CLOVES Syndrome

Genetic MONDO:0013038 Pathograph 5 PIK3CA-related overgrowth spectrum Vascular malformation syndromes Overgrowth syndromes

CLOVES syndrome (Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, and Skeletal/spinal anomalies) is a rare congenital overgrowth disorder caused by somatic activating mutations in PIK3CA. It is part of the PIK3CA-related overgrowth spectrum (PROS). The condition is characterized by progressive, asymmetric tissue overgrowth with lipomatous masses predominantly affecting the trunk, complex vascular malformations (lymphatic, capillary, and venous), epidermal nevi, and skeletal anomalies including scoliosis and limb overgrowth. Because the mutations are somatic and mosaic, the distribution and severity of features vary widely depending on the timing and location of the mutation during embryonic development.

Mappings

Definitions

Histopathology

Subtypes

Differentials

Datasets

Trials

Models

Literature

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Classifications

Harrison's Chapter

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Inheritance

Somatic Mosaicism

CLOVES syndrome is caused by post-zygotic somatic activating mutations in PIK3CA. The mutations arise de novo during embryonic development and are present in a mosaic pattern. The condition is not inherited in a traditional Mendelian fashion and recurrence risk for unaffected parents is negligible.

Show evidence (1 reference)

PMID:22658544 SUPPORT Human Clinical

"We hypothesized that CLOVES syndrome would be caused by a somatic mutation arising during early embryonic development. Therefore, we employed massively parallel sequencing to search for somatic mosaic mutations in fresh, frozen, or fixed archival tissue from six affected individuals. We..."

Confirms that CLOVES syndrome is caused by post-zygotic somatic mosaic mutations in PIK3CA with variable allele frequencies in affected tissues.

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Pathophysiology

Constitutive PI3K Activation

Somatic gain-of-function mutations in PIK3CA (encoding the p110alpha catalytic subunit of PI3K) increase enzymatic activity, resulting in elevated PIP3 production in affected cells.

PIK3CA link

PI3K Signaling link

phosphatidylinositol 3-kinase activity link

Show evidence (1 reference)

PMID:34568242 SUPPORT Human Clinical

"These conditions are caused by somatic gain-of-function mutations in PIK3CA, which encodes the 110-kD catalytic alpha subunit of PI3K (p110alpha). These PIK3CA mutations occur as post-zygotic events and lead to a gain of function of PI3K, with consequent constitutional activation of the..."

Establishes that PIK3CA gain-of-function mutations constitutively activate PI3K enzymatic activity.

AKT/mTOR Pathway Hyperactivation

Constitutive PI3K activation leads to enhanced AKT phosphorylation and downstream mTOR signaling. This results in increased cell proliferation, growth, and survival in affected tissues, driving the overgrowth phenotype.

Endothelial cell link Adipocyte link

Cell Proliferation link

Show evidence (1 reference)

PMID:34074347 SUPPORT In Vitro

"In vitro studies revealed that p.X1069Trpfs*4 mutant exhibited increased AKT phosphorylation significantly to that of the wildtype, which could be inhibited by PI3K/AKT/mTOR pathway inhibitors."

In vitro functional studies confirm that CLOVES-associated PIK3CA mutations significantly increase AKT phosphorylation, demonstrating constitutive pathway activation.

Aberrant Vascular Development

PIK3CA gain-of-function mutations in endothelial and lymphatic endothelial cells drive abnormal vascular morphogenesis, resulting in complex combined vascular malformations. These include slow-flow lymphatic, capillary, and venous malformations that are progressive and can cause significant morbidity through mass effect, coagulopathy, and infection risk.

Endothelial cell link

Angiogenesis link Lymphangiogenesis link

Show evidence (2 references)

PMID:27426476 SUPPORT Human Clinical

"These mutations are responsible for the clinical manifestations of the syndrome, which include low- and high-flow vascular malformations, thoracic lipomatous hyperplasia, asymmetric growth, and visceral and neurological disorders."

Review confirms that PIK3CA mutations drive the full spectrum of CLOVES vascular malformations including low- and high-flow types.

PMID:29899452 SUPPORT Human Clinical

"Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated."

Demonstrates that vascular malformations are a key clinical feature that responds to targeted PIK3CA inhibition therapy.

Lipomatous Overgrowth

Constitutive PI3K activation in adipose precursor cells promotes excessive adipogenesis and lipomatous tissue expansion. The overgrowth is typically truncal, asymmetric, and progressive, and can involve both subcutaneous and visceral compartments.

Adipocyte link

Adipogenesis link

Show evidence (1 reference)

PMID:22658544 SUPPORT Human Clinical

"Congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies (CLOVES) is a sporadically occurring, nonhereditary disorder characterized by asymmetric somatic hypertrophy and anomalies in multiple organs."

Confirms lipomatous overgrowth as a defining feature of CLOVES syndrome.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

Blood 1

Thromboembolism OCCASIONAL Thromboembolism (HP:0001907)

Show evidence (1 reference)

PMID:31334068 SUPPORT Human Clinical

"central phlebectasia/thromboembolism in CLOVES syndrome need active or prophylactic surgical/medical interventions to improve quality of life."

Thromboembolism recognized as a complication of CLOVES syndrome requiring active or prophylactic intervention.

Cardiovascular 6

Venous Malformation VERY_FREQUENT Venous malformation (HP:0012721)

Show evidence (1 reference)

PMID:29899452 SUPPORT Human Clinical

"CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth..."

Confirms vascular malformations as a defining clinical feature of CLOVES syndrome.

Spinal Arteriovenous Malformation OCCASIONAL Spinal arteriovenous malformation (HP:0002390)

Show evidence (1 reference)

PMID:21310861 SUPPORT Human Clinical

"CLOVES syndrome is a complex disorder of congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal/scoliosis/spinal anomalies. We report the occurrence of spinal-paraspinal fast-flow lesions within or adjacent to the truncal overgrowth or a cutaneous birthmark in 6..."

Documents spinal-paraspinal fast-flow (arteriovenous) lesions in 6 CLOVES patients, establishing this as a recognized complication.

Lymphatic Malformation VERY_FREQUENT Lymphangioma (HP:0100764)

Show evidence (1 reference)

PMID:34568242 SUPPORT Human Clinical

"We present an 8-year-old girl with CLOVES syndrome, born with a large cystic lymphangioma involving the left hemithorax and flank, multiple lipomas, and hypertrophy of the left foot and leg. She developed severe scoliosis."

Case report documenting a large cystic lymphangioma as a presenting feature of CLOVES syndrome.

Cutis Marmorata OCCASIONAL Cutis marmorata (HP:0000965)

Show evidence (1 reference)

PMID:24782230 SUPPORT Human Clinical

"Other skin abnormalities included a dermal melanocytic nevus, café-au-lait macules, hypopigmented macules, cutis marmorata, pigmented nevi, and patchy hyperpigmentation in 12/33 (36%) patients."

Cutis marmorata documented in 36% of patients in the largest clinical delineation study of PIK3CA-related overgrowth spectrum.

Arteriovenous Malformation FREQUENT Arteriovenous malformation (HP:0100026)

Show evidence (2 references)

PMID:31334068 SUPPORT Human Clinical

"All patients show lymphatic, venous and capillary (low-flow), or arteriovenous malformations (port-wine stains) with or without arteriovenous fistulae (high-flow vascular anomalies) that usually become evident during childhood."

Arteriovenous malformations documented as occurring in all CLOVES patients alongside other vascular anomalies.

PMID:24782230 SUPPORT Human Clinical

"there were 15/35 patients (43%) with vascular malformations, including capillary venous or lymphatic malformations. Some of these 15 individuals had combined venous/lymphatic malformations."

Vascular malformations documented in 43% of PROS patients (n=35). The FREQUENT designation accounts for combined low- and high-flow vascular anomalies across the spectrum.

Splenomegaly OCCASIONAL Splenomegaly (HP:0001744)

Show evidence (2 references)

PMID:31334068 SUPPORT Human Clinical

"Visceral anomalies occur in the form of renal agenesis/hypoplasia, Wilms tumor, splenic lesions, and extensive deep retroperitoneal and pelvic fatty and lymphatic malformation."

Splenic lesions documented among visceral anomalies in CLOVES syndrome.

PMID:24782230 SUPPORT Human Clinical

"hip subluxation/dislocation, spina bifida occulta, tethered cord, extra segments in the vertebrae, uterine fibroids, and splenic cysts"

Splenic cysts documented among malformations in the PROS cohort (n=35), consistent with splenic involvement.

Genitourinary 3

Nephroblastoma (Wilms Tumor) OCCASIONAL Nephroblastoma (HP:0002667)

Show evidence (2 references)

PMID:28627003 SUPPORT Human Clinical

"A total of 122 patients with CLOVES syndrome were found in our database (mean age 7.7 years, range 0-53 years). Four patients developed WT; all were diagnosed by 2 years of age. The incidence of WT in our CLOVES patient population (3.3%) was significantly greater than the incidence of WT in the..."

Large cohort study at Boston Children's Hospital documenting 3.3% Wilms tumor incidence in 122 CLOVES patients, significantly above general population risk, supporting screening recommendations.

PMID:36804444 SUPPORT Human Clinical

"Wilms tumor is the most common pediatric renal mass and occurs in up to 10% of predisposition syndromes. One such syndrome is CLOVES syndrome, an extremely rare disorder within the umbrella of PIK3CA-related overgrowth spectrum disorders."

Case report of bilateral Wilms tumor in a CLOVES patient, confirming the association and highlighting management complexity.

Renal Anomalies OCCASIONAL Abnormality of the kidney (HP:0000077)

Show evidence (1 reference)

PMID:31334068 SUPPORT Human Clinical

"Visceral anomalies occur in the form of renal agenesis/hypoplasia, Wilms tumor, splenic lesions, and extensive deep retroperitoneal and pelvic fatty and lymphatic malformation."

Renal agenesis/hypoplasia documented as visceral anomalies in CLOVES.

Testicular Lipomatosis OCCASIONAL Testicular lipomatosis (HP:0025476)

Show evidence (1 reference)

PMID:31334068 SUPPORT Human Clinical

"The major deformities invariably include deposition of adipose tissue in all body regions and tissue spaces including face, scrotum, paraspinal musculature, epidural spaces, mediastinum, and pleura."

