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The American Journal of Dermatopathology Feb 2021Grover disease is an acquired acantholytic dermatosis affecting middle-aged men, with pruritus being the most commonly associated symptom. Grover disease tends to wax...
Grover disease is an acquired acantholytic dermatosis affecting middle-aged men, with pruritus being the most commonly associated symptom. Grover disease tends to wax and wane and can last between several months to several years. Although Grover disease is usually papular, we report here a patient who presented with mainly vesicular and bullous lesions on his back originally concerning for folliculitis, contact dermatitis, or disseminated herpes simplex viral infection. Skin biopsy demonstrated acantholysis, suprabasal blisters, and a predominantly lymphocytic dermal infiltrate. Tzanck preparation for giant cells, immunohistochemistry for viral markers, and direct immunofluorescence staining were all negative. A diagnosis of bullous Grover disease was made based on clinicopathological correlation. Minocycline was recommended based on report of its efficacy. However, patient declined treatment and his rash self-resolved within a couple of months. This case brings awareness to this atypical variant of Grover disease and encourages physician to include Grover disease in their differential of vesiculobullous disorders.
Topics: Acantholysis; Aged; Biopsy; Blister; Diagnosis, Differential; Humans; Ichthyosis; Immunohistochemistry; Male; Predictive Value of Tests; Remission, Spontaneous; Skin
PubMed: 32732687
DOI: 10.1097/DAD.0000000000001756 -
The Journal of Dermatology Apr 2023Netherton syndrome (NS) is a rare disorder of cornification associated with high morbidity. It is caused by bi-allelic mutations in SPINK5 encoding the serine protease...
Netherton syndrome (NS) is a rare disorder of cornification associated with high morbidity. It is caused by bi-allelic mutations in SPINK5 encoding the serine protease inhibitor LEKTI. Previous studies have shown Th17 skewing with IL-23 upregulation in NS, raising the possibility that targeting these inflammatory pathways may alleviate disease manifestations. We ascertained the therapeutic efficacy of six doses of ustekinumab administered to three patients with NS over a period of 13 months using the Ichthyosis Area and Severity Index (IASI), the Dermatology Life Quality Index (DLQI), a visual analogue scale (VAS) for itch and the peak-pruritus numeric rating scale (PP-NRS). Histopathology analysis including CD3, CD4, CD8 and interleukin 17 (IL-17) immunostaining, was performed at baseline and 4 weeks following the last ustekinumab dose. Total IASI scores were reduced by 28% in two patients at week 16 with sustained response by week 56. No consistent improvement in DLQI, VAS for itch and PP-NRS scores was observed. The inflammatory infiltrate and the degree of acanthosis were slightly reduced at week 56 as compared to baseline. No significant change in immunostaining of the various inflammatory markers was observed at week 56. In conclusion, this case series did not demonstrate a significant therapeutic effect of ustekinumab in NS.
Topics: Humans; Netherton Syndrome; Ustekinumab; Ichthyosis; Mutation; Serine Peptidase Inhibitor Kazal-Type 5
PubMed: 36419401
DOI: 10.1111/1346-8138.16645 -
Journal of Medical Genetics Oct 2020X-linked ichthyosis (XLI) is an uncommon dermatological condition resulting from a deficiency of the enzyme steroid sulfatase (STS), often caused by X-linked deletions...
BACKGROUND
X-linked ichthyosis (XLI) is an uncommon dermatological condition resulting from a deficiency of the enzyme steroid sulfatase (STS), often caused by X-linked deletions spanning . Some medical comorbidities have been identified in XLI cases, but small samples of relatively young patients has limited this. is highly expressed in subcortical brain structures, and males with XLI and female deletion carriers appear at increased risk of developmental/mood disorders and associated traits; the neurocognitive basis of these findings has not been examined.
METHODS
Using the UK Biobank resource, comprising participants aged 40-69 years recruited from the general UK population, we compared multiple medical/neurobehavioural phenotypes in males (n=86) and females (n=312) carrying genetic deletions spanning (0.8-2.5 Mb) (cases) to male (n=190 577) and female (n=227 862) non-carrier controls.
RESULTS
We identified an elevated rate of atrial fibrillation/flutter in male deletion carriers (10.5% vs 2.7% in male controls, Benjamini-Hochberg corrected p=0.009), and increased rates of mental distress (p=0.003), irritability (p<0.001) and depressive-anxiety traits (p<0.05) in male deletion carriers relative to male controls completing the Mental Health Questionnaire. While academic attainment was unaffected, male and female deletion carriers exhibited impaired performance on the Fluid Intelligence Test (Cohen's d≤0.05, corrected p<0.1). Neuroanatomical analysis in female deletion carriers indicated reduced right putamen and left nucleus accumbens volumes (Cohen's d≤0.26, corrected p<0.1).
