Rhabdomyomas: an additional BHD hamartoma phenotype?

Hamartomas are benign, focal malformations formed by an excess of normal tissue growing in a disorganised fashion. Several hamartoma syndromes have been linked to aberrant mTOR signalling including BHD and Tuberous Sclerosis Complex (TSC). In addition to the predisposition of BHD patients to develop hair follicle hamartomas or fibrofolliculomas (Birt et al., 1977), Fuyura et al., (2012) propose that the pulmonary cysts in BHD patients are hamartoma-like cystic alveolar formations. The benign nature of these BHD growth phenotypes, in comparison to the potentially malignant growth of BHD renal cell carcinomas, shows that folliculin (FLCN) haploinsufficiency gives a less severe pathology than FLCN loss-of-function.

A recently published study from Bondavalli et al., (2015) was the first report of a cardiac rhabdomyoma (hamartoma) in an infant carrying a FLCN mutation. Cardiac rhabdoyomas are the most common cardiac tumour in children and can be sporadic or syndromic. Syndromic cardiac rhabdomyomas are associated with TSC and mutations in the TSC1 and TSC2 genes, however no such mutations were found in the infant.

A diagnosis of BHD in the extended family subsequently led to identification of a three base pair deletion in FLCN (c.469_471delTTC) in the infant, his mother and grandmother. Although genetic testing for BHD, typically an adult onset disease, is not always recommended for children it was deemed necessary in this case to determine if the child require further monitoring for TSC-associated phenotypes. Examination of the extended family identified a history of fibrofolliculomas but only one case of pneumothorax and one case of RCC.

Two other rhabdomyomas have been reported in BHD patients to date. A laryngeal rhabdomyoma was reported among the cohort assessed in Toro et al (2008). The second patient was diagnosed with BHD and multiple endocrinopathoes and found to have an adult rhabdomyoma in a presumed parathyroid adenoma (Mikesell et al., 2014). In addition cardiac rhabdomyomas have been reported in the Nihon rat model of BHD (n=15/125, Kouchi et al., 2009).

Cardiac rhabdomyomas in TSC patients have been linked to aberrant mTOR signalling (Kotulska et al., 2009) through the loss of regulation by the hamartin (TSC1) and tuberin (TSC2) complex. The mechanism by which FLCN regulates mTOR signalling is not fully understood and appears to be context dependent, but its dysregulation has been linked to the acknowledged BHD pathologies (Baba et al., 2006, Fuyura et al., 2012). Further research is required to determine if FLCN haploinsufficiency in muscle tissue also affects mTOR signalling and can subsequently be linked to rhabdomyoma formation in BHD patients and models.

Bondavalli et al. raise the possibility that mutations in FLCN could be the cause of cardiac rhabdomyomas and argue for BHD to be included in the differential diagnosis of these hamartomas. However they also believe that routine cardiac monitoring of children from BHD is not required. It is possible that the presence of FLCN mutations in patients with these hamartomas is more common but a limited knowledge of BHD, especially among paediatric cardiologists, is resulting in cases going unrecognised. These few reports, whilst insufficient to causatively link BHD and rhabdomyomas, could suggest an additional source of hamartomas associated with a haploinsufficiency of FLCN.


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One thought on “Rhabdomyomas: an additional BHD hamartoma phenotype?

  1. I found the document on rhamdomyomas very information since I had a large benign rhamdomyomas tumour removed as part of a large neck resection surgery. I was diagnosed with BHD when I was 61, late in life I suppose. The document answers the question I had as to whether the neck tumour I had was linked to the BHD.

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