Segregation, immunohistochemical, molecular and functional analyses classify a novel missense variant in fumarate hydratase (FH) as pathogenic.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant cancer predisposition syndrome characterized by cutaneous leiomyomas, uterine leiomyomas, and aggressive renal cancer. Germline variants in the fumarate hydratase (FH) gene predispose to HLRCC. Identifying germline pathogenic FH variants enables lifetime renal cancer screening and genetic testing for family members. In this report, we present a FH missense variant (c.1039T>C (p.S347P)), initially classified as a variant of uncertain significance. Clinical assessment, histopathological findings, molecular genetic studies, and enzymatic activity studies support the re-classification of the FH c.1039T>C variant to "pathogenic" based on ACMG/AMP criteria. Further insights into pathological recognition of FH-deficient renal cancer are discussed and should be recognized. This study has shown how (a) detailed multi-disciplinary analyses of a single variant can reclassify rare missense variants in FH and (b) careful pathological review of renal cancers is obligatory when HLRCC is suspected.

Increased Occurrence of Cutaneous Leiomyomas and Dermatofibromas in Patients with Uterine Leiomyomas without Fumarate Hydratase Gene Mutations.

Leiomyomas are smooth muscle-derived benign neoplasms that can affect all organs, most frequently in the uterus. Fumarate hydratase gene (FH) mutation is characterised by an autosomal dominant disease with increased occurrence of renal tumours, but also by cutaneous (CLs) and uterine leiomyomas (ULs). So far, an increased occurrence of skin tumours in non-mutated patients with ULs has not been verified. To this aim, a case-group of women who were FH non-mutated patients surgically treated for ULs (n = 34) was compared with a control-group (n = 37) of consecutive age-matched healthy women. The occurrence of skin neoplasms, including CLs and dermatofibromas (DFs), was evaluated. Moreover, the microscopic features of FH non-mutated skin tumours were compared with those of an age-matched population group (n = 70) who presented, in their clinical history, only one type of skin tumour and no ULs. Immunohistochemical and in vitro studies analysed TGFß and vitamin D receptor expression. FH non-mutated patients with ULs displayed a higher occurrence of CLs and DFs (p < 0.03 and p < 0.001), but not of other types of skin tumours. Immunohistochemistry revealed a lower vitamin D receptor (VDR) expression in CLs and DFs from the ULs group compared with those from the population group (p < 0.01), but a similar distribution of TGFß-receptors and SMAD3. In vitro studies documented that TGFß-1 treatment and vitamin D3 have opposite effects on α-SMA, TGFßR2 and VDR expression on dermal fibroblast and leiomyoma cell cultures. This unreported increased occurrence of CLs and DFs in FH non-mutated patients with symptomatic ULs with vitamin D deficiency suggests a potential pathogenetic role of vitamin D bioavailability also for CLs and DFs.

The spectrum of clinical and genetic findings in hereditary leiomyomatosis and renal cell cancer (HLRCC) with relevance to patient outcomes: a retrospective study from a large academic tertiary referral center.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant condition attributed to pathogenic variants in fumarate hydratase (FH) and presents with cutaneous leiomyomas (CLMs), uterine leiomyomas (ULMs) and renal cell cancer (RCC). The objective of this study was to characterize the spectrum of clinical and genetic findings in HLRCC at a large academic tertiary care referral center with a focus on dermatologic manifestations. Fifty-seven patients, 41 female and 16 male, with 27 unique pathogenic or likely-pathogenic FH variants were identified from 38 families. Mean age of HLRCC diagnosis was 44.4 years (range 8-82). CLMs were the primary reason for referral in 49.1% (n=28). CLMs were present in 43/56 patients who underwent full skin examination. Three of these 56 patients were diagnosed with cutaneous leiomyosarcoma. Incidence of ULMs was 37/41 female patients; no uterine leiomyosarcomas were observed. RCC was observed in 6/57 patients (mean age of diagnosis: 47.3 years (range 28-79)). CLMs predated RCC in the 3 patients diagnosed with both. Dermatologists have an opportunity to recognize cutaneous manifestations of HLRCC, including cutaneous leiomyomas and rarely cutaneous leiomyosarcomas, and refer for genetic evaluation to provide definitive diagnosis. Identification of HLRCC can promote family cascade testing and screening for RCC.

Sonographic Characteristics of Leiomyomatous Tumors of Skin and Nail: a Case Series.