CONCLUSION
Adult males with XLI disease-causing deletions are apparently at increased risk of cardiac arrhythmias and self-reported mood problems; altered basal ganglia structure may underlie altered function and XLI-associated psychiatric/behavioural phenotypes. These results provide information for genetic counselling of deletion-carrying individuals and reinforce the need for multidisciplinary medical care.
Topics: Adult; Aged; Arrhythmias, Cardiac; Biological Specimen Banks; Female; Gene Deletion; Genetic Association Studies; Genetic Predisposition to Disease; Heterozygote; Humans; Ichthyosis, X-Linked; Male; Mental Disorders; Middle Aged; Phenotype; Skin; Steryl-Sulfatase; Surveys and Questionnaires; United Kingdom
PubMed: 32139392
DOI: 10.1136/jmedgenet-2019-106676 -
JAMA Dermatology Jan 2022Ichthyoses are clinically and genetically heterogeneous disorders characterized by scaly skin. Despite decades of investigation identifying pathogenic variants in more...
IMPORTANCE
Ichthyoses are clinically and genetically heterogeneous disorders characterized by scaly skin. Despite decades of investigation identifying pathogenic variants in more than 50 genes, clear genotype-phenotype associations have been difficult to establish.
OBJECTIVE
To expand the genotypic and phenotypic spectra of ichthyosis and delineate genotype-phenotype associations.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study recruited an international group of individuals with ichthyosis and describes characteristic and distinguishing features of common genotypes, including genotype-phenotype associations, during a 10-year period from June 2011 to July 2021. Participants of all ages, races, and ethnicities were included and were enrolled worldwide from referral centers and patient advocacy groups. A questionnaire to assess clinical manifestations was completed by those with a genetic diagnosis.
MAIN OUTCOMES AND MEASURES
Genetic analysis of saliva or blood DNA, a phenotyping questionnaire, and standardized clinical photographs. Descriptive statistics, such as frequency counts, were used to describe the cases in the cohort. Fisher exact tests identified significant genotype-phenotype associations.
RESULTS
Results were reported for 1000 unrelated individuals enrolled from around the world (mean [SD] age, 50.0 [34.0] years; 524 [52.4%] were female, 427 [42.7%] were male, and 49 [4.9%] were not classified); 75% were from the US, 12% from Latin America, 4% from Canada, 3% from Europe, 3% from Asia, 2% from Africa, 1% from the Middle East, and 1% from Australia and New Zealand. A total of 266 novel disease-associated variants in 32 genes were identified among 869 kindreds. Of these, 241 (91%) pathogenic variants were found through multiplex amplicon sequencing and 25 (9%) through exome sequencing. Among the 869 participants with a genetic diagnosis, 304 participants (35%) completed the phenotyping questionnaire. Analysis of clinical manifestations in these 304 individuals revealed that pruritus, hypohydrosis, skin pain, eye problems, skin odor, and skin infections were the most prevalent self-reported features. Genotype-phenotype association analysis revealed that the presence of a collodion membrane at birth (odds ratio [OR], 6.7; 95% CI, 3.0-16.7; P < .001), skin odor (OR, 2.8; 95% CI, 1.1-6.8; P = .02), hearing problems (OR, 2.9; 95% CI, 1.6-5.5; P < .001), eye problems (OR, 3.0; 95% CI, 1.5-6.0; P < .001), and alopecia (OR, 4.6; 95% CI, 2.4-9.0; P < .001) were significantly associated with TGM1 variants compared with other ichthyosis genotypes studied. Skin pain (OR, 6.8; 95% CI, 1.6-61.2; P = .002), odor (OR, 5.7; 95% CI, 2.0-19.7; P < .001), and infections (OR, 3.1; 95% CI, 1.4-7.7; P = .03) were significantly associated with KRT10 pathogenic variants compared with disease-associated variants in other genes that cause ichthyosis. Pathogenic variants were identified in 869 (86.9%) participants. Most of the remaining individuals had unique phenotypes, enabling further genetic discovery.
CONCLUSIONS AND RELEVANCE
This cohort study expands the genotypic and phenotypic spectrum of ichthyosis, establishing associations between clinical manifestations and genotypes. Collectively, the findings may help improve clinical assessment, assist with developing customized management plans, and improve clinical course prognostication.
