Multiple cutaneous and uterine leiomyomata resulting from missense mutations in the fumarate hydratase gene

Multiple cutaneous and uterine leiomyomata (MCL) is an autosomal dominant disorder characterized by the development of benign smooth muscle tumours (leiomyomas) in the skin and uterus of affected women, and in the skin of affected men. In rare cases, MCL has been associated with a predisposition to the rare type II papillary renal cell cancer, also known as hereditary leiomyomatosis and renal cell cancer. The genetic locus for MCL has been mapped to chromosome 1q42.3-43 and subsequently, germline mutations in the fumarate hydratase (FH) gene have been identified. In addition, analysis of FH in some tumours of MCL patients revealed a second mutation inactivating the wild-type allele, suggesting that FH may function as a tumour suppressor gene. Here, we report two cases of MCL patients with FH mutations, designated as T287P and R190L. T287P represents a novel mutation of a highly conserved amino acid of the FH protein. In addition, a patient with an unusual clinical presentation of MCL was found to have the recurrent mutation, R190L, raising the possibility of incorporating FH sequencing as a diagnostic tool. Our findings extend the allelic series of mutations in FH and support its status as the underlying cause of MCL.     

Fumarate hydratase mutations and predisposition to cutaneous leiomyomas, uterine leiomyomas and renal cancer

Germline heterozygous loss-of-function mutations of fumarate hydratase (FH) predispose to the autosomal dominant syndrome of multiple cutaneous and uterine leiomyomatosis (MCUL). Forty-five distinct FH mutations have been identified in 76 of 89 (85%) reported probands with skin leiomyomas. This suggests that MCUL is a genetically homogeneous condition and that most patients presenting with skin leiomyomas will have underlying FH mutations. FH mutations identified include 26/45 (58%) missense; 12/45 (27%) frameshift, 4/45 (9%) nonsense changes and 3/45 (7%) different whole gene deletions. In MCUL kindreds, the majority of females with FH mutations have both skin and uterine leiomyomas. A proportion of individuals with FH mutations have associated renal cancer, a variant known as hereditary leiomyomatosis and renal cell cancer (HLRCC). If selection bias is removed, the prevalence of renal cancer in MCUL lies between one of 46 (2%) families who were not radiologically screened, and two of 32 (6%) families who were radiologically screened. Truncating, particularly frameshift, mutations appear to be significantly associated with renal cancer (P = 0.003), suggesting a possible basis for selective screening. There may also be a significantly increased rate of renal cancer in females (P = 0.004), suggesting a possible role for hormonal factors. Review of the literature suggests that, unlike most individuals presenting with skin leiomyomas, the majority of patients presenting with uterine leiomyomas or renal cancer will not have underlying FH mutations.     

Diffuse and segmental variants of cutaneous leiomyomatosis: novel mutations in the fumarate hydratase gene and review of the literature

Multiple cutaneous and uterine leiomyomatosis (MCUL; OMIM 150800) is an autosomal dominantly inherited disease characterized by leiomyomas of the skin and uterine leiomyomas. Recently, association of MCUL with different forms of renal cancer has been described. This syndrome is referred to as hereditary leiomyomatosis and renal cell cancer (OMIM 605839). Both disorders result from heterozygous germline mutations in the fumarate hydratase (FH) gene that may function as a tumor suppressor. Interestingly, cutaneous leiomyomas do not only manifest in a diffuse and symmetric fashion. Rather frequently, a segmental or band-like manifestation pattern can be observed, usually following the lines of Blaschko. Here, we sought to elucidate the molecular basis of diffuse and segmental cutaneous leiomyomatosis in six unrelated Dutch and Spanish patients and their families. We identified six novel FH mutations, including one missense and one nonsense mutation, two deletions and two splice-site mutations. The segmental phenotype that was observed in various patients with FH mutations most likely reflects a type 2 segmental manifestation of cutaneous leiomyomatosis as previously also described for other autosomal dominantly inherited skin diseases. The results presented here extend the current data on the molecular basis of familial cutaneous leiomyomatosis and comprise, to the best of our knowledge, the first genetic study in Dutch and Spanish patients with this disorder. In addition, we review the clinical and molecular aspects of the disease.     