Introduction: The clinical appearance of the uncommon cutaneous leiomyomatous tumors (LMT) is nonspecific, leading to an extensive differential diagnosis. A non-invasive tool such as high-frequency ultrasound (HFUS) is required for characterizing LMTs in the clinical setting. Although the sonographic features of their uterine counterpart had been well reported, there are only scant reports on the use of ultrasound for studying leiomyomatous neoplasms of the skin and nail. Objectives: To identify and well characterize common sonographic features of LMT. Methods: A retrospective analysis of HFUS images of LMT in three different patients, two of them with multiple cutaneous leiomyomas and another with a subungual leiomyosarcoma. Results: In all cases, several shared ultrasound characteristics were found. Moreover, we describe a new ultrasonographic sign in cutaneous leiomyomas called the "pine tree" sign, with other features not previously reported. Conclusions: These ultrasonographic characteristics would strengthen the clinical diagnosis, assist with treatment management, and may help avoid serial biopsies in cases with multiple cutaneous lesions.

Cutaneous Leiomyoma: A Clinical Study of 152 Patients.

BACKGROUND: Cutaneous leiomyoma (CL) is a benign smooth muscle tumour included in painful skin tumours. Multiple CLs are cutaneous markers of hereditary leiomyomatosis and renal cell cancer (HLRCC). OBJECTIVES: To retrospectively review our series of patients with CLs to analyse their clinical features and the association with HLRCC. METHODS: Cases coded as CL in the database of the pathology department between 2004 and 2019 were included in the study. Medical records were retrospectively reviewed to obtain the following data: age, sex, location, number of lesions, diameter, evolution time at diagnosis, suspected clinical diagnosis, tenderness, status of resection margins, development of recurrence, follow-up time, and association with HLRCC. RESULTS: 152 patients had CLs, 89 women and 63 men, mean age 56.26, SD 16.030 years. Subtypes were piloleiomyoma in 62 patients, angioleiomyoma in 80, and genital leiomyoma in 10. All of our 11 patients with multiple lesions corresponded to piloleiomyomas, and HLRCC was confirmed in 8 of them (73%). Patients with HLRCC were younger than patients with piloleiomyomas without HLRCC (34.88 vs. 56.17 years, p = 0.009). Vascular and genital leiomyomyomas were solitary and were not associated with HLRCC. CONCLUSION: In patients with multiple piloleiomyomas HLRCC must be ruled out as it is confirmed in a high proportion of cases. The probability of fumarate hydratase mutation is greater in multiple piloleiomyomas involving both the trunk and upper extremities in the same patient.

Gene Polymorphisms of Interleukin-27 Correlate with the Susceptibility, Severity, and Clinical Outcomes of Elderly People with Guillain-Barré Syndrome.

INTRODUCTION: Guillain-Barré syndrome (GBS) is a common autoimmune disease in the peripheral nervous system. This study aimed to elucidate the role of IL-27 gene polymorphisms in elderly people with GBS. METHODS: A total of 395 healthy subjects and 422 GBS patients with an average age of 63 years old were included in this study. Peripheral blood samples were collected. The 2 single-nucleotide polymorphisms (SNPs) of IL-27, namely, rs153109 and rs785575, of GBS patients were analyzed using the PCR method and compared with those of the healthy controls. The correlations of IL-27 SNPs with disease severity, disease outcome, level of anti-GM1 antibodies, and Campylobacter jejuni infection were assessed. Serum levels of IL-27 of healthy subjects and GBS patients were analyzed using enzyme-linked immunosorbent assay. RESULTS: No significant differences in the frequencies of rs785575 SNPs between GBS and healthy subjects were observed. In analyzing rs153109 SNPs, the G allele was found to be more prevalent in the GBS patients (p = 0.012). More alleles show GG genotype in GBS patients (p = 0.023). The -964A>G allele has a higher prevalence in severely affected and anti-GM1-Ab-positive GBS patients. GBS patients with the rs153109 SNP showed a poor clinical outcome than those without rs153109 SNP (p = 0.012). GBS patients showed higher serum IL-27 levels than healthy subjects (p < 0.001). The levels of IL-27 were also higher in GBS patients with genotypes of AG and GG, and those with GG genotypes showed the highest IL-27 levels. CONCLUSION: The rs153109 SNP is more prevalent in GBS patients with the GG and G allele and is associated with severer GBS, poorer clinical outcomes, and higher IL-27 levels.

Nipple leiomyoma: A rare neoplasm with a broad spectrum of histologic appearances.

Cutaneous leiomyomas are rare benign smooth-muscle tumors. These lesions are distinguished based on their cell of origin and are subclassified as pilar leiomyoma, angioleiomyoma, and genital-type leiomyoma. Nipple leiomyoma is the least common genital-type leiomyoma, arising from the dartoic muscle cell of the nipple. Histologic examination of the lesion is necessary for definitive diagnosis, and these uncommon tumors can pose a diagnostic challenge. We describe herein a series of six nipple leiomyomas with a spectrum of histologic appearances.