Adipose tissue deposition in the scrotum is documented as part of CLOVES syndrome, consistent with testicular lipomatosis.

Head and Neck 3

Facial Asymmetry OCCASIONAL Facial asymmetry (HP:0000324)

Show evidence (1 reference)

PMID:31334068 SUPPORT Human Clinical

"ipsilateral asymmetrical deformity of skull, and large left cerebral hemisphere with mild ipsilateral ventriculomegaly were peculiar to him denoting an uncommon phenotype."

Ipsilateral skull/facial asymmetry documented in a CLOVES patient, consistent with mosaic overgrowth pattern.

Webbed Neck OCCASIONAL Webbed neck (HP:0000465)

Delayed Eruption of Teeth OCCASIONAL Delayed eruption of teeth (HP:0000684)

Show evidence (1 reference)

PMID:31334068 SUPPORT Human Clinical

"He had delayed canine eruption and dental hypoplasia."

Delayed canine eruption documented in a CLOVES patient with craniofacial involvement.

Integument 3

Epidermal Nevus OCCASIONAL Epidermal nevus (HP:0010816)

Show evidence (1 reference)

PMID:24782230 SUPPORT Human Clinical

"Vascular malformations were found in 15/35 (43%) and epidermal nevi in 4/35 (11%) patients, lower than in Proteus syndrome."

Largest clinical delineation study documents epidermal nevi in 11% of PROS patients, confirming OCCASIONAL frequency.

Capillary Malformation VERY_FREQUENT Capillary malformation (HP:0025104)

Show evidence (1 reference)

PMID:27426476 SUPPORT Human Clinical

"CLOVES (Congenital Lipomatous asymmetric Overgrowth of the trunk with lymphatic, capillary, venous, and combined-type Vascular malformations, Epidermal naevi, Scoliosis/Skeletal and spinal anomalies)"

Capillary malformations are explicitly part of the CLOVES phenotypic definition.

Skin Tags OCCASIONAL Skin tags (HP:0010609)

Limbs 5

Macrodactyly FREQUENT Macrodactyly (HP:0004099)

Show evidence (1 reference)

PMID:34074347 SUPPORT Human Clinical

"Sandal gap toe and wide foot with second and third toes macrodactyly caused by skeletal elongation and adipose overgrowth."

Case report documenting macrodactyly of toes caused by skeletal elongation and adipose overgrowth in a CLOVES patient.

Sandal Gap FREQUENT Sandal gap (HP:0001852)

Show evidence (1 reference)

PMID:31334068 SUPPORT Human Clinical

"the lower limbs show soft tissue overgrowth of feet and broad forefoot, large bulbous toes, wide first toe web (sandal gap), plantar creases, lipomatous masses on plantar and dorsal feet, and wide gaps between metatarsal heads in 50% of 18 cases reviewed."

Sandal gap (wide first toe web) documented in 50% of reviewed CLOVES cases.

Polydactyly OCCASIONAL Polydactyly (HP:0010442)

Show evidence (1 reference)

PMID:24782230 SUPPORT Human Clinical

"Other limb findings included postaxial or preaxial polydactyly and cutaneous syndactyly, which involved only the toes. In particular, four had polydactyly: two with postaxial polydactyly (one unilateral left foot and one bilateral feet), one central and one with preaxial polydactyly (of the hallux)."

Polydactyly documented in 4 of 35 PROS patients in the largest clinical delineation study, with both postaxial and preaxial forms.

Cutaneous Syndactyly OCCASIONAL Cutaneous syndactyly (HP:0012725)

Show evidence (1 reference)

PMID:24782230 SUPPORT Human Clinical

"There were seven with cutaneous syndactyly: two with unilateral 2–3 toes, two with unilateral 2–4 toes, one bilateral with 2–5 toes (Right) and 2–4 toes (Left), and two unspecified"

Cutaneous syndactyly of the toes documented in 7 of 35 PROS patients in the largest clinical delineation study.

Broad Palm OCCASIONAL Broad palm (HP:0001169)

Show evidence (1 reference)

PMID:31334068 SUPPORT Human Clinical

"The prominent upper limb deformities include symmetrical overgrowth of digit(s), laxity of collateral ligaments of metacarpophalangeal and interphalangeal joints, and broad spade like hands with ulnar deviation of digits."

Broad spade-like hands explicitly documented as a prominent upper limb deformity in CLOVES syndrome.

Musculoskeletal 5

Lipomatous Overgrowth VERY_FREQUENT Multiple lipomas (HP:0001012)

Show evidence (1 reference)

PMID:27426476 SUPPORT Human Clinical

Lipomatous overgrowth is a defining feature of CLOVES syndrome, forming part of the acronym itself.

Scoliosis FREQUENT Scoliosis (HP:0002650)

Show evidence (1 reference)

PMID:34568242 SUPPORT Human Clinical

Case report of a CLOVES patient demonstrating severe scoliosis as a significant clinical feature.

Increased Adipose Tissue VERY_FREQUENT Increased adipose tissue (HP:0009126)

Show evidence (2 references)

PMID:31334068 SUPPORT Human Clinical

Confirms widespread adipose tissue deposition as a major invariable feature of CLOVES syndrome.

PMID:24782230 SUPPORT Human Clinical

"Dysregulated adipose tissue (either lipomatous lesions or regional lipohypoplasia) was seen in all patients"

In the largest PROS cohort (n=35), dysregulated adipose tissue was present in all 35 patients (100%), confirming VERY_FREQUENT designation.

Pectus Excavatum OCCASIONAL Pectus excavatum (HP:0000767)

Hip Dysplasia OCCASIONAL Hip dysplasia (HP:0001385)

Show evidence (1 reference)

PMID:24782230 SUPPORT Human Clinical

"hip subluxation/dislocation, spina bifida occulta, tethered cord, extra segments in the vertebrae, uterine fibroids, and splenic cysts"

Hip subluxation/dislocation documented among skeletal malformations in the largest clinical delineation study of PROS patients.

Nervous System 8

Spinal Anomalies FREQUENT Spinal dysraphism (HP:0010301)

Show evidence (2 references)

PMID:21310861 SUPPORT Human Clinical

Documents spinal-paraspinal fast-flow vascular lesions as a recognized feature of CLOVES syndrome in 6 patients from a cohort study.

PMID:31334068 SUPPORT Human Clinical

"Central nervous system (CNS) manifestations include polymicrogyria, noncontiguous abnormalities of the gray and white matter, a four-layered cortex, ventriculomegaly, hemimegalencephaly, dysgenesis of the corpus callosum, neuronal migration defects and consequent seizures, tethered spinal cord,..."

Comprehensive review listing tethered spinal cord and neural tube defects among the CNS manifestations of CLOVES syndrome.

Tethered Cord OCCASIONAL Tethered cord (HP:0002144)

Show evidence (1 reference)

PMID:31334068 SUPPORT Human Clinical

Tethered spinal cord listed among recognized CNS manifestations of CLOVES syndrome in comprehensive review.

Seizures OCCASIONAL Seizure (HP:0001250)

Show evidence (2 references)

PMID:31334068 SUPPORT Human Clinical

Seizures documented as a CNS manifestation of CLOVES syndrome, consequent to cortical malformations.

PMID:31334068 PARTIAL Human Clinical

"Some degree of neuorologic impairment has been reported in almost 50% cases in a large series."

Neurological impairment reported in approximately 50% of CLOVES cases, though this includes motor deficits and developmental delay, not exclusively seizures.

Hemimegalencephaly OCCASIONAL Hemimegalencephaly (HP:0007206)

Show evidence (1 reference)

PMID:31334068 SUPPORT Human Clinical

Hemimegalencephaly explicitly listed among CNS manifestations of CLOVES.

Polymicrogyria OCCASIONAL Polymicrogyria (HP:0002126)

Show evidence (1 reference)

PMID:31334068 SUPPORT Human Clinical

Polymicrogyria listed among CNS manifestations of CLOVES syndrome.

Ventriculomegaly OCCASIONAL Ventriculomegaly (HP:0002119)

Show evidence (1 reference)

PMID:31334068 SUPPORT Human Clinical

"large left cerebral hemisphere with mild ipsilateral ventriculomegaly were peculiar to him denoting an uncommon phenotype."

Ventriculomegaly documented in a CLOVES patient with hemimegalencephaly.

Spina Bifida OCCASIONAL Spina bifida (HP:0002414)

Show evidence (2 references)

PMID:31334068 SUPPORT Human Clinical

Neural tube defects (including spina bifida) listed among CNS manifestations of CLOVES syndrome.

PMID:24782230 SUPPORT Human Clinical

"hip subluxation/dislocation, spina bifida occulta, tethered cord, extra segments in the vertebrae, uterine fibroids, and splenic cysts"

Spina bifida occulta documented among malformations in the PROS cohort (n=35).

Gait Disturbance OCCASIONAL Gait disturbance (HP:0001288)

Show evidence (1 reference)

PMID:34074347 SUPPORT Human Clinical

"Symptoms of claudication caused by the unilateral deformation worsened with age."

Claudication (gait disturbance) documented as a progressive symptom caused by unilateral limb deformation in a CLOVES patient.

Constitutional 1

Pain FREQUENT Pain (HP:0012531)

Show evidence (1 reference)

PMID:31334068 SUPPORT Human Clinical

"This will also prevent cutaneous and visceral morbidities, neurological deficit, pain, breathing difficulties, and possible complications such as hemoptysis, gastrointestinal bleeding or obstruction, and pulmonary embolism arising from vascular anomalies."

Pain explicitly mentioned as a morbidity requiring intervention in CLOVES syndrome management.

Growth 3

Hemihypertrophy FREQUENT Hemihypertrophy (HP:0001528)

Show evidence (1 reference)

PMID:29899452 SUPPORT Human Clinical

"Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated."

Hemihypertrophy documented as a major feature that responded to alpelisib treatment in PROS patients.

Lower Limb Asymmetry VERY_FREQUENT Lower limb asymmetry (HP:0100559)

Show evidence (2 references)

PMID:31334068 SUPPORT Human Clinical

"He had bilateral genu valgum, and his left lower limb was longer by 2 cm than the right one but showed no deformity of hands and feet."

