Filaggrin-Associated Atopic Skin, Eye, Airways, and Gut Disease, Modifying the Presentation of X-Linked Reticular Pigmentary Disorder (XLPDR).

BACKGROUND: X-linked reticular pigmentary disorder (XLPDR) is a rare condition characterized by skin hyperpigmentation, ectodermal features, multiorgan inflammation, and recurrent infections. All probands identified to date share the same intronic hemizygous POLA1 hypomorphic variant (NM_001330360.2(POLA1):c.1393-354A > G) on the X chromosome. Previous studies have supported excessive type 1 interferon (IFN) inflammation and natural killer (NK) cell dysfunction in disease pathogenesis. Common null polymorphisms in filaggrin (FLG) gene underlie ichthyosis vulgaris and atopic predisposition. CASE: A 9-year-old boy born to non-consanguineous parents developed eczema with reticular skin hyperpigmentation in early infancy. He suffered recurrent chest infections with chronic cough, clubbing, and asthma, moderate allergic rhinoconjunctivitis with keratitis, multiple food allergies, and vomiting with growth failure. Imaging demonstrated bronchiectasis, while gastroscopy identified chronic eosinophilic gastroduodenitis. Interestingly, growth failure and bronchiectasis improved over time without specific treatment. METHODS: Whole-genome sequencing (WGS) using Illumina short-read sequencing was followed by both manual and orthogonal automated bioinformatic analyses for single-nucleotide variants, small insertions/deletions (indels), and larger copy number variations. NK cell cytotoxic function was assessed using 51Cr release and degranulation assays. The presence of an interferon signature was investigated using a panel of six interferon-stimulated genes (ISGs) by QPCR. RESULTS: WGS identified a de novo hemizygous intronic variant in POLA1 (NM_001330360.2(POLA1):c.1393-354A > G) giving a diagnosis of XLPDR, as well as a heterozygous nonsense FLG variant (NM_002016.2(FLG):c.441del, NP_0020.1:p.(Arg151Glyfs*43)). Compared to healthy controls, the IFN signature was elevated although the degree moderated over time with the improvement in his chest disease. NK cell functional studies showed normal cytotoxicity and degranulation. CONCLUSION: This patient had multiple atopic manifestations affecting eye, skin, chest, and gut, complicating the presentation of XLPDR. This highlights that common FLG polymorphisms should always be considered when assessing genotype-phenotype correlations of other genetic variation in patients with atopic symptoms. Additionally, while the patient exhibited an enhanced IFN signature, he does not have an NK cell defect, suggesting this may not be a constant feature of XLPDR.

Adalimumab therapy is associated with increased faecal short chain fatty acids in hidradenitis suppurativa.

Altered gut microbiota composition has been observed in individuals with hidradenitis suppurutiva (HS) and many other inflammatory diseases, including obesity, type 1 and type 2 diabetes. Here, we addressed whether adalimumab, a systemic anti-inflammatory therapy, may impact the microbiota biochemical profile, particularly on beneficial metabolites such as short-chain fatty acids (SCFAs). We conducted an observational single-arm pilot trial to assess gut microbiota composition by 16S rRNA gene sequence analysis and to detect metabolite signatures by gas chromatography in stool samples from participants with HS prior to and 12 weeks after commencing adalimumab therapy. HS individuals that better responded to adalimumab treatment showed a shift in the composition and function of the gut microbiota with significantly increased SCFA acetate and propionate compared to age, gender and BMI-matched healthy controls. A positive correlation was observed between propionate with Prevotella sp and Faecalibacterium prausnitsii. Increased SCFAs, changes in gut microbiota composition, function and metabolic profile following 12 weeks of adalimumab suggest that targeting SCFAs may be considered a potential biomarker to be evaluated as a complementary protective factor or as a diagnostically relevant signal in HS.

Zosteriform cutaneous metastases: an unusual presentation of metastatic lung carcinoma.

