Precalcaneal congenital fibrolipomatous hamartomas: is there a pathogenetic relationship with Gardner Syndrome?

ARTICLE

Auteur(s) : Peter H Itin¹, Karl Heinimann², Michèle Attenhofer², Nemya Boesch², Rosaria De Lorenzo¹, Swantje Trüb¹, Bettina Burger³

¹Department of Dermatology, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland
²Research Group Human Genetics, Department of Biomedicine and Division of Medical Genetics, University Children’s Hospital, Basel, Switzerland
³Department of Biomedicine, University Hospital Basel, Switzerland

Precalcaneal congenital fibrolipomatous hamartoma (PCFH) was first described in 1977 by Elsahy and Lorimer, who termed them congenital fibrolipomata [1]. In 1990, the same condition was described in a series of 4 cases [2]. PCFH are clinically characterized by the presence of unilateral or bilateral, symmetric papulous lesions in the medial precalcaneal plantar region of the heel. Because of their distinctive shape and location, diagnosis is usually made clinically. In most cases the lesions appear within the first few months of life but they can be present at birth. The aetiology of PCFH is unknown. Histological examination of lesions shows mature adipose tissue enveloped in predominantly collagenous fibrous sheaths. The differential diagnosis of PCFH, recently discussed in detail [3], includes numerous entities, e.g. juvenile plantar fibromatosis and calcified nodules. However, all of these differ markedly from PCFH, with respect to clinical features.

Gardner syndrome, a variant of familial adenomatous polyposis (FAP), is an autosomal dominant cancer disease caused by mutations in APC (5q21) and is often associated with multiple lipomas and fibromas. The question arises if molecular alterations in Wnt signalling pathway components are involved in PCFH.

We report the occurrence of PCFH in two generations of a family with Gardner syndrome and show that total involution is not obligatory in PCFH. The index patient was a 42-year-old man with Gardner syndrome and a confirmed heterozygous germline mutation in APC exon 15n (c.5942delA, pAsn1981IlefsX62). Physical examination showed malpositioning of the teeth and several pigmented nevi. In addition, two symmetric plantar nodules had been present since birth. The nodules were lipomatous and located medially in the region of the proximal metatarsal bone 1 and the calcaneus. The nodules were about 4 cm in diameter (figure 1). The patient never had pain or discomfort because of the lesions. As germline alterations in PTEN (tumor suppressor phosphatase and tensin homolog) can lead to several syndromes which are associated with lipomas and hamartomas, the coding sequence of the gene was sequenced in our index patient without evidence for pathogenic or polymorphic sequence variants.

The 61-year-old mother of the index patient had similar, but somewhat less pronounced, precalcaneal lesions. She never had subjective or objective problems with her PCFH. Whether substantial regression had taken place was difficult to certify. As further cutaneous manifestations, the patient had had a mucinous cyst operated on her left hand, missing and malpositioned teeth and some pigmented nevi. FAP had been recognized at the age of 55 and confirmed by identification of the same heterozygous mutation as in the son.

Only few reports about long-term evolution of PCFH exist. Interestingly, one of the patients described here is the oldest ever reported with PCFH and gives some insight on the natural course of the disease. The aetiology of PCFH is unclear, although several hypotheses have been proposed. Jacob and Kumm suggest a distinctive form of plantar fibromatosis [4]. Even though most cases occur sporadically, an underlying genetic mechanism is discussed, either of autosomal dominant or of X-linked inheritance. An autosomal dominant inheritance with high penetrance and variable expression has recently been suggested [5]. Our cases also suggest an autosomal dominant mode of transmission and raise the question whether PCFH is related to Gardner syndrome, often associated with multiple lipomas and fibromas, and whether alterations in the Wnt signalling pathway are involved in development of PCFH. Although lipomas are rather prevalent in patients with PTEN mutations, sequencing for PTEN in our index patient showed no pathogenic germline mutation [6]. Further studies are needed to clarify whether there is a mutual step in the APC related Wnt signalling pathway as a clue for a pathogenetic relationship between Gardner syndrome and PCFH.

Acknowledgements

References

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