CLDN1 Arg81His founder variant causes ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis (ILVASC) syndrome in Moroccan Jews.

Neonatal ichthyosis and sclerosing cholangitis syndrome (NISCH), also known as ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis (ILVASC), is an extremely rare disease of autosomal recessive inheritance, resulting from loss of function of the tight junction protein claudin-1. Its clinical presentation is highly variable, and is characterized by liver and ectodermal involvement. Although most ILVASC cases described to date were attributed to homozygous truncating variants in CLDN1, a single missense variant CLDN1 p.Arg81His, associated with isolated skin ichthyosis phenotype, has been recently reported in a family of Moroccan Jewish descent. We now describe seven patients with ILVASC, originating from four non consanguineous families of North African Jewish ancestry (including one previously reported family), harboring CLDN1 p.Arg81His variant, and broaden the phenotypic spectrum attributed to this variant to include teeth, hair, and liver/bile duct involvement, characteristic of ILVASC. Furthermore, we provide additional evidence for pathogenicity of the CLDN1 p.Arg81His variant by transmission electron microscopy of the affected skin, revealing distorted tight junction architecture, and show through haplotype analysis in the vicinity of the CLDN1 gene, that this variant represents a founder variant in Jews of Moroccan descent with an estimated carrier frequency of 1:220.

Acral collodion membrane associated with ichthyosis due to a heterozygous pathogenic variant of ELOVL4 gene.

A female twin presented at birth with a collodion membrane on the hands and feet. After the membrane resolved over the first months of life, she was initially diagnosed with acral self-healing collodion membrane. However, she subsequently developed brown well-defined geometric scales on the trunk and extremities, consistent with ichthyosis. Genetic testing showed a heterozygous pathogenic variant in ELOVL4, a gene associated with syndromic ichthyosis with developmental delay, seizures, and spasticity. Although acral collodion membrane is considered to be a benign variant of the more generalized collodion, usually described as "self-healing," it may be the initial presentation of more diffuse ichthyosis.

A case of self-improving collodion ichthyosis associated with a rare variant of the ALOX12B gene.

Collodion baby is usually a manifestation of autosomal recessive congenital ichthyosis, a heterogeneous group of congenital hyperkeratotic genodermatoses with highly variable severity and genetic background. Herein, we report a case of self-improving collodion ichthyosis, a rare subtype of autosomal recessive congenital ichthyosis, characterized by an almost-complete spontaneous resolution of symptoms.

Proteoglycan Combined with Hyaluronic Acid and Hydrolyzed Collagen Restores the Skin Barrier in Mild Atopic Dermatitis and Dry, Eczema-Prone Skin: A Pilot Study.

Dry and eczema-prone skin conditions such as atopic dermatitis and xerotic eczema primarily indicate an impaired skin barrier function, which leads to chronic pruritus. Here, we investigated the effects of a novel emollient containing H.ECMTM liposome, which contains a soluble proteoglycan in combination with hydrolyzed collagen and hyaluronic acid. A prospective, single-arm study was conducted on 25 participants with mild atopic dermatitis or dry skin to assess the hydration and anti-inflammatory effect of the novel emollient applied daily over four weeks. All efficacy parameters, including itching severity, transepidermal water loss, and skin hydration, improved significantly after four weeks. The in vitro and ex vivo studies confirmed the restoration of the skin's barrier function. The study revealed the clinical and laboratory efficacy of H.ECMTM liposome in reducing itching and improving the skin's barrier integrity. Thus, the use of H.ECMTM liposome can be considered a therapeutic option for dry and eczema-prone skin.

A case of self-improving collodion ichthyosis in Vietnam.

Autosomal recessive congenital ichthyosis is a heterogeneous group of congenital disorders characterized by aberrant skin cornification and diffuse skin scaling. Some patients with this condition are born encased in a collodion membrane which is later shed, revealing the underlying skin disorder. Self-healing collodion baby (SHCB) is a less common phenotype of this disorder, accounting for about 10% of the patients, in which the membrane peels after several weeks, leaving no underlying skin aberration. Here, we report and discuss the diagnosis and management of an infant with SHCB in Vietnam due to compound heterozygous pathogenic mutations in TGM1.

