Activating <i>PIK3CA</i> somatic mutation in congenital unilateral isolated muscle overgrowth of the upper extremity

Castiglioni, Claudia; Bertini, Enrico; Orellana, Paulina; Villarroel, Cynthia; Heras, Facundo Las; Hinzpeter, Daniel; Paolinelli, Paola; Bevilacqua, Jorge A.

doi:10.1002/ajmg.a.36651

Cited by 16 publications

(14 citation statements)

References 13 publications

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“…In order to characterize the mutation spectrum of patients with congenital/early childhood onset PROS without overgrowth of the brain, we performed an extensive literature search, and have presented the results together with the data of the seven patients described here [Kurek et al, ; Lindhurst et al, ; Rios et al, ; Castiglioni et al, ; Cohen et al, ; Emrick et al, ; Keppler‐Noreuil et al, ; Maclellan et al, ; Rasmussen et al, ; Couto et al, ; Limaye et al, ; Loconte et al, ; Luks et al, ; Osborn et al, ; Castillo et al, ; Hucthagowder et al, ; Mirzaa et al, ; Tripolszki et al, ]. We found that the three highly recurrent cancer‐associated mutations, p.(Glu542Lys), p.(Glu545Lys), and p.(His1047Arg) [Mirzaa et al, ], can be seen in about 70% of patients with PROS; whereas p.(Cys420Arg) and p.(His1047Leu) accounts for nearly 20% of the patients (Fig.…”

Section: Discussionmentioning

confidence: 99%

Somatic PIK3CA mutations in seven patients with PIK3CA‐related overgrowth spectrum

Yeung

Chow

et al. 2017

American J of Med Genetics Pt A

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Somatic mutations in PIK3CA cause many overgrowth syndromes that have been recently coined the "PIK3CA-Related Overgrowth Spectrum." Here, we present seven molecularly confirmed patients with PIK3CA-Related Overgrowth Spectrum, including patients with Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, Scoliosis/Skeletal and Spinal syndrome, Klippel-Trenaunay syndrome, lymphatic malformation and two with atypical phenotypes that cannot be classified into existing disease categories. The literature on PIK3CA-Related Overgrowth Spectrum, suggests that PIK3CA c.1258T>C; p.(Cys420Arg), c.1624G>A; p.(Glu542Lys), c.1633G>A; p.(Glu545Lys), c.3140A>G; p.(His1047Arg), and c.3140A>T; p.(His1047Leu) can be identified in approximately 90% of patients without brain overgrowth. Therefore, droplet digital polymerase chain reaction targeting these mutation hotspots could be used as the first-tier genetic test on patients with PIK3CA-Related Overgrowth Spectrum who do not have signs of overgrowth in their central nervous system. © 2017 Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

Somatic PIK3CA mutations in seven patients with PIK3CA‐related overgrowth spectrum

Yeung

Chow

et al. 2017

American J of Med Genetics Pt A

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“…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.…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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PIK3CA-related overgrowth spectrum is a group of rare genetic disorders with asymmetric overgrowth caused by somatic mosaic PIK3CA mutations. Here, we report clinical data and molecular findings from two patients with congenital muscular upper limb overgrowth and aberrant anatomy. During debulking surgery, numerous ectopic muscles were found in the upper limbs of the patients. DNA sequencing, followed by digital polymerase chain reaction, was performed on DNA extracted from biopsies from hypertrophic ectopic muscles and identified the somatic mosaic PIK3CA hotspot mutations c.3140A > G, p.(His1047Arg) and c.1624G > A, p.(Glu542Lys) in a male (patient 1) and a female (patient 2) patient, respectively. Patient 1 had four ectopic muscles and unilateral isolated muscular overgrowth while patient 2 had 13 ectopic muscles and bilateral isolated muscular overgrowth of both upper limbs, indicating that her mutation occurred at early pre-somitic mesoderm state. The finding of PIK3CA mutations in ectopic muscles highlights the importance of PIK3CA in cell fate in early human embryonic development. Moreover, our findings provide evidence that the disease phenotype depends on the timing of PIK3CA mutagenesis during embryogenesis and confirm the diagnostic entity PIK3CA-related muscular overgrowth with ectopic accessory muscles. K E Y W O R D Saccessory, cell fate, ectopic, muscle hypertrophy, muscular hypertrophy, PIK3CA, PROS Tobias Laurell and Ann Nordgren contributed equally.

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“…We also found two similar cases reported in the Genetics literature. Castiglioni et al [10] reported on a 6-year old girl with unilateral isolated upper limb muscle overgrowth. The authors only commented on the ulnar drift of the index finger; although the illustrations also showed hypoplasia of the index finger.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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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.

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Activating PIK3CA somatic mutation in congenital unilateral isolated muscle overgrowth of the upper extremity

Cited by 16 publications

References 13 publications

Somatic PIK3CA mutations in seven patients with PIK3CA‐related overgrowth spectrum

Somatic PIK3CA mutations in seven patients with PIK3CA‐related overgrowth spectrum

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

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

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