Case report documenting lower limb length discrepancy in a CLOVES patient, consistent with asymmetric overgrowth.

PMID:24782230 SUPPORT Human Clinical

"More individuals had involvement of the lower extremities (24/35) than upper extremities (6/35, P = 0.041), and three of 35 had overgrowth of both upper and lower extremities."

In the largest PROS cohort (n=35), 24/35 (69%) had lower extremity involvement, supporting VERY_FREQUENT designation for lower limb asymmetry.

Asymmetric Growth VERY_FREQUENT Asymmetric growth (HP:0100555)

Show evidence (1 reference)

PMID:27426476 SUPPORT Human Clinical

Asymmetric growth explicitly listed as a clinical manifestation of CLOVES syndrome in this review.

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Genetic Associations

PIK3CA Somatic Mutations (Causative)

Show evidence (3 references)

PMID:22658544 SUPPORT Human Clinical

"We identified mutations in PIK3CA in all six individuals, and mutant allele frequencies ranged from 3% to 30% in affected tissue from multiple embryonic lineages. Interestingly, these same mutations have been identified in cancer cells, in which they increase phosphoinositide-3-kinase activity...."

Landmark study identifying PIK3CA somatic mosaic mutations as the cause of CLOVES syndrome in all six patients studied, with mutant allele frequencies of 3-30% in affected tissues.

PMID:34568242 SUPPORT Human Clinical

"PIK3CA-related cancers and PROS share almost the same PIK3CA mutational profile, with about 80% of mutations occurring at three hotspots, E542, E545, and H1047. These hotspot mutations show the most potent effect on enzymatic activation of PI3K and consequent downstream biological responses."

Confirms the three major hotspot mutations (E542, E545, H1047) account for about 80% of PIK3CA mutations in PROS/CLOVES.

PMID:34074347 SUPPORT In Vitro

"We have identified the first frameshift mutation in PIK3CA that causes CLOVES syndrome, which was confirmed to overactive PI3K/AKT/mTOR pathway by transient transfection assays."

Expands the mutational spectrum beyond missense mutations, demonstrating that frameshift mutations affecting the PIK3CA stop codon can also cause CLOVES syndrome through PI3K/AKT/mTOR pathway overactivation.

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Treatments

Alpelisib (BYL719)

Action: PI3K inhibitor therapy Ontology label: enzyme inhibitor agent therapy MAXO:0000648

Alpelisib is a selective PI3Kalpha inhibitor that has shown efficacy in reducing overgrowth and vascular malformations in patients with PROS including CLOVES syndrome. It was granted accelerated approval by the FDA on April 5, 2022 for patients with PROS aged two years and older requiring systemic therapy.

Show evidence (3 references)

PMID:29899452 SUPPORT Human Clinical

"On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated...."

Landmark study demonstrating that BYL719 (alpelisib) improved symptoms in all 19 PROS patients treated, including tumor shrinkage, improved heart failure, reduced hemihypertrophy, and attenuated scoliosis.

PMID:38025143 SUPPORT Human Clinical

"For patients two years of age and older requiring systemic therapy, alpelisib is an option which was recently granted accelerated approval by the US Food and Drug Administration (FDA) on April 5, 2022. Alpelisib is an inhibitor of PI3K, slowing the progression of existing lesions and preventing..."

Confirms FDA accelerated approval of alpelisib for PROS in patients aged 2 years and older.

PMID:34568242 SUPPORT Human Clinical

"we decided to discontinue Sirolimus and start targeted therapy with Alpelisib (50 mg/day). We noticed a decrease in fibroadipose overgrowth at the dorsal level, an improvement in in posture and excellent tolerability."

Case report demonstrating alpelisib efficacy in a CLOVES patient with decreased fibroadipose overgrowth and improved posture after switching from sirolimus.

Sirolimus (Rapamycin)

Action: mTOR inhibitor therapy Ontology label: enzyme inhibitor agent therapy MAXO:0000648

mTOR inhibitor used to manage vascular malformations and lymphatic anomalies. May slow progression of overgrowth and reduce vascular malformation volume, though response is often limited compared to direct PI3K inhibition.

Show evidence (2 references)

PMID:29899452 PARTIAL Human Clinical

"Eight patients had received previous rapamycin treatment for18 months without clinical or radiological improvement."

Eight PROS patients treated with rapamycin for 18 months showed no clinical or radiological improvement, demonstrating limited efficacy of mTOR inhibition compared to direct PI3K inhibition.

PMID:34568242 PARTIAL Human Clinical

"She then started treatment with Rapamycin from May 2019, without significant improvement in both vascular malformation and leg hypertrophy."

Case report demonstrating limited efficacy of rapamycin/sirolimus in a CLOVES patient, prompting switch to alpelisib.

Surgical Debulking

Action: Surgical debulking Ontology label: surgical procedure MAXO:0000004

Surgical resection of lipomatous masses and overgrown tissue. Often requires multiple procedures and recurrence is common.

Show evidence (1 reference)

PMID:34568242 SUPPORT Human Clinical

"Traditional therapeutic approaches, such as sclerotherapy and surgical debulking, are often not curative in PROS patients, leading to a recrudescence of the overgrowth in the treated area."

Confirms that surgical debulking is a standard approach but often not curative with frequent recurrence.

Sclerotherapy

Action: Sclerotherapy Ontology label: surgical procedure MAXO:0000004

Percutaneous sclerotherapy for lymphatic and venous malformations to reduce mass effect and symptoms.

Show evidence (1 reference)

PMID:34568242 SUPPORT Human Clinical

"Many therapeutic approaches have been attempted, including Sildenafil treatment, scleroembolization, laser therapy, and multiple debulking surgeries, but none of these were of benefit to our patient's clinical status."

Documents sclerotherapy (scleroembolization) as an attempted treatment modality in CLOVES syndrome management.

Wilms Tumor Screening

Action: Ultrasonographic renal screening Ontology label: cancer screening MAXO:0000126

Quarterly abdominal ultrasonography recommended for children with CLOVES syndrome until age 7 years, given the 3.3% incidence of Wilms tumor. Screening may be most beneficial for patients under 3 years of age.

Show evidence (1 reference)

PMID:28627003 SUPPORT Human Clinical

"Patients with CLOVES syndrome have an increased risk of WT. Given the benefits of early detection and treatment, children with CLOVES syndrome should be considered for quarterly abdominal ultrasonography until age 7 years. Screening may be most beneficial for patients under 3 years of age."

Evidence-based screening recommendation from a cohort of 122 CLOVES patients with 3.3% Wilms tumor incidence.

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Literature Summaries

Falcon ▸

Disease Pathophysiology Research Template

Edison Scientific Literature 33 citations 2026-03-07T05:15:54.228174

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Pathophysiology Research Template

Target Disease

Disease Name: CLOVES Syndrome
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on the pathophysiology of CLOVES Syndrome. Focus on the molecular and cellular mechanisms underlying disease progression.

Required Information

1. Core Pathophysiology

What are the primary pathophysiological mechanisms?
What molecular pathways are dysregulated?
What cellular processes are affected?

2. Key Molecular Players

Genes/Proteins: Which genes are causally involved or implicated?
Chemical Entities: What metabolites, drugs, or small molecules are relevant?
Cell Types: Which cell types are primarily affected?
Anatomical Locations: Which tissues/organs are involved?

3. Biological Processes (for GO annotation)

What biological processes (GO terms) are disrupted?
Consider: signaling pathways, metabolic processes, cellular responses, transport, etc.

4. Cellular Components

Where in the cell do key processes occur?
Consider: organelles, membrane compartments, extracellular space, etc.

5. Disease Progression

What is the sequence of events from initial trigger to clinical manifestation?
Are there distinct stages or phases?

6. Phenotypic Manifestations

What are the key clinical phenotypes?
How do they relate to the underlying mechanisms?

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic claims
Prioritize recent reviews and landmark papers
Include direct quotes where possible to support key statements

Output Format

Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs

Comprehensive Research Report: CLOVES Syndrome Pathophysiology (PROS)

Disease identifiers

Disease name: CLOVES syndrome
MONDO ID: MONDO:0013038 (Open Targets disease entry; association evidence not reproduced here)
Category: Mendelian/segmental mosaic (post-zygotic somatic)

1) Key concepts and definitions (current understanding)

1.1 Definition and disease class

CLOVES syndrome (Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, and Skeletal/Spinal anomalies) is a severe phenotype within the PIK3CA-related overgrowth spectrum (PROS) caused by post-zygotic (somatic) mosaic activating variants in PIK3CA, leading to segmental/asymmetric overgrowth and combined vascular malformations. (henuzet2025…lipomatousovergrowth pages 2-6, seront2024molecularlandscapeand pages 3-5, podolec2025clovessyndromea pages 5-8)

1.2 Mosaicism as a pathophysiology-defining concept

A central concept for CLOVES is somatic mosaicism: the pathogenic variant is enriched in affected tissue and may be absent/undetectable in blood, which determines both phenotype distribution and diagnostic strategy. Large-scale PROS sequencing supports that strongly activating variants are rarely detectable in blood and are most reliably found in affected tissue. (mussa2023genotypesandphenotypes pages 4-4, mussa2023genotypesandphenotypes pages 1-2)

2) Core pathophysiology (molecular and cellular mechanisms)

2.1 Primary driver: PIK3CA gain-of-function → PI3K pathway hyperactivation

PIK3CA encodes the catalytic subunit p110α of phosphatidylinositol-3-kinase (PI3Kα). Activating hotspot variants (e.g., p.Glu542Lys) can “disrupt autoinhibitory interactions and result in constitutive kinase activation,” producing sustained downstream signaling through the PI3K axis. (lakhmawar¹2025bilateralrenalanomaliesa pages 2-4)

In vascular anomalies and PROS, this is described as direct activation of PI3K–AKT–mTOR, resulting in abnormal growth and vascular malformations. (seront2024molecularlandscapeand pages 3-5)

2.2 Endothelial-cell–centric mechanism for vascular malformations

A 2024 mechanistic study developed an endothelial-restricted PIK3CA GOF mouse model (PIK3CA^Tie2-CreER) that recapitulates capillary–venous malformations (a common vascular component in PROS/CLOVES-like disease). Endothelial PIK3CA activation increased AKT/mTOR signaling, caused endothelial hypertrophy, increased proliferation (KI67+), and produced 3D vascular disorganization and thrombosis-like pathology consistent with slow-flow malformations. (zerbib2024targetedtherapyfor pages 1-3, zerbib2024targetedtherapyfor pages 3-5)

