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

Abstract

The clinical diagnostic criteria for Proteus syndrome were defined before the discovery of the AKT1 c.49G>A; p.(Glu17Lys) causal variant and used a combination of general and specific phenotypic attributes that could be combined to make a clinical diagnosis. The most heavily weighted specific criterion was the cerebriform connective tissue nevus (CCTN). Here, we describe two individuals with connective tissue nevi (CTNs) and some general attributes of Proteus syndrome who were found to have mosaic PIK3CA variants. CTNs on the soles of individuals with PIK3CA-related overgrowth typically exhibit thickening of the soft tissues with at most a wrinkled surface, but these two patients had firm plaques with ridges and furrows characteristic of CCTNs, which was histologically confirmed in one. These data show that CCTNs are not specific to Proteus syndrome and that clinicians should be cautious in diagnosing individuals with Proteus syndrome based on the CCTN alone. Rather, a complete evaluation should include careful assessment of other attributes of the diagnostic criteria and, whenever possible, genetic analysis of affected tissue.

Keywords: connective tissue nevi; overgrowth.

Figure 1.

Individual 1 (OG.194). Left foot and ankle overgrowth with cerebriform connective tissue nevus (CCTN) on the sole of the foot. (A) Left foot, lateral view showed soft tissue overgrowth on the dorsal foot and CCTN on the sole of the foot. Toes two through four are absent status postamputation. (B) Left foot, medial view showed additional CCTN involvement of the heel. (C) Plantar and medial surfaces views demonstrated the cerebriform character of the connective tissue nevus with deep sulci and gyri.

Figure 2.

Individual 1 (OG.194). (A) Lateral and (B) AP radiographs of her left foot demonstrated partially absent second, third, and fourth phalanges, widening of the second to fourth metatarsal heads and shafts, calcific enthesopathy of the insertion of Achilles’ tendon and plantar fascia, and prominence of plantar, midfoot dorsal soft tissue.

Figure 3.

Histopathology of the connective tissue nevus on the left foot of individual 1 (OG.194). (A) 2× H&E staining showing the overall architecture of the CCTN histology. (B) 10× H&E staining confirmed there were primarily coarse bands of collagen and decreased elastic fibers. The thick bundles of collagen are oriented perpendicular to the surface of the reticular tissue. (C) 2× elastic tissue stain showed absent elastic tissue (black staining) displaced by thick bundles of collagen. (D) 2× immunohistochemistry staining of trichrome (blue staining) showed abundant, abnormal collagen fiber bundles.

Figure 4.

Individual 2 (OG.111). Right foot, plantar view showed cerebriform connective tissue nevus on the mid- and distal foot with involvement of the first toe. The second toe is absent status postamputation.

Figure 5.

Individual 2 (OG.111). Radiographs of right foot showed absent second toe and metatarsal. A surgical clip is present in the soft tissues of forefoot. (A) Oblique view. (B) AP view.

Figure 6.

Radiographs of distorting bone lesion in PS. (A) Lateral and (B) AP radiographs of a patient with AKT1 c.49G>A-positive Proteus syndrome. Note the severe, distorted skeletal architecture with major distortion of numerous long and short bones of the foot. Note also the bizarre lateral fusions of the metatarsals. This foot had not been subjected to major orthopedic surgery as had that of the two individuals with PROS reported here.