Topics: Cohort Studies; Female; Genomics; Humans; Ichthyosis; Ichthyosis, Lamellar; Male; Phenotype
PubMed: 34851365
DOI: 10.1001/jamadermatol.2021.4242 -
Pediatrics and Neonatology Nov 2022
Topics: Humans; Infant, Newborn; Ichthyosis, Lamellar
PubMed: 35659753
DOI: 10.1016/j.pedneo.2022.04.006 -
The Journal of Investigative Dermatology Jul 2021The Mendelian disorders of cornification consist of a highly heterogeneous group of diseases, and the majority of nonsyndromic cases belong to the family of autosomal...
The Mendelian disorders of cornification consist of a highly heterogeneous group of diseases, and the majority of nonsyndromic cases belong to the family of autosomal recessive congenital ichthyosis. Mutations in SDR9C7 have been associated with autosomal recessive congenital ichthyosis, and clinical manifestations include mild to moderately dry, scaly skin with or without hyperkeratosis, palmoplantar keratoderma, and erythroderma. SDR9C7, with short-chain dehydrogenase and/or reductase activity, is known as nicotinamide adenine dinucleotide‒ or nicotinamide adenine dinucleotide phosphate‒dependent oxidoreductase and has been shown to be involved in the final step of epidermal lipid barrier formation by covalent binding of acylceramide to the cornified envelope. In this study, we present the clinical and molecular description of 19 patients with autosomal recessive congenital ichthyosis in five consanguineous families with SDR9C7 mutations. We also downregulated the expression of SDR9C7 in keratinocytes using the small interfering RNA technique in three-dimensional organotypic skin constructs. Our results demonstrated morphological and histological abnormalities in these constructs ex vivo, similar to those observed in patients with ichthyosis. Moreover, the results from keratinocyte migration and epidermal dye penetration assays provided evidence for the role of SDR9C7 in the disease pathomechanism. Collectively, our results indicate that SDR9C7 deficiency by itself is sufficient to disrupt epidermal barrier function leading to ichthyotic phenotype.
Topics: Cell Movement; Consanguinity; Epidermis; Female; Gene Knockdown Techniques; HaCaT Cells; Humans; Ichthyosis; Male; Oxidoreductases; Pedigree; Water Loss, Insensible
PubMed: 33422619
DOI: 10.1016/j.jid.2020.11.030 -
International Journal of Molecular... Sep 2021Dry and eczema-prone skin conditions such as atopic dermatitis and xerotic eczema primarily indicate an impaired skin barrier function, which leads to chronic pruritus....
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.ECM 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.ECM liposome in reducing itching and improving the skin's barrier integrity. Thus, the use of H.ECM liposome can be considered a therapeutic option for dry and eczema-prone skin.
Topics: Administration, Topical; Adult; Animals; Anti-Inflammatory Agents; Cell Line; Collagen; Dermatitis, Atopic; Eczema; Emollients; Female; Humans; Hyaluronic Acid; Ichthyosis; Liposomes; Male; Mice; Middle Aged; Pilot Projects; Proteoglycans; Pruritus; RAW 264.7 Cells; Severity of Illness Index; Skin; Water Loss, Insensible; Young Adult
PubMed: 34638528
DOI: 10.3390/ijms221910189 -
Journal of the European Academy of... Jul 2022The broad differential diagnosis of neonatal erythroderma often poses a diagnostic challenge. Mortality of neonatal erythroderma is high due to complications of the... (Review)
Review
The broad differential diagnosis of neonatal erythroderma often poses a diagnostic challenge. Mortality of neonatal erythroderma is high due to complications of the erythroderma itself and the occasionally severe and life-threatening underlying disease. Early correct recognition of the underlying cause leads to better treatment and prognosis. Currently, neonatal erythroderma is approached on a case-by-case basis. The purpose of this scoping review was to develop a diagnostic approach in neonatal erythroderma. After a systematic literature search in Embase (January 1990 - May 2020, 74 cases of neonatal erythroderma were identified, and 50+ diagnoses could be extracted. Main causes were the ichthyoses (40%) and primary immunodeficiencies (35%). Congenital erythroderma was present in 64% (47/74) of the cases, predominantly with congenital ichthyosis (11/11; 100%), Netherton syndrome (12/14, 86%) and Omenn syndrome (11/23, 48%). Time until diagnosis ranged from 102 days to 116 days for cases of non-congenital erythroderma and congenital erythroderma respectively. Among the 74 identified cases a total of 17 patients (23%) died within a mean of 158 days and were related to Omenn syndrome (35%), graft-versus-host disease (67%) and Netherton syndrome (18%). Disease history and physical examination are summarized in this paper. Age of onset and a collodion membrane can help to narrow the differential diagnoses. Investigations of blood, histology, hair analysis, genetic analysis and clinical imaging are summarized and discussed. A standard blood investigation is proposed, and the need for skin biopsies with lympho-epithelial Kazal-type related Inhibitor staining is highlighted. Overall, this review shows that diagnostic procedures narrow the differential diagnosis in neonatal erythroderma. A 6-step flowchart for the diagnostic approach for neonatal erythroderma during the first month of life is proposed. The approach was made with the support of expert leaders from international multidisciplinary collaborations in the European Reference Network Skin-subthematic group Ichthyosis.
