Genomics-based treatment in a patient with two overlapping heritable skin disorders: Epidermolysis bullosa and acrodermatitis enteropathica.

Next-generation sequencing (NGS) is helpful in diagnosing complex genetic disorders and phenotypes, particularly when more than one overlapping condition is present. From a large cohort of 362 families with clinical manifestations of skin and mucosal fragility, referred by several major medical centers, one patient was found by NGS to have two overlapping heritable skin diseases, recessive dystrophic epidermolysis bullosa (RDEB; COL7A1 mutations) and acrodermatitis enteropathica (AE; SLC39A4 mutations). The pathogenicity of the variants was studied at gene expression as well as ultrastructural and tissue levels. Although there is no specific treatment for RDEB except avoiding trauma, supplementation with oral zinc (3 mg·kg-1 ·day-1 ) for the AE resulted in rapid amelioration of the skin findings. This case demonstrates the power of NGS in identifying two genetically unlinked diseases that led to effective treatment with major clinical benefits as an example of genomics-guided treatment.

Acrodermatitis Enteropathica Presenting with Recurrent Diarrhea and Vomiting in an Infant Reluctant to Breastfeed, and a Peculiar Erythemato-Eczematous Eruption around the Oral and Anogenital Regions.

A 6-month-old, 4-kg, dehydrated girl, an Indian native, was admitted with recurrent episodes of diarrhea that had occurred since age 2 months. She had stopped breastfeeding. She had also had concomitant vomiting and loss of appetite. Later, the mother noticed progressively increasing erythematous eruptions around the anogenital and the oral region. The baby had been born to a short-stature mother and was delivered by lower segment cesarean section. Regular antenatal follow-up was normal.

Tatami Mats: A Source of Pitted Keratolysis in a Martial Arts Athlete?

