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Central conducting lymphatic anomaly (CCLA) due to congenital maldevelopment of the lymphatics can result in debilitating and life-threatening disease with limited treatment options. We identified 4 individuals with CCLA, lymphedema, and microcystic lymphatic malformation due to pathogenic, mosaic variants in KRAS. To determine the functional impact of these variants and identify a targeted therapy for these individuals, we used primary human dermal lymphatic endothelial cells (HDLECs) and zebrafish larvae to model the lymphatic dysplasia. Expression of the p.Gly12Asp and p.Gly13Asp variants in HDLECs in a 2‑dimensional (2D) model and 3D organoid model led to increased ERK phosphorylation, demonstrating these variants activate the RAS/MAPK pathway. Expression of activating KRAS variants in the venous and lymphatic endothelium in zebrafish resulted in lymphatic dysplasia and edema similar to the individuals in the study. Treatment with MEK inhibition significantly reduced the phenotypes in both the organoid and the zebrafish model systems. In conclusion, we present the molecular characterization of the observed lymphatic anomalies due to pathogenic, somatic, activating KRAS variants in humans. Our preclinical studies suggest that MEK inhibition should be studied in future clinical trials for CCLA due to activating KRAS pathogenic variants.

Nail unit melanoma (NUM) is an uncommon form of melanoma and is often diagnosed at later stages. Approximately two-thirds of NUMs are present clinically as longitudinal melanonychia, but longitudinal melanonychia has a broad differential diagnosis. Clinical examination and dermoscopy are valuable for identifying nail findings concerning malignancy, but a biopsy with histopathology is necessary to confirm a diagnosis of NUM. Surgical treatment options for NUM include en bloc excision, digit amputation, and Mohs micrographic surgery. Newer treatments for advanced NUM include targeted and immune systemic therapies. NUM in pediatric patients is extremely rare and diagnosis is challenging since both qualitative and quantitative parameters have only been studied in adults. There is currently no consensus on management in children; for less concerning melanonychia, some physicians recommend close follow-up. However, some dermatologists argue that the "wait and see" approach can cause delayed diagnosis. This article serves to enhance the familiarity of NUM by highlighting its etiology, clinical presentations, diagnosis, and treatment options in both adults and children.

Infantile digital fibromatosis (IDF), or inclusion body fibromatosis, is a rare benign tumor that commonly presents as a solitary nodule composed of spindle cells within the dermis on the digits of infants and children. Evaluation often includes a biopsy and typical therapies include observation, intralesional corticosteroid injections, and complete surgical resection. Given the rarity of IDF, few clinicians have direct or extensive experience diagnosing or treating it. Here we present a comprehensive review of the presentation, diagnosis, and treatment for IDF., Competing Interests: Joy Wan has received research and fellowship funding from Pfizer, Inc. for work unrelated to this manuscript., (Copyright © 2022 by S. Karger AG, Basel.)

Context.—: Acral lentiginous melanoma is a rare and aggressive type of cutaneous melanoma that arises on the acral skin and the nail unit. The prognostic significance of subungual anatomic site in acral lentiginous melanoma is not established., Objective.—: To assess the impact of subungual anatomic site on overall survival and disease-specific survival in acral lentiginous melanoma., Design.—: Retrospective cohort analysis. Clinicopathologic characteristics of 627 primary acral lentiginous melanomas (45 [7%] subungual and 582 [93%] nonsubungual) were summarized, and the impact of these characteristics on overall survival and disease-specific survival was determined using univariate and multivariable analyses., Results.—: No significant differences in clinicopathologic features were identified between the subungual and nonsubungual acral lentiginous melanomas. The 1-, 5-, and 10-year overall survival rates were 81%, 40%, and 28%, respectively, for subungual acral lentiginous melanoma and 94%, 59%, and 38%, respectively, for nonsubungual acral lentiginous melanoma (P = .04); risk of death was significantly higher for subungual tumors (hazard ratio [95% confidence interval] = 1.59 [1.02-2.50]; P = .04). The 1-, 5-, and 10-year disease-specific survival rates were 94%, 56%, and 48%, respectively, for subungual acral lentiginous melanoma versus 96%, 69%, and 55%, respectively, for nonsubungual acral lentiginous melanoma (P = .18). By multivariable analysis, independent poor prognostic factors included older age and ulceration for overall survival and greater Breslow thickness and sentinel lymph node positivity for overall survival and disease-specific survival. Subungual anatomic site was not an independent prognostic factor for overall or disease-specific survival., Conclusions.—: Subungual anatomic site is not an independent prognostic factor for acral lentiginous melanoma., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article at https://meridian.allenpress.com/aplm in the August 2021 table of contents.