Topics: Dermatitis, Exfoliative; Diagnosis, Differential; Humans; Ichthyosis; Ichthyosis, Lamellar; Infant, Newborn; Netherton Syndrome; Severe Combined Immunodeficiency
PubMed: 35238435
DOI: 10.1111/jdv.18043 -
Journal of Obstetrics and Gynaecology... Apr 2020Keratitis-ichthyosis-deafness (KID) syndrome is a congenital ectodermal disorder characterized by keratitis, ichthyosis, and deafness. This syndrome affects multiple...
BACKGROUND
Keratitis-ichthyosis-deafness (KID) syndrome is a congenital ectodermal disorder characterized by keratitis, ichthyosis, and deafness. This syndrome affects multiple systems and can be fatal.
CASE
A 34-year-old G2, P1 woman was admitted to the Ege University School of Medicine in Izmir, Turkey because of a rapid increase in abdominal circumference at 32 weeks gestation. Fetal anatomic screening revealed complete chorioamniotic separation, hypoplasia of the cerebellar vermis, and dysmorphic facial findings such as frontal bulging. After the delivery, the baby's whole body had granular thickened skin. Bilateral dry eye, corneal edema, and bilateral retinopathy of prematurity were diagnosed.
CONCLUSION
This case report highlights the importance of prenatal diagnosis through ultrasonography and magnetic resonance imaging. This is the first case report that has antenatal ultrasonographic features in the literature.
Topics: Adult; Deafness; Female; Humans; Ichthyosis; Infant, Newborn; Keratitis; Magnetic Resonance Imaging; Pregnancy; Prenatal Diagnosis; Turkey; Ultrasonography
PubMed: 31421982
DOI: 10.1016/j.jogc.2019.06.005 -
Frontiers in Immunology 2022Comèl-Netherton syndrome (NS) is a rare disease caused by pathogenic variants in the gene, leading to severe skin barrier impairment and proinflammatory upregulation....
BACKGROUND
Comèl-Netherton syndrome (NS) is a rare disease caused by pathogenic variants in the gene, leading to severe skin barrier impairment and proinflammatory upregulation. Given the severity of the disease, treatment of NS is challenging. Current treatment regimens are mainly topical and supportive. Although novel systemic treatment options for NS have been suggested in recent literature, little is known about their outcomes.
OBJECTIVE
to provide an overview of systemic treatment options and their outcomes in adults and children with NS.
METHODS
Embase, MEDLINE, Web of Science, Cochrane Central Register of Controlled Trials, and Google Scholar were searched up to July 22, 2021. Empirical studies published in English language mentioning systemic treatment in NS were enrolled. Studies that did not define a treatment period or report at least one outcome were excluded. Methodological quality was evaluated by the Joanna Briggs Institute critical appraisal checklist for case reports or case series. Overall quality of evidence of the primary outcome, skin, was assessed by the GRADE approach.
RESULTS
36 case series and case reports were included. The effects of 15 systemic therapies were described in 48 patients, of which 27 were children. Therapies included retinoids, prednisolone, cyclosporine, immunoglobulins, and biologicals. In retinoids both worsening (4/15 cases) and improvement (6/15 cases) of the skin was observed. Use of prednisolone and cyclosporine was only reported in one patient. Immunoglobulins (13/15 cases) and biologicals (18/21 cases) showed improvement of the skin. Certainty of evidence was rated as very low.
CONCLUSION
NS is a rare disease, which is reflected in the scarce literature on systemic treatment outcomes in children and adults with NS. Studies showed large heterogeneity in outcome measures. Adverse events were scarcely reported. Long-term outcomes were reported in a minority of cases. Nonetheless, a general beneficial effect of systemic treatment was found. Immunoglobulins and biologicals showed the most promising results and should be further explored. Future research should focus on determining a core outcome set and measurement instruments for NS to improve quality of research.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=217933, PROSPERO (ID: 217933).
Topics: Adult; Child; Cyclosporine; Humans; Netherton Syndrome; Prednisolone; Rare Diseases; Retinoids
PubMed: 35464459
DOI: 10.3389/fimmu.2022.864449