Homozygous Loss-of-Function Mutations in AP1B1, Encoding Beta-1 Subunit of Adaptor-Related Protein Complex 1, Cause MEDNIK-like Syndrome.

MEDNIK syndrome (mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma) is an autosomal-recessive disorder caused by bi-allelic mutations in AP1S1, encoding the small σ subunit of the AP-1 complex. Central to the pathogenesis of MEDNIK syndrome is abnormal AP-1-mediated trafficking of copper transporters; this abnormal trafficking results in a hybrid phenotype combining the copper-deficiency-related characteristics of Menkes disease and the copper-toxicity-related characteristics of Wilson disease. We describe three individuals from two unrelated families in whom a MEDNIK-like phenotype segregates with two homozygous null variants in AP1B1, encoding the large ß subunit of the AP-1 complex. Similar to individuals with MEDNIK syndrome, the affected individuals we report display abnormal copper metabolism, evidenced by low plasma copper and ceruloplasmin, but lack evidence of copper toxicity in the liver. Functional characterization of fibroblasts derived from affected individuals closely resembles the abnormal ATP7A trafficking described in MEDNIK syndrome both at baseline and in response to copper treatment. Taken together, our results expand the list of inborn errors of copper metabolism.

PLACK syndrome is potentially treatable with intralipids.

We describe an 11-year-old girl with PLACK Syndrome (peeling skin, leukonychia, acral punctate keratosis, cheilitis, and knuckle pads), who was found to have a novel homozygous variant in CAST, the pathogenicity of which was confirmed using blood-derived RNA. There is no established treatment for PLACK syndrome. However, we demonstrate for the first time that this condition is associated with low levels of vitamin A and essential fatty acids, which prompted us to consider a potential treatment strategy. Indeed, we initiated this patient on intravenous lipid infusion (Vitalipid®; an emulsion of fat-soluble vitamins and lipofundin-MCT/LCT 20%) and the response was dramatic. Following the fourth monthly course of treatment, pruritis disappeared and the skin lesions showed remarkable objective improvement. PLACK syndrome is a very rare genodermatosis and only six families have been described to date with pathogenic CAST variants. This is the first report of an objective response to a therapeutic agent, which suggests that PLACK is a potentially treatable condition. The remarkable response we report and the relative safety of the intervention should prompt healthcare providers who care for PLACK syndrome patients to explore this as a potential treatment strategy in future studies.

KDF1, encoding keratinocyte differentiation factor 1, is mutated in a multigenerational family with ectodermal dysplasia.

Ectodermal dysplasia is a highly heterogeneous group of disorders that variably affect the derivatives of the ectoderm, primarily skin, hair, nails and teeth. TP63, itself mutated in ectodermal dysplasia, links many other ectodermal dysplasia disease genes through a regulatory network that maintains the balance between proliferation and differentiation of the epidermis and other ectodermal derivatives. The ectodermal knockout phenotype of five mouse genes that regulate and/or are regulated by TP63 (Irf6, Ikkα, Ripk4, Stratifin, and Kdf1) is strikingly similar and involves abnormal balance towards proliferation at the expense of differentiation, but only the first three have corresponding ectodermal phenotypes in humans. We describe a multigenerational Saudi family with an autosomal dominant form of hypohidrotic ectodermal dysplasia in which positional mapping and exome sequencing identified a novel variant in KDF1 that fully segregates with the phenotype. The recapitulation of the phenotype we observe in this family by the Kdf1-/- mouse suggests a causal role played by the KDF1 variant.

Exome sequencing identifies novel NTRK1 mutations in patients with HSAN-IV phenotype.

