Leiomyomatosis hereditary with renal cell carcinoma

Very rare, autosomal dominant inherited systemic disease ( OMIM 605839) with multiple leiomyomas of the skin and uterus associated with papillary renal cell carcinoma.

The disease is caused by germline mutations of the FH gene(fumarate hydratase gene). The FH gene is located on chromosome 1 (1q42.3-43), consists of 10 exons and codes for the enzyme of the citric acid cycle, fumarate hydratase. Of the 155 mutations detected, 58% are missense mutations, 27% are frameshift mutations, and 9% are nonsense mutations. A correlation between the genotype of the FH mutation and the phenotype could not be established so far.

The mutations lead to an accumulation of fumarate, which in turn leads to an increase in HIF via various mechanisms. This in turn leads to an increase in HIF(hypoxia-induced factor) via various mechanisms. The increased HIF level induces the transcription of growth factors such as VEGF (vascular endothelial growth factor) and GLUT-1 (glucose-transporter type 1), a condition that leads to the corresponding tumor proliferation in the present genetic disposition.

The leading symptom of HLRCC are cutaneous, rarely solitary, but mostly multiple, grouped, also arranged in stripes, 0.2 - 1.0 cm large, skin-colored to brownish, often pressure painful nodules and plaques. Leiomyomas are found in approximately 75% of patients with this syndrome. Leiomyomas of the uterus occur in almost all affected women. In addition, renal cell carcinomas are diagnosed in about 15% of affected patients (usually unilateral, solitary, and aggressive in course). Uterine sarcomas, prostate carcinomas and breast carcinomas have also been described in combination with HLRCC.

In patients with cutaneous leiomyomatosis, molecular genetic testing is indicated. If this confirms a mutation of the FH gene, close tumor screening is indicated for family members who are also genetically affected.

Diagnostic criteria for hereditary leiomyomatosis, adapted from Schmidt et al.

Main criteria (high probability of the presence of hereditary leiomyomatosis):

• - Multiple cutaneous leiomyomas with at least one confirmatory histologic finding
• Secondary criteria (suspected presence of hereditary leiomyomatosis)
• -Solitary cutaneous leiomyoma with positive family history
• -Early occurrence of papillary renal cell carcinoma type II
• -Multiple, early-onset (<40 years), symptomatic uterine leiomyomas

Definitive diagnosis

• - Molecular genetically proven germline mutation of the FH gene

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4. Valero T et al (2016) Painful nodules. J Dtsch Dermatol Ges 14: 627-629