Absence of fumarate hydratase mutation in a family with cutaneous leiomyosarcoma and renal cancer

A 41-year-old man was diagnosed with a cutaneous leiomyosarcoma on the left shoulder. Family history revealed that his brother had died of a metastatic kidney tumor at young age. Although apparently rare, the familial occurrence of cutaneous leiomyosarcoma with renal cancer has been described in the context of hereditary cutaneous leiomyomatosis and renal cell cancer (HLRCC). This rare genetic syndrome is caused by heterozygous mutations in the fumarate hydratase (FH) gene. Hence, the manifestation of these two rare malignancies within one family was strongly suggestive of a common underlying genetic defect. However, mutation analysis in the FH gene excluded HLRCC in this family. Although the familial occurrence of these rare tumors might be coincidental, it cannot be ruled out that, beside FH, mutations in another as yet unknown gene could give rise to both leiomyosarcoma and kidney cancer.     

Familial multiple cutaneous and uterine leiomyomas associated with papillary renal cell cancer

Multiple cutaneous and uterine leiomyomas is an autosomal dominant condition that results in benign smooth muscle tumours of the skin and, in females, uterine fibroids. This syndrome overlaps with hereditary leiomyomatosis and renal cell cancer syndrome in which affected individuals may develop the rare type II papillary renal cell cancer, in addition to skin leiomyomas. Recently, heterozygous mutations in the gene encoding fumarate hydratase have been found to underlie both conditions. Fumarate hydratase is an enzyme that catalyses the conversion of fumarate to malate in the Kreb's cycle and may also function as a tumour suppressor gene. We report a family with multiple leiomyomas, uterine fibroids and papillary renal cell cancer. The proband is a 77-year-old Polish woman who developed multiple cutaneous leiomyomas on her right upper arm in her thirties and subsequently underwent a hysterectomy for uterine fibroids in her forties. She has four offspring: her eldest daughter also has skin and uterine leiomyomas with a similar onset; her son has multiple skin leiomyomas and in addition was diagnosed with metastatic papillary renal cell cancer at the age of 50 years; the two youngest daughters are unaffected. DNA sequencing in all the affected individuals disclosed a heterozygous G-->C substitution at nucleotide 173 of the fumarate hydratase gene, that converts an arginine residue (CGA) to proline (CCA). This missense mutation has not been reported previously and is designated R58P. Interestingly, the clinically asymptomatic 20-year-old son of the individual with renal cancer was also found to be heterozygous for R58P. It is likely that he will develop skin leiomyomas in the future but the risk of renal cancer is difficult to predict. Nevertheless, detection of this mutation has important implications for screening and genetic counselling in this and other family members.     

The syndrome of hereditary leiomyomatosis and renal cell cancer (HLRCC): The clinical features of an individual with a fumarate hydratase gene mutation

A 55-year-old woman presented with multiple cutaneous leiomyomas and multiple uterine leiomyomas (fibroids). The clinical diagnosis of the autosomal dominant hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome was confirmed by identification of a fumarate hydratase gene mutation. This case highlights the need to consider the possibility of renal and uterine cancer in members of cutaneous leiomyomatosis families.     

Hereditary cutaneous leiomyomatosis

The occurrence of multiple cutaneous leiomyomas can be indicative of hereditary cutaneous leiomyomatosis. This autosomal dominant disorder is due to germline mutations in the fumarate hydratase (FH) gene. Associations with uterine myomas and renal cell carcinomas have been described and are referred to as Multiple Cutaneous and Uterine Leiomyomas (MCUL) or Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC), respectively. A 34-year-old man presented with multiple red-brown papules and nodules. After histopathologic confirmation of piloleiomyomas, we made the diagnosis of hereditary cutaneous leiomyomatosis. Taking into consideration the aforementioned complications, close interdisciplinary management of these patients and regular screening examinations within affected families are mandatory.     

Clinical features of multiple cutaneous and uterine leiomyomatosis: an underdiagnosed tumor syndrome

OBJECTIVE: To investigate the clinical features of the multiple cutaneous and uterine leiomyomatosis (MCUL) syndrome, including the hereditary leiomyomatosis and renal cell cancer syndrome. DESIGN: A case series of patients with multiple skin leiomyomas solicited via a circular letter to dermatologists. SETTING: Research institute. PATIENTS: A total of 108 affected individuals, including 46 probands and 62 affected relatives. MAIN OUTCOME MEASURES: The proportion of probands with underlying fumarate hydratase (FH) mutations, the penetrance of FH mutations, and clinicopathologic features of MCUL. RESULTS: Forty-one (89%) of 46 probands with multiple skin leiomyomas had evidence of germline FH mutations, which were highly penetrant. All 26 male mutation carriers had skin leiomyomas. Of 67 women with FH mutations, 46 (69%) had both skin and uterine leiomyomas; 10 (15%) had only skin leiomyomas; 5 (7%) had only uterine leiomyomas; and 6 (9%) were clinically unaffected. Patients presented with skin leiomyomas at a mean age of 24 years and had a mean of 25 lesions. Forty-one individuals (89%) reported painful lesions, particularly in response to cold or trauma. Fibroids were histologically unremarkable, highly symptomatic, and associated with a high risk of early hysterectomy. One individual had a very aggressive collecting duct renal cancer. The G354R FH mutation predisposed patients to uterine fibroids without skin leiomyomas (P = .03). Many patients with skin leiomyomas had not previously presented for medical attention. Fibroids were rarely recognized as cases of MCUL. CONCLUSIONS: Highly penetrant FH mutations underlie MCUL. Increased clinical awareness is important because of the associated risk of severe uterine fibroids and, in some cases, aggressive renal cancer.     