Zosteriform cutaneous metastases are an unusual and rare morphological variant. We discuss the case of a 78-year-old gentleman with a background of end-stage renal disease with metastatic adenocarcinoma of the lung which was diagnosed due to the development of zosteriform cutaneous metastases around his vascular catheter (vascath) site. The vascath may have acted as a traumatic nidus for lymphatic spread.

Prevalence of inflammatory bowel disease (IBD) in hidradenitis suppurativa (HS): systematic review and adjusted meta-analysis.

BACKGROUND: Several case reports and case series have recently explored the association between hidradenitis suppurativa (HS) and inflammatory bowel disease (IBD). OBJECTIVE: We performed a systematic review and meta-analysis of case-control studies to determine  (i) the pooled prevalence of IBD in HS cohorts, and (ii) whether HS is more strongly associated with Crohn's disease or ulcerative colitis. METHODS: Electronic searches were performed using five databases, from their inception to August 2018. Case-control studies reporting the proportion of IBD cases in HS cohorts were included and meta-analysis performed. RESULTS: From six included studies, a significant association between HS and IBD after pooling of adjusted effect sizes was identified (OR 2.12; 95% CI 1.62-2.77; P = 0.03). Subgroup analysis demonstrated a significant association between HS and Crohn's disease (OR 2.25; 95% CI 1.52-3.32; P < 0.0001, I2  = 92%) and with ulcerative colitis (OR 1.56; 95% CI 1.26-1.94; P < 0.0001; I2  = 36%). LIMITATIONS: Studies reviewed were observational by design which are susceptible to bias and lack of randomization. CONCLUSIONS: Our results indicate a statistically significant association between HS and IBD. Our results highlight that all patients with HS should be clinically screened for symptoms of IBD and symptomatic patients referred for further investigations.

Cutaneous malignancies in Indigenous Peoples of urban Sydney.

INTRODUCTION: Despite 3% of Australians identifying as Indigenous, cutaneous malignancies in these patients, including incidence, risk factors and outcomes have not been investigated. This is despite recognition that cancer outcomes in this population are significantly poorer. METHODS: We undertook a retrospective case series of Indigenous Peoples who presented to two urban cancer therapy centres for the management of cutaneous malignancies from 2003 to 2017. Risk factors, tumour-specific characteristics, treatments and outcomes were reviewed. RESULTS: Twenty-two patients identified as Aboriginal and/or Torres Strait Islander. The median age at presentation was 61 years and the majority were male (63.6%) and had skin phototype III (86.4%). Patients presented with basal cell carcinoma (50%), squamous cell carcinoma (31.8%), melanoma (9.1%) and cutaneous sarcomas (9.1%). The majority (68.2%) presented with stage II or higher disease, and there were high rates of immunosuppression (45.5%). At the time of reporting, 68.2% patients were alive, 18.2% had died from their skin cancers and 13.6% had died from unrelated causes. CONCLUSION: This cohort has demonstrated late-stage presentation of skin cancers, with substantial morbidity and mortality from potentially treatable cutaneous malignancies. This parallels other health conditions in Indigenous Australians and has highlighted the need for improved data collection of Indigenous status to better quantify the epidemiology of skin cancer in this population. There is an imperative to improve skin cancer awareness in this population to allow earlier detection and management to ensure better outcomes.

Cutaneous presentation of gastrointestinal adenocarcinoma.

Seeding of a central nervous system malignancy to the abdominal cavity is an uncommon but well documented complication of a ventriculoperitoneal (VP) shunt. However, the metastasis of a primary gastrointestinal cancer to the skin via a VP shunt is extremely rare. We report the clinical case of an 85-year-old male who presented with a right upper quadrant nodule over his shunt, which on histopathology and tumour marker profile was diagnosed as an adenocarcinoma of likely upper gastrointestinal origin. This case illustrates the importance of proceeding to biopsy to inform prognosis and management, despite the risks of shunt infection.