Dear Editor, Pitted keratolysis (PK), also known as keratosis plantaris sulcatum, is a non-inflammatory, bacterial, superficial cutaneous infection, characterized by many discrete superficial crateriform ''pits'' and erosions in the thickly keratinized skin of the weight-bearing regions of the soles of the feet (1). The disease often goes unnoticed by the patient, but when it is noticed it is because of the unbearable malodor and hyperhidrosis of the feet, which are socially unacceptable and cause great anxiety to many of the patients. PK occurs worldwide, with the incidence rates varying based on the environment and occupation. The prevalence of this condition does not differ significantly based on age, sex, or race. People who sweat profusely or wash excessively, who wear occlusive footwear, or are barefoot especially in hot and humid weather are extremely prone to this condition (2). Physicians commonly misdiagnose it as tinea pedis or plantar warts. Treatment is quite simple and straightforward, with an excellent expected outcome if treated properly. We report a case of a 32-year-old male patient with skin changes of approximately one-year duration diagnosed as plantar verrucae, who was referred to our Department for cryotherapy. The patient presented with asymptomatic, malodorous punched-out pits and erosions along with hyperkeratotic skin on the heel and metatarsal region of the plantar aspect of both feet. The arches, toes, and sides of the feet were spared (Figure 1). Except for these skin changes, the patient was healthy and denied any other medical issues. He was an athlete active in martial arts and had a history of sweating of feet and training barefoot on the tatami mat for extended periods of time. The diagnosis of PK was established based on the clinical findings (crateriform pitting and malodor), negative KOH test for hyphae, and a history of prolonged sweating in addition to contact of the skin with tatami mats, which are often a source of infection if hygiene measures are not adequately implemented. Swabs could have been helpful to identify causative organisms, but they were not crucial for the diagnosis and treatment. The patient was prescribed with general measures to prevent excessive sweating (cotton socks, open footwear, and proper hygiene), antiseptic potassium permanganate foot soaks followed by clindamycin 1% and benzoyl peroxide 5% in a gel vehicle twice daily. At the one-month follow-up visit, the skin changes, hyperhidrosis, and malodor were entirely resolved (Figure 2). Pitted keratolysis is common among athletes (3,4). The manifestations of PK are due to a superficial cutaneous infection caused by several bacterial Gram-positive species including Corynebacterium species, Kytococcus sedentarius, Dermatophilus congolensis, Actynomices keratolytica, and Streptomyces that proliferate and produce proteinase and sulfur-compound by-products under appropriate moist conditions (5-7). Proteinases digest the keratin and destroy the stratum corneum, producing the characteristic skin findings, while sulfur compounds (sulfides, thiols, and thioesters) are responsible for the malodor. Athletes and soldiers who wear occlusive footwear for prolonged periods of time or even barefooted people that sweat extensively and spend time on wet surfaces such as laborers, farmers, and marine workers are more prone to this problem (3,4,8-11). Martial arts athletes are at greater risk of skin infections due to the constant physical contact that can lead to transmission of viral, bacterial, and fungal pathogens directly but also indirectly through contact with the mat and the skin flora of an another infected individual. A national survey of the epidemiology of skin infections among US high school athletes conducted by Ashack et al. supported the prevalent theory that contact sports are associated with an increased risk of skin infections. In this study, wrestling had the highest skin infection rate of predominantly bacterial origin (53.8%), followed by tinea (35.7%) and herpetic lesions (6.7%), which is consistent with other literature reporting (12). Being barefoot on the tatami mat in combination with excessive sweating and non-compliance with hygiene measures makes martial arts athletes more susceptible to skin infections, including PK. The diagnosis is clinical, by means of visual examination and recognition of the characteristic odor. Dermoscopy can be useful, revealing abundant pits with well-marked walls that sometimes show the bacterial colonies (13). Cultures, if taken, show Gram-positive bacilli or coccobacilli. Because of the ease of diagnosis on clinical findings, biopsy of pitted keratolysis is rarely performed. Skin scraping is often performed to exclude tinea pedis, which is one of the main differential diagnosis, the others including verrucae, punctate palmoplantar keratoderma, keratolysis exfoliativa, circumscribed palmoplantar hypokeratosis, and basal cell nevus syndrome. If unrecognized and left untreated, skin findings and smelly feet can last for many years. Sometimes, if unrecognized, PK can be mistreated with antifungals, or even with aggressive treatment modalities such as cryotherapy. Appropriate treatment includes keeping feet dry with adequate treatment of hyperhidrosis, preventive measures, and topical antibiotic therapy. Topical forms of salicylic acid, sulfur, antibacterial soaps, neomycin, erythromycin, mupirocin, clindamycin and benzoyl peroxide, clotrimazole, imidazoles, and injectable botulinum toxin are all successful in treatment and prevention of PK (14,15). Topical antibiotics are the first line of medical treatment, among which fusidic acid, erythromycin 1% (solution or gel), mupirocin 2%, or clindamycin are the most recommended (14). As in our case, a fixed combination of two approved topical drugs - clindamycin 1%-benzoyl peroxide 5% gel, had been already demonstrated by Vlahovich et al. as an excellent treatment option with high adherence and no side-effect (16). The combined effect of this combination showed significantly greater effect due to the bactericidal and keratolytic properties of benzoyl peroxide. Additionally, this combination also lowers the risk of resistance of causative microorganisms to clindamycin. Skin infections are an important aspect of sports-related adverse events. Due to the interdisciplinary nature, dermatologists are not the only ones who should be aware of the disease, but also family medicine doctors, sports medicine specialists, and occupational health doctors who should educate patients about the etiology of the skin disorder, adequate prevention, and treatment. Athletes must enforce the disinfecting and sanitary cleaning of the tatami mats and other practice areas. Keeping up with these measures could significantly limit the spread of skin infections that can infect athletes indirectly, leading to significant morbidity, time loss from competition, and social anxiety as well.

Acrodermatitis enteropathica: the need for sustained high dose zinc supplementation.

