Successful treatment of acrodermatitis continua of Hallopeau coexisting with generalized pustular psoriasis with spesolimab: a case report.

Generalized pustular psoriasis (GPP) is a rare chronic inflammatory pustular dermatosis that presents as painful erythema with sterile pustules on nonacral skin. No unified standard and guideline for the treatment of GPP has been established. Several biologics have been tried for GPP, with varying success. Acrodermatitis continua of Hallopeau (ACH) is a very rare disabling variant of pustular psoriasis characterized by sterile pustules on the fingers and toes, including the nail bed. Comparatively, treating ACH is highly challenging due to its commonly therapy-resistant disease course. The pathogenic role of IL-36 signaling axis has been currently identified in GPP development. Spesolimab, the first anti-interleukin-36 receptor biologic, has been approved for treating GPP flares and shown promising results. In view of a shared pathogenesis between GPP and ACH, specolimab may be an effective treatment for ACH. Currently, there is no case and clinical trial data exist on this condition. Therefore, this case was aim to describe real-world experience of spesolimab use in ACH coexisting with GPP. We report an Asian patient with a 16-year-history of GPP and ACH with marked pustulosis on the nail bed and onychodystrophy. He received conventional systemic regimen acitretin, cyclosporine and biologics adalimumab and secukinumab, but experienced relapse for skin lesions and refractory for nail lesions. He was then treated with a single dose of spesolimab in combination with secukinumab, which resulted in skin clearance and nearly complete resolution of nail lesions over a 32-week period. Our observation suggests that spesolimab should be considered for the treatment of ACH, especially in the patients with intractable nail lesions and concomitant GPP.

A retrospective analysis of 65 patients with acrodermatitis continua of Hallopeau.

There are limited data on acrodermatitis continua of Hallopeau (ACH), particularly among Asian populations. The primary aim was to evaluate the clinical features of ACH and treatment approaches in a sizeable multicentre Asian cohort. We analysed data from adult patients diagnosed with ACH. Of 65 patients with ACH, seven patients had ACH with GPP. Females were more frequently affected in both conditions. Five (71.4%) developed GPP 5-33 years after ACH onset, while two (28.6%) developed GPP concurrently with ACH. The onset age for ACH with GPP (27.9 ± 13.6 years) was earlier than that of isolated ACH (39.8 ± 17.3 years). Metabolic comorbidities were common. ACH exhibited a chronic persistent course. Among systemic non-biologics, acitretin was the most frequently prescribed, followed by ciclosporin and methotrexate. Acitretin and ciclosporin demonstrated similar marked response rates, which surpassed that of methotrexate. Regarding biologics, a marked response was more commonly observed with interleukin-17 inhibitors than with tumour necrosis factor inhibitors. Females are predominant in both conditions. The onset age for ACH among Asian patients is earlier (late 30s) than that for Caucasian patients (late 40s). Interleukin-17 inhibitors may be more effective than tumour necrosis factor inhibitors in managing ACH.

Acrodermatitis continua of Hallopeau and generalised pustular psoriasis: Should they be the same or different entities?

Pustular psoriasis is characterised by eruptions of neutrophilic sterile pustules. The European Rare and Severe Psoriasis Expert Network consensus defines pustular psoriasis into three subtypes; generalised pustular psoriasis (GPP), palmoplantar pustulosis and acrodermatitis continua of Hallopeau (ACH). Mixed forms are categorised according to their predominant features. However, the Japanese Dermatological Association includes ACH under the diagnosis of GPP. This article aims to review the similarities and differences between ACH and GPP. Based on our review, interleukin (IL)-36RN mutations, the most frequent genetic findings in pustular psoriasis are found most commonly in GPP, followed by ACH. Genotypes of IL-36RN mutations among GPP patients and ACH patients are different between European and Asian ethnicities. IL-36 signalling pathway is the main mechanism. Metabolic diseases are common comorbidities and joint involvement can occur in 20.5%-36.4% of both conditions. Associated plaque psoriasis is more common in GPP than in ACH. Generally, ACH, even the generalised type, does not have systemic inflammation whereas GPP can occur with or without systemic inflammation. ACH can occur before, simultaneously, or after the development of GPP. However, response to treatment for GPP and ACH even in the same patients appear to be different. ACH seemed to be more recalcitrant to treatment than GPP but severe flare of GPP can lead to morbidity and mortality. Although GPP and ACH share genotypes and pathogenesis, we believe that ACH should be classified separately from GPP, and not under diagnosis of GPP. Future research is warranted to satisfactorily distinguish the two conditions.