Hereditary sensory autonomic neuropathy type IV (HSAN-IV) is a rare autosomal recessive disorder that usually begins in infancy and is characterized by anhidrosis, insensitivity to noxious stimuli leading to self-mutilating behavior, and intellectual disability. HSAN-IV is caused by mutations in the neurotrophic tyrosine kinase receptor type 1 gene, NTRK1, encoding the high-affinity receptor of nerve growth factor (NGF) which maps to chromosome 1q21-q22. Patients with HSAN-IV lack all NGF-dependent neurons, the primary afferents and sympathetic postganglionic neurons leading to lack of pain sensation and the presence of anhidrosis, respectively. Herein, we report nine patients from nine unrelated families with HSAN-IV due to various mutations in NTRK1, five of which are novel. These are three missense and two nonsense mutations distributed in various domains of NTRK1 involved in binding of NGF. The affected patients had variable intellectual deficits, and some had delayed diagnosis of HSAN-IV. In addition to being the first report of HSAN-IV from the Arabian Peninsula, this report expands the mutational spectrum of patients with NTRK1 mutations and provides further insights for molecular and clinical diagnosis.

Hidradenitis Suppurativa in Down Syndrome: A Case Series.

BACKGROUND/OBJECTIVES: Many dermatologic and systemic diseases have been reported in association with hidradenitis suppurativa, but its association with Down syndrome is rarely mentioned in the literature. The objective of the current study was to assess the frequency of hidradenitis suppurativa in patients with Down syndrome who visited our clinic over 4 years. METHODS: We recorded the presenting complaints and dermatologic problems of patients with Down syndrome who visited our clinic from January 2011 to December 2014. Medical photographs were taken. Patients with hidradenitis suppurativa were assessed according to severity and treated with topical and systemic medications. RESULTS: Twenty-nine new patients with Down syndrome visited our clinic during this period. Eleven had hidradenitis suppurativa. Disease severity included Hurley stages I and II. CONCLUSION: The presence of hidradenitis suppurativa in 38% of patients with Down syndrome is far higher than would be expected by chance alone.

Patient-reported burden in adults with atopic dermatitis: an international qualitative study.

The objective was to study a large, international, ethnically diverse population of patients with atopic dermatitis (AD) to support the creation of patient-centric recommendations for AD management. Qualitative data were generated from 45-min, 1:1 telephone interviews conducted across 15 countries in each patient's native language. Interviews explored the impact of AD on patients' lives, patients' most important symptoms, treatment expectations, and treatment decision-making. Participants were also questioned on their current knowledge of AD scoring systems and what was most important to include in these tools. In total, 88 adult patients (≥ 18 years old) receiving treatment for AD were recruited through a market research database, clinician referrals, and local advertising. All patients were screened to ensure a balanced and diverse sample in terms of age, gender, educational level, employment status, geographic location, and AD severity. Patients involved in market research or activities supporting advocacy groups within the previous 6 months or affiliated with or employed by pharmaceutical companies were excluded. AD had a substantial impact on patients' lives. Itch, skin redness, and dry/flaky skin were the most frequently reported symptoms, with > 75% of patients experiencing these symptoms every 1-3 days. Mental health issues were common and resulted in the greatest negative impact on patients' daily lives. Patients perceived clinicians to underestimate the burden of their AD. Patients had little awareness of AD scoring systems and indicated a preference for these to be more clearly incorporated in clinical practice. For an ideal scoring system, patients favored using a combination of patient-reported and clinician-reported outcomes to reflect disease burden and ensure consistency across all settings. This global study generated diverse patient perspectives on the disease burden of AD, their expectations of treatment, and their views on AD scoring methods. These data provide evidence to support the development of patient-centric recommendations for AD management.

Expert consensus on unmet needs, referral criteria and treatment goals for hidradenitis suppurativa in Saudi Arabia.

Purpose: There is limited information about the diagnosis and treatment of hidradenitis suppurativa (HS) in the Kingdom of Saudi Arabia (KSA). This Delphi consensus study was conducted to develop recommendations for the management of HS in the KSA.Methods: The expert panel including 12 dermatologists with extensive experience treating HS patients provided nine consensus statements and recommendations on diagnosis and assessment, management, comorbidities and multidisciplinary approach, and education. The experts also developed clinical questions pertaining to the management of HS and rolled out as a survey to 119 dermatologists practising in the KSA.Results: The topics covered included: referring physicians' awareness of HS; referral criteria for HS; definition of moderate-to-severe HS; treatment goals; definition of treatment success; treatment and biologic initiation; comorbidities and multidisciplinary approach; patient education and awareness of HS. Full consensus (100%) from the expert dermatologists was received on all the topics except referring physicians' awareness of HS, definition of treatment success, and treatment and biologic initiation. The survey results resonated with the expert opinion.Conclusion: As HS is a chronic disease with negative impact on quality-of-life, timely diagnosis and treatment, early identification of comorbid conditions and a multidisciplinary care approach are crucial for effective management of HS.

