[A man with a red umbilicus]. / Een man met een rode navel.

A 76-year-old man was sent to the dermatology department because of a red, sore belly button since 3 weeks. Based on histology, a CT-scan and increased Cancer Antigen 19-9 levels, this was interpreted as a pancreas carcinoma metastasis. This type of metastasis is also called a 'Sister Mary Joseph's nodule'.

Hereditary leiomyomatosis and renal cell cancer presenting as metastatic kidney cancer at 18 years of age: implications for surveillance.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant syndrome characterized by skin piloleiomyomas, uterine leiomyomas and papillary type 2 renal cancer caused by germline mutations in the fumarate hydratase (FH) gene. Previously, we proposed renal imaging for FH mutation carriers starting at the age of 20 years. However, recently an 18-year-old woman from a Dutch family with HLRCC presented with metastatic renal cancer. We describe the patient and family data, evaluate current evidence on renal cancer risk and surveillance in HLRCC and consider the advantages and disadvantages of starting surveillance for renal cancer in childhood. We also discuss the targeted therapies administered to our patient.

Clinical and molecular genetic aspects of hereditary multiple cutaneous leiomyomatosis.

Multiple cutaneous and uterine leiomyomatosis syndrome (MCUL; OMIM 150800) is an autosomal dominantly inherited tumor predisposition disorder, characterized by leiomyomas of the skin and uterus. When associated with kidney cancer, this syndrome is known as hereditary leiomyomatosis and renal cell cancer (HLRCC; OMIM 605839). All disease variants result from heterozygous mutations in the fumarate hydratase (FH) gene. Cutaneous leiomyoma can easily be recognized and confirmed by histological examination. Recognition of these benign skin tumors can lead to the diagnosis of MCUL or HLRCC. Timely diagnosis is crucial for offering affected individuals and families potentially life-saving regular prophylactic screening examinations for renal tumors. Here we provide an overview of clinical and genetic features of this complex tumor syndrome and discuss patient management and current therapeutic strategies.

Molecular pathways involved in hair follicle tumor formation: all about mammalian target of rapamycin?

Hair follicle tumors show a broad range of phenotypic variability and diverse histopathological characteristics. To date, different genes and signalling cascades have been implicated in the development and growth of these tumors including the sonic hedgehog, nuclear factor kappa-B and wingless pathway. While the former three have received ample attention, little is known about the possible role of mammalian target of rapamycin (mTOR) in trichofollicular tumorigenesis. Here, we delineate how mTOR can link the various signalling pathways, thereby proposing a unifying model for hair follicle tumor formation.

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.

Secondary erythromelalgia involving the ears probably preceding lupus erythematosus.

Secondary erythromelalgia is a rare disease characterized by burning pain, marked erythema, edema, and hyperthermia of the affected limbs. Secondary erythromelalgia can be associated with various systemic diseases. Here, we describe a patient who developed secondary erythromelalgia involving the ears and concomitant clinical and laboratory, probably, indicating the initial stage of a developing lupus erythematosus.

Porphyria cutanea tarda in pre-existent lupus erythematosus--is there an association?

In lupus erythematosus (LE), vesicles and bullae are only rarely seen. However, in some instances such efflorescences might suggest an association with distinct cutaneous diseases, including erythema multiforme, toxic epidermal necrolysis or autoimmune blistering disorders such as bullous pemphigoid, pemphigus vulgaris, and dermatitis herpetiformis Duhring. Another blistering disease that has been described in association with cutaneous and systemic LE is porphyria cutanea tarda (PCT). PCT is a metabolic disorder caused by a deficiency of the fifth enzyme in heme biosynthesis, uroporphyrinogen decarboxylase. Here, we report on a 57-year-old Caucasian woman of Dutch origin with a medical history of mild cutaneous LE who developed skin fragility, blistering skin lesions, milia, and facial hypertrichosis. Subsequent porphyrin analysis in urine and feces confirmed the suspected simultaneous manifestation of LE and PCT.

Dual porphyrias revisited.

The porphyrias are clinically and genetically heterogeneous metabolic diseases, which predominantly result from a hereditary dysfunction in the pathway of haeme biosynthesis. Currently, at least eight different forms of porphyrias can be differentiated, all of them characterized by a specific enzyme deficiency that is either inherited in an autosomal-dominant fashion, autosomal recessively or, in the case of porphyria cutanea tarda, might also be acquired. All genes encoding these enzymes have been cloned and several mutations underlying the different types of porphyrias have been reported. Traditionally, the diagnosis of porphyria is made on the basis of clinical symptoms, characteristic biochemical findings and enzyme assays. In some porphyria patients and families, however, these diagnostic tools can reveal simultaneous findings compatible with two different forms of porphyria, a phenomenon referred to as dual porphyria. Here, we give an overview on what is currently known about these peculiar variants of porphyria and suggest that, whenever feasible, molecular genetic analysis should complement the analytical techniques used to characterize patients and families in which a double enzymatic deficiency within the haeme biosynthetic pathway is assumed.

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.