Enterokinase deficiency with novel TMPRSS15 gene mutation masquerading as acrodermatitis enteropathica.

Enterokinase deficiency (EKD) is a rare autosomal recessive inherited disorder caused by loss-of-function mutations of the transmembrane protease serine 15 (TMPRSS15) gene. To date, only 12 cases of EKD have been described in the literature and skin involvement has seldom been described. We identified a novel homozygous nonsense mutation in the TMPRSS15 gene (c.1216C>T, p.R406*) in a female infant, who manifested with acrodermatitis enteropathica (AE)-like lesions that were dramatically relieved within 11 days after initiation of a protein-rich hydrolyzed formula. Our case shows that AE-like rashes can be a manifestation of EKD and expands the spectrum of causative mutations in the TMPRSS15 gene.

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A girl, aged 11 years, was admitted due to recurrent rash on the whole body and mucosa for 10 years, and typical rash was erythema at the perioral region, hand-foot joints, vulva, and perianal region, with blisters, erosions, and ulcers on the erythema. The girl was improved after zinc supplementation. Her younger brother had similar rash and medical history. The histopathological examination showed epidermal parakeratosis with mild hyperkeratosis, severe spongiform edema of the stratum corneum, significant proliferation of acanthocytes, and vacuolation of keratinocytes. The genetic testing revealed that both the girl and her younger brother had a homozygous mutation of c.1456(exon9)delG in the SLC39A4 gene, and thus the girl was diagnosed with acrodermatitis enteropathica. It is concluded that for children with recurrent rash on the limbs and at the perioral region, genetic testing should be performed as early as possible to make a confirmed diagnosis, and a sufficient dose of zinc supplementation should be given, while the levels of trace elements such as blood zinc should be regularly monitored.

Acroangiodermatitis presenting as unilateral hypertrophic verrucous plaques.

Acroangiodermatitis (AAD)[KL1] is a rare vasoproliferative disorder often involving the extremities that has been classified into two variants. Mali-type AAD is more common and associated with chronic venous stasis. Stewart-Bluefarb syndrome[KL2], the other variant, is associated with underlying arteriovenous abnormalities. Mali-type AAD is a relatively benign diagnosis but it may mimic more harmful etiologies such as Kaposi sarcoma both clinically and histologically. A 67-year-old woman with a history of varicose veins, deep vein thrombosis, stroke, and obesity presented to our outpatient clinic with verrucous red-brown papules and plaques on her right lower extremity worsening for three years. Biopsy was consistent with a diagnosis of Mali-type AAD. Providers should be aware of AAD and its variants to accurately differentiate it from more harmful entities.

Oral adverse events due to zinc deficiency after pancreaticoduodenectomy requiring continuous intravenous zinc supplementation: a case report and literature review.