2.3 Partial AKT dependence and AKT-independent PI3K outputs

A notable refinement from 2024 mechanistic data is that PIK3CA-driven malformations may only partially signal through AKT proteins; in the endothelial model, disease depended partially on AKT1 (not AKT2), and genetic deletion of AKT1 delayed but did not prevent lesions—supporting important AKT-independent PI3K outputs (e.g., direct mTOR-dependent and/or metabolic/cytoskeletal programs). (zerbib2024targetedtherapyfor pages 1-3, zerbib2024targetedtherapyfor pages 3-5)

2.4 Metabolic reprogramming and systemic coagulopathy signals in severe vascular disease

In the same 2024 endothelial PIK3CA model, systemic consequences included regenerative anemia, thrombocytopenia, elevated D-dimers, and broad metabolic changes (e.g., amino-acid accumulation, mitochondrial respiration intermediates, and urea-cycle activation). These observations support a model in which PI3Kα hyperactivation in vascular endothelium is sufficient to drive local lesion biology and systemic secondary effects (coagulation and metabolism). (zerbib2024targetedtherapyfor pages 3-5)

2.5 Dysregulated cellular processes (summary)

Across mechanistic and clinical sources, key affected processes include: - Cell growth/proliferation and survival (PI3K-driven tissue overgrowth; endothelial hypertrophy and proliferation). (lakhmawar¹2025bilateralrenalanomaliesa pages 2-4, zerbib2024targetedtherapyfor pages 3-5) - Angiogenesis and vascular morphogenesis with malformed thin-walled channels and thrombosis risk. (zerbib2024targetedtherapyfor pages 1-3, podolec2025clovessyndromea pages 5-8) - Lymphangiogenesis/lymphatic malformation biology, supported by therapeutic sensitivity to mTOR inhibition and model evidence that sirolimus inhibits lymphangiogenesis. (kane2024targetedtherapiesfor pages 1-2, podolec2025clovessyndromea pages 5-8) - Extracellular matrix and cell morphology dysregulation, with PI3Kα inhibition reported to normalize abnormal AKT phosphorylation, morphology, and extracellular fibronectin in patient-derived cellular contexts. (gu2024pik3cagenemutation pages 5-6)

3) Key molecular players, cell types, and anatomical locations

3.1 Genes/proteins

PIK3CA (PI3Kα/p110α): causal; somatic GOF mosaic variants. (gu2024pik3cagenemutation pages 3-5, seront2024molecularlandscapeand pages 3-5)
AKT (especially AKT1 in endothelium): partially mediates lesion signaling in vivo. (zerbib2024targetedtherapyfor pages 3-5, zerbib2024targetedtherapyfor pages 1-3)
mTOR pathway effectors (e.g., p-S6RP readouts in lesion tissue) are downstream functional mediators and therapeutic targets. (zerbib2024targetedtherapyfor media 80420135)
TEK/TIE2: upstream activator converging on PI3Kα signaling in related vascular malformations; contributes to phenotypic overlap and shared therapeutic logic (PI3Kα inhibition). (zerbib2024targetedtherapyfor pages 1-3, seront2024molecularlandscapeand pages 3-5)

3.2 Chemical entities / drugs and pathway probes

Alpelisib (PI3Kα inhibitor): directly targets the causal pathway, with regulatory approval for severe PROS. (singh2024fdaapprovalsummary pages 1-3)
Sirolimus (mTOR inhibitor): downstream pathway blockade used off-label for vascular anomalies and PROS manifestations. (borst2024targetedmedicaltherapies pages 1-3, kane2024targetedtherapiesfor pages 3-5)
Miransertib (AKT inhibitor): investigational; illustrates the pathway node-specific approach and supports AKT-dependent components in some tissues/cells. (gu2024pik3cagenemutation pages 5-6)

3.3 Cell types primarily implicated

Endothelial cells: lesion-resident somatic PIK3CA variants documented; endothelial-restricted PIK3CA activation recapitulates disease biology in mice. (gu2024pik3cagenemutation pages 3-5, zerbib2024targetedtherapyfor pages 3-5)
Fibroblast-lineage cells (context-dependent): in vitro data cited for AKT-inhibitor responsiveness and PI3K-inhibitor normalization of morphology/ECM. (gu2024pik3cagenemutation pages 5-6)

3.4 Main tissues/organs involved (with examples)

Clinical synthesis indicates a multi-tissue, mosaic distribution including: - Adipose tissue/soft tissue: congenital, progressive lipomatous overgrowth, commonly truncal/posterolateral. (podolec2025clovessyndromea pages 5-8) - Cutaneous/epidermal: epidermal nevi; capillary malformations. (podolec2025clovessyndromea pages 5-8, faivre2023lowriskof pages 4-4) - Vascular/lymphatic: combined capillary/venous/lymphatic malformations and slow-flow channels. (podolec2025clovessyndromea pages 5-8, zerbib2024targetedtherapyfor pages 1-3) - Skeletal/spine: scoliosis, limb asymmetry; paraspinal/epidural extension and vascular shunts can produce neurologic compromise. (podolec2025clovessyndromea pages 5-8) - Kidney: reported renal anomalies; clinical sources recommend renal surveillance due to renal involvement and Wilms tumor concern. (lakhmawar¹2025bilateralrenalanomaliesa pages 2-4, podolec2025clovessyndromea pages 5-8) - Gastrointestinal tract: rare but clinically significant vascular malformations/venous anomalies causing bleeding (hematochezia), including abnormal mesenteric venous drainage. (stpierre2023gastrointestinalmanifestationsof pages 1-2)

4) Biological processes (GO-style) and cellular components

4.1 Disrupted biological processes (GO-like)

A mechanism-to-process mapping consistent with the evidence includes: - PI3K signaling (upstream driver of abnormal growth and vascular development). (zerbib2024targetedtherapyfor pages 1-3) - Angiogenesis / vascular morphogenesis (endothelial proliferation, disorganized vessel architecture). (zerbib2024targetedtherapyfor pages 3-5) - Lymphangiogenesis (lymphatic malformations; sirolimus inhibits lymphangiogenesis in experimental systems and is clinically used). (kane2024targetedtherapiesfor pages 1-2) - Cell proliferation and growth (endothelial KI67+; segmental soft-tissue overgrowth). (zerbib2024targetedtherapyfor pages 3-5, podolec2025clovessyndromea pages 5-8) - Extracellular matrix organization/cell adhesion (abnormal fibronectin and morphology reported as reversible with PI3Kα inhibition in disease-derived cellular contexts). (gu2024pik3cagenemutation pages 5-6)

4.2 Cellular components (GO-like)

Key molecular events occur in: - Plasma membrane and phosphoinositide signaling compartments (PIK3CA-mediated PIP2→PIP3 conversion and recruitment of signaling complexes). (zerbib2024targetedtherapyfor pages 1-3) - Cytosol/kinase signaling modules (AKT phosphorylation and downstream signaling). (zerbib2024targetedtherapyfor pages 1-3) - mTOR signaling nodes (mTORC1 readouts such as p-S6RP) in lesion tissue. (zerbib2024targetedtherapyfor media 80420135) - Extracellular space / ECM (fibronectin changes). (gu2024pik3cagenemutation pages 5-6)

5) Disease progression: sequence of events from initial trigger to phenotype

Post-zygotic activating mutation in PIK3CA occurs during embryogenesis, creating a mosaic clone. (seront2024molecularlandscapeand pages 3-5)
Mutant clone(s) drive cell-autonomous PI3Kα hyperactivation, particularly evident in vascular endothelium for malformation components. (gu2024pik3cagenemutation pages 3-5, zerbib2024targetedtherapyfor pages 3-5)
Aberrant growth and vascular/lymphatic development produce congenital lesions (lipomatous masses, mixed slow-flow malformations, epidermal nevi), typically present at birth and progressively enlarging. (podolec2025clovessyndromea pages 5-8, henuzet2025…lipomatousovergrowth pages 6-7)
Secondary complications arise from lesion architecture and flow abnormalities: thrombosis/PE risk from venous malformations, neurologic compromise from spinal/paraspinal involvement, organ-specific effects (renal anomalies; GI bleeding from vascular anomalies). (podolec2025clovessyndromea pages 5-8, stpierre2023gastrointestinalmanifestationsof pages 1-2)

6) Phenotypic manifestations and mechanistic links

6.1 Core phenotypes

CLOVES is characterized by congenital lipomatous overgrowth, mixed vascular malformations (capillary/venous/lymphatic/arteriovenous), epidermal nevi, and skeletal/spinal anomalies including scoliosis and limb asymmetry. (podolec2025clovessyndromea pages 5-8)

6.2 Mechanistic linkage

Lipomatous overgrowth is consistent with PI3K-driven growth programs in mesodermal soft tissues and may recur after surgery due to persistence of mosaic mutant cells. (podolec2025clovessyndromea pages 5-8)
Vascular malformations reflect endothelial PI3Kα pathway hyperactivation causing abnormal vessel structure and thrombosis susceptibility; animal modeling directly supports an endothelial mechanism. (zerbib2024targetedtherapyfor pages 1-3, zerbib2024targetedtherapyfor pages 3-5)
Thrombotic complications are linked to slow-flow venous malformations and coagulopathy markers (elevated D-dimer noted in long-term clinical follow-up). (wang2024combinedsurgeryand pages 2-5, podolec2025clovessyndromea pages 5-8)
Neurologic/spinal symptoms can result from mass infiltration or arteriovenous shunts leading to venous hypertension and cord injury. (podolec2025clovessyndromea pages 5-8)
GI bleeding may reflect congenital absence/dysplasia of deep venous drainage with intramural venous malformations. (stpierre2023gastrointestinalmanifestationsof pages 1-2)

7) Recent developments and latest research (prioritizing 2023–2024)

