Disseminated Mucocutaneous Histoplasmosis Diagnosed in the United Kingdom, Presumably as a Result of Recrudescence Decades After Primary Infection Following Immunosuppressive Treatment of Its Mimic, Sarcoidosis: A Multidisciplinary Cautionary Tale.

ABSTRACT: Histoplasmosis is a dimorphic fungal infection, which is rare outside endemic pockets in North, Central, and South America, Asia, and Africa. Herein, we describe a woman in her 80s living in the Scottish Borders region of the United Kingdom with a recent diagnosis of granulomatous rosacea, who on receiving escalating immunosuppression for suspected sarcoidosis, and long-standing rheumatoid arthritis developed a striking eruption involving her eyelids along with painful ulceration of the oral and nasal mucosa. Histopathologic examination of the skin and mucosal lesions demonstrated granulomatous inflammation with numerous yeast forms of fungal organisms with morphological characteristics of Histoplasma species. This was confirmed to be H. capsulatum on fungal culture and direct panfungal polymerase chain reaction assay. Although the patient had not left the United Kingdom for more than 20 years, she gave a travel history involving multiple trips to countries where histoplasmosis is known to occur, before that. This case exemplifies the challenges involved in making a diagnosis of histoplasmosis in nonendemic regions for both clinicians and pathologists alike. In this particular patient, the diagnostic difficulties were compounded by the clinicopathological overlap with other cutaneous and systemic granulomatous disorders like granulomatous rosacea and suspected sarcoidosis and also the exceptionally long latency period between the purported historical primary infection and recent recrudescence. We highlight this unusual case to increase an awareness of histoplasmosis, which is very rare in nonendemic regions like the United Kingdom and involves cases acquired during residence in or travel to endemic areas, to ensure its prompt recognition and treatment.

A conserved role for the ALS-linked splicing factor SFPQ in repression of pathogenic cryptic last exons.

The RNA-binding protein SFPQ plays an important role in neuronal development and has been associated with several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease. Here, we report that loss of sfpq leads to premature termination of multiple transcripts due to widespread activation of previously unannotated cryptic last exons (CLEs). These SFPQ-inhibited CLEs appear preferentially in long introns of genes with neuronal functions and can dampen gene expression outputs and/or give rise to short peptides interfering with the normal gene functions. We show that one such peptide encoded by the CLE-containing epha4b mRNA isoform is responsible for neurodevelopmental defects in the sfpq mutant. The uncovered CLE-repressive activity of SFPQ is conserved in mouse and human, and SFPQ-inhibited CLEs are found expressed across ALS iPSC-derived neurons. These results greatly expand our understanding of SFPQ function and uncover a gene regulation mechanism with wide relevance to human neuropathologies.

Non-nuclear Pool of Splicing Factor SFPQ Regulates Axonal Transcripts Required for Normal Motor Development.

Recent progress revealed the complexity of RNA processing and its association to human disorders. Here, we unveil a new facet of this complexity. Complete loss of function of the ubiquitous splicing factor SFPQ affects zebrafish motoneuron differentiation cell autonomously. In addition to its nuclear localization, the protein unexpectedly localizes to motor axons. The cytosolic version of SFPQ abolishes motor axonal defects, rescuing key transcripts, and restores motility in the paralyzed sfpq null mutants, indicating a non-nuclear processing role in motor axons. Novel variants affecting the conserved coiled-coil domain, so far exclusively found in fALS exomes, specifically affect the ability of SFPQ to localize in axons. They broadly rescue morphology and motility in the zebrafish mutant, but alter motor axon morphology, demonstrating functional requirement for axonal SFPQ. Altogether, we uncover the axonal function of the splicing factor SFPQ in motor development and highlight the importance of the coiled-coil domain in this process. VIDEO ABSTRACT.

Skin cancer in children and young adults: 28 years' experience from the Northern Region Young Person's Malignant Disease Registry, UK.

Little population-based data has been published about skin cancers in children and young adults. In this study, 200 cases of melanoma and non-melanoma skin cancers diagnosed under 25 years of age in the North of England from 1968-1995 were obtained from the Northern Region Young Persons' Malignant Disease Registry. The incidence was 1.2 cases per million per year for children (aged 0-14 years) and was 13 cases per million per year for young adults (aged 15-24 years). Melanoma accounted for 138 cases, of which 16 were in subjects aged < 15 years at diagnosis. The incidence of melanoma increased in females at a rate of 5.6 per million per decade (95% confidence interval [CI] 2.2-8.9, P = 0.002), largely due to an increased incidence of primary lower limb tumours. The incidence for males was unchanged. Survival improved significantly over time for both males and females (P < or = 0.02). Of the 62 patients with non-melanoma skin cancers, 66% were diagnosed with primary non-basal cell carcinoma, 13% with dermatofibrosarcoma protuberans, 10% with squamous cell carcinoma and 11% with other tumours. Two cases were iatrogenic second malignancies following treatment for an earlier primary brain tumour. The incidence of non-melanoma skin cancers was significantly higher during 1982-1995 than during 1968-1981 (rate ratio 1.7, 95% CI 1.0-2.8). There were three deaths from non-melanoma skin cancer, and the overall 5 year survival rate was 98% (95% CI 89-100%). The reason for the increasing incidence of both melanoma and non-melanoma skin cancer in young people is unknown, but it is likely that ultraviolet exposure plays an aetiological role. It is important that families continue to be advised of the need for vigilance with regard to childhood sun exposure.