Multiple cutaneous leiomyomas leading to discovery of novel splice mutation in the fumarate hydratase gene associated with HLRCC.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare autosomal dominant condition, which manifests as cutaneous leiomyomas (CL), uterine fibroids and renal cell cancer (RCC). We describe the case of a 53-year-old woman who presented with multiple CL with a novel heterozygous canonical splice site mutation in intron 9 of the fumarate hydratase (FH) gene IVS 9-1 G>C (NM_000143.3:c 1391-1 G>C) that was not detected on initial screening of a mutation hotspot but was picked up on sequencing the remaining exons and splice site junctions. This report highlights the importance of clinical suspicion in the diagnosis of HLRCC in the absence of a family or personal history of cancer and despite initial genetic testing being negative.

Leiomioma cutáneo atípico en un paciente con leiomiomatosis cutánea y mutación de la enzima fumarato hidratasa / Atypical leiomyoma in a patient with cutaneous leiomyomatosis and mutation of the enzyme fumarate hydratase

Se presenta un varón de 56 años con un leiomioma atípico en el contexto de una leiomiomatosis cutánea, con antecedentes familiares de miomatosis uterina y con estudio genético que revela una mutación en el gen de la enzima fumarato hidratasa, sin que hasta el momento presente ningún tipo de neoplasia maligna renal. El leiomioma atípico es un tumor poco frecuente, que usualmente ocurre de forma aislada, siendo excepcional la presentación en pacientes con leiomiomatosis cutánea. Es ampliamente conocida la relación de la mutación de la enzima fumarato hidratasa con leiomiomas mútiples, miomas uterinos y el mayor riesgo de desarrollar cáncer renal; sin embargo, el papel de esta mutación en el desarrollo de leiomiomas atípicos es por hoy imposible de esclarecer debido a los escasos casos recogidos en la literatura.

We report the case of a 56 year-old male with an atypical leiomyoma in the context of a cutaneous leiomyomatosis and a family history of uterine leiomyomatosis. The genetic study revealed a mutation in the gene for the enzyme fumarate hydratase, but he has not had any renal malignancy so far. Atypical leiomyoma is a rare tumor that usually presents as a single lesion and is exceptional in patients with cutaneous leiomyomatosis. The relation between fumarate hydratase enzyme mutations with multiple leiomyomas, uterine leiomyomatosis and an increased risk of developing kidney cancer is widely known. However, the role of these mutations in the development of atypical leiomyomas is still impossible to clarify given the few cases reported in the literature.

Novel splice site mutation in the fumarate hydratase (FH) gene is associated with multiple cutaneous leiomyomas in a Japanese patient.

Cutaneous leiomyoma is a benign skin tumor that originates from the smooth muscle, such as the arrector pili muscle of the hair follicles. Familial cases with multiple cutaneous leiomyomas exist, which typically show an autosomal dominant inheritance trait. Most patients with the disease are known to carry heterozygous germ line mutations in the fumarate hydratase (FH) gene and can be complicated by tumors in internal organs, especially uterine leiomyoma and renal cell cancer in high frequency. In this study, we identified a Japanese male patient with multiple cutaneous leiomyomas and found a novel heterozygous splice site mutation, c.738 + 2T>A, in the FH gene of the patient, which was unexpectedly inherited from his unaffected father. Further analysis demonstrated loss of heterozygosity in the tumor tissue, which resulted in a hemizygote state of the mutant allele. Expression studies with the tumor tissue showed that the mutation led to skipping of exon 5 at mRNA levels, which was predicted to cause an in-frame deletion of FH protein (p.Ser186_Gln246del). The protein structure analysis strongly suggested that the deletion would severely disrupt the conformation of the FH protein including the substrate-binding domain, and thus would severely affect the expression and the function. Our findings further disclose the molecular basis of multiple cutaneous leiomyomas and also provide precious information to the mutation carriers in the family for an early diagnosis of renal cell cancer in the future.

A Case of Reed's Syndrome: An Underdiagnosed Tumor Disorder.

Cutaneous leiomyomas are uncommon, benign smooth muscle tumors originating from the arrector pili muscle of the hair follicle that are frequently unrecognized and underdiagnosed by clinicians. They sometimes coexist with common uterine fibroids in an inherited disorder named multiple cutaneous and uterine leiomyomatosis, also referred to as Reed's syndrome. We report a case of Reed's syndrome in a young woman who had been misdiagnosed for many years.

A Case of Reed's Syndrome / 대한피부과학회지

Reed's syndrome is characterized by multiple cutaneous and uterine leiomyomas. The pattern of inheritance is consistent with autosomal dominant transmission. The affected families often reveal uterine leiomyomas and they have a predisposition to renal cell carcinoma. Here, we report a 51 year-old woman diagnosed with Reed's syndrome and renal angiomyolipoma. Due to the possibility of renal cell carcinoma, Reed's syndrome patients should be evaluated on the basis of renal disease.

