Upper limb muscle overgrowth with hypoplasia of the index finger: a new over-growth syndrome caused by the somatic PIK3CA mutation c.3140A>G

Abstract

BackgroundScientists have previously described an overgrowth syndrome in Saudi patients and named it ‘Upper limb muscle overgrowth with hypoplasia of the index finger’ syndrome.Case presentationWe describe a new case and document that the syndrome is caused by the somatic PIK3CA mutation c.3140A>G, p.His1047Arg. We also recruited one of the previously reported cases and found the same somatic mutation in the affected muscles. A wider classification of ‘PIK3CA-related pathology spectrum’ is presented which includes cancer, benign skin lesions/tumors, Cowden syndrome, isolated vascular malformations and various overgrowth syndromes. The latter entity is sub-divided into 3 sub-groups: overgrowth with brain involvement, overgrowth with multiple lipomatosis, and overgrowth without brain involvement/multiple lipomatosis.ConclusionOur literature review indicated that “upper limb muscle overgrowth with hypoplasia of the index finger” is not as rare as previously thought to be. This overgrowth syndrome is unique and is caused by the somatic PIK3CA mutation c.3140A>G.

Early activating somatic PIK3CA mutations promote ectopic muscle development and upper limb overgrowth

“…Aberrant accessory muscles have also been reported in other surgically treated patients with upper limb muscle hypertrophy and in some cases of carpal tunnel syndrome, but no genetic analysis of aberrant muscles have been performed to rule out somatic mosaic PIK3CA mutations. To the best of our knowledge, there are three patients previously described with isolated upper limb muscle overgrowth and with a confirmed PIK3CA mutation . In 2014, Castiglioni et al reported the first mosaic PIK3CA mutation in a patient with unilateral isolated muscular hypertrophy of the left hand and arm and aberrant muscles.…”

“…3 The variable expression of symptoms within PROS is mainly explained by the timing and location of the initiating PIK3CA mutation, but the reason behind the high degree of interindividual phenotypic heterogeneity is unknown. 7,8 Somatic activating PIK3CA mutations are common in at least 12 different cancer types. 5 It has been proposed that an increased number of neuromuscular junctions and a change in the muscle-tendon ratio is involved in muscle hypertrophy development.…”

“…6 The etiology remains still undetermined but it has recently been reported that isolated congenital muscular upper limb overgrowth can be related to somatic mosaic PIK3CA mutations. 7,8 Somatic activating PIK3CA mutations are common in at least 12 different cancer types. 1,[9][10][11] Previous studies show that the same PIK3CA hotspot mutations found in cancer are found in PROS.…”

“…The terminology “aberrant muscle syndrome” or “accessory muscle syndrome” has been suggested to describe patients with “hypertrophy of the hand and arm because of aberrant muscles with or without hypertrophy of the muscles.” It has been proposed that an increased number of neuromuscular junctions and a change in the muscle‐tendon ratio is involved in muscle hypertrophy development . The etiology remains still undetermined but it has recently been reported that isolated congenital muscular upper limb overgrowth can be related to somatic mosaic PIK3CA mutations …”

Late-onset multiple venous malformations confined to the upper limb: link to somaticMAP3K3mutations

“…Another interesting feature of the phenotype in our series is the presence of the malformations in the upper limbs only. An isolated muscle overgrowth syndrome (without any vascular malformations) confined to the upper limbs and linked to somatic P1K3CA mutations has been described (Al-Qattan et al., 2018). The reason for the confinement of these lesions to the upper limb remains a mystery.…”