<scp>CLOVES</scp> syndrome: review of a <scp>PIK3CA</scp>‐related overgrowth spectrum (<scp>PROS</scp>)

Martínez-López, Antonio; Blasco‐Morente, Gonzalo; Pérez-López, Israel; Herrera-García, José David; Luque‐Valenzuela, Maria; Sánchez‐Cano, Daniel; López‐Gutiérrez, Juan Carlos; Ruíz‐Villaverde, Ricardo; Tercedor-Sánchez, J.

doi:10.1111/cge.12832

Cited by 110 publications

(101 citation statements)

References 46 publications

(66 reference statements)

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“…We did not find any of the common PIK3CA mutations in the KLA cells that have been found in vascular anomalies associated with tissue overgrowth including Klippel–Trenaunay syndrome (KTS) and congenital lipomatous overgrowth vascular malformations epidermal nevi and scoliosis/skeletal/spinal anomalies (CLOVES) . In the Glaser study, whole‐exome sequencing of KLA‐derived cells identified a potential pathogenic variant in one KLA patient (which is patient 1607 in our study), a 3‐base pair deletion resulting in loss of Serine 1043 in tuberous sclerosis complex 1 (TSC1).…”

Section: Discussionmentioning

confidence: 59%

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Signaling pathways and inhibitors of cells from patients with kaposiform lymphangiomatosis

Boscolo

Pastura

Glaser

et al. 2019

Pediatric Blood & Cancer

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Background Kaposiform lymphangiomatosis (KLA) is a rare lymphatic anomaly with significant morbidity and mortality. KLA is characterized by diffuse multifocal lesions comprised of focal areas of “kaposiform” spindled cells accompanying malformed lymphatic channels. The goal of this study was to identify activated signaling pathways in cells isolated from three KLA patients for the purpose of testing new therapies. Procedure Cells were obtained from the lungs of one patient isolated at autopsy and the spleen of two patients removed in surgery due to disease complications. A protein kinase array was performed on the KLA cell lysates and normal lymphatic endothelial cells. Results Higher activation of key signaling pathways in the KLA cells, including PRAS40, AKT1/2/3, and ERK‐1/2, was identified by protein kinase array and confirmed by Western blot analysis. This indicated a role for highly activated PI3K–AKT and MAPK–ERK‐1/2 signaling pathways in KLA cells. Cell proliferation studies assessed PI3K inhibitors (LY294002; BYL719), AKT inhibitor ARQ092, mTOR inhibitor rapamycin, and MAPK inhibitor U0126. These studies demonstrated that PI3K–AKT–mTOR and MAPK signaling are important mediators of KLA cell proliferation. BYL719 and rapamycin were more effective at inhibiting KLA cell proliferation than U0126. Conclusions Our studies using cells from KLA patient lesions demonstrate that these cells are highly proliferative and the PI3K–AKT–mTOR and MAPK pathways are promising therapeutic targets. Development and clinical trials of PI3K, AKT, and MAPK inhibitors for cancer treatment and the data in this study lend support for early clinical trials assessing the efficacy of these inhibitors in KLA patients.

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Section: Discussionmentioning

confidence: 59%

“…Our kinase array study and verification with Western blot analysis showed high AKT activation as well as MAPK. Hyperactive PI3K–AKT–mTOR signaling has also been found in a number of vascular malformations …”

Section: Discussionmentioning

confidence: 99%

Signaling pathways and inhibitors of cells from patients with kaposiform lymphangiomatosis

Boscolo

Pastura

Glaser

et al. 2019

Pediatric Blood & Cancer

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“…Klippel-Trenaunay syndrome (progressive growth of the lower limb with cutaneous capillary malformations and deep vascular malformations), and upper limb MO - hypoplasia IF are also included in this group. All of these disorders are associated with PIK3CA somatic mutations[1, 12, 18, 22–25] and the current report…”

Section: Discussionmentioning

confidence: 82%

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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“…602501) and CLOVES (congenital lipomatous asymmetrical overgrowth of the trunk with lymphatic, capillary, venous and combined‐type vascular malformations, epidermal nevi, scoliosis/skeletal and spinal anomalies; OMIM no. 612918) syndrome …”

Section: Discussionmentioning

confidence: 99%

LUMBAR syndrome: A case manifesting as cutaneous infantile hemangiomas of the lower extremity, perineum and gluteal region, and a review of published work

Zhang

et al. 2017

The Journal of Dermatology

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We herein report a rare case of LUMBAR syndrome. A 1-month-old female infant presented with extensive segmental hemangiomas on the left lower extremity, left perineum and gluteal region with ulceration. Bilateral labia minoras were asymmetrical. Both legs were asymmetrical with left leg atrophy, and the intergluteal cleft was deviated. A dark red pustule and a sacrococcygeal dimple could be seen in the lumbosacral region. Lipomyelomeningocele, tethered cord and sacrum dysplasia were noted by magnetic resonance imaging. The patient was found to have an absent left kidney at 32 weeks of pregnancy. Eventually, we draw the diagnosis of LUMBAR syndrome. In addition, we discuss the clinical manifestation, diagnosis, treatment and pathogenesis by a review of published work.

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CLOVES syndrome: review of a PIK3CA‐related overgrowth spectrum (PROS)

Cited by 110 publications

References 46 publications

Signaling pathways and inhibitors of cells from patients with kaposiform lymphangiomatosis

Signaling pathways and inhibitors of cells from patients with kaposiform lymphangiomatosis

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

LUMBAR syndrome: A case manifesting as cutaneous infantile hemangiomas of the lower extremity, perineum and gluteal region, and a review of published work

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