Acrodermatitis enteropathica (AE) is a rare congenital disorder owing to an abnormality with intestinal absorption and/or transportation of zinc. We describe two male siblings, who presented with evidence of both acute and chronic zinc deficiency, despite being diagnosed with AE very early in life. We wish to highlight the importance of sustained high-dose zinc supplementation and regular monitoring in AE cases. Proper counselling of parents about the need for life long supplementation and increasing requirements with age is essential.

AcroangiodermatitisA Presentation of Two Cases of Nonhealing Ulcerations in the Lower Extremity.

Acroangiodermatitis (AAD), also known as pseudo-Kaposi's sarcoma, is an uncommon benign angioproliferative condition most commonly seen in the lower extremities. This condition often presents as discolored patches that progress to painful ulcerations. The list of vascular conditions associated with this diagnosis is vast. Acroangiodermatitis presents similarly to more aggressive conditions such as Kaposi's sarcoma, making histopathologic examination helpful in its diagnosis. We present two cases of AAD in the setting of chronic venous insufficiency.

Itch Management in Childhood.

Itch in children is a very common symptom and is mainly related to a skin disease rather than an underlying systemic disorder. The most common dermatoses include atopic dermatitis, contact dermatitis, insect bites, scabies, and pediculosis capitis. There are specific diagnostic patterns which require the evaluation of a careful history and dermatological examination. For dermatological treatment, we have to consider that children, especially infants, show differences in physiology and pathophysiology, and also in pharmacokinetics and pharmacodynamics compared with adults.

Acrodermatitis dysmetabolica in an infant with maple syrup urine disease.

Acrodermatitis dysmetabolica (AD) is a rare, newly termed, and poorly understood disease that appears to be clinically similar to acrodermatitis enteropathica (AE). Both diseases are characterized by the triad of periorificial and acral dermatitis, diarrhoea, and alopecia. Unlike AE, which is caused by zinc deficiency, AD is caused by numerous metabolic disorders. One such disorder is maple syrup urine disease (MSUD), a genetic deficiency of branched chain α-ketoacid dehydrogenase, the enzyme that degrades the branched-chain amino acids (BCAAs) isoleucine, leucine and valine. Treatment involves restricting BCAAs to prevent accumulation. We report a case of an infant being treated for MSUD, who developed the triad of AE/AD after a period of poor BCAA formula intake. The child was found to have low isoleucine and normal zinc levels. Increasing the isoleucine dose improved the eruption, thus the diagnosis of AD secondary to isoleucine deficiency was made. This case emphasizes the importance of carefully balancing BCAA levels while treating MSUD, as deficiency can precipitate AD.

Acrodermatitis Dysmetabolica in a Child with Cystic Fibrosis.

Acrodermatitis dysmetabolica is an umbrella term encompassing the other metabolic causes of an erosive periorificial and acral dermatitis that mimics acrodermatitis enteropathica. Causes include acquired zinc, amino acid, biotin, and fatty acid deficiencies. We present the case of an exclusively breastfed, 2-month-old boy with known cystic fibrosis admitted with failure to thrive and erosive dermatitis. A diagnosis of acrodermatitis dysmetabolica was made when investigations revealed a normal zinc level but low amino acid levels.

Acropigmentación reticulada de Dohi: revisión de genodermatosis con pigmentación reticular a partir de un caso clínico / Reticulated acropigmentation of Dohi: review of genodermatosis with reticular pigmentation

La acropigmentación reticulada de Dohi (ARD) o discromía simétrica hereditaria se encuentra dentro de los desórdenes con pigmentación reticular hereditaria. Es una rara entidad que se describió por primera vez en 1929 en Japón por Toyama. Presenta herencia autosómica dominante y el gen responsable se encuentra en el cromosoma 1q21 que codifica para una proteína ARN-adenosina desaminasa (ADAR1 o DSRAD). A pesar, que es un desorden benigno y no reviste complicaciones suele ser estéticamente desfigurante. A continuación, se presenta un caso clínico y se realizará una revisión de la literatura de los otras genodermatosis con pigmentación reticular.

