Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum

Abstract

Somatic mutations in the phosphatidylinositol/AKT/mTOR pathway cause segmental overgrowth disorders. Diagnostic descriptors associated with PIK3CA mutations include fibroadipose overgrowth (FAO), Hemihyperplasia multiple Lipomatosis (HHML), Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, Scoliosis/skeletal and spinal (CLOVES) syndrome, macrodactyly, and the megalencephaly syndrome, Megalencephaly-Capillary malformation (MCAP) syndrome. We set out to refine the understanding of the clinical spectrum and natural history of these phenotypes, and now describe 35 patients with segmental overgrowth and somatic PIK3CA mutations. The phenotypic data show that these previously described disease entities have considerable overlap, and represent a spectrum. While this spectrum overlaps with Proteus syndrome (sporadic, mosaic, and progressive) it can be distinguished by the absence of cerebriform connective tissue nevi and a distinct natural history. Vascular malformations were found in 15/35 (43%) and epidermal nevi in 4/35 (11%) patients, lower than in Proteus syndrome. Unlike Proteus syndrome, 31/35 (89%) patients with PIK3CA mutations had congenital overgrowth, and in 35/35 patients this was asymmetric and disproportionate. Overgrowth was mild with little postnatal progression in most, while in others it was severe and progressive requiring multiple surgeries. Novel findings include: adipose dysregulation present in all patients, unilateral overgrowth that is predominantly left-sided, overgrowth that affects the lower extremities more than the upper extremities and progresses in a distal to proximal pattern, and in the most severely affected patients is associated with marked paucity of adipose tissue in unaffected areas. While the current data are consistent with some genotype-phenotype correlation, this cannot yet be confirmed.

Keywords: CLOVES syndrome; PIK3CA gene; fibroadipose overgrowth; macrodactyly; segmental overgrowth; somatic mosaicism.

FIG 1

Genotype/Phenotype Correlations in 35 patients with the predicted amino acid changes from PIK3CA mutations. When the predicted mutations are categorized by the two main functional domains of the protein (coiled vs. catalytic domains), there is a correlation of the domain location and phenotype (P = 0.0014).

FIG 2

Spectrum of overgrowth in patients with somatic PIK3CA mutations (A) Patient 2 at 13 days of age with macrodactyly of the left second toe; (B) Patient 7 at 18 months of age (1) Dorsal view of the left foot with overgrowth following surgical resection of T2, (2) Ventral views of both feet show overgrowth of the middle to distal ventral region of the left foot; (C) Patient 9 at 11 months of age (1–3) Enlargement of the left T1—3 with ballooning appearance of the distal portion, and increased circumference and length of the entire left foot, (4) X-ray of the left foot shows enlarged phalanges of T1–3; (D) Patient 15 (1) At 1 day of age, an enlarged right foot, (2) At 18 months of age, medial deviation and progressive widening of both feet, (3) Areas of hypopigmentation on the legs and (4) back, (5) T1-weighted MRI scan shows a cystic lesion adjacent to the lumbar spine; (E) Patient 19 at 5 years 6 months of age (1) Frontal view shows overgrowth of the left leg following trans-tibial amputation at four years of age, (2) Posterior view of the legs, (3) X-ray of the legs shows an enlarged left femur, tibia and fibula; (F) Patient 20 at 49 years of age (1) Enlarged left shoulder, arm and hand: left F4, 5 appeared normal, left F2,3 are missing following surgical amputation, and there is a 2 cm lipoma between the PIP and DIP joints of F4, (2) Left F1 is enlarged and surgically repositioned, (3) X-rays show her hand following surgical resection of F2, 3 and an enlarged left humerus; (G) Patient 28 at 10 years of age (1 and 2) Enlargement of the feet and legs, more severe on the left, (3) Enlargement and angular deformity of the right F3, 4, (4) X-rays of the hands show bone and soft tissue overgrowth of the phalanges of the right F3, 4, (5) X-rays of the feet: left foot shows four toes following surgical resection of T2, 3 and overgrowth of the metatarsals, the right foot shows four toes with absent T2, overgrowth of metatarsals and phalanges of T1 and T3, bony fusion with an “H” configuration of metatarsals of T1 and T3, and small second cuneiform.

