Familial multiple discoid fibromas is linked to a locus on chromosome 5 including the FNIP1 gene.

Previously, we reported a series of families presenting with trichodiscomas, inherited in an autosomal dominant pattern. The phenotype was named familial multiple discoid fibromas (FMDF). The genetic cause of FMDF remained unknown so far. Trichodiscomas are skin lesions previously reported to be part of the same spectrum as the fibrofolliculoma observed in Birt-Hogg-Dubé syndrome (BHD), an inherited disease caused by pathogenic variants in the FLCN gene. Given the clinical and histological differences with BHD and the exclusion of linkage with the FLCN locus, the phenotype was concluded to be distinct from BHD. We performed extensive clinical evaluations and genetic testing in ten families with FMDF. We identified a FNIP1 frameshift variant in nine families and genealogical studies showed common ancestry for eight families. Using whole exome sequencing, we identified six additional rare variants in the haplotype surrounding FNIP1, including a missense variant in the PDGFRB gene that was found to be present in all tested patients with FMDF. Genome-wide linkage analysis showed that the locus on chromosome 5 including FNIP1 was the only region reaching the maximal possible LOD score. We concluded that FMDF is linked to a haplotype on chromosome 5. Additional evaluations in families with FMDF are required to unravel the exact genetic cause underlying the phenotype. When evaluating patients with multiple trichodisomas without a pathogenic variant in the FLCN gene, further genetic testing is warranted and can include analysis of the haplotype on chromosome 5.

The pathogenesis of pneumothorax in Birt-Hogg-Dubé syndrome: a hypothesis.

The development and natural course of lung cysts in patients with Birt-Hogg-Dubé syndrome (BHD) is still unclear, and the relationship between lung cysts and pneumothorax is not fully clarified. Based on the follow-up results of thoracic imaging in six patients with BHD, we hypothesize that decreased potential for stretching of the cysts' wall and extensive contact with the visceral pleura are probably responsible for rupture of the cyst wall resulting in increased risk for pneumothorax.

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

BACKGROUND: Previously, 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. OBJECTIVE: We 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. METHODS: In 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. RESULTS: The 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. LIMITATIONS: The prevalence of FMDF is presently unknown. The underlying gene defect has not yet been identified. CONCLUSIONS: FMDF is clinically distinct from BHD and is not linked to the FLCN locus.

[A 12-year-old girl with blisters on the arm]. / Een tiener met blaren op de armen.

This case concerns a girl with geometrically round blisters, mainly on the left arm since 1 month. Histopathologic examination of a skin biopsy showed a necrotic epidermis with subepidermalclefting suggesting thermal damage. Recently, similar thermal burns have been observed more often in adolescents following a so-called 'deo challenge'.

Renal imaging in 199 Dutch patients with Birt-Hogg-Dubé syndrome: Screening compliance and outcome.

Birt-Hogg-Dubé syndrome is associated with an increased risk for renal cell carcinoma. Surveillance is recommended, but the optimal imaging method and screening interval remain to be defined. The main aim of our study was to evaluate the outcomes of RCC surveillance to get insight in the safety of annual US in these patients. Surveillance data and medical records of 199 patients with Birt-Hogg-Dubé syndrome were collected retrospectively using medical files and a questionnaire. These patients were diagnosed in two Dutch hospitals and data were collected until June 2014. A first screening for renal cell carcinoma was performed in 172/199 patients (86%). Follow-up data were available from 121 patients. The mean follow-up period per patient was 4.2 years. Of the patients known to be under surveillance, 83% was screened at least annually and 94% at least every two years. Thirty-eight renal cell carcinomas had occurred in 23 patients. The mean age at diagnosis of the first tumour was 51. Eighteen tumours were visualized by ultrasound. Nine small tumours (7-27 mm) were visible on MRI or CT and not detected using ultrasound. Our data indicate that compliance to renal screening is relatively high. Furthermore, ultrasound might be a sensitive, cheap and widely available alternative for MRI or part of the MRIs for detecting clinically relevant renal tumours in BHD patients,but the limitations should be considered carefully. Data from larger cohorts are necessary to confirm these observations.

