Anetoderma arising in Reed syndrome: a case report and review of the literature.

Anetoderma is a cutaneous disorder characterized by loss of dermal elastic tissue resulting in papules from herniation of subcutaneous tissue or circumscribed areas of atrophic, wrinkled skin. Familial leiomyomatosis cutis et uteri (Reed syndrome) is an autosomal dominant disorder characterized by cutaneous and uterine leiomyomas. We report a 23-year-old male with Reed syndrome who presented with asymptomatic pearly white, atrophic, flaccid papules on the upper back and shoulder that depressed when palpated. Pathologic examination showed an unremarkable epidermis and central loss of dermal elastin, bordered by clumped elastin, as revealed with an elastin stain. The correlation of clinical and pathologic findings indicated a diagnosis of anetoderma arising in a patient with Reed syndrome.

[Hereditary cutaneous leiomyomatosis]. / Hereditäre kutane Leiomyomatose.

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.

The glycolytic shift in fumarate-hydratase-deficient kidney cancer lowers AMPK levels, increases anabolic propensities and lowers cellular iron levels.

Inactivation of the TCA cycle enzyme, fumarate hydratase (FH), drives a metabolic shift to aerobic glycolysis in FH-deficient kidney tumors and cell lines from patients with hereditary leiomyomatosis renal cell cancer (HLRCC), resulting in decreased levels of AMP-activated kinase (AMPK) and p53 tumor suppressor, and activation of the anabolic factors, acetyl-CoA carboxylase and ribosomal protein S6. Reduced AMPK levels lead to diminished expression of the DMT1 iron transporter, and the resulting cytosolic iron deficiency activates the iron regulatory proteins, IRP1 and IRP2, and increases expression of the hypoxia inducible factor HIF-1α, but not HIF-2α. Silencing of HIF-1α or activation of AMPK diminishes invasive activities, indicating that alterations of HIF-1α and AMPK contribute to the oncogenic growth of FH-deficient cells.

Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase.

Fumarate hydratase (FH) is an enzyme of the tricarboxylic acid cycle (TCA cycle) that catalyses the hydration of fumarate into malate. Germline mutations of FH are responsible for hereditary leiomyomatosis and renal-cell cancer (HLRCC). It has previously been demonstrated that the absence of FH leads to the accumulation of fumarate, which activates hypoxia-inducible factors (HIFs) at normal oxygen tensions. However, so far no mechanism that explains the ability of cells to survive without a functional TCA cycle has been provided. Here we use newly characterized genetically modified kidney mouse cells in which Fh1 has been deleted, and apply a newly developed computer model of the metabolism of these cells to predict and experimentally validate a linear metabolic pathway beginning with glutamine uptake and ending with bilirubin excretion from Fh1-deficient cells. This pathway, which involves the biosynthesis and degradation of haem, enables Fh1-deficient cells to use the accumulated TCA cycle metabolites and permits partial mitochondrial NADH production. We predicted and confirmed that targeting this pathway would render Fh1-deficient cells non-viable, while sparing wild-type Fh1-containing cells. This work goes beyond identifying a metabolic pathway that is induced in Fh1-deficient cells to demonstrate that inhibition of haem oxygenation is synthetically lethal when combined with Fh1 deficiency, providing a new potential target for treating HLRCC patients.

Morphologic features of uterine leiomyomas associated with hereditary leiomyomatosis and renal cell carcinoma syndrome: a case report.

Patients with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome are prone to develop smooth muscle tumors of the uterus and skin and also renal carcinomas. The morphologic features of renal tumors that arise in the setting of HLRCC are well described, the hallmark feature being the presence of prominent eosinophilic nucleoli surrounded by a clear halo. Renal tumors associated with HLRCC are aggressive and often present late with high-stage disease. Early detection of patients with HLRCC could lead to surveillance for renal carcinomas. Women with HLRCC often present at a young age with uterine leiomyomas and frequently undergo hysterectomy as a result. HLRCC associated uterine leiomyomas show nuclear features similar to those described in HLRCC associated renal tumors. Therefore, presence of these nuclear features in uterine smooth muscle tumors may aid in early detection of HLRCC, resulting in surveillance for renal carcinoma. We present a case of a 32-year-old woman who underwent hysterectomy for uterine fibroids and subsequently presented 5 years later with high-stage renal carcinoma. Histologic evaluation of uterine leiomyomas and renal carcinoma revealed identical nuclear features, that is, prominent nucleoli with perinucleolar halos, raising the possibility of HLRCC. Subsequent testing confirmed a fumarate hydratase mutation. The presence of above-described nuclear features in uterine leiomyomas should raise the possibility of HLRCC.