BACKGROUND: Zinc is mainly absorbed in the duodenum and proximal jejunum, which are removed during pancreaticoduodenectomy (PD). Little is known about the adverse oral events and skin disorders caused by zinc deficiency after PD. Herein, we reviewed studies on the development of zinc deficiency after PD and reported about a patient with zinc deficiency after PD who required home intravenous zinc replacement. CASE PRESENTATION: A 73-year-old woman with glossitis, taste disorder, and acrodermatitis enteropathica-like eruption on her fingers presented to the Division of Dentistry and Oral Surgery 69 days after PD. Her serum zinc level markedly decreased to 30 µg/dL. Oral zinc administration was inadequate to treat hypozincemia after PD; therefore, multi-trace elements were injected intravenously during readmission. Her serum zinc levels recovered, and her lesions gradually improved. Furthermore, a central venous port was implanted to maintain normal serum zinc levels, and she continued self-injecting zinc at home. CONCLUSIONS: Zinc deficiency after PD rarely occurs. The clinical oncologist community, including dentists responsible for the oral care of cancer patients, should be aware of the oral adverse events, such as dysgeusia, glossitis, and oral pain, associated with zinc deficiency after cancer surgery and that induced by chemotherapy or head and neck radiation therapy.

A persistent plaque on the back of the hand.

We report the case of a 75-year-old woman presenting with acrodermatitis chronica atrophicans affecting the right hand dorsum, developing after an insect bite sustained in Greece. Diagnosis was confirmed by serology, PCR and histopathological findings. The plaque resolved following a 3-week course of oral doxycycline. Click https://www.wileyhealthlearning.com/#/online-courses/4ebea04b-e4de-49d3-9bbb-0d3355007e92 for the corresponding questions to this CME article.

Acquired Acrodermatitis Enteropathica in an Infant.

Acrodermatitis enteropathica (AE) is an acquired or inborn (congenital) disorder of zinc metabolism that leads to zinc deficiency. The congenital form typically presents in infants during the first few months of life when they are weaned from breast milk, presenting even earlier in those who are formula fed. Acquired deficiency may be seen at any age. The characteristic clinical features of AE include erythematous, dry, scaly papules and plaques that may evolve into crusted, erosive, pustular lesions. These lesions typically are distributed in an acral and periorificial pattern and are associated with alopecia and diarrhea. Evidence-based recommendations are sparse but generally indicate 3 mg/kg/d of oral zinc supplementation for both congenital and acquired AE. Appropriate dosing helps to avoid acute zinc toxicity involving nausea and vomiting. We report a case of a 3-month-old female infant with acquired AE who was successfully treated with zinc supplementation over the course of 3 weeks.

A Missense Variant in SLC39A4 in a Litter of Turkish Van Cats with Acrodermatitis Enteropathica.

In a litter of Turkish Van cats, three out of six kittens developed severe signs of skin disease, diarrhea, and systemic signs of stunted growth at 6 weeks of age. Massive secondary infections of the skin lesions evolved. Histopathological examinations showed a mild to moderate hyperplastic epidermis, covered by a thick layer of laminar to compact, mostly parakeratotic keratin. The dermis was infiltrated with moderate amounts of lymphocytes and plasma cells. Due to the severity of the clinical signs, one affected kitten died and the other two had to be euthanized. We sequenced the genome of one affected kitten and compared the data to 54 control genomes. A search for private variants in the two candidate genes for the observed phenotype, MKLN1 and SLC39A4, revealed a single protein-changing variant, SLC39A4:c.1057G>C or p.Gly353Arg. The solute carrier family 39 member 4 gene (SLC39A4) encodes an intestinal zinc transporter required for the uptake of dietary zinc. The variant is predicted to change a highly conserved glycine residue within the first transmembrane domain, which most likely leads to a loss of function. The genotypes of the index family showed the expected co-segregation with the phenotype and the mutant allele was absent from 173 unrelated control cats. Together with the knowledge on the effects of SLC39A4 variants in other species, these data suggest SLC39A4:c.1057G>C as candidate causative genetic variant for the phenotype in the investigated kittens. In line with the human phenotype, we propose to designate this disease acrodermatitis enteropathica (AE).

Zinc transporter mutations linked to acrodermatitis enteropathica disrupt function and cause mistrafficking.

