Theo M. Starink

Cheilitis granulomatosa: overview of 13 patients with long‐term follow‐up – results of management

Background Cheilitis granulomatosa, often regarded as a subtype of orofacial granulomatosis, is characterized by recurrent or persistent swelling of one or both lips. Classically, a non‐necrotizing granulomatous inflammation is seen at histologic examination. Although a relationship has been proposed between Melkersson–Rosenthal syndrome (and the monosymptomatic form, cheilitis granulomatosa) and Crohn’s disease on the basis of the orofacial swelling and similar histology, several studies of Melkersson–Rosenthal syndrome have not found an association with Crohn’s disease.

Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis

Smit DL, Mensenkamp AR, Badeloe S, Breuning MH, Simon MEH, van Spaendonck KY, Aalfs CM, Post JG, Shanley S, Krapels IPC, Hoefsloot LH, van Moorselaar RJA, Starink TM, Bayley J‐P, Frank J, van Steensel MAM, Menko FH. Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis.

Renal cancer and pneumothorax risk in Birt-Hogg-Dubé syndrome; an analysis of 115 FLCN mutation carriers from 35 BHD families.

Background:Birt–Hogg–Dubé (BHD) syndrome is an autosomal dominant condition caused by germline FLCN mutations, and characterised by fibrofolliculomas, pneumothorax and renal cancer. The renal cancer risk, cancer phenotype and pneumothorax risk of BHD have not yet been fully clarified. The main focus of this study was to assess the risk of renal cancer, the histological subtypes of renal tumours and the pneumothorax risk in BHD.Methods:In this study we present the clinical data of 115 FLCN mutation carriers from 35 BHD families.Results:Among 14 FLCN mutation carriers who developed renal cancer 7 were <50 years at onset and/or had multifocal/bilateral tumours. Five symptomatic patients developed metastatic disease. Two early-stage cases were diagnosed by surveillance. The majority of tumours showed characteristics of both eosinophilic variants of clear cell and chromophobe carcinoma. The estimated penetrance for renal cancer and pneumothorax was 16% (95% minimal confidence interval: 6–26%) and 29% (95% minimal confidence interval: 9–49%) at 70 years of age, respectively. The most frequent diagnosis in families without identified FLCN mutations was familial multiple discoid fibromas.Conclusion:We confirmed a high yield of FLCN mutations in clinically defined BHD families, we found a substantially increased lifetime risk of renal cancer of 16% for FLCN mutation carriers. The tumours were metastatic in 5 out of 14 patients and tumour histology was not specific for BHD. We found a pneumothorax risk of 29%. We discuss the implications of our findings for diagnosis and management of BHD.

Lupus miliaris disseminatus faciei: A Distinctive Rosacea-Like Syndrome and Not a Granulomatous Form of Rosacea

Background: Lupus miliaris disseminatus faciei is an eruption of discrete red-brown, dome-shaped papules, histologically characterized by epithelioid cell granulomas. The pathogenesis of the disorder remains controversial. Objective: The authors discuss the place of lupus miliaris disseminatus faciei among granulomatous disorders. Methods: This report reviews the available literature and presents 3 patients with lupus miliaris disseminatus faciei. Results: The histopathologic characteristics of lupus miliaris disseminatus faciei – an epithelioid cell granuloma with central necrosis – may be found in granulomatous rosacea, whilst the clinical features and course of lupus miliaris disseminatus faciei are often similar to cutaneous sarcoidosis. Conclusions: We put forward lupus miliaris disseminatus faciei as a distinctive rosacea-like syndrome and not as a granulomatous form of rosacea.

Linear IgA bullous dermatosis in a patient with renal cell carcinoma

Linear IgA bullous dermatosis (LABD) is an autoimmune subepidermal bullous disease with heterogeneous clinical manifestations, characterized by linear deposition of IgA along the epidermal basement membrane zone. We report a patient with a metastasized renal cell carcinoma who developed an extensive blistering eruption. The lesions showed immunopathological findings characteristic of LABD. The patient showed a fair response to prednisolone and dapsone. Treatment to control the LABD was no longer required when interferon‐alfa was started as palliative therapy for the metastasized renal cell carcinoma. The association of LABD and malignancies has been documented before and is not due to mere chance alone.

Orofacial granulomatosis in a patient with Crohn's disease

Orofacial granulomatosis encompasses the previously recognized clinical entities Melkersson-Rosenthal syndrome and cheilitis granulomatosa. We report the case of a 39-year-old patient with cheilitis granulomatosa, intestinal Crohns disease, and optic neuropathy. Cheilitis granulomatosa and optic neuropathy represent 2 rare manifestations of orofacial granulomatosis in Crohns disease.