Kindler's Syndrome with Recurrent Neutropenia: Report of Two Cases from Saudi Arabia.

Kindler syndrome (KS) is a rare photosensitivity disorder with autosomal recessive mode of inheritance. It is characterized by acral blistering in infancy and childhood, progressive poikiloderma, skin atrophy, abnormal photosensitivity, and gingival fragility. Besides these major features, many minor presentations have also been reported in the literature. We are reporting two cases with atypical features of the syndrome and a new feature of recurrent neutropenia. Whole exome sequencing analysis was done using next-generation sequencing which detected a homozygous loss-of-function (LOF) variant of FERMT1 in both patients. The variant is classified as a pathogenic variant as per the American College of Medical Genetics and Genomics guidelines. Homozygous LOF variants of FERMT1 are a common mechanism of KS and as such confirm the diagnosis of KS in our patients even though the presentation was atypical.

Certolizumab to treat hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition that affects apocrine gland-bearing skin. The management of HS with biologics has expanded significantly over the past few years. Certolizumab pegol is a pegylated (polyethylene glycol) antigen-binding fragment of a recombinant humanized anti-TNF-α monoclonal antibody, which is approved for psoriasis, rheumatoid arthritis, ankylosing spondylitis, and Crohn's disease. In recent years many reports have been merging on the use of certolizumab in treating hidradenitis suppurativa. The electronic database MEDLINE was searched through PubMed in February 2022 using the following search terms: Certolizumab "[All Fields] OR" certolizumab pegol"[All Fields] AND "Hidradenitis suppurativa"[ All Fields]. The search revealed that certolizumab was used in 6 case reports to treat HS with a total of 7 patients. We can conclude that there are few cases in the literature discussing the use of certolizumab in HS, all of which, show a good and promising response with no reported side effects.

The impact of social media on dermatologists and in captivating their patients: a cross-sectional study.

BACKGROUND: Dermatology practice has been impacted in the modern era of connectivity and social media (SM). Users' choice of dermatology practice may be influenced by SM. This study surveyed dermatologists for the use of SM as part of their practice, and the general population to assess the effect of SM on the practice of dermatology. METHODS: This nationwide, cross-sectional study among dermatologists and the general population used two questionnaires, with the first (S1) targeting a random sample of the Saudi general population and the second (S2) addressing dermatologists. RESULTS: Out of 965 participants in the first questionnaire. 53.78% (n = 519) of the responders followed dermatologists on SM, 57.8% did so to learn about treatment of dermatologic diseases. On the other hand, the S2 was completed by 58 dermatologists. Of them, 82.8% believed that SM had changed the practice of dermatology, 98.3% (n = 57) believed that it changed their own practice. When following a dermatologist on SM, a main reason (26.5%) was to evaluate before-and-after images. CONCLUSION: SM plays a significant role in a physician's reputation and the practice of dermatology. It is a new era that is mainly fueled by technology; keeping pace with these advancements is an essential way to thrive.

National Saudi Consensus Statement on the Management of Atopic Dermatitis (2021).

Atopic dermatitis (AD) is a chronic inflammatory skin disease with an increasing prevalence regionally and globally. It is characterized by intense itching and recurrent eczematous lesions. With the increase in the availability of treatment options for healthcare practitioner and patients, new challenges arise for treatment selection and approach. The current consensus statement has been developed to provide up-to-date evidence and evidence-based recommendations to guide dermatologists and healthcare professionals managing patients with AD in Saudi Arabia. By an initiative from the Ministry of Health (MOH), a multidisciplinary work group of 11 experts was convened to review and discuss aspects of AD management. Four consensus meetings were held on January 14, February 4, February 25, and March 18 of 2021. All consensus content was voted on by the work group, including diagnostic criteria, AD severity assessment, comorbidities, and therapeutic options for AD. Special consideration for the pediatric population, as well as women during pregnancy and lactation, was also discussed. The present consensus document will be updated as needed to incorporate new data or therapeutic agents.