[Oral manifestations of KID syndrome: rare clinical case]. / Stomatologicheskie proiavleniia KID-sindroma: redkii klinicheskii sluchai.

The paper presents a rare clinical case of an infant with KID (Keratitis, Ichthyosis, Deafness) syndrome (about 100 patients reported so far) admitted for histological verification of oral mucosa lesions. Disease pathogenesis defines inadequate reparation and skin and mucosa innate immunity defect leading to higher incidence of bacterial and fungal infections, so the 4-years old girl received treatment for vegetating candidiasis of the oral mucosa for several weeks with no clinical improvement. Initial examination showed that the oral lesions resulted from sharp edges of severely affected carious teeth. Histological study of multifocal biopsy revealed pyogenic granulomas and no signs of SCC. Teeth extraction and symptomatic treatment leaded to significant clinical improvement and some remained mucosal changes may be attributed to syndrome manifestations.

Topical enzyme-replacement therapy restores transglutaminase 1 activity and corrects architecture of transglutaminase-1-deficient skin grafts.

Transglutaminase-1 (TG1)-deficient autosomal-recessive congenital ichthyosis (ARCI) is a rare and severe genetic skin disease caused by mutations in TGM1. It is characterized by collodion babies at birth, dramatically increased transepidermal water loss (TEWL), and lifelong pronounced scaling. The disease has a tremendous burden, including the problem of stigmatization. Currently, no therapy targeting the molecular cause is available, and the therapeutic situation is deplorable. In this study, we developed the basis for a causative therapy aiming at the delivery of the enzyme to the inner site of the keratinocytes' plasma membrane. We prepared sterically stabilized liposomes with encapsulated recombinant human TG1 (rhTG1) and equipped with a highly cationic lipopeptide vector to mediate cellular uptake. The liposomes overcame the problems of insufficient cutaneous delivery and membrane penetration and provided excellent availability and activity of rhTG1 in primary keratinocytes. To demonstrate the general feasibility of this therapeutic approach in a humanized context, we used a skin-humanized mouse model. Treatment with rhTG1 liposomes resulted in considerable improvement of the ichthyosis phenotype and in normalization of the regenerated ARCI skin: in situ monitoring showed a restoration of TG1 activity, and cholesterol clefts vanished ultrastructurally. Measurement of TEWL revealed a restoration of epidermal barrier function. We regard this aspect as a major advance over available nonspecific approaches making use of, for example, retinoid creams. We conclude that this topical approach is a promising strategy for restoring epidermal integrity and barrier function and provides a causal cure for individuals with TG1 deficiency.

Autosomal recessive ALOX12B gene and consecutive collodion baby.

Autosomal recessive congenital ichthyosis is a type of inherited ichthyosis which is a rare cluster of genetic disorders leading to defective keratinisation. The combined prevalence for lamellar ichthyosis and congenital ichthyosiform erythroderma is almost 1 per 200 000-300 000 people. Among all the mutations in this gene, missense and frameshift mutations are most common which account for 80% of the cases. Our patient had a mutation in R-type arachidonate 12-lipoxygenase gene (ALOX12B, OMIM*603741).

Case report of self-improving collodion ichthyosis in the newborn.

Self-improving collodion ichthyosis (SICI) is a relatively rare subtype of autosomal recessive congenital ichthyosis (ARCI) that is often characterized by a collodion baby (CB) phenotype at birth. A newborn girl, just 1 hour old, presented with taut, shiny, thick yellow crusts, like parchment, and scales on her trunk and upper limbs. The tightening effect had caused both upper eyelids to appear everted, and her lips and auricles were deformed. Based on whole-exome sequencing and examination of the clinical phenotype, the patient was diagnosed with ARCI. After admission, the exposed mucosa was covered with a sterile Vaseline gauze dressing, and she was placed in an incubator set to a temperature of 32°C with a humidity level of 75%. One week later, the parchment-like scales had begun to flake off, and at the age of 3 weeks, all bodily skin appeared normal. SICI was diagnosed. After discharge, the patient was followed up to 3 months of age, at which time her growth and development were comparable to those of her peers. Clinicians should consider SICI as a possible diagnosis when analyzing the prognosis of patients with CB. Reducing water loss and maintaining the electrolyte balance are particularly important for SICI treatment.