Hereditary symmetric dyschromatosis, also known as reticulated acropigmentation of Dohi is included within a spectrum of reticulate pigment disorders of the skin. It’s a pigmentary disorder characterized by the presence of hypopigmented and hyperpigmented macules giving a reticular pattern in acral areas. It is a rare entity first described in 1929 by Toyama in Japan. It has autosomal dominant inheritance and the responsible gene codes for an RNA adenosine deaminase protein (ADAR1 or dsRAD) on chromosome 1q21. Although, it`s a benign disorder, it can be aesthetically disfiguring. We present a case report and review of the literature of genodermatosis with reticular pigmentation.

SLC39A4 mutation in zinc deficiency patients.

OBJECTIVE: To analyze the clinical presentation and SLC39A4 mutations in zinc deficiency patients. MATERIAL AND METHOD: The authors conducted a cross-sectional study on all cases of zinc deficiency treated at Queen Sirikit National Institute of Child Health between January 2004 and December 2012. Demographic data, clinical manifestations, laboratory results, treatment and outcome were analyzed. Genetic, SLC39A4 for acrodermatitis enteropathic (AE), mutation analysis was performed in all cases. RESULTS: There were 15 cases, 10 males and 5 females. The age of onset was between 2 and 10 months (median 3 months). Duration of the disease ranged between 3 days and 17 months (median 2 months). Acral and periorificial dermatitis, diarrhea and alopecia were present in 15 cases (100%), 12 cases (80%) and 8 cases (53%) respectively. The characteristic triad of acral and periorificial dermatitis, diarrhea and alopecia was observed in only 6 patients (40%). Serum zinc level ranged between 10 and 111 mcg/dl (mean 49.69 ± 33.87 mcg/100 ml). Low serum zinc level was observed in 10 cases (67%). All of the patients were treated with zinc sulfate 5 mg/kg/day. All cutaneous lesions and diarrhea had resolved within 7 days of starting therapy. A genetic study of SLC39A4 gene in our 15 patients revealed that 3 patients had homozygous c.1878_1879ins21 (p.G627_T633dup) in exonl2. These three patients have to receive lifelong zinc supplementation to prevent recurrence of the disease. The other twelve patients, who did not carry the gene mutation, did not have symptoms after discontinuance of oral zinc therapy. This is the first report of genetically confirmed acrodermatitis enteropathic in Thailand. CONCLUSION: Acrodermatitis enteropathica is a rare disease, which needs lifelong zinc supplementation. A genetic study of SLC39A4 gene will confirm the diagnosis. Most of patients presenting with characteristic triad of acral and periorificial dermatitis, diarrhea and alopecia in Thailand were acquired zinc deficiency. Early recognition and treatment of the disease will decrease morbidity and mortality.

Non-healing ulcer on the foot: early onset unilateral Mali-type acroangiodermatitis.

Acroangiodermatitis (pseudo-Kaposi's sarcoma, AAD) is a benign vascular dermatosis that resembles Kaposi's sarcoma clinically and histopathologically (1). Four types have been defined: the Stewart-Bluefarb type accompanying chronic arteriovenous malformations, the Mali type accompanying stasis dermatitis, a type accompanying the first gestation, and a type accompanying arteriovenous shunts in patients with chronic kidney failure (3). Although AAD development is associated with chronic venous failure, less frequently AAD can develop as a complication of extremity paralysis, hemodialysis, post-traumatic arteriovenous fistula, amputated extremities, and vascular malformations (e.g., Klippel-Trénaunay syndrome). Pseudo-Kaposi's sarcoma can be histopathologically and clinically confused with malignant diseases such as Kaposi's sarcoma (1, 4). A 22-year-old male was referred to our outpatient clinic with a complaint of a non-healing wound on the distal phalanx of the left first toe. The patient was referred to various centers for 2 years and stated that he had received infection treatments but that his complaints did not disappear. An AAD diagnosis was established for the patient based on clinical and histopathologic evidence. Because he had early-onset disease and it was unilateral, the diagnosis was delayed. In addition, due to the rare occurrence of the disease, we histopathologically diagnosed this patient as having acroangiodermatitis.