Management of Atopic Dermatitis in Adults in Saudi Arabia: Consensus Recommendations from the Dermatological Expert Group.

Background: Atopic dermatitis (AD) is a long-term, pruritic, recurrent, systemic, inflammatory skin disorder. In the Middle East region, the burden of AD is understudied, and there is a dearth of AD guideline documents for practitioners. Methods: An expert panel meeting, encompassing 12 dermatologists from the Kingdom of Saudi Arabia (KSA), was congregated to develop evidence- and experience-based consensus recommendations for AD management, especially in adults in KSA. They completed a questionnaire with seven clinical statements, and a consensus was defined when the responses of ≥75% of participants coincided. Results: The expert recommendations were as follows: American Association of Dermatology guidelines are to be followed for defining AD; Eczema Area and Severity Index or SCORing atopic dermatitis index may be used to quantify the disease severity; Dermatology Life Quality Index may be used to determine the impact of AD on patients' quality of life; Atopic Dermatitis Control Tool may be used to assess long-term disease control in AD patients; and the European guidelines are to be followed for the management of AD. In AD patients who are inadequately controlled with topical or systemic therapies, the preferred systemic agent for use either alone or in combination with topical treatments is dupilumab, cyclosporine, methotrexate, phototherapy, or other available systemic treatments that may include mycophenolate mofetil or oral corticosteroids. Conclusion: These expert recommendations assist physicians by providing a reference framework for optimal care of adult AD patients.

Saudi consensus statement on biologic treatment of chronic plaque psoriasis (2020).

Psoriasis is a common chronic and complex inflammatory skin disease that affects over 125 million people worldwide. Management of psoriasis in daily clinical practice in Saudi Arabia is variable. Local preferences for management differ, which may have a bearing on the treatment selection. Biologic therapy is now a well-established strategy for managing moderate-to-severe plaque psoriasis. There is a clear need for national consensus statements due to the extended role and high availability of literature on these agents. As a result of an initiative of the Ministry of Health, a multidisciplinary expert panel of dermatologists and pharmacists with practical experience in the clinical management of psoriasis were invited to be part of a work group to update the previous practical guidelines on the biologic treatment of psoriasis published in the Journal of Dermatological Treatment, 2014. The overall aim of this consensus document is to deliver evidence-based recommendations on the use, screening, and monitoring of biologic therapy in patients with moderate-to-severe plaque psoriasis. These recommendations also address the use of biologic therapy in special patient populations. They were developed after rigorous evaluation of existing international guidelines as well as the latest emerging evidence. Updates of the present consensus document will be provided as needed to incorporate new data or agents.

CD109 release from the cell surface in human keratinocytes regulates TGF-ß receptor expression, TGF-ß signalling and STAT3 activation: relevance to psoriasis.

Transforming growth factor (TGF)-ß is an important cytokine that negatively regulates keratinocyte proliferation. Deregulation of TGF-ß signalling has been reported in psoriasis, where despite increased expression of TGF-ß, psoriatic keratinocytes continue to hyperproliferate. Recently, we have identified CD109, a glycosyl phosphatidylinositol (GPI)-anchored protein, as a novel co-receptor and negative regulator of TGF-ß signalling. In the current work, we demonstrate that release of CD109 from the cell surface or the addition of CD109 protein results in downregulation of TGF-ß signalling and TGF-ß receptor expression in human keratinocytes. Moreover, these effects are associated with an increase in phospho-STAT3 levels, enhanced total STAT3 and Bcl-2 expression and an increase in cell growth and survival, suggesting that released/soluble CD109 is able to induce molecular changes that are known to occur in psoriasis. Analysis of CD109 expression in psoriasis patients reveals that CD109 protein expression is markedly decreased in psoriatic epidermis as compared to adjacent uninvolved skin. In contrast, CD109 mRNA expression is unchanged in psoriatic plaques in comparison with normal skin. This raises a possibility that CD109 protein release is enhanced in psoriatic keratinocytes. Furthermore, psoriatic epidermis displays decreased expression of TGF-ß receptors, consistent with the results obtained in vitro in keratinocytes with CD109 release or addition of CD109 recombinant protein. Together our findings suggest that aberrant CD109 release from the cell surface in human keratinocytes may induce molecular changes that are usually observed in psoriasis and may explain TGF-ß receptor downregulation and decrease in TGF-ß signalling in psoriasis.