7.1 2024: Mechanistic in vivo model clarifying signaling topology

Zerbib et al. (June 2024; Signal Transduction and Targeted Therapy; https://doi.org/10.1038/s41392-024-01862-9) provides mechanistic evidence that endothelial PIK3CA GOF drives malformation formation, clarifies that signaling is partially AKT1-dependent, and supports direct PI3Kα inhibition as an effective strategy in preclinical and human contexts. (zerbib2024targetedtherapyfor pages 1-3, zerbib2024targetedtherapyfor pages 3-5)

Immunofluorescence evidence of increased p-AKT and p-S6RP in lesion tissue and clinical response graphics/tables are visible in the extracted figure/table region. (zerbib2024targetedtherapyfor media 80420135)

7.2 2023: Large cohort/systematic review enabling quantitative genotype–phenotype and testing strategy insights

Mussa et al. (Mar 2023; Journal of Medical Genetics; https://doi.org/10.1136/jmedgenet-2021-108093) provides quantitative tissue testing yields and genotype-strength correlations across PROS: - In the 150-patient cohort, detection in skin biopsies was much higher than in blood. (mussa2023genotypesandphenotypes pages 4-4) - Strong hotspot variants were far more common in non-CNS phenotypes than CNS phenotypes, emphasizing developmental selection and tissue distribution effects. (mussa2023genotypesandphenotypes pages 6-7) - CLOVES cases in that cohort showed mutation detection in skin biopsy but not in blood/swab in those sampled, reinforcing tissue-based testing. (mussa2023genotypesandphenotypes pages 4-4)

7.3 2024: Targeted therapy as a precision-medicine paradigm in vascular anomalies

Hematology-focused 2024 reviews emphasize that a growing proportion of vascular anomalies are driven by somatic variants activating PI3K/AKT/mTOR (or Ras/MAPK), making genotype-driven therapy selection and standardized monitoring central to practice. (borst2024targetedmedicaltherapies pages 1-3, seront2024molecularlandscapeand pages 3-5)

8) Current applications and real-world implementations

8.1 Molecular diagnosis (implementation)

Because CLOVES is mosaic, recent cohort evidence supports testing affected tissue and, when possible, multiple tissues: - In the Mussa et al. 2023 cohort, positives by sample type were 93/130 skin biopsies, 15/38 swabs, and 12/63 blood, illustrating the superiority of tissue sampling. (mussa2023genotypesandphenotypes pages 4-4) - Ultra-deep sequencing depth (mean 2500–3000×; minimum >1000× for low VAF detection) was used in this cohort. (mussa2023genotypesandphenotypes pages 3-4)

8.2 Targeted systemic therapy: alpelisib (PI3Kα inhibitor)

Regulatory/real-world milestone: The FDA granted accelerated approval to alpelisib on April 5, 2022 for adults and pediatric patients (≥2 years) with severe PROS requiring systemic therapy (publication: Aug 2024, Clinical Cancer Research; https://doi.org/10.1158/1078-0432.CCR-23-1270). (singh2024fdaapprovalsummary pages 1-3)

Quantitative efficacy: In EPIK-P1 (expanded access/real-world data; NCT04285723), radiologic response at Week 24 was defined as ≥20% reduction in the sum of volumetric target lesion(s), with no progression/new lesions. In the efficacy population (n=37), response rate was 27% (95% CI 14–44); among responders, 60% had responses lasting ≥12 months. (singh2024fdaapprovalsummary pages 1-3, singh2024fdaapprovalsummary pages 3-4)

Safety statistics (EPIK-P1): Adverse reactions ≥5% included diarrhea (~16%), stomatitis (~16%), hyperglycemia (~12%), eczema/dry skin (~7%), alopecia/headache/cellulitis (~5%); no grade 5 ARs were reported, and the only grade 3–4 AR described in the excerpt was cellulitis. (singh2024fdaapprovalsummary pages 12-13)

8.3 Real-world mechanistic translation in vascular malformations

In a 2024 translational study of capillary–venous malformations, alpelisib improved lesions in a treated patient series and reduced lesion volumes over 6 months (summarized visually with per-patient tabulation in the extracted table/figure region). (zerbib2024targetedtherapyfor media 80420135)

8.4 mTOR inhibition and procedural care

Sirolimus remains widely used off-label as a pathway-targeted option; reviews emphasize it inhibits lymphangiogenesis in experimental systems and has early clinical case-series support in complex vascular anomalies. (kane2024targetedtherapiesfor pages 1-2)

Procedures (sclerotherapy and staged debulking surgery) remain important for symptom control and function; a 13-year CLOVES follow-up reported improvement in deformity and scoliosis after serial ethanol sclerotherapy plus resections. (wang2024combinedsurgeryand pages 2-5)

9) Expert opinions / authoritative analysis (with monitoring and care delivery considerations)

9.1 Genotype-driven therapy selection and monitoring

A 2024 Hematology review emphasizes that somatic PI3K/AKT/mTOR-driven vascular anomalies require targeted therapy expertise, and provides practical monitoring recommendations during targeted therapy (e.g., routine labs every 1–3 months including CBC/CMP/electrolytes and HbA1c; and coagulation markers such as D-dimer/fibrinogen when relevant). (borst2024targetedmedicaltherapies pages 1-3)

9.2 FDA perspective on evidence standards and long-term uncertainty

The FDA approval summary explicitly frames alpelisib’s approval as supported by real-world evidence with blinded central imaging review, but highlights the need for postmarketing requirements to better characterize response in non-CLOVES/less frequent variants and to study long-term safety in children given expected chronic use and nonclinical bone/dental findings. (singh2024fdaapprovalsummary pages 6-8, singh2024fdaapprovalsummary pages 1-3)

9.3 Multidisciplinary implementation

Clinical practice articles stress multidisciplinary management involving genetics, vascular anomalies specialists, hematology/oncology, surgery/interventional radiology, orthopedics, and organ-specific specialists (e.g., nephrology) due to risks of thrombosis, neurologic compromise, and renal involvement. (kane2024targetedtherapiesfor pages 1-2, lakhmawar¹2025bilateralrenalanomaliesa pages 2-4)

10) Relevant recent statistics and data points (selected)

10.1 Mosaicism / detection statistics (PROS cohorts)

Specimen yield (150-patient PROS cohort): positive tests were 93/130 skin biopsies, 15/38 swabs, and 12/63 blood. (mussa2023genotypesandphenotypes pages 4-4)
CLOVES subset (same cohort): 5/5 CLOVES cases were positive in skin biopsies; swab and blood were negative in sampled cases (0/2 each). (mussa2023genotypesandphenotypes pages 4-4)
Sequencing depth: mean 2500–3000×; >1000× as minimum to detect ~1% VAF in that workflow. (mussa2023genotypesandphenotypes pages 3-4)

10.2 Targeted therapy outcomes (alpelisib)

Radiologic response threshold: ≥20% volumetric reduction in up to 3 lesions at Week 24. (singh2024fdaapprovalsummary pages 1-3, singh2024fdaapprovalsummary pages 3-4)
Response rate: 27% (95% CI 14–44) at Week 24 (n=37). (singh2024fdaapprovalsummary pages 1-3)
Durability: 60% of responders with response ≥12 months. (singh2024fdaapprovalsummary pages 1-3)
Adverse reactions: diarrhea/stomatitis/hyperglycemia are common; detailed AE frequencies provided in FDA summary excerpts. (singh2024fdaapprovalsummary pages 12-13)

10.3 Mechanistic quantitative signals (preclinical)

In endothelial PIK3CA GOF disease modeling, AKT1 deletion produced only modest survival/lesion-delay benefit and did not prevent lesions, supporting partial AKT dependence. (zerbib2024targetedtherapyfor pages 3-5)

Structured knowledge-base elements

Component	Mechanism & Description	Key Findings & Quantitative Data	Source(s)
Genetic Etiology	Somatic mosaic gain-of-function (GOF) mutations in PIK3CA. Occurs post-zygotically; not usually inherited.	Hotspots: p.His1047Arg, p.Glu542Lys, p.Glu545Lys account for severe phenotypes. Mosaicism: Variant Allele Fraction (VAF) ranges from <1% to ~46% in affected tissues; typically very low/absent in blood.	(lakhmawar¹2025bilateralrenalanomalies pages 2-4, gu2024pik3cagenemutation pages 3-5, mussa2023genotypesandphenotypes pages 4-4, faivre2023lowriskof pages 4-4, mussa2023genotypesandphenotypes pages 1-2)
Signaling Pathways	Hyperactivation of the PI3K-AKT-mTOR axis. Mutant p110α (PI3K) increases PIP3, recruiting PDK1 and phosphorylating AKT.	AKT Dependence: Endothelial lesions signal partially through AKT1 (not AKT2); some effects are AKT-independent. Upstream: TEK/TIE2 mutations can activate the same axis in related vascular anomalies.	(gu2024pik3cagenemutation pages 3-5, zerbib2024targetedtherapyfor pages 3-5, zerbib2024targetedtherapyfor pages 1-3, seront2024molecularlandscapeand pages 3-5)
Cellular Processes	Dysregulated cell growth, survival, and metabolism leading to tissue overgrowth and vascular anomalies.	Endothelial Cells: Hypertrophy, increased proliferation (KI67+), 3D vascular disorganization. Metabolism: Reprogramming observed (e.g., urea cycle activation, increased mitochondrial respiration).	(zerbib2024targetedtherapyfor pages 3-5, zerbib2024targetedtherapyfor pages 1-3, kane2024targetedtherapiesfor pages 1-2)
Affected Tissues	Multi-system involvement: Adipose, Vascular, Skeletal, Cutaneous, and Renal tissues.	Adipose: Congenital lipomatous overgrowth (often truncal). Vascular: Capillary, venous, lymphatic malformations (high risk of thrombosis). Skeletal: Scoliosis, limb hypertrophy. Renal: Anomalies, Wilms tumor risk (~2-3%).	(lakhmawar¹2025bilateralrenalanomalies pages 2-4, henuzet2025…lipomatousovergrowth pages 2-6, podolec2025clovessyndromea pages 5-8)
Diagnostic Yield	Diagnosis relies on detecting mosaic variants in affected tissue rather than blood.	Sensitivity: Skin biopsy over vascular malformation: ~66% yield; over overgrown tissue: ~73% yield. Seq. Depth: High depth (~1500x-3000x) often required to detect low VAF.	(mussa2023genotypesandphenotypes pages 4-4, mussa2023genotypesandphenotypes pages 3-4)

Table: Summary of the molecular and cellular mechanisms underlying CLOVES syndrome, including genetic drivers, signaling dysregulation, and tissue-specific manifestations.