Familial leiomyomatosis cutis et uteri

A 45-year-old woman presented with multiple, small, asymptomatic, hyperpigmented to skin-colored, smooth, dermal papules on the right temple as well as with uterine fibroids. She has a family history of uterine fibroids and cutaneous leiomyomas. An autosomal dominant disorder of multiple cutaneous leiomyomas and uterine fibroids (Reed syndrome) has been localized to a gene on chromosome 1q42.3-43. This gene encodes fumarate hydratase, which is an enzyme in the Kreb cycle, that acts as a tumor suppressor in this familial disorder. A subset of people may be at risk for papillary renal cell carcinoma.     

Hereditary leiomyomatosis and renal cell carcinoma syndrome: a case report

The simultaneous occurrence of multiple cutaneous leiomyomas, uterine leiomyomatosis, and renal cancer is described as a cancer syndrome with an autosomal dominant pattern of inheritance. We report a 79-year-old man who presented with multiple hyperkeratotic, erythematous nodules on his right leg with a histological diagnosis of pilar leiomyoma. In a review of systems, gross hematuria, weight loss, and bone pain were noted. His pathologic diagnosis was determined to be metastatic papillary renal cell carcinoma. A family history revealed that his sister had a hysterectomy for uterine leiomyomas. The findings in this case can be attributed to hereditary leiomyomatosis and renal cell carcinoma syndrome.     

Familial leiomyomatosis: a review and discussion of pathogenesis

Multiple cutaneous leiomyomas of pilar origin have long been recognized to have an autosomal dominant inheritance. While the skin tumors are relatively uncommon and benign, women of affected families often develop uterine fibroids with associated infertility, pain and bleeding. In addition, a subset of these families harbors a predisposition to papillary renal cell carcinoma. Germline mutations in a recently identified classical tumor suppressor gene encoding fumarate hydratase are observed in these individuals. Appropriate screening measures for associated disorders are mandatory.     

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.     

The dermatologist's guide to hereditary syndromes with renal tumors

Patients with hereditary syndromes with renal tumors initially may present to the dermatologist. It is essential that dermatologists recognize these syndromes because the early diagnosis of renal cancer may prove to be lifesaving. The 4 hereditary syndromes with cutaneous manifestations are von Hippel-Lindau (VHL) syndrome, Birt-Hogg-Dube (BHD) syndrome, tuberous sclerosis (TS), and hereditary leiomyoma renal cell carcinoma (HLRCC) syndrome. This article reviews these disorders, emphasizing their cutaneous features and renal manifestations.     

Multiple linear leiomyomas of the forehead as the presenting sign of Reed syndrome

A 62‐year‐old female presented with a linear arrangement of multiple asymptomatic, discrete, dome‐shaped, smooth, skin‐colored papules and nodules involving the left forehead. Histopathology showed a poorly circumscribed nodule of haphazardly arranged fascicles of smooth muscle cells involving the papillary and superficial reticular dermis. Genetic testing revealed the patient to be heterozygous for the R233H mutation in the fumarate hydratase gene. Clinical, microscopic, and genetic findings were consistent with a diagnosis of Reed syndrome. Reed syndrome is a rare disorder defined by cutaneous and uterine leiomyomas and, uncommonly, renal cell carcinoma.     