Nail plate brittleness (or fragility) is a common complaint affecting up to 20% of the population, especially women over 50 years of age, with fingernail fragility being more prevalent than toenail fragility. Nail brittleness is characterized by nails that split, flake and crumble, become soft and lose elasticity. The main clinical presentations are: onychoschizia, onychorrhexis, superficial granulation of keratin and worn-down nails. According to causative factors, we can distinguish 2 forms of nail fragility (NF): a primary "idiopathic or brittle nail syndrome" form and NF secondary to different causes such as inflammatory nail disorders, infections, systemic diseases and general conditions, traumas and alteration of the nail hydration. Optimal management requires treatment of the primary cause of brittle nails, when possible. In idiopathic NF oral supplementation, vitamins (especially biotin, also known as vitamin B7), trace elements and amino acids (especially cysteine) have been reported to be useful. In addition, several products, such as topical moisturizers and lacquers could be considered to restructure the affected nail plate and to reduce psychological impacts of this common problem.

Human WNT10A mutations are associated with developmental tooth abnormalities and adolescent onset of a broad range of ectodermal defects. Here we show that β-catenin pathway activity and adult epithelial progenitor proliferation are reduced in the absence of WNT10A, and identify Wnt-active self-renewing stem cells in affected tissues including hair follicles, sebaceous glands, taste buds, nails and sweat ducts. Human and mouse WNT10A mutant palmoplantar and tongue epithelia also display specific differentiation defects that are mimicked by loss of the transcription factor KLF4. We find that β-catenin interacts directly with region-specific LEF/TCF factors, and with KLF4 in differentiating, but not proliferating, cells to promote expression of specialized keratins required for normal tissue structure and integrity. Our data identify WNT10A as a critical ligand controlling adult epithelial proliferation and region-specific differentiation, and suggest downstream β-catenin pathway activation as a potential approach to ameliorate regenerative defects in WNT10A patients.

Trachyonychia is a disorder of the nail unit that most commonly presents with rough, longitudinally ridged nails (opaque trachyonychia) or less frequently, uniform, opalescent nails with pits (shiny trachyonychia). The term trachyonychia refers to 'rough nails.' This article comprehensively reviews the clinical, histologic, and therapeutic aspects of trachyonychia. The authors' preferred evaluation and management strategies of trachyonychia are included.

Background: Diffuse large B-cell lymphoma (DLBCL) typically leads to effacement of the nodal architecture by an infiltrate of malignant cells. Rarely (<1%), DLBCL can present with an interfollicular pattern (DLBCL-IF) preserving the lymphoid follicles. It has been postulated that DLBCL-IF is derived from marginal zone B cells and may represent a large-cell transformation of marginal zone lymphoma (MZL), however no direct evidence has been provided to date. Here we describe a rare case of a diagnostically challenging DLBCL-IF involving a lymph node in a patient with a prior history of lymphadenopathy for several years and MZL involving skin., Case Presentation: A 53-year old man presented to our Dermatology Clinic due to a 1-year history of generalized itching, fatigue of 2-3 month's duration, nausea and mid back rash that was biopsied. PET (positron emission tomography)/CT (computed tomography) was performed and revealed inguinal, pelvic, retroperitoneal, axillary, and cervical lymphadenopathy. The patient was referred to surgery for excisional biopsy of a right inguinal lymph node. Diagnostic H&E stained slides and ancillary studies were reviewed for the lymph node and skin specimens. B-cell clonality by PCR and sequencing studies were performed on both specimens. We demonstrate that this patient's MZL and DLBCL-IF are clonally related, strongly suggesting that transformation of MZL to DLBCL had occurred. Furthermore, we identified a novel deletion of the long arm of chromosome 20 (del(20q12)) and a missense mutation in BIRC3 (Baculoviral IAP repeat-containing protein 3) in this patient's DLBCL that are absent from his MZL, suggesting that these genetic alterations contributed to the large cell transformation., Conclusions: To our knowledge, this is the first report providing molecular evidence for a previously suspected link between MZL and DLBCL-IF. In addition, we describe for the first time del(20q12) and a missense mutation in BIRC3 in DLBCL. Our findings also raise awareness of DLBCL-IF and discuss the diagnostic pitfalls of this rare entity.

Junctional epidermolysis bullosa with pyloric atresia (JEB-PA) is an autosomal recessive blistering disease including lethal and non-lethal variants due to mutations in ITGB4 and ITGA6. It is unclear whether PA is caused directly by the mutations in these genes or by other factors. Skin biopsies from patients with JEB were processed for immunofluorescence mapping. When staining for integrin beta4 or alpha6 was absent or reduced, ITGB4 was screened for mutations. A review of known mutations of ITGB4 and the phenotypes of patients with JEB-PA was undertaken. Three novel ITGB4 mutations were identified in 3 families with JEB-PA: 2 splice-site and one insertion mutation. Two families with lethal phenotypes (EB-050 and EB-049) were due to combinations of premature termination codons and missense mutations (658delC/R252C and 3903dupC/G273D, respectively). The third family EB-013 has 2 JEB affected siblings; a brother with PA and a sister without PA. Both were homo notzygous for ITGB4 264G>A/3111-1G>A. Two cases had no gastrointestinal symptoms or signs of PA. PA is an inconstant feature of the subtype of epidermolysis bullosa known as JEB-PA. It is most likely that multiple factors influence the development of PA and its presence is not predictive of a poor outcome. It is possible that institutions that do not routinely screen immunofluore notscence mapping for integrin alpha6beta4 staining in the absence of PA are missing this form of epidermolysis bullosa.