A novel splice variant of the Fas gene in patients with cutaneous T-cell lymphoma.

Defective apoptosis signaling has been implicated in the pathogenesis of primary cutaneous T-cell lymphomas (CTCLs), a group of malignancies derived from skin-homing T cells. An important mediator of apoptosis in T cells is the Fas receptor. We identified a novel splice variant of the Fas gene that displays retention of intron 5 and encodes a dysfunctional Fas protein in 13 of 22 patients (59%) in both early and advanced CTCL. Impairment of Fas-induced apoptosis resulting from aberrant splicing potentially contributes to the development and progression of CTCL by allowing continued clonal expansion of activated T cells and by reducing susceptibility to antitumor immune responses.

Are lung cysts in renal cell cancer (RCC) patients an indication for FLCN mutation analysis?

Renal cell cancer (RCC) represents 2-3% of all cancers and is the most lethal of the urologic malignancies, in a minority of cases caused by a genetic predisposition. Birt-Hogg-Dubé syndrome (BHD) is one of the hereditary renal cancer syndromes. As the histological subtype and clinical presentation in BHD are highly variable, this syndrome is easily missed. Lung cysts--mainly under the main carina--are reported to be present in over 90% of all BHD patients and might be an important clue in differentiating between sporadic RCC and BHD associated RCC. We conducted a retrospective study among patients diagnosed with sporadic RCC, wherein we retrospectively scored for the presence of lung cysts on thoracic CT. We performed FLCN mutation analysis in 8 RCC patients with at least one lung cysts under the carina. No mutations were identified. We compared the radiological findings in the FLCN negative patients to those in 4 known BHD patients and found multiple basal lung cysts were present significantly more frequent in FLCN mutation carriers and may be an indication for BHD syndrome in apparent sporadic RCC patients.

Amyloidosis of the tongue as a paraneoplastic marker of plasma cell dyscrasia.

OBJECTIVE: Our objective was to study the results of the medical workup in patients with amyloidosis of the oral cavity. STUDY DESIGN: Patients diagnosed with amyloidosis of the oral cavity during the period from January 1971 to January 2001 at the Departments of Oral and Maxillofacial Surgery/Oral Pathology and Dermatology of the VU University Medical Center, Amsterdam, The Netherlands, were included in this retrospective case study. In total, this series comprised 11 patients, 9 women and 2 men. The patients' medical workup and final diagnoses were traced by means of the medical records. RESULTS: All but one patient presented with amyloidosis of the tongue, most of them manifesting as macroglossia. In 7 of the 11 included patients a diagnosis of myeloma could be established shortly after their referral to the above-stated departments. Three of the 4 remaining patients appeared to have a monoclonal gammopathy of undetermined significance, and 1 patient was diagnosed with a lymphoplasmacytoid non-Hodgkin lymphoma (immunocytoma). CONCLUSIONS: Amyloidosis of the oral cavity predominantly involves the tongue, mainly manifesting as macroglossia. Amyloidosis of the tongue is associated with an occult underlying plasma cell dyscrasia, in particular myeloma, and, therefore, should be regarded as a paraneoplastic phenomenon of these hematologic diseases.

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 (p = 1.000 for doctors opinion, p = 0.344 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; p = 0.625). 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.

A de novo FLCN mutation in a patient with spontaneous pneumothorax and renal cancer; a clinical and molecular evaluation.

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant condition due to germline FLCN (folliculin) mutations, characterized by skin fibrofolliculomas, lung cysts, pneumothorax and renal cancer. We identified a de novo FLCN mutation, c.499C>T (p.Gln167X), in a patient who presented with spontaneous pneumothorax. Subsequently, typical skin features and asymptomatic renal cancer were diagnosed. Probably, de novo FLCN mutations are rare. However, they may be under-diagnosed if BHD is not considered in sporadic patients who present with one or more of the syndromic features. Genetic and immunohistochemical analysis of the renal tumour indicated features compatible with a tumour suppressor role of FLCN. The finding that mutant FLCN was expressed in the tumour might indicate residual functionality of mutant FLCN, a notion which will be explored in future studies.