Multiple familial cutaneous leiomyoma

INTRODUCTION: Cutaneous leiomyoma is a benign tumor, the discovery of which may suggest a hereditary form. We report a family in which 5 generations developed cutaneous and uterine leiomyomas. The originality of this report lies in the large number of generations developing the disease and the association with chronic myeloid leukemia. OBSERVATIONS: We have studied 16 members of a family with cutaneous and uterine leiomyomas spanning five generations. Eight members of the family (6 women and 2 men) presented with cutaneous leiomyomas. All 6 women also had uterine myomas with complications (menometrorrhagia, miscarriage, premature delivery and hysterectomy). Pathological association was also confirmed: polycythemia (1 case), papillary renal carcinoma (1 case) and chronic myeloid leukemia (1 case). DISCUSSION: Piloleiomyoma can develop sporadically or can be transmitted genetically. To our knowledge, we report the fifth case of a family of more than 2 generations presenting with piloleiomyoma. By studying the family tree, we were able to confirm the dominant autosomal nature of the mode of transmission found by other authors. The association of piloleiomyoma and uterine myoma is classified as Reed's syndrome. In such cases, the uterine myoma requires particularly careful monitoring since it is associated with significant risk of gynecological complications (menometrorrhagia, miscarriage, premature delivery and postpartum hemorrhage). Moreover, in our observations we describe diseases associated with piloleiomyoma: polycythemia (1 case), papillary renal carcinoma (1 case), but also the association of piloleiomyoma with chronic myeloid leukemia (1 case). A previous report described the same genetic deletion in uterine myoma as in chronic myeloid leukemia, which gives further weight to this association.     

Treatment of three hereditary leiomyomatosis patients with cryotherapy

Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome is an autosomal dominant disorder characterized by cutaneous leiomyomas (CLM), uterine leiomyomas, and the increased risk of renal cell carcinoma. Piloleiomyomas develop from the arrectorpili muscle and are usually painful. For 22% of the affected patients, the pain is reported to impair their life quality. Since there are few case reports about cryotherapy for cutaneous leiomyomas in the literature, we have decided to present three patients who had painful cutaneous leiomyomas treated with cryotherapy.     

Novel mutations in the BHD gene and absence of loss of heterozygosity in fibrofolliculomas of Birt-Hogg-Dubé patients

Birt-Hogg-Dubé (BHD) syndrome is an autosomal-dominantly inherited cancer syndrome characterized by fibrofolliculomas, lung cysts leading to pneumothorax, and chromophobic/oncocytic renal cell carcinoma. The disease is caused by heterozygous mutations in the BHD gene encoding folliculin and all mutations reported putatively lead to protein truncation. Although the function of folliculin is unknown, it is thought to be a tumor suppressor, with loss of heterozygosity (LOH) initiating tumor formation. Here, we report on four novel BHD gene mutations, including two splice-site mutations, in patients presenting with skin lesions only. We further show that LOH cannot be detected in fibrofolliculomas from three patients, suggesting that for the manifestation of cutaneous tumors in BHD syndrome haplo-insufficiency of folliculin is sufficient to initiate uncontrolled growth. Renal microscopic oncocytosis in BHD is considered as a precursor to malignant kidney tumors and may likewise be the result of haplo-insufficiency, with somatic second-hit mutations or LOH giving rise to malignancy later in life.     

Multiple cutaneous and uterine leiomyomatosis (Reed's syndrome)

A 51-year-old woman with a history of uterine fibroids status post myomectomy and hysterectomy presented for evaluation and treatment of intermittently painful papules of the left shoulder. Histopathologic examination showed a proliferation of smooth muscle fascicles consistent with the diagnosis of cutaneous leiomyomas. Genetic sequencing demonstrated a novel mutation in the fumarate hydratase gene that confirmed the diagnosis of Reed's syndrome. A subset of individuals with Reed's syndrome is predisposed to develop a papillary renal-cell carcinoma, so appropriate radiologic examinations should be performed. Treatment of the pain caused by cutaneous leiomyomas includes the use of nifedipine, nitroglycerine, phenoxybenzamine, surgical excision, and carbon dioxide laser ablation.     

Association of multiple familial cutaneous leiomyoma with a uterine symplastic leiomyoma

We describe a patient who has familial cutaneous leiomyoma in association with a symplastic uterine leiomyoma. This association has not been described previously.     

Familial cutaneous and uterine leiomyomas: case report

Cutaneous leiomyomas are rare, benign tumors arising from the arrectores pilorum muscles of the skin, the tunica dartos of the scrotum, muscles of the areola of the nipple, and vulvar or vascular smooth muscles. Multiple cutaneous leiomyomas originate from the arrectores pilorum muscles of the skin (piloleiomyomata cutis). Occasionally, they seem hereditary and may be associated with uterine myomas. We present a family in which the mother and 4 of her 6 daughters had uterine myomas. All sisters had to undergo hysterectomy before the age of 40, and three of them had multiple cutaneous leiomyomas simultaneously. Our observations support the suggestion that this kind of leiomyomas is a disorder with autosomal dominant inheritance with incomplete gene penetration. Moreover, the data indicate the necessity of periodical examinations to rule out the presence of uterine myomas not only in cutaneous leiomyoma patients, but also in other women in a given family.