Lack of mutation–histopathology correlation in a patient with Proteus syndrome

Abstract

Proteus syndrome (PS) is characterized by progressive, disproportionate, segmental overgrowth and tumor susceptibility caused by a somatic mosaic AKT1 activating mutation. Each individual has unique manifestations making this disorder extremely heterogeneous. We correlated three variables in 38 tissue samples from a patient who died with PS: the gross affection status, the microscopic affection status, and the mutation level. The AKT1 mutation was measured using a PCR-based RFLP assay. Thirteen samples were grossly normal; six had detectable mutation (2-29%) although four of these six were histopathologically normal. Of the seven grossly normal samples that had no mutation, only four were histologically normal. The mutation level in the grossly abnormal samples was 3-35% and all but the right and left kidneys, skull, and left knee bone, with mutation levels of 19%, 15%, 26%, and 17% respectively, had abnormal histopathology. The highest mutation level was in a toe bone sample while the lowest levels were in the soft tissue surrounding that toe, and an omental fat nodule. We also show here that PS overgrowth can be caused by cellular proliferation or by extracellular matrix expansion. Additionally, papillary thyroid carcinoma was identified, a tumor not previously associated with PS. We conclude that gross pathology and histopathology correlate poorly with mutation levels in PS, that overgrowth can be mediated by cellular proliferation or extracellular matrix expansion, and that papillary thyroid carcinoma is part of the tumor susceptibility of PS. New methods need to be developed to facilitate genotype-phenotype correlation in mosaic disorders.

Characterization of the hepatosplenic and portal venous findings in patients with Proteus syndrome

“…Both died from pulmonary emboli. One patient was the subject of a recent case report (Doucet, Bloomhardt, Moroz, Lindhurst, & Biesecker, ) and was found to have numerous dark brown to black nodular lesions in her spleen that microscopically were identified as cavernous VMs.…”

Prenatal diagnosis of Proteus syndrome: Diagnosis of an AKT1 mutation from amniocytes

“…Tissue from an overgrown area is ideal to test for variants in overgrowth disorders, however, sampling may be technically difficult, and still may not discover a causative variant. Doucet, Bloomhardt, Moroz, Lindhurst, and Biesecker (2016) performed targeted mutation testing from multiple postmortem tissues in a patient with Proteus syndrome, and reported that the level of detectable mutation did not correlate with demonstrable gross or microscopic findings. Cell culturing may enhance diagnostic yield in overgrowth disorders, as culturing may select for cells with a positive variant and thus a proliferative advantage (Chang et al, 2017; Lalonde et al, 2019).…”

Molecular heterogeneity of the cerebriform connective tissue nevus in mosaic overgrowth syndromes

“…Analogous to the argument above regarding tumor susceptibility, given that PROS is at least 100× as common as Proteus, CCTN is very rare in PROS, compared to Proteus. We speculate that the pathophysiology of the two disorders is not entirely similar and that the natural history of Proteus (with primarily postnatal growth) and the mechanism of overgrowth in Proteus (which can be either hyperplasia or excess extracellular matrix [ECM]) (Doucet et al 2016) is subtly distinct from PROS. PROS overgrowth is primarily prenatal and, to our knowledge, entirely hyperplastic (i.e., not attributable to excess ECM).…”