[Spontaneous pneumothorax as the first manifestation of a hereditary condition with an increased renal cancer risk]. / Spontane pneumothorax als eerste uiting van een erfelijke aandoening met een verhoogde kans op nierkanker.

Spontaneous pneumothorax can be due to Birt-Hogg-Dubé syndrome (BHD syndrome), an autosomal dominant predisposition for fibrofolliculomas, multiple lung cysts, pneumothorax and renal cancer. The syndrome is the result of germline mutations in the FLCN (folliculin) gene. Its clinical presentation is highly variable. Consequently, this syndrome is probably under-diagnosed. An illustrative kindred is presented in which the index patient, a man aged 26, had recurrent episodes of pneumothorax without apparent skin lesions or renal abnormalities. He had bilateral mostly basally-located lung cysts. There was a family history of fibrofolliculomas, lung cysts, pneumothorax and clear cell renal cancer. Recognition of BHD is important since carriers of the mutation can be offered surveillance for early detection and treatment of renal cancer.

Birt-Hogg-Dubé syndrome: clinical and genetic studies of 20 families.

Birt-Hogg-Dubé syndrome (BHD) is an autosomal-dominant genodermatosis characterized by skin fibrofolliculomas and an increased risk of spontaneous pneumothorax, renal and possibly other tumors. A causative gene (FLCN) on chromosome 17p has recently been identified. We here report clinical and genetic studies of 20 BHD families ascertained by the presence of multiple fibrofolliculomas or trichodiscomas in the proband. Pathogenic FLCN germline mutations were found in 11 (69%) of 16 probands tested and in 14 family members. Six different FLCN germline mutations were detected, four of which have not been reported previously. The clinical features were variable. None and less than 10 skin lesions were observed in two mutation carriers at the age of 67 and 29 years, respectively. Spontaneous pneumothorax was reported in four and renal carcinoma of mixed histological types in two of 36 BHD-affected individuals and/or FLCN mutation carriers. Both the prevalence of spontaneous pneumothorax and renal tumors appeared to be relatively low compared with previously reported data. Various other extracutaneous tumors were observed in 11 of 36 BHD-affected individuals and/or FLCN mutation carriers. This study of the second largest cohort to date contributes to the expanding data on the variable phenotype and underlying gene defects in BHD.

HPV-associated flat penile lesions in men of a non-STD hospital population: less frequent and smaller in size than in male sexual partners of women with CIN.

Human papillomavirus (HPV) infections and HPV-associated penile lesions are frequently found in male sexual partners of women with cervical intraepithelial neoplasia (CIN). To determine the significance of these findings, we studied the prevalence of HPV and HPV associated penile lesions in a male hospital population with non-STD complaints. Penoscopy was performed after application of acetic acid to identify flat lesions, papular lesions, condylomata acuminata and pearly penile papules (PPPs). Presence of HPV DNA in penile scrapes was tested by GP5+6+ PCR. In case of HPV 16 positivity, viral loads were quantified using a LightCycler based real-time PCR method. Comparing the non-STD male hospital population (n = 118) with the male sexual partners of women with CIN (n = 238), flat penile lesions were found in 14% vs. 60% and penile HPV in 25% vs. 59% of the men, respectively. We found that the presence of penile HPV and, in case of HPV 16 positivity, higher viral loads were associated with the presence of flat penile lesions. Amongst the HPV-positive men, flat penile lesions were more common and larger in size in male sexual partners of women with CIN than in the non-STD hospital population. HPV infections and HPV-associated flat penile lesions are commonly found in the non-STD male population. However, these lesions are less frequently present and smaller in size than in male sexual partners of women with CIN. Higher viral loads in penile scrapes of male sexual partners of women with CIN are reflected by a higher prevalence of flat penile lesions and a larger size of these lesions.

