im), SRD5A3-CDG (CDG-Iq) and PIGL-CDG (CHIME syndrome, Zunich neuroectodermal syndrome). MPDU1-CDG is a defect in the N-glycan assembly in the endoplasmic reticulum (ER). The four reported patients showed skin involvement (ichthyosis and/or erythroderma). Other features included psychomotor retardation, seizures, hypotonia, gastrointestinal problems, visual impairment, dwarfism and transient growth hormone deficiency. The MPDU1 protein is considered to be a chaperone favoring the efficient utilization of dolicholphosphoglucose and dolicholphosphomannose in glycosylation. A reduced level of the glycosylphosphatidylinositol (GPI)-anchor CD59 has been found in these patients suggesting that they have also a deficiency in GPI-anchor biosynthesis (see PIGL-CDG).2, 3 DOLK-CDG is a defect in dolichol kinase, the last step of the dolichol phosphate biosynthesis. It shows a clinical spectrum with at one end a non-syndromic dilated cardiomyopathy (reported in nine patients),4 and at the other end a severe syndrome (reported in four patients) with ichthyosis, as well as dilated cardiomyopathy, epilepsy, microcephaly, visual impairment, hypoglycemia and death within the first 6 months.5 SRD5A3-CDG is a defect in polyprenol reductase, involved in the biosynthesis of dolichol. This cerebro-cerebello-oculo-cutaneous syndrome has been described in some 15 patients. Its skin component consists of ichthyosis, erythroderma and/or dry skin.6, 7 PIGL-CDG or CHIME syndrome is characterized by colobomas, congenital heart defects, early-onset migratory ichthyosiform dermatosis, mental retardation and ear anomalies, besides other clinical manifestations. This is a defect in an ER-localized enzyme that catalyzes the second step of GPI-anchor biosynthesis, the de-N-acetylation of N-acetylglucosaminyl-phosphatidylinositol that occurs on the cytoplasmic side of the ER. It has been reported in eight patients.8

Care of the newborn with ichthyosis

Mendelian disorders of cornification (ichthyosis; MeDOC) often present in the neonatal period with little warning to providers or parents. This report reviews the majority of ichthyoses with congenital findings. The neonatal presentation of many MeDOC often differs from the later phenotype because of the changes in the skin that occur with transition from an intrauterine to extrauterine environment. While differentiation of ichthyosis subtypes in the neonatal period is difficult, there are certain phenotypic groups within which these neonates fall, recognition of which can guide initial work up and treatment. For this report, these are categorized as: exuberant vernix; collodion baby/harlequin ichthyosis (HI); ichthyosiform erythroderma; blistering; and normal skin/xerosis phenotypes.