Pathogenic PSAT1 Variants and Autosomal Recessive Axonal Charcot-Marie-Tooth Disease With Ichthyosis.

BACKGROUND: Biallelic pathogenic phosphoserine aminotransferase 1 (PSAT1) variants generally cause a severe phenotype predominantly involving the central nervous system. Here, for the first time, we report two patients harboring pathogenic PSAT1 variants only manifested as polyneuropathy and ichthyosis. METHODS: Two patients from unrelated families presenting with polyneuropathy and ichthyosis were enrolled. Whole exome sequencing was performed to identify possible disease-causing variants. Their clinical, electrophysiological, imaging, biochemical, and pathologic changes were in detail assessed and investigated. RESULTS: Homozygous variant c.43G>C and compound heterozygous variants c.112A>C and c.43G>C in PSAT1 were identified in patients 1 and 2, respectively. Nerve conduction studies revealed preserved or mild slowing motor nerve conduction velocities of the median nerves in the two patients, whereas the compound motor action potential in patient 1 was severely decreased. Brain magnetic resonance imaging of the two patients found no abnormalities. Median nerve enlargement was observed on ultrasound in patient 1. Both patients had normal level of serine and glycine in plasma and cerebrospinal fluid. Sural nerve biopsy found severe loss of myelinated fibers. Electron microscopy revealed neurofilament accumulation and mitochondrial aggregation in axons. Both variants in PSAT1 were classified as likely pathogenic or pathogenic variants according to the standard guidelines. CONCLUSIONS: Our study confirms that pathogenic PSAT1 variants can cause a mild phenotype, predominantly as autosomal recessive axonal Charcot-Marie-Tooth disease.

Fatal neonatal nephrocutaneous syndrome in 18 Roma children with EGFR deficiency.

Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein with tyrosine-kinase signaling activity, involved in many cellular functions including cell growth and differentiation. Germ line loss-of-function mutations in EGFR lead to a severe neonatal skin disorder (Online Mendelian Inheritance in Man #131550). We report 18 premature Roma children from 16 families with birthweights ranging 440-1470 g and multisystem diseases due to the homozygous mutation c.1283G˃A (p.Gly428Asp) in EGFR. They presented with thin, translucent, fragile skin (14/15), skin desquamation (10/17), ichthyosis (9/17), recurrent skin infections and sepsis (9/12), nephromegaly (10/16) and congenital heart defects (7/17). Their prognosis was poor, and all died before the age of 6 months except one 13-year-old boy with a severe skin disorder, dentinogenesis imperfecta, Fanconi-like syndrome and secondary hyperaldosteronism. Management of ion and water imbalances and extremely demanding skin care may improve the unfavorable outcome of such patients.

Clinical and muscle MRI features in a family with tubular aggregate myopathy and novel STIM1 mutation.

Heterozygous mutations in the stromal interaction molecule-1-gene (STIM1) cause a clinical phenotype varying from tubular aggregate myopathy with single or multiple signs of Stormorken syndrome to the full Stormorken phenotype. We identified a novel heterozygous mutation c.325C > T (p.H109Y) in the EF-hand domain of STIM1 in six patients of a large Belgian family, and performed a detailed clinical (N = 6), histopathological (N = 2) and whole-body muscle MRI (N = 3) study. The clinical phenotype was characterized by a slowly progressive, predominant proximal muscle weakness in all patients (100%), and additional exercise-induced myalgia in three (60%). Patients experienced symptom onset between 10 and 20 years, remained ambulatory into late adulthood, showed elevated serum creatine kinase levels and tubular aggregates in type 1 and type 2 fibers on muscle biopsy. Interestingly, jaw contractures and hyperlaxity, as well as non-muscular multisystemic features such as menorrhagia, easy bruising and ichthyosis occurred in one patient, and miosis in another. Whole-body muscle MRI revealed predominant involvement of superficial neck extensors, subscapularis, obliquus abdominis externus, lumbar extensors, rectus femoris, biceps femoris longus, medial head of gastrocnemius and flexor hallucis longus. Our findings in patients with myopathy with tubular aggregates and a STIM1 mutation further support the concept of a continuous spectrum with Stormorken syndrome.