Therapy	Target / Mechanism	Status	Key Efficacy Findings	Key Safety / Adverse Events	Source(s)
Alpelisib (Vijoice)	PIK3CA (PI3Kα) Inhibitor Directly inhibits mutant p110α.	FDA Accelerated Approval (2022) For severe PROS ≥2 years requiring systemic therapy.	EPIK-P1 (n=37): 27% confirmed radiologic response (≥20% volume reduction); 74% clinical benefit rate. 60% of responders durable ≥12 months. Mouse Model: Prevented lesions/improved established ones.	Common: Diarrhea (16%), stomatitis (16%), hyperglycemia (12%), cellulitis. Pediatric: Potential growth plate/dental abnormalities.	Singh 2024 (singh2024fdaapprovalsummary pages 4-6, singh2024fdaapprovalsummary pages 1-3); Lakhmawar 2025 (lakhmawar¹2025bilateralrenalanomaliesa pages 2-4); Zerbib 2024 (zerbib2024targetedtherapyfor pages 1-3)
Sirolimus (Rapamycin)	mTOR Inhibitor Downstream blockade of mTORC1.	Off-label Historical standard of care for vascular anomalies.	Modest reduction in lesion volume; improvement in pain, bleeding, and lymphorrhea. Used when PI3K inhibitors unavailable.	Mucositis, immunosuppression, hyperlipidemia, pneumonitis, risk of rebound upon discontinuation.	Borst 2024 (borst2024targetedmedicaltherapies pages 1-3); Kane 2024 (kane2024targetedtherapiesfor pages 3-5); Gu 2024 (gu2024pik3cagenemutation pages 5-6)
Miransertib	AKT Inhibitor Inhibits AKT phosphorylation.	Investigational Compassionate use reported.	Case reports of reduced fatty overgrowth; anti-proliferative effects in patient-derived fibroblasts. Inefficacy noted in some PROS cohorts.	Generally well-tolerated in reported cases; requires monitoring for class effects.	Gu 2024 (gu2024pik3cagenemutation pages 3-5, gu2024pik3cagenemutation pages 5-6); Zerbib 2024 (zerbib2024targetedtherapyfor pages 1-3)
Surgery & Sclerotherapy	Mechanical / Chemical Ablation Debulking or vessel sclerosis.	Standard Adjunctive Symptom-directed intervention.	Immediate reduction of bulk or cysts. Serial procedures (e.g., over 13 years) can improve deformity/function.	High risk of nerve damage, bleeding, infection, and rapid regrowth (lipomas are invasive/resistant).	Wang 2024 (wang2024combinedsurgeryand pages 2-5); Podolec 2025 (podolec2025clovessyndromea pages 5-8)

Table: Overview of pharmacological and procedural management strategies for CLOVES syndrome, detailing molecular targets, regulatory status, efficacy statistics, and safety profiles based on recent (2023-2025) evidence.

Entity Type	Term Label (ID)	Rationale & Relationship to CLOVES	Source(s)
Gene	PIK3CA (HGNC:8975)	Causal somatic mosaic gain-of-function mutations driving pathway hyperactivation.	(lakhmawar¹2025bilateralrenalanomalies pages 2-4, gu2024pik3cagenemutation pages 3-5)
GO Biological Process	Phosphatidylinositol 3-kinase signaling (GO:0014065)	Primary dysregulated pathway; mutant p110α increases PIP3 and downstream signaling.	(gu2024pik3cagenemutation pages 3-5, zerbib2024targetedtherapyfor pages 1-3)
GO Biological Process	Angiogenesis (GO:0001525)	Aberrant vessel formation leads to high-flow and low-flow vascular malformations.	(zerbib2024targetedtherapyfor pages 3-5, gu2024pik3cagenemutation pages 3-5)
GO Biological Process	Lymphangiogenesis (GO:0001906)	Pathologic development of lymphatic structures (macrocystic/microcystic lesions).	(gu2024pik3cagenemutation pages 3-5, kane2024targetedtherapiesfor pages 1-2)
Cell Type	Endothelial cell (CL:0000115)	Primary mutated cell lineage in vascular lesions; shows hypertrophy and proliferation.	(zerbib2024targetedtherapyfor pages 3-5, zerbib2024targetedtherapyfor pages 1-3)
Anatomy	Adipose tissue (UBERON:0001013)	Site of congenital, progressive lipomatous overgrowth (often truncal).	(henuzet2025…lipomatousovergrowth pages 2-6, podolec2025clovessyndromea pages 5-8)
Anatomy	Spinal cord (UBERON:0002240)	Involved via arteriovenous shunts or paraspinal mass infiltration causing compression.	(podolec2025clovessyndromea pages 5-8)
Anatomy	Kidney (UBERON:0002113)	Risk of anomalies (agenesis, cysts) and Wilms tumor (~2-3% risk).	(lakhmawar¹2025bilateralrenalanomalies pages 2-4, lakhmawar¹2025bilateralrenalanomaliesa pages 2-4)
Phenotype	Hemihypertrophy (HP:0001528)	Asymmetric overgrowth of limbs or body segments.	(henuzet2025…lipomatousovergrowth pages 2-6, henuzet2025…lipomatousovergrowth pages 6-7)
Phenotype	Vascular malformation (HP:0002561)	Complex mixed lesions (capillary, venous, lymphatic) predisposing to thrombosis.	(gu2024pik3cagenemutation pages 5-6, podolec2025clovessyndromea pages 5-8)
Phenotype	Epidermal nevus (HP:0001052)	Linear keratinocytic nevi are a cardinal cutaneous feature.	(faivre2023lowriskof pages 4-4, henuzet2025…lipomatousovergrowth pages 6-7)
Phenotype	Scoliosis (HP:0002650)	Common skeletal deformity secondary to tissue overgrowth and mass effect.	(henuzet2025…lipomatousovergrowth pages 2-6, wang2024combinedsurgeryand pages 2-5)
Chemical/Drug	Alpelisib (CHEBI:135936)	PI3Kα-specific inhibitor; FDA-approved for severe PROS.	(singh2024fdaapprovalsummary pages 4-6, lakhmawar¹2025bilateralrenalanomaliesa pages 2-4)
Chemical/Drug	Sirolimus (CHEBI:9168)	mTOR inhibitor; off-label standard for vascular anomalies/overgrowth.	(borst2024targetedmedicaltherapies pages 1-3, kane2024targetedtherapiesfor pages 3-5)

Table: A structured mapping of CLOVES syndrome mechanisms and manifestations to standardized ontology terms (HGNC, GO, CL, UBERON, HP, CHEBI), linking molecular drivers to clinical phenotypes.

Evidence items (PMID-oriented note)

Several of the cited sources are peer-reviewed and provide DOIs/URLs and publication months/years within the evidence above. In the retrieved excerpts available for this report, PMIDs were not consistently provided in-text, so this report cites primary sources via DOI/URL and the evidence context identifiers.

Visual evidence (figures/tables)

Extracted figure/table regions from the 2024 translational study show pathway activation readouts (p-AKT and p-S6RP staining) and clinical lesion-volume reductions under alpelisib, including per-patient volume change summaries. (zerbib2024targetedtherapyfor media 80420135)

Notes on scope and limitations

This report focuses on mechanistic and translational evidence explicitly present in the retrieved full-text excerpts. Some clinically important domains (e.g., precise epidemiology across populations, comprehensive staging frameworks, and high-resolution single-cell lesion atlases) may exist in additional literature not captured in the current retrieval set.