Central nervous system involvement in early and late syphilis: The problem of asymptomatic neurosyphilis

Patients with syphilitic infections are at risk of development of symptomatic neurosyphilis. Adequate treatment with 2.4-7.2 x 10(6) units benzyl penicillin-G intramuscularly within 1 year after infection will rule out this risk. However, more than 1 year after infection this treatment is not fully reliable. In asymptomatic CNS involvement (asymptomatic neurosyphilis) only intravenous penicillin treatment is considered to be adequate in the prevention of neurosyphilis. In this study we redefined criteria for this condition by comparing serum and cerebrospinal fluid (CSF) samples of symptomatic neurosyphilitic patients with those of latent syphilitic patients without CNS involvement. Diagnostic criteria of the World Health Organization and of Centers of Disease Control for asymptomatic neurosyphilis (positive CSF Venereal Disease Research Laboratory (VDRL) test, combined with raised CSF cell count and/or protein content) were studied and compared with some newer parameters such as signs of intrathecal treponemal antibody production (Treponema pallidum haemagglutination assay and intrathecal Treponema pallidum assay index), immunoglobulin G (IgG) and M (IgM) index. The results of this study in 203 syphilitic patients revealed that either a positive CSF-VDRL or combination of a raised IgG and/or IgM index with an elevated CSF cell count both are useful criteria for ruling-in asymptomatic neurosyphilis.

Topical Rapamycin as a Treatment for Fibrofolliculomas in Birt-Hogg-Dubé Syndrome: A Double-Blind Placebo-Controlled Randomized Split-Face Trial

Background Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant disorder characterised by the occurrence of benign, mostly facial, skin tumours called fibrofolliculomas, multiple lung cysts, spontaneous pneumothorax and an increased renal cancer risk. Current treatments for fibrofolliculomas have high rates of recurrence and carry a risk of complications. It would be desirable to have a treatment that could prevent fibrofolliculomas from growing. Animal models of BHD have previously shown deregulation of mammalian target of rapamycin (mTOR). Topical use of the mTOR inhibitor rapamycin is an effective treatment for the skin tumours (angiofibromas) in tuberous sclerosis complex, which is also characterised by mTOR deregulation. In this study we aimed to determine if topical rapamycin is also an effective treatment for fibrofolliculomas in BHD. Methods We performed a double blinded, randomised, facial left-right controlled trial of topical rapamycin 0.1% versus placebo in 19 BHD patients. Trial duration was 6 months. The primary outcome was cosmetic improvement as measured by doctors and patients. Changes in fibrofolliculoma number and size were also measured, as was occurrence of side effects. Results No change in cosmetic status of fibrofolliculomas was reported in the majority of cases for the rapamycin treated (79% by doctors, 53% by patients) as well as the placebo treated facial sides (both 74%). No significant differences between rapamycin and placebo treated facial halves were observed (pu200a=u200a1.000 for doctors opinion, pu200a=u200a0.344 for patients opinion). No significant difference in fibrofolliculoma number or change in size of the fibrofolliculomas was seen after 6 months. Side effects occurred more often after rapamycin treatment (68% of patients) than after placebo (58% of patients; pu200a=u200a0.625). A burning sensation, erythema, itching and dryness were most frequently reported. Conclusions This study provides no evidence that treatment of fibrofolliculomas with topical rapamycin in BHD results in cosmetic improvement. Trial Registration ClinicalTrials.gov +NCT00928798

Familial multiple discoid fibromas: a look-alike of Birt-Hogg-Dubé syndrome not linked to the FLCN locus.

BACKGROUNDnPreviously, we proposed that familial multiple trichodiscomas (OMIM 190340) is distinct from Birt-Hogg-Dubé syndrome (BHD) (OMIM #135150). BHD is characterized by multiple fibrofolliculomas/trichodiscomas, lung cysts, pneumothorax, and renal cell cancer. Germline FLCN mutations can be detected in most but not all BHD families.nnnOBJECTIVEnWe sought to evaluate familial multiple trichodiscomas at a clinical and genetic level. We now renamed this condition familial multiple discoid fibromas (FMDF) to emphasize the distinction from BHD.nnnMETHODSnIn 8 additional families with an autosomal dominant pattern of multiple discoid fibromas we assessed the clinical findings and the histopathological features of skin lesions. FLCN germline mutation analysis was completed in 7 families. In two of these families segregation analysis was performed using polymorphic DNA markers in and around the FLCN locus.nnnRESULTSnThe clinical findings in FMDF are different from those in BHD with early onset of skin lesions, prominent involvement of the pinnae, and discoid fibromas without the follicular epithelial component characteristic of the fibrofolliculoma/trichodiscoma spectrum of BHD. In addition, there were no evident pulmonary or renal complications. In none of the families were pathogenic FLCN germline mutations identified. Using segregation analysis we could exclude involvement of the FLCN locus in the two kindreds tested.nnnLIMITATIONSnThe prevalence of FMDF is presently unknown. The underlying gene defect has not yet been identified.nnnCONCLUSIONSnFMDF is clinically distinct from BHD and is not linked to the FLCN locus.

Paraneoplastic pemphigus caused by an epithelioid leiomyosarcoma and associated with fatal respiratory failure

A patient is described who initially presented with pemphigus vulgaris, limited to the oral cavity, and weight loss. Although the various laboratory studies pointed to the diagnosis of paraneoplastic pemphigus (PNP), the underlying neoplasm was not detected until 6 months later, when the patient developed shortness of breath and routine physical examination on admission revealed an abdominal mass, which eventually was proven to be an epithelioid leiomyosarcoma. In spite of radical excision of the tumour and intensive treatment of the dyspnoea, the patient died of respiratory failure 19 months after the PNP had been diagnosed. Early diagnosis of PNP is stressed to possibly prevent fatal pulmonary involvement.