Mucocutaneous manifestations in 150 HIV-infected Indian patients and their relationship with CD4 lymphocyte counts.

Mucocutaneous findings in 150 HIV+ve cases (F, 79; M, 71) were evaluated over a one-year period. Mucocutaneous manifestations were seen in 96% with 2.9 mean number of dermatoses and mean cluster of differentiation (CD4) count of 196.33 cells/mm(3). The highest number of mean dermatoses, 3.29, was seen in individuals with severe immunosuppression. The most common mucocutaneous manifestation seen was candidiasis (35.33%), followed by seborrhoeic dermatitis (31.33%), oral pigmentation (29.33%), xerosis/ichthyosis (22.67%), pyodermas (22%), periodontitis (17.33%) and nail pigmentation (16.67%). Patient stratification according to the WHO immunological staging, according to CD4 counts, showed a statistically significant association (P < 0.05) for candidiasis, scabies, paronychia, oral pigmentation and diffuse hair loss. Nail and oral pigmentary changes, trichomegaly and subcutaneous fungal infections caused by dermatophytes were highlights of the study. Incidences of xerosis/ichthyosis, pyodermas, scabies and molluscum contagiosum reported in our study were higher and pruritic popular eruptions was lower than those in previous Indian studies. Cutaneous neoplasms were not seen in the present study.

Autosomal recessive ichthyosis with hypotrichosis syndrome: further delineation of the phenotype.

Autosomal recessive ichthyosis with hypotrichosis (ARIH) syndrome, which is characterized by congenital ichthyosis, abnormal hair and corneal involvement, has recently been shown in one consanguineous Israeli Arab family to be caused by a mutation in the ST14 gene, which encodes serine protease matriptase. No other families have so far been described since the original report. In this current report we describe a female patient from a second family with ARIH syndrome who carries a homozygous novel mutation, p.M1I. The patient has congenital ichthyosis, light brown, curly, sparse hair, improving with age, and sparse body hair, eyebrows and eyelashes. She does not suffer from photophobia, but has blepharitis. The phenotype of this patient closely resembles that of the affected individuals in the previously reported family, although she does not have tooth abnormalities and the ichthyosis is milder.

A report of GJB2 (N14K) Connexin 26 mutation in two patients--a new subtype of KID syndrome?

Keratitis-ichthyosis-deafness syndrome is a rare congenital ectodermal disorder, characterized by presence of skin lesions, neurosensory hearing loss, and vascularizing keratitis. Several autosomal dominant mutations in the Connexin 26 gene (GJB2) have been discovered as a cause of this syndrome. We report two patients who presented with a combination of clinical features of keratitis-ichthyosis-deafness syndrome (e.g., congenital bilateral neurosensory hearing loss and erythrokeratoderma), however, lacking other characteristics typical of this condition. In addition, they both demonstrated striking mucocutaneous findings (e.g., chronic lip fissuring, gingival hyperemia), resulting in diagnostic difficulties. In both patients, a GJB2 mutation (N14K) was identified, which shares the same gene with classic Keratitis-ichthyosis-deafness syndrome but has never been described in patients with this condition. We propose that the findings observed in our patients are a distinct subtype of Keratitis-ichthyosis-deafness syndrome, thus expanding the spectrum of connexin-associated keratodermias.

Contiguous gene syndrome due to an interstitial deletion in Xp22.3 in a boy with ichthyosis, chondrodysplasia punctata, mental retardation and ADHD.