Leiomyoma cutis: a clinicopathological series of 37 cases.

BACKGROUND: Cutaneous leiomyomas are benign smooth muscle tumors that comprise three distinct types such as piloleimyoma, angioleiomyoma, and genital leiomyoma. AIM: The objective of this study was to report a series of cases seen in last 8 years in a tertiary care hospital in north India and to discuss their clinicopathologic findings. MATERIAL AND METHODS: Paraffin-embedded blocks of cases reported as cutaneous leiomyoma from 1999 to 2007 were retrieved from the Institute of Pathology, New Delhi, and their clinical parameters were noted. Their histopathological features were reviewed on hematoxylin-eosin stained slides. Immunohistochemistry was performed where necessary. RESULTS: Twenty-seven cases of piloleiomyoma, three cases of angioleiomyoma, five breast leiomyomas, and two scrotal leiomyomas were seen in patients ranging from 21 to 65 years of age, with an average of 38.2 years at presentation. There was a male predominance with 26 males and 11 females (M:F = 2.2:1). Solitary lesions (n = 21) were more common than multiple ( n = 16). The trunk and upper limbs were involved most commonly, comprising 23 of 37 (62.2%) cases. This was followed by lower limb, face, breast, and scrotum. CONCLUSION: Cutaneous leiomyomas are rare lesions and form an important clinical differential diagnosis of painful papulonodules. These must be biopsied in order to differentiate them from other spindle cell lesions.

A Case of Cutaneous Leiomyoma Presenting as a Large Nipple / 대한피부과학회지

Cutaneous leiomyoma is a rare, benign tumor of smooth-muscle fibers. Five types of cutaneous leiomyoma include multiple piloleiomyomas, solitary piloleiomyoma, solitary genital leiomyoma, solitary angioleiomyoma and leiomyoma with additional mesenchymal elements. Genital leiomyoma is uncommon, and leiomyomas of the nipple is a rare type of genital leiomyoma. We report a case of cutaneous leiomyoma presenting as a large nipple in a middle-aged woman.

A Case of Cutaneous Leiomyoma Clinically Mimicking Mondor's Disease / 대한피부과학회지

A 45-year-old man presented with linear cord-like nodules on the left chest and abdomen. He complained of episodic pain and mild tenderness of the lesion. The clinical impression was Mondor's disease and skin biopsy was done. The histopathologic findings revealed a poorly circumscribed tumor composed of interlacing smooth muscle fiber bundles with intermingled collagen, consistent with cutaneous leiomyoma. We report a case of cutaneous leiomyoma clinically mimicking Mondor's disease.

A Case of Linear Multiple Cutaneous Leiomyoma / 대한피부과학회지

We report a case of linear arranged multiple cutaneous leiomyoma in a 45-year-old man. About 20 years ago, multiple normal skin colored firm papules developed on the left anterior chest and increased in number and size arranging in linear pattern. Some larger nodular lesions changed into brown in color and became painful after cold exposure. The lesions looked like keloid at first sight but the histopathologic finding showed typical leiomyoma in which the interlacing bundles of smooth muscle fibers with varying amount of collagen bundles intermingled.

Cutaneous leiomyoma-a clinical and histopathological study / 대한피부과학회지

We reviewed 50 skin biopsies obtained from 40 patients with cutaneous leiomyoma during a 10 year period from January 1980 to December 1989. The result.s were summarized as follows: 1) Sex distribution showed a female preponderance with male.female ratio of 1: 1.9. 2) The age distribution was relatively even from childhood to old age. The mean age was 47,8 years, 3) The most common site of lesion was lower leg(34%) followed by hand(24%), foot(12% ), anterior chest(8% ), face(6% ), neck(4%), upper arm(4% ), labia major(2 %) and nipple(2%). 4) The lesions were relatively well circumscribed subcutaneous nodule, papule, plaque and nodule which measured between 0.3cm to 5cm in size and their colors were erythematous to light brown. 5) The most common clinical and histopathologic type was angioleiomyoma(75%) followed by solitary piloleiomyoma(12.5%), multiple piloleiomyoma(7,5%) and solitary genital leiomyoma(5% ). Angioleiomyomas were clincally associated with cavernous hemangioma, myoma of uterus and systemic lupus erythematosus. 7) The clinical diagnoses were mass(30% ), epidermal cyst(20%), dermatofibroma (12.5% ), leiomyoma(12,5%), neurilemmoma(5%), lipoma(5%), calcifying epithelioma(2.5%), metastatic carcinoma(2.5%), morphea(2.5% ), fibrocystic disease(2.5%), glomus tumor(2.5 % ) and Dupuytrens contracuture(2..5%).