ZIP4 is a representative member of the Zrt-/Irt-like protein (ZIP) transporter family and responsible for zinc uptake from diet. Loss-of-function mutations of human ZIP4 (hZIP4) drastically reduce zinc absorption, causing a life-threatening autosomal recessive disorder, acrodermatitis enteropathica (AE). These mutations occur not only in the conserved transmembrane zinc transport machinery, but also in the extracellular domain (ECD) of hZIP4, which is only present in a fraction of mammalian ZIPs. How these AE-causing ECD mutations lead to ZIP4 malfunction has not be fully clarified. In this work, we characterized all seven confirmed AE-causing missense mutations in hZIP4-ECD and found that the variants exhibited completely abolished zinc transport activity in a cell-based transport assay. Although the variants were able to be expressed in HEK293T cells, they failed to traffic to the cell surface and were largely retained in the ER with immature glycosylation. When the corresponding mutations were introduced in the ECD of ZIP4 from Pteropus Alecto, a close homolog of hZIP4, the variants exhibited structural defects or reduced thermal stability, which likely accounts for intracellular mistrafficking of the AE-associated variants and as such a total loss of zinc uptake activity. This work provides a molecular pathogenic mechanism for AE.

Acrodermatitis chronica atrophicans: clinical and microbiological characteristics of a cohort of 693 Slovenian patients.

BACKGROUND: Information on large groups of patients with acrodermatitis chronica atrophicans (ACA) is limited. METHODS: We assessed clinical and microbiological characteristics of patients with ACA diagnosed at a single medical centre and compared findings in periods 1991-2004 vs. 2005-2018. The cohort is representative of Slovenian ACA patients. RESULTS: We assessed 693 patients: 461 females and 232 males, with median age of 64 years. Median duration of ACA before diagnosis was 12 months. In all but 2 patients, the skin lesions were located on extremities, more often on the lower (70.0%) than the upper (45.2%), bilaterally in 42.4%. Reddish-blue discoloration, swelling, thinning and wrinkling of skin were present in 95.2%, 28.1%, 46.4% and 20.5% of patients, respectively. Overall, 64.4% of patients reported constitutional symptoms, 23.1% had local symptoms, and 20.8% had symptoms/signs of peripheral neuropathy. Nodules, arthritis, joint deformity, muscle atrophy and paresis were rare (<3%). Borreliae were isolated from 200/664 (30.1%) skin samples; 92.8% were Borrelia afzelii. B. garinii and B. burgdorferi s.s. were more often isolated from the skin of male patients (OR = 4.17) and from those with arthropathy (OR = 11.74). Patients included in the more recent period were older, complained less often of constitutional symptoms but more often of local symptoms, and more often had local swelling but less often skin atrophy and bilateral involvement, probably as a consequence of earlier diagnosis. CONCLUSIONS: ACA, typically caused by B. afzelii, usually affects older women. Clinical presentation depends on the duration of illness and probably on the Borrelia species causing the disease.

Skin Manifestations Associated with COVID-19: Current Knowledge and Future Perspectives.

BACKGROUND: Coronavirus disease-19 (COVID-19) is an ongoing global pandemic caused by the "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2), which was isolated for the first time in Wuhan (China) in December 2019. Common symptoms include fever, cough, fatigue, dyspnea and hypogeusia/hyposmia. Among extrapulmonary signs associated with COVID-19, dermatological manifestations have been increasingly reported in the last few months. SUMMARY: The polymorphic nature of COVID-19-associated cutaneous manifestations led our group to propose a classification, which distinguishes the following six main clinical patterns: (i) urticarial rash, (ii) confluent erythematous/maculopapular/morbilliform rash, (iii) papulovesicular exanthem, (iv) chilblain-like acral pattern, (v) livedo reticularis/racemosa-like pattern, (vi) purpuric "vasculitic" pattern. This review summarizes the current knowledge on COVID-19-associated cutaneous manifestations, focusing on clinical features and therapeutic management of each category and attempting to give an overview of the hypothesized pathophysiological mechanisms of these conditions.