Microdeletions of Xp22.3 can result in contiguous gene syndromes, showing the variable association of apparently unrelated clinical manifestations such as ichthyosis, chondrodysplasia punctata, hypogonadotropic hypogonadism, anosmia, ocular albinism, short stature and mental retardation. We report on a boy with ichthyosis, dysmorphic features and mental retardation with ADHD. The patient was born at term after a pregnancy complicated by threatened abortion; decreased fetal movements and low estriol serum levels were reported during the last trimester. The boy was referred to us at the age of 13 years. He presented with aggressive and hyperactive behavior. He had dry hair, a flat face, bilateral lens opacities, a small nose with hypoplastic tip, alae nasi and nares, a high-arched palate with a very small cleft, mixed dentition with 7 unerupted permanent teeth, left sensorineural and right mixed hearing loss with a calcified plaque of the tympanic membrane, marked shortness of terminal phalanges of hands and feet, ichthyosis of trunk and limbs. The genomic interval between AFM248th5 and KAL1 was investigated. PCR analysis showed a deletion in Xp22.3, with the distal breakpoint between the marker AFM248th5 and PABX and the proximal one between DXS278 and KAL1. Array-CGH and FISH analysis confirmed the interstitial deletion (of about 5.5 Mb) and refined the breakpoints. We discuss the phenotype of our patient in relationship to the deleted segment and the possibility of mental retardation and ADHD genes in the region.

Oral health in Veterans Affairs patients diagnosed with serious mental illness.

OBJECTIVES: We evaluated patient and medication treatment factors associated with self-reported oral health status in patients diagnosed with serious mental illness (SMI) in a large, national sample of patients in the Veterans Affairs (VA) health system. METHODS: 4,769 patients (mean age = 55, 7.8 percent women) were included from the VA's 1999 National Psychosis Registry (NPR) for whom the oral health information gathered by the VA's Large Health Survey of Veterans was available. Current (1999) psychotropic medication data were ascertained from the NPR. Multivariable logistic regression analyses were used to determine the patient factors (e.g., sociodemographic, enabling, and treatment factors) associated with poor or fair overall dental health, and with having tooth or mouth problems that made it difficult to eat. RESULTS: While 61.0 percent of persons with SMI self-reported fair to poor dental health, 34.1 percent reported that oral health problems made it difficult for them to eat. Patients who were not employed, experiencing financial strain, who smoked, who were prescribed tricyclic antidepressants, or prescribed selective serotonin reuptake inhibitors were more likely to report poor or fair dental health. These variables were also associated with having tooth or mouth problems. CONCLUSIONS: Suboptimal oral health was self-reported with substantial prevalence among patients with SMI, a problematic finding given its consequences for general health, social functioning, and quality of life. Greater efforts are needed to improve oral health outcomes among patients with SMI by facilitating access to dental care and addressing mutable factors such as smoking and medication side effects.

Seasonal variations in dermatologic and dermatopathologic diagnoses: a retrospective 15-year analysis of dermatopathologic data.

BACKGROUND: Certain dermatologic conditions are known to show seasonal variations in frequency, the reasons for which are unclear but in some cases may be attributable to changes in ambient weather conditions. OBJECTIVES: The current study was conducted to determine whether seasonal trends might exist for dermatologic conditions including erythema multiforme, guttate psoriasis, erythema dyschromicum perstans (ashy dermatosis), pityriasis lichenoides, and pityriasis rosea. METHODS: Data were derived from a 15-year retrospective review of electronic records from a large dermatopathology laboratory located in the mid-Atlantic region of the USA. Numbers of diagnoses per month and "per season" were determined. Pairwise comparisons of seasonal data were made using two-sample t-tests with significance set at P ≤ 0.05. RESULTS: Perniosis (chilblains) was significantly more common in winter and spring (P = 0.001). Hand, foot, and mouth disease was statistically more prevalent in summer and autumn (P = 0.028). Erythema multiforme was most common in spring and summer (P = 0.004). Grover's disease was most common in winter and spring (P = 0.000039). Guttate psoriasis was non-significantly more common in winter and spring (P = 0.076). No statistically significant seasonal variation was found for erythema dyschromicum perstans (P = 0.899), pityriasis rosea (P = 0.727), or pityriasis lichenoides (P = 0.366). CONCLUSIONS: This study found statistically significant seasonal trends for several dermatologic conditions. The study was primarily epidemiologic and was not intended to address histopathologic differences that might underlie the seasonal variations observed. However, further investigation of seasonal differences in the histopathology of erythema multiforme may prove interesting.