D-penicillamine-induced pseudo-pseudoxanthoma elasticum and extensive elastosis perforans serpiginosa with excellent response to acitretin.

D-penicillamine (DPA)-induced pseudo-pseudoxanthoma elasticum (PXE) and elastosis perforans serpiginosa (EPS) has been reported in the past, but most of the treatment modalities used before have a sub.optimal response. We report a case of DPA-induced pseudo-PXE with extensive EPS who had an excellent rapid response to acitretin. To the best of our knowledge no such report has been published in the past, even though there is a single report of effectiveness of isotretinoin in elastosis perforans serpiginosa. SIMILAR CASES PUBLISHED: One similar case but with a different medication (reference 13).

Rituximab/IVIG in pemphigus - a 10-year study with a long follow-up.

BACKGROUND: Pemphigus is a chronic potentially life-threatening autoimmune blistering disease affecting the skin and/or mucous membranes. Rituximab is being increasingly used and found efficacious in the treatment of pemphigus. OBJECTIVE: To present the Middle-Eastern experience with the use of rituximab in pemphigus. METHODS: A retrospective analysis of patient files was conducted which revealed 23 patients of pemphigus who were treated with rituximab (either alone or with IVIG) in the dermatology department of a tertiary care hospital from July 2004 to December 2014. RESULTS: The mean time to disease control was 8 weeks (median 5 weeks and range 2-30 weeks). 90.9% attained early study end point with the first cycle of rituximab. The remaining 9.1% needed an additional course of rituximab + IVIG to attain disease control. 90.5% of our patients attained complete remission during the study period. The average time to attain complete remission on minimal treatment was 25.4 weeks and partial remission on minimal treatment was attained after a mean period of 18.3 weeks. Rituximab was well tolerated by our patients and the rate of adverse-effects in our cohort was comparable to the previous reports. CONCLUSIONS: Rituximab is an effective and safe treatment for pemphigus and should be considered earlier in the algorithm of pemphigus treatment.

Nonmelanoma skin cancer in Saudi Arabia: single center experience.

BACKGROUND: Skin cancer is the most common cancer worldwide; one in every three diagnosed malignancies is a skin cancer. However, skin cancer is rarely reported in Saudi Arabia so we conducted this study to highlight these underreported neoplasms. OBJECTIVES: Determine the prevalence and patterns of basal cell carcinoma (BCC) and primary squamous cell carcinoma (SCC), the most common types of nonmelanoma skin cancer (NMSC) with respect to age, sex, and anatomic location and to identify potentially associated risk factors. DESIGN: Retrospective, descriptive medical record review. SETTING: A tertiary care centre. PATIENTS AND METHODS: We did a retrospective chart review of all patients diagnosed with basal cell carcinoma and primary squamous cell carcinoma between 2003-2016. MAIN OUTCOME MEASURES: Prevalence and pattern of BCC and SCC with respect to age, sex, and anatomic location. RESULTS: Of 593 cases reviewed, 279 had NMSC. Most (95%) were diagnosed with BCC or SCC or both in a few cases. The mean age at diagnosis was 59 (19.5) years. Sixty-two percent of the patients were males. However, 24.3% (n=68) of skin cancers occurred in patients younger than 50 years. The frequency of BCC and SCC was 50.2% and 44.8%, respectively. The head and neck was the most common location (79.6%). In patients younger than 50 years, xeroderma pigmentosum and previously treated solid malignancies were the major factors. CONCLUSIONS: BCC and SCC are uncommon but not rare. However, skin cancers are underreported in our population. NMSC in individuals younger than 50 years of age requires more careful evaluation of possible risk factors. LIMITATIONS: Retrospective in a single tertiary care setting.