Linear hamartoma syndrome
Overview
Cowden's disease An AD condition characterized by ↑ susceptibility to ectodermal, mesodermal, endodermal mucocutaneous hamartomas, as well as malignancies–eg, papillary or follicular thyroid CA, breast CA, osteosarcoma. Cf Chromosomal breakage syndromes, Li-Fraumani syndrome.
Diagnosis
Proteus syndrome is a rare, sporadic hamartoma syndrome that is characterized by overgrowth of multiple tissues resulting in progressive skeletal deformities, invasive lipomata, vascular malformations, and benign and malignant tumors.1 The features of Proteus syndrome develop early in life and continue to progress throughout life. Diagnostic guidelines and recommendations for the management of Proteus syndrome have been published.1 Mutations in PTEN have been identified in a small number of patients with Proteus syndrome.2 Other conditions characterized by the presence of a germline PTEN mutation include Cowden, Bannayan–Riley–Ruvalcaba and Proteus-like syndromes.6 While there is extensive clinical overlap between these conditions, the mandatory criteria for diagnosis of Proteus disease are mosaic distribution of lesions, progressive course, and sporadic occurrence. Specific criteria include disproportionate overgrowth and epidermal nevi. All of these features were present in this patient. Additionally, he did not have other clinical features usually found in Cowden or Bannayan-Riley-Ruvalcaba syndromes, such as trichilemmomas and mucocutaneous papillomatosis.7 Top of page
Treatment
There is no established therapy for the morbidity caused by the benign tumors seen in hamartoma syndromes. Patients with such syndromes, including tuberous sclerosis complex and Peutz–Jeghers syndrome, harbor germline mutations in tumor suppressor genes that as well as causing the overgrowth of multiple tissues, lead to aberrant mTOR signaling.8 Rapamycin has recently been successfully trialed in patients with tuberous sclerosis complex, in whom it caused regression of subependymal giant cell astrocytomas.9 The high prevalence of somatic PTEN alterations in multiple sporadic tumors, including breast, glioblastoma and endometrial cancer,10 suggests that a broad range of patients with cancer might respond to therapies designed to inhibit the PI3-K/mTOR pathway. Blockade of PI3-K/mTOR signaling using a combination of upstream EGFR inhibitors (gefitinib or erlotinib) along with rapamycin, has shown promise both in cancer cell lines11, 12 and in a pilot clinical trial of recurrent malignant gliomas.13 The identification of causative mutations in genes and/or dysregulation of signaling pathways in certain rare congenital disorders and cancer (e.g. mutations in germline fibroblast growth factor receptor 2 in Apert syndrome and in somatic fibroblast growth factor receptor 2 in certain sporadic cancers) raises the possibility of molecular therapies being developed for some of these rare pediatric syndromes.14 Without the identification of such molecular targets it is unlikely that specific therapies could be developed