Novel FH mutations in families with hereditary leiomyomatosis and renal cell cancer (HLRCC) and patients with isolated type 2 papillary renal cell carcinoma.

BACKGROUND: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder predisposing humans to cutaneous and uterine leiomyomas; in 20% of affected families, type 2 papillary renal cell cancers (PRCCII) also occur with aggressive course and poor prognosis. HLRCC results from heterozygous germline mutations in the tumour suppressor fumarate hydratase (FH) gene. METHODS: As part of the French National Cancer Institute (INCa) 'Inherited predispositions to kidney cancer' network, sequence analysis and a functional study of FH were preformed in 56 families with clinically proven or suspected HLRCC and in 23 patients with isolated PRCCII (5 familial and 18 sporadic). RESULTS: The study identified 32 different germline FH mutations (15 missense, 6 frameshifts, 4 nonsense, 1 deletion/insertion, 5 splice site, and 1 complete deletion) in 40/56 (71.4%) families with proven or suspected HLRCC and in 4/23 (17.4%) probands with PRCCII alone, including 2 sporadic cases. 21 of these were novel and all were demonstrated as deleterious by significant reduction of FH enzymatic activity. In addition, 5 asymptomatic parents in 3 families were confirmed as carrying disease-causing mutations. CONCLUSIONS: This study identified and characterised 21 novel FH mutations and demonstrated that PRCCII can be the only one manifestation of HLRCC. Due to the incomplete penetrance of HLRCC, the authors propose to extend the FH mutation analysis to every patient with PRCCII occurring before 40 years of age or when renal tumour harbours characteristic histologic features, in order to discover previously ignored HLRCC affected families.

Hereditary leiomyomatosis and renal cell cancer: update on clinical and molecular characteristics.

Hereditary leiomyomatosis and renal cell cancer (HLRCC, also known as multiple cutaneous and uterine leiomyomatosis, MCUL) is a highly penetrant autosomal dominant tumor predisposition syndrome characterized by benign leiomyomas of the skin and the uterus. Renal cell carcinomas, occurring in a subset of the HLRCC families, are exceptionally aggressive. Therefore careful, frequent surveillance strategies are recommended. Association of malignant smooth-muscle tumors, leiomyosarcomas, with HLRCC has been observed but the risk appears to be smaller than initially estimated. To date inactivating heterozygous mutations in the fumarate hydratase (FH, fumarase) gene, predisposing to HLRCC, have been found in approximately 180 families worldwide. The most extensively studied hypothesis on molecular mechanisms of HLRCC tumorigenesis is activation of the hypoxia pathway due to aberrant stabilization of the HIF1 transcription factor. HIF1 regulates transcription of genes relevant for vascularization, glucose transport and glycolysis, processes that facilitate tumor growth. However, additional mechanisms underlying tumor formation are likely to exist.

Genetics of familial renal cancers.

Renal cell carcinoma (RCC) is a heterogeneous disorder. A variety of histopathological subtypes occur, and the molecular mechanisms associated with these subtypes can differ. Only a small fraction of all RCC is accounted for by inherited cases (e.g. von Hippel-Lindau disease, Birt-Hogg-Dubé syndrome, hereditary leiomyomatosis renal cell cancer), but such cases can pose specific clinical management issues and offer opportunities for early cancer detection and prevention. Furthermore, inherited RCC syndromes have provided important paradigms to study the molecular basis of renal tumourigenesis. The identification of molecular mechanisms of carcinogenesis in inherited RCC syndromes should lead to novel approaches to personalized therapeutics.