Sadhanna Badeloe

Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis

Smit DL, Mensenkamp AR, Badeloe S, Breuning MH, Simon MEH, van Spaendonck KY, Aalfs CM, Post JG, Shanley S, Krapels IPC, Hoefsloot LH, van Moorselaar RJA, Starink TM, Bayley J‐P, Frank J, van Steensel MAM, Menko FH. Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis.

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

Abstract:  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.

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?

Abstract:  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.

Wilms tumour as a possible early manifestation of hereditary leiomyomatosis and renal cell cancer

Hereditary leiomyomatosis and renal cell cancer (HLRCC) (OMIM 605839) is a autosomal dominantly inherited tumour predisposition syndrome, characterized by cutaneous and uterine leiomyoma and renal cell cancer (RCC). It is caused by heterozygous mutations in the fumarate hydratase (FH) gene that codes for the enzyme fumarate hydratase (FH) and catalyses the conversion of fumarate to malate in the Krebs cycle. The exact mechanism by which improper FH function leads to tumour formation is still unclear. However, recent studies suggest a pseudohypoxic drive as a possible link between FH dysfunction, the von HippelLindau–hypoxia-inducible factor (HIF) pathway, and cancer development. To date, only four different types of RCC have been observed in HLRCC: papillary type 2 RCC; collecting duct carcinoma; and RCC with oncocytic and with clear cell foci.

Chanarin-Dorfman syndrome caused by a novel splice site mutation in ABHD5.

SIR, Chanarin–Dorfman syndrome (CDS; OMIM 275630) is a rare autosomal recessive metabolic disorder with deposition of cytoplasmic neutral lipid droplets in many cell types, in particular hepatocytes, keratinocytes and granulocytes. CDS is characterized by nonbullous congenital ichthyosiform erythroderma, hepatomegaly and varying developmental delay. Muscle weakness (or myopathy), ataxia, neurosensory hearing loss, subcapsular cataracts and nystagmus can be present. Expression of the syndrome is variable, but the diagnosis can be easily confirmed by a peripheral blood smear, which shows lipid droplets in granulocytes, known as Jordan’s anomaly. Mutations in the ABHD5 (formerly CGI-58) gene on chromosome 3p21 have recently been identified as the genetic defect responsible for CDS. The ABHD5 gene product is a necessary cofactor for adipose triglyceride lipase (ATGL)mediated lipolysis and may also function in arachidonic acid metabolism. A 10-year-old boy with dry scaling skin was known to us from the age of 2 years onward. He was born from a fullterm normal pregnancy to consanguineous (first cousins) Turkish parents. No other family member had a similar skin disorder. The ichthyosis reportedly developed shortly after birth, but there was no history of erythroderma. On the most recent examination, the skin was slightly erythematous with fine scaling. The neck showed skin lichenification. On the trunk we saw nummular scaly patches with adherent fine grey-white scaling (Fig. 1a, b). We observed a diffuse white lamellar scaling on the face with a mild lateral ectropion of the lower eyelids. The scalp also showed white scaling with a clear-cut border following the hairline. The knees showed hyperkeratosis. The palms and soles were spared hyperkeratosis; nails and teeth were normal. He was under paediatric care for lactose intolerance and small stature. Several diagnoses had been entertained, including lamellar ichthyosis, erythrokeratodermia variabilis and, lately, nonbullous congenital ichthyosiform erythroderma. However, the last physical examination revealed hepatomegaly, suggestive of CDS. Ultrasound examination subsequently confirmed an enlarged liver with homogeneous normal echogenicity. When asked during the examination, both the patient and his parents could not recall him having had significant abdominal complaints. A peripheral blood smear showed leucocytes containing prominent lipid vacuoles (Jordan bodies; Fig. 1c), a pathognomonic finding in CDS. A skin biopsy was refused. Laboratory tests including full blood cell count, electrolytes and muscle enzymes were normal. Liver enzymes were slightly elevated: aspartate aminotransferase 89 IU L (reference 15–35 IU L), alanine aminotransferase 81 IU L (reference 15–35 IU L) and alkaline phosphatase 230 IU L (reference 10–140 IU L). After obtaining informed consent from the parents and assent from the patient, we drew ethylenediamine tetraacetic acid blood samples from the patient and his parents and isolated DNA from peripheral blood leucocytes using a saltingout procedure as described elsewhere. All coding exons and splice junctions of the ABHD5 gene were amplified using polymerase chain reaction (PCR; primer sequences and reaction conditions available upon request). We then directly sequenced the PCR products on an ABI 3730 capillary system (Applied Biosystems, Nieuwerkerk a ⁄d Ijssel, the Netherlands). Sequence traces were assembled using the Phred-Phrap-Consed software package. We found a novel homozygous point mutation affecting the predicted splice-donor site of intron 6 (IVS6+6 A>T). For reverse transcriptase (RT)-PCR, we extracted RNA from whole blood using the RNEasy RNA extraction kit (Qiagen Benelux BV, Venlo, the Netherlands). First-strand cDNA synthesis was performed using the Superscript first-strand synthesis system (Invitrogen, Groningen, the Netherlands) according to the manufacturer’s instructions.

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.

Granulomatous rosacea and Crohn’s disease in a patient homozygous for the Crohn-associated NOD2/CARD15 polymorphism R702W

Abstract:  NOD2/CARD15 belongs to the N‐terminal caspase recruitment domain family of proteins involved in regulating NF‐kB activation in response to inflammatory stimuli transduced through Toll‐like receptors. Mutations and polymorphisms in the NOD2/CARD15 gene reduce antibacterial responses and are associated with granulomatous inflammatory conditions such as Blau syndrome and early‐onset sarcoidosis. The polymorphism R702W (arginine to tryptophan) is strongly associated with susceptibility to Crohn’s disease in Caucasian populations. Skin abnormalities (other than cutaneous manifestations of Crohn’s disease) have not been previously associated with R702W. We report on a female patient homozygous for R702W who developed granulomatous rosacea at the age of 12 years old. From the occurrence in the context of Crohn associated with R702W, we speculate that granulomatous rosacea may be an entity distinct from other forms of rosacea, which are associated with increased production of antibacterial proteins such as cathelicidin.

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.

Dual porphyrias revisited

Abstract:  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.