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.

Genetic and clinical mosaicism in a patient with neurofibromatosis type 1.

Patients with typical features of neurofibromatosis type 1 (NF1) limited to a specific body segment are usually referred to as having "segmental NF1", which is generally assumed to be the result of somatic mosaicism for a NF1 mutation. Mosaicism has also been demonstrated at the molecular level in some sporadic cases with phenotypically classic NF1. In the present report, we describe a patient with NF1 disease manifestations throughout the whole body, but leaving a few sharply delineated segments of the skin unaffected, suggestive of revertant mosaicism. A large intragenic deletion was found by mutation analysis using long-range RT-PCR. The intra-exonic breakpoints were characterized in exon 13 and exon 28, resulting in a deletion of 99,571 bp at the genomic level. The presence of two genetically distinct cell populations, confirming mosaicism for this NF1 mutation, was shown by analysis of several tissues. Revertant mosaicism was excluded by demonstrating heterozygosity for markers residing in the deletion region. The findings in this patient demonstrate two things: (1) although the entire body is affected, mosaicism can still be suspected at clinical examination and proven by DNA analysis and skin biopsies; (2) long-range RT-PCR is a feasible method for demonstrating large intragenic deletions in NF1.

Condom use promotes regression of human papillomavirus-associated penile lesions in male sexual partners of women with cervical intraepithelial neoplasia.

Penile HPV-associated lesions are frequently seen in male sexual partners of women with CIN. The natural course and clinical significance of these lesions are unclear. Women with CIN and their male sexual partners were randomized for condom use (condom group n = 68, noncondom group n = 68). Males were screened for the presence of penile lesions, i.e., flat lesions, papular lesions and condylomata acuminata, and of HPV in their penile swabs by PCR testing. Median follow-up time was 13.1 months (range 2.9-57.4). The outcome of our study was clinical regression of penile lesions defined as disappearance of lesions at penoscopy. Potentially prognostic factors, i.e., HPV status, lesion type and age, were studied as well. Outcomes were assessed in 57 men of the condom group and in 43 men of the noncondom group. Condom use shortened the median time to regression of flat penile lesions (7.4 months condom group vs. 13.9 months noncondom group; HR = 2.1, 95% CI 1.2-3.7). This effect was not found for papular lesions (HR = 0.5, 95% CI 0.1-2.8). HPV-negative men showed a significantly shorter median time to regression of flat lesions (3.8 months) compared to men with either HPV-positive status (8.5 months; HR = 0.4, 95% CI 0.2-0.9) or inconsistent HPV status (13.1 months; HR = 0.2, 95% CI 0.1-0.6). Regression of flat penile lesions is HPV-dependent and accelerated by condom use. This effect is probably the result of blocking viral transmission between sexual partners.

Pearly penile papules: still no reason for uneasiness.

BACKGROUND: Penile lesions and pearly penile papules (PPP) are frequently found in male sexual partners of women with cervical intraepithelial neoplasia (CIN). The former have been associated with human papillomavirus (HPV). OBJECTIVES: We estimated the prevalence of PPP in male sexual partners of women with CIN, and investigated the association between PPP and flat and papular penile lesions found in these men. We further evaluated a possible association between PPP and HPV, age, and CIN grade of the female partner. METHODS: We evaluated by penoscopy the presence of HPV-associated penile lesions and PPP in 226 male sexual partners of women with CIN. HPV was tested by polymerase chain reaction-enzyme immunoassay and in situ hybridization. RESULTS: The prevalence of PPP was 34% and was not associated with the presence of penile lesions or a positive HPV test. Age and CIN grade of the female partner were not related to the presence of PPP. CONCLUSION: The prevalence of PPP in male sexual partners of women with CIN is comparable with the prevalence described in men of more diverse populations. Our data do not support a causative role for HPV in the genesis of PPP.