FIG 3

Spectrum of overgrowth in patients with somatic PIK3CA mutations. A: Patient 26 at 14 years 6 months of age (1) Frontal view shows the upper body lipohypoplasia and bilateral leg overgrowth, more severe on the left, (2) Dorsal view of the feet show bilateral postaxial polydactyly with more severe overgrowth of the left foot, (3) X-rays of the feet: the right foot shows marked overgrowth of the metatarsals of T1—4, unusual epiphyses of all rays, and a supernumerary metatarsal, the left foot shows six toes with an enlarged metatarsal of T1 and proximal fusion of the metatarsal bones, (4) MRI of the lateral spine shows a large mass over her upper thoracic region; multiple neural foraminal masses at several levels in the thoracic spine, some of these are associated with dural ectatic changes and prominent CSF in the nerve root sheath, (5) MRI scan of the legs shows extensive soft tissue overgrowth, primarily in the fatty tissues with fat tissue intermixed with muscle in the left leg, (6 and 7) X-rays of the pelvis and legs show marked asymmetry and enlargement of the left hemipelvis and leg, completely dislocated left hip with unusual overgrowth pattern of the lesser trochanter and proximal femur, an enlarged left distal femur, particularly the medial femoral condyle, a displaced left patella, an abnormal configuration of the left anterior tibia, and an enlargement and bowing of the left fibula, subluxation with shallow acetabulum of the right hip, and overgrown and elongated right fibula and greater trochanter, (8) X-rays of the spine show scoliosis of the mid-thoracic spine centered at T6, and elongated and overgrown lower thoracic and lumbar vertebral bodies; (B) Patient 30 at 4 years of age (1) Posterior view of her whole body shows multiple lipomatous lesions involving her abdomen, chest and back, and upper body lipohypoplasia, (2) Views of her legs and feet show asymmetry of the leg positioning and size, widened feet with splayed toes with the left side larger than the right, and the left leg with prominent superficial veins, (3) Lateral view shows her barrel-chest and prominent abdomen with multiple lipomatous masses involving her abdomen and back, (4) Frontal view shows her chest and arms with lipohypoplasia, and protuberant abdomen with multiple lipomatous masses, (5) MRI scan of the lateral lower thoracic, lumbar and sacral vertebrae shows multi-level foraminal soft tissue masses, some of which are associated with dural ectatic changes, and subcutaneous soft tissue masses most compatible with the lipomas involving the back, and the extra segmentation in coccyx, (6) X-ray of the pelvis and upper legs shows right hip dislocation, abnormal acetabulum and femoral head; (C) Patient 31 at 43 years of age (1) Posterior view of her head, back and abdomen shows multiple masses and scars on her back from surgical excision of the venolymphatic malformations, and an epidermal nevus on her right cheek and pinna, (2) X-ray of the spine shows thoracolumbar scoliosis following surgical rod placement, (3–5) MRI scans of the chest, abdomen, and pelvis show scoliosis, marked fatty intermixture of the paraspinal muscles, splenomegaly with multiple cysts, irregular enhancement of the muscles of the posterior chest wall on the left, obesity with marked intra-abdominal fat, periaortic and paracaval foci compatible with additional collateral vessels or small vascular masses, and grossly normal caliber of the superior and inferior vena cava, the thoracic and abdominal aorta, and the common iliac vessels.

FIG 4

Epidermal nevi and vascular malformations in patients with somatic PIK3CA mutations. A: Patient 31 at 43 years of age shows an epidermal nevus involving the right cheek, pinna and neck, (B) Patient 32 at 46 years of age shows an epidermal nevus and vascular malformation involving the abdomen, (C) Patient 28 at 10 years of age shows a vascular malformation involving the left trunk

FIG 5

Polydactyly and cutaneous syndactyly. Patient 26 at 14 years 6 months of age (A) Dorsal view of the left foot and (B) Ventral view of the left foot show both show widening and postaxial polydactyly with shortened T5, 6 and partial cutaneous syndactyly of T2, 3, and wrinkling of the skin of the sole of the foot, (C) Dorsal view of the feet and ankles shows bilateral postaxial polydactyly, overgrowth of the left foot and leg, and the right foot with decreased subcutaneous tissue, prominent veins, and abnormal toes including small T1, 6, complete cutaneous syndactyly of T3, 4, and overgrowth of T3, 4, 5.