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.

 

  • Baba M, Hong SB, Sharma N, Warren MB, Nickerson ML, Iwamatsu A, Esposito D, Gillette WK, Hopkins RF 3rd, Hartley JL, Furihata M, Oishi S, Zhen W, Burke TR Jr, Linehan WM, Schmidt LS, Zbar B. Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proc Natl Acad Sci U S A. 2006 Oct 17;103(42):15552-7. PubMed PMID: 17028174.
  • Birt AR, Hogg GR, Dubé WJ. Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol. 1977 Dec;113(12):1674-7. PubMed PMID: 596896.
  • Bondavalli D, White SM, Steer A, Pflaumer A, Winship I. Is cardiac rhabdomyoma a feature of Birt Hogg Dubé syndrome? Am J Med Genet A. 2015 Apr;167(4):802-4. PubMed PMID: 25655561.
  • Furuya M, Tanaka R, Koga S, Yatabe Y, Gotoda H, Takagi S, Hsu YH, Fujii T, Okada A, Kuroda N, Moritani S, Mizuno H, Nagashima Y, Nagahama K, Hiroshima K, Yoshino I, Nomura F, Aoki I, Nakatani Y. Pulmonary cysts of Birt-Hogg-Dubé syndrome: a clinicopathologic and immunohistochemical study of 9 families. Am J Surg Pathol. 2012 Apr;36(4):589-600. PubMed PMID: 22441547.
  • Kotulska K, Larysz-Brysz M, Grajkowska W, Jóźwiak J, Włodarski P, Sahin M, Lewin-Kowalik J, Domańska-Pakieła D, Jóźwiak S. Cardiac rhabdomyomas in tuberous sclerosis complex show apoptosis regulation and mTOR pathway abnormalities. Pediatr Dev Pathol. 2009 Mar-Apr;12(2):89-95. Epub 2007 Jul 30. PubMed PMID: 17990907.
  • Kouchi M, Okimoto K, Matsumoto I, Tanaka K, Yasuba M, Hino O. Natural history of the Nihon (Bhd gene mutant) rat, a novel model for human Birt-Hogg-Dubé syndrome. Virchows Arch. 2006 Apr;448(4):463-71. PubMed PMID: 16447066.
  • Luijten MN, Basten SG, Claessens T, Vernooij M, Scott CL, Janssen R, Easton JA, Kamps MA, Vreeburg M, Broers JL, van Geel M, Menko FH, Harbottle RP, Nookala RK, Tee AR, Land SC, Giles RH, Coull BJ, van Steensel MA. Birt-Hogg-Dube syndrome is a novel ciliopathy. Hum Mol Genet. 2013 Nov 1;22(21):4383-97. PubMed PMID: 23784378.
  • Mikesell KV, Kulaylat AN, Donaldson KJ, Saunders BD, Crist HS. A rare soft tissue tumor masquerading as a parathyroid adenoma in a patient with birt-hogg-dubé syndrome and multiple cervical endocrinopathies. Case Rep Pathol. 2014; 2014:753694. PubMed PMID: 25610687.
  • Toro JR, Wei MH, Glenn GM, Weinreich M, Toure O, Vocke C, Turner M, Choyke P, Merino MJ, Pinto PA, Steinberg SM, Schmidt LS, Linehan WM. BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports. J Med Genet. 2008 Jun;45(6):321-31. Review. PubMed PMID: 18234728.
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