References

(henuzet2025…lipomatousovergrowth pages 2-6): E Henuzet, L Boon, D Dumitriu, and L Peetermans. … lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal anomalies (cloves) syndrome: a case report and literature review. Unknown journal, 2025.
(seront2024molecularlandscapeand pages 3-5): Emmanuel Seront, Angela Queisser, Laurence M. Boon, and Miikka Vikkula. Molecular landscape and classification of vascular anomalies. Hematology, 2024:700-708, Dec 2024. URL: https://doi.org/10.1182/hematology.2024000598, doi:10.1182/hematology.2024000598. This article has 6 citations and is from a peer-reviewed journal.
(podolec2025clovessyndromea pages 5-8): Julianna Podolec, Silvia Ciraolo, Joanna Wojda, Adam Sobiński, Zuzanna Kościuszko, Katarzyna Kurza, Agnieszka Kulczycka-Rowicka, Matylda Czerwonka, Katarzyna Lesiczka-Fedoryj, and Anna Walczak. Cloves syndrome: a review of clinical, genetic, and therapeutic aspects. Quality in Sport, 38:58253, Feb 2025. URL: https://doi.org/10.12775/qs.2025.38.58253, doi:10.12775/qs.2025.38.58253. This article has 0 citations.
(mussa2023genotypesandphenotypes pages 4-4): Alessandro Mussa, Chiara Leoni, Matteo Iacoviello, Diana Carli, Carlotta Ranieri, Antonino Pantaleo, Paola Sabrina Buonuomo, Rosanna Bagnulo, Giovanni Battista Ferrero, Andrea Bartuli, Daniela Melis, Silvia Maitz, Daria Carmela Loconte, Antonella Turchiano, Marilidia Piglionica, Annunziata De Luisi, Francesco Claudio Susca, Nenad Bukvic, Cinzia Forleo, Angelo Selicorni, Giuseppe Zampino, Roberta Onesimo, Gerarda Cappuccio, Livia Garavelli, Chiara Novelli, Luigi Memo, Carla Morando, Matteo Della Monica, Maria Accadia, Martina Capurso, Carmelo Piscopo, Anna Cereda, Marilena Carmela Di Giacomo, Veronica Saletti, Alessandro Mauro Spinelli, Patrizia Lastella, Romano Tenconi, Veronika Dvorakova, Alan D Irvine, and Nicoletta Resta. Genotypes and phenotypes heterogeneity in pik3ca-related overgrowth spectrum and overlapping conditions: 150 novel patients and systematic review of 1007 patients with pik3ca pathogenetic variants. Journal of Medical Genetics, 60(2):163-173, Mar 2023. URL: https://doi.org/10.1136/jmedgenet-2021-108093, doi:10.1136/jmedgenet-2021-108093. This article has 44 citations and is from a domain leading peer-reviewed journal.
(mussa2023genotypesandphenotypes pages 1-2): Alessandro Mussa, Chiara Leoni, Matteo Iacoviello, Diana Carli, Carlotta Ranieri, Antonino Pantaleo, Paola Sabrina Buonuomo, Rosanna Bagnulo, Giovanni Battista Ferrero, Andrea Bartuli, Daniela Melis, Silvia Maitz, Daria Carmela Loconte, Antonella Turchiano, Marilidia Piglionica, Annunziata De Luisi, Francesco Claudio Susca, Nenad Bukvic, Cinzia Forleo, Angelo Selicorni, Giuseppe Zampino, Roberta Onesimo, Gerarda Cappuccio, Livia Garavelli, Chiara Novelli, Luigi Memo, Carla Morando, Matteo Della Monica, Maria Accadia, Martina Capurso, Carmelo Piscopo, Anna Cereda, Marilena Carmela Di Giacomo, Veronica Saletti, Alessandro Mauro Spinelli, Patrizia Lastella, Romano Tenconi, Veronika Dvorakova, Alan D Irvine, and Nicoletta Resta. Genotypes and phenotypes heterogeneity in pik3ca-related overgrowth spectrum and overlapping conditions: 150 novel patients and systematic review of 1007 patients with pik3ca pathogenetic variants. Journal of Medical Genetics, 60(2):163-173, Mar 2023. URL: https://doi.org/10.1136/jmedgenet-2021-108093, doi:10.1136/jmedgenet-2021-108093. This article has 44 citations and is from a domain leading peer-reviewed journal.
(lakhmawar¹2025bilateralrenalanomaliesa pages 2-4): NN Lakhmawar¹, N Khadke, A Shinde, and SN Mhaske. Bilateral renal anomalies and macrocephaly in cloves syndrome: a rare case report with pik3ca hotspot mutation. Unknown journal, 2025.
(zerbib2024targetedtherapyfor pages 1-3): Lola Zerbib, Sophia Ladraa, Antoine Fraissenon, Charles Bayard, Marina Firpion, Quitterie Venot, Sanela Protic, Clément Hoguin, Amandine Thomas, Sylvie Fraitag, Jean-Paul Duong, Sophie Kaltenbach, Estelle Balducci, Coline Lefevre, Patrick Villarese, Vahid Asnafi, Christine Broissand, Nicolas Goudin, Ivan Nemazanyy, Gwennhael Autret, Bertrand Tavitian, Christophe Legendre, Nadia Arzouk, Veronique Minard-Colin, Caroline Chopinet, Michael Dussiot, Denise M. Adams, Tristan Mirault, Laurent Guibaud, Paul Isenring, and Guillaume Canaud. Targeted therapy for capillary-venous malformations. Signal Transduction and Targeted Therapy, Jun 2024. URL: https://doi.org/10.1038/s41392-024-01862-9, doi:10.1038/s41392-024-01862-9. This article has 27 citations and is from a peer-reviewed journal.
(zerbib2024targetedtherapyfor pages 3-5): Lola Zerbib, Sophia Ladraa, Antoine Fraissenon, Charles Bayard, Marina Firpion, Quitterie Venot, Sanela Protic, Clément Hoguin, Amandine Thomas, Sylvie Fraitag, Jean-Paul Duong, Sophie Kaltenbach, Estelle Balducci, Coline Lefevre, Patrick Villarese, Vahid Asnafi, Christine Broissand, Nicolas Goudin, Ivan Nemazanyy, Gwennhael Autret, Bertrand Tavitian, Christophe Legendre, Nadia Arzouk, Veronique Minard-Colin, Caroline Chopinet, Michael Dussiot, Denise M. Adams, Tristan Mirault, Laurent Guibaud, Paul Isenring, and Guillaume Canaud. Targeted therapy for capillary-venous malformations. Signal Transduction and Targeted Therapy, Jun 2024. URL: https://doi.org/10.1038/s41392-024-01862-9, doi:10.1038/s41392-024-01862-9. This article has 27 citations and is from a peer-reviewed journal.
(kane2024targetedtherapiesfor pages 1-2): Gavin Kane and Israel Fernandez-Pineda. Targeted therapies for vascular malformations. Frontiers in Medicine, Sep 2024. URL: https://doi.org/10.3389/fmed.2024.1446046, doi:10.3389/fmed.2024.1446046. This article has 3 citations.
(gu2024pik3cagenemutation pages 5-6): Meng Gu, Xuanzhe Zhu, and Yi Zhun Zhu. Pik3ca gene mutation induced rare vascular diseases. Journal of Asian Association of Schools of Pharmacy, 13:12-19, Jan 2024. URL: https://doi.org/10.62100/jaasp.2024.13103, doi:10.62100/jaasp.2024.13103. This article has 0 citations.
(gu2024pik3cagenemutation pages 3-5): Meng Gu, Xuanzhe Zhu, and Yi Zhun Zhu. Pik3ca gene mutation induced rare vascular diseases. Journal of Asian Association of Schools of Pharmacy, 13:12-19, Jan 2024. URL: https://doi.org/10.62100/jaasp.2024.13103, doi:10.62100/jaasp.2024.13103. This article has 0 citations.
(zerbib2024targetedtherapyfor media 80420135): Lola Zerbib, Sophia Ladraa, Antoine Fraissenon, Charles Bayard, Marina Firpion, Quitterie Venot, Sanela Protic, Clément Hoguin, Amandine Thomas, Sylvie Fraitag, Jean-Paul Duong, Sophie Kaltenbach, Estelle Balducci, Coline Lefevre, Patrick Villarese, Vahid Asnafi, Christine Broissand, Nicolas Goudin, Ivan Nemazanyy, Gwennhael Autret, Bertrand Tavitian, Christophe Legendre, Nadia Arzouk, Veronique Minard-Colin, Caroline Chopinet, Michael Dussiot, Denise M. Adams, Tristan Mirault, Laurent Guibaud, Paul Isenring, and Guillaume Canaud. Targeted therapy for capillary-venous malformations. Signal Transduction and Targeted Therapy, Jun 2024. URL: https://doi.org/10.1038/s41392-024-01862-9, doi:10.1038/s41392-024-01862-9. This article has 27 citations and is from a peer-reviewed journal.
(singh2024fdaapprovalsummary pages 1-3): Sonia Singh, Diana Bradford, Xiaoxue Li, Pallavi S. Mishra-Kalyani, Yuan-Li Shen, Lingshan Wang, Hong Zhao, Ye Xiong, Jiang Liu, Rosane Charlab, Jeffrey Kraft, Sachia Khasar, Claudia P. Miller, Donna R. Rivera, Paul G. Kluetz, Richard Pazdur, Julia A. Beaver, Harpreet Singh, and Martha Donoghue. Fda approval summary: alpelisib for pik3ca-related overgrowth spectrum (pros). Clinical cancer research : an official journal of the American Association for Cancer Research, 30:23-28, Aug 2024. URL: https://doi.org/10.1158/1078-0432.ccr-23-1270, doi:10.1158/1078-0432.ccr-23-1270. This article has 52 citations.
(borst2024targetedmedicaltherapies pages 1-3): Alexandra Borst. Targeted medical therapies for vascular anomalies. Hematology, 2024:709-717, Dec 2024. URL: https://doi.org/10.1182/hematology.2024000599, doi:10.1182/hematology.2024000599. This article has 4 citations and is from a peer-reviewed journal.
(kane2024targetedtherapiesfor pages 3-5): Gavin Kane and Israel Fernandez-Pineda. Targeted therapies for vascular malformations. Frontiers in Medicine, Sep 2024. URL: https://doi.org/10.3389/fmed.2024.1446046, doi:10.3389/fmed.2024.1446046. This article has 3 citations.
(faivre2023lowriskof pages 4-4): Laurence Faivre, Jean‐Charles Crépin, Manon Réda, Sophie Nambot, Virginie Carmignac, Caroline Abadie, Tristan Mirault, Cécile Faure‐Conter, Juliette Mazereeuw‐Hautier, Aude Maza, Eve Puzenat, Marie‐Agnès Collonge‐Rame, Anne‐Claire Bursztejn, Christophe Philippe, Christel Thauvin‐Robinet, Martin Chevarin, Claire Abasq‐Thomas, Jeanne Amiel, Stéphanie Arpin, Sébastien Barbarot, Geneviève Baujat, Didier Bessis, Emmanuelle Bourrat, Odile Boute, Nicolas Chassaing, Christine Coubes, Bénédicte Demeer, Patrick Edery, Salima El Chehadeh, Alice Goldenberg, Smail Hadj‐Rabia, Damien Haye, Bertrand Isidor, Marie‐Line Jacquemont, Philippe Khau Van Kien, Didier Lacombe, Daphné Lehalle, Laetitia Lambert, Ludovic Martin, Annabel Maruani, Fanny Morice‐Picard, Florence Petit, Alice Phan, Lucile Pinson, Massimiliano Rossi, Renaud Touraine, Clémence Vanlerberghe, Marie Vincent, Catherine Vincent‐Delorme, Sandra Whalen, Marjolaine Willems, Nathalie Marle, Virginie Verkarre, Christine Devalland, Mojgan Devouassoux‐Shisheboran, Marine Abad, Nathalie Rioux‐Leclercq, Bertille Bonniaud, Yannis Duffourd, Jehanne Martel, Christine Binquet, Paul Kuentz, and Pierre Vabres. Low risk of embryonic and other cancers in pik3ca‐related overgrowth spectrum: impact on screening recommendations. Clinical Genetics, 104:554-563, Aug 2023. URL: https://doi.org/10.1111/cge.14410, doi:10.1111/cge.14410. This article has 13 citations and is from a peer-reviewed journal.
(stpierre2023gastrointestinalmanifestationsof pages 1-2): Joëlle St-Pierre, Anirudh Mirakhur, and Nauzer Forbes. Gastrointestinal manifestations of cloves syndrome. ACG Case Reports Journal, 10:e01050, May 2023. URL: https://doi.org/10.14309/crj.0000000000001050, doi:10.14309/crj.0000000000001050. This article has 6 citations.
(henuzet2025…lipomatousovergrowth pages 6-7): E Henuzet, L Boon, D Dumitriu, and L Peetermans. … lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal anomalies (cloves) syndrome: a case report and literature review. Unknown journal, 2025.
(wang2024combinedsurgeryand pages 2-5): Shi-Qiang Wang and Siming Yuan. Combined surgery and sclerotherapy for 13 years: a case report of a patient with cloves. Frontiers in Pediatrics, Mar 2024. URL: https://doi.org/10.3389/fped.2024.1336358, doi:10.3389/fped.2024.1336358. This article has 1 citations.
(mussa2023genotypesandphenotypes pages 6-7): Alessandro Mussa, Chiara Leoni, Matteo Iacoviello, Diana Carli, Carlotta Ranieri, Antonino Pantaleo, Paola Sabrina Buonuomo, Rosanna Bagnulo, Giovanni Battista Ferrero, Andrea Bartuli, Daniela Melis, Silvia Maitz, Daria Carmela Loconte, Antonella Turchiano, Marilidia Piglionica, Annunziata De Luisi, Francesco Claudio Susca, Nenad Bukvic, Cinzia Forleo, Angelo Selicorni, Giuseppe Zampino, Roberta Onesimo, Gerarda Cappuccio, Livia Garavelli, Chiara Novelli, Luigi Memo, Carla Morando, Matteo Della Monica, Maria Accadia, Martina Capurso, Carmelo Piscopo, Anna Cereda, Marilena Carmela Di Giacomo, Veronica Saletti, Alessandro Mauro Spinelli, Patrizia Lastella, Romano Tenconi, Veronika Dvorakova, Alan D Irvine, and Nicoletta Resta. Genotypes and phenotypes heterogeneity in pik3ca-related overgrowth spectrum and overlapping conditions: 150 novel patients and systematic review of 1007 patients with pik3ca pathogenetic variants. Journal of Medical Genetics, 60(2):163-173, Mar 2023. URL: https://doi.org/10.1136/jmedgenet-2021-108093, doi:10.1136/jmedgenet-2021-108093. This article has 44 citations and is from a domain leading peer-reviewed journal.
(mussa2023genotypesandphenotypes pages 3-4): Alessandro Mussa, Chiara Leoni, Matteo Iacoviello, Diana Carli, Carlotta Ranieri, Antonino Pantaleo, Paola Sabrina Buonuomo, Rosanna Bagnulo, Giovanni Battista Ferrero, Andrea Bartuli, Daniela Melis, Silvia Maitz, Daria Carmela Loconte, Antonella Turchiano, Marilidia Piglionica, Annunziata De Luisi, Francesco Claudio Susca, Nenad Bukvic, Cinzia Forleo, Angelo Selicorni, Giuseppe Zampino, Roberta Onesimo, Gerarda Cappuccio, Livia Garavelli, Chiara Novelli, Luigi Memo, Carla Morando, Matteo Della Monica, Maria Accadia, Martina Capurso, Carmelo Piscopo, Anna Cereda, Marilena Carmela Di Giacomo, Veronica Saletti, Alessandro Mauro Spinelli, Patrizia Lastella, Romano Tenconi, Veronika Dvorakova, Alan D Irvine, and Nicoletta Resta. Genotypes and phenotypes heterogeneity in pik3ca-related overgrowth spectrum and overlapping conditions: 150 novel patients and systematic review of 1007 patients with pik3ca pathogenetic variants. Journal of Medical Genetics, 60(2):163-173, Mar 2023. URL: https://doi.org/10.1136/jmedgenet-2021-108093, doi:10.1136/jmedgenet-2021-108093. This article has 44 citations and is from a domain leading peer-reviewed journal.
(singh2024fdaapprovalsummary pages 3-4): Sonia Singh, Diana Bradford, Xiaoxue Li, Pallavi S. Mishra-Kalyani, Yuan-Li Shen, Lingshan Wang, Hong Zhao, Ye Xiong, Jiang Liu, Rosane Charlab, Jeffrey Kraft, Sachia Khasar, Claudia P. Miller, Donna R. Rivera, Paul G. Kluetz, Richard Pazdur, Julia A. Beaver, Harpreet Singh, and Martha Donoghue. Fda approval summary: alpelisib for pik3ca-related overgrowth spectrum (pros). Clinical cancer research : an official journal of the American Association for Cancer Research, 30:23-28, Aug 2024. URL: https://doi.org/10.1158/1078-0432.ccr-23-1270, doi:10.1158/1078-0432.ccr-23-1270. This article has 52 citations.
(singh2024fdaapprovalsummary pages 12-13): Sonia Singh, Diana Bradford, Xiaoxue Li, Pallavi S. Mishra-Kalyani, Yuan-Li Shen, Lingshan Wang, Hong Zhao, Ye Xiong, Jiang Liu, Rosane Charlab, Jeffrey Kraft, Sachia Khasar, Claudia P. Miller, Donna R. Rivera, Paul G. Kluetz, Richard Pazdur, Julia A. Beaver, Harpreet Singh, and Martha Donoghue. Fda approval summary: alpelisib for pik3ca-related overgrowth spectrum (pros). Clinical cancer research : an official journal of the American Association for Cancer Research, 30:23-28, Aug 2024. URL: https://doi.org/10.1158/1078-0432.ccr-23-1270, doi:10.1158/1078-0432.ccr-23-1270. This article has 52 citations.
(singh2024fdaapprovalsummary pages 6-8): Sonia Singh, Diana Bradford, Xiaoxue Li, Pallavi S. Mishra-Kalyani, Yuan-Li Shen, Lingshan Wang, Hong Zhao, Ye Xiong, Jiang Liu, Rosane Charlab, Jeffrey Kraft, Sachia Khasar, Claudia P. Miller, Donna R. Rivera, Paul G. Kluetz, Richard Pazdur, Julia A. Beaver, Harpreet Singh, and Martha Donoghue. Fda approval summary: alpelisib for pik3ca-related overgrowth spectrum (pros). Clinical cancer research : an official journal of the American Association for Cancer Research, 30:23-28, Aug 2024. URL: https://doi.org/10.1158/1078-0432.ccr-23-1270, doi:10.1158/1078-0432.ccr-23-1270. This article has 52 citations.
(lakhmawar¹2025bilateralrenalanomalies pages 2-4): NN Lakhmawar¹, N Khadke, A Shinde, and SN Mhaske. Bilateral renal anomalies and macrocephaly in cloves syndrome: a rare case report with pik3ca hotspot mutation. Unknown journal, 2025.
(singh2024fdaapprovalsummary pages 4-6): Sonia Singh, Diana Bradford, Xiaoxue Li, Pallavi S. Mishra-Kalyani, Yuan-Li Shen, Lingshan Wang, Hong Zhao, Ye Xiong, Jiang Liu, Rosane Charlab, Jeffrey Kraft, Sachia Khasar, Claudia P. Miller, Donna R. Rivera, Paul G. Kluetz, Richard Pazdur, Julia A. Beaver, Harpreet Singh, and Martha Donoghue. Fda approval summary: alpelisib for pik3ca-related overgrowth spectrum (pros). Clinical cancer research : an official journal of the American Association for Cancer Research, 30:23-28, Aug 2024. URL: https://doi.org/10.1158/1078-0432.ccr-23-1270, doi:10.1158/1078-0432.ccr-23-1270. This article has 52 citations.

{ }

Source YAML

click to show

name: CLOVES Syndrome
creation_date: "2026-03-07T00:00:00Z"
updated_date: "2026-04-06T23:42:38Z"
category: Genetic
description: >
  CLOVES syndrome (Congenital Lipomatous Overgrowth, Vascular malformations,
  Epidermal nevi, and Skeletal/spinal anomalies) is a rare congenital overgrowth
  disorder caused by somatic activating mutations in PIK3CA. It is part of the
  PIK3CA-related overgrowth spectrum (PROS). The condition is characterized by
  progressive, asymmetric tissue overgrowth with lipomatous masses predominantly
  affecting the trunk, complex vascular malformations (lymphatic, capillary, and
  venous), epidermal nevi, and skeletal anomalies including scoliosis and limb
  overgrowth. Because the mutations are somatic and mosaic, the distribution and
  severity of features vary widely depending on the timing and location of the
  mutation during embryonic development.
disease_term:
  preferred_term: CLOVES syndrome
  term:
    id: MONDO:0013038
    label: CLOVES syndrome
parents:
- PIK3CA-related overgrowth spectrum
- Vascular malformation syndromes
- Overgrowth syndromes
inheritance:
- name: Somatic Mosaicism
  description: >
    CLOVES syndrome is caused by post-zygotic somatic activating mutations in
    PIK3CA. The mutations arise de novo during embryonic development and are
    present in a mosaic pattern. The condition is not inherited in a traditional
    Mendelian fashion and recurrence risk for unaffected parents is negligible.
  evidence:
  - reference: PMID:22658544
    reference_title: "Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We hypothesized that CLOVES syndrome would be caused by a somatic mutation
      arising during early embryonic development. Therefore, we employed massively
      parallel sequencing to search for somatic mosaic mutations in fresh, frozen,
      or fixed archival tissue from six affected individuals. We identified mutations
      in PIK3CA in all six individuals, and mutant allele frequencies ranged from 3%
      to 30% in affected tissue from multiple embryonic lineages.
    explanation: >-
      Confirms that CLOVES syndrome is caused by post-zygotic somatic mosaic
      mutations in PIK3CA with variable allele frequencies in affected tissues.
prevalence:
- population: Global reported literature
  percentage: Unknown
  notes: >-
    Population prevalence has not been established. CLOVES syndrome remains a
    sporadic mosaic disorder described mainly in case reports, discovery
    cohorts, and broader PIK3CA-related overgrowth spectrum reviews rather than
    in population-based prevalence studies.
  evidence:
  - reference: PMID:22658544
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies (CLOVES) is a sporadically occurring, nonhereditary disorder characterized by asymmetric somatic hypertrophy and anomalies in multiple organs."
    explanation: >-
      The original molecular series characterizes CLOVES as a sporadic disorder
      and reflects the case-series nature of the literature.
  - reference: PMID:34568242
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The common clinical denominator of PROS disorders is that they are sporadic conditions, presenting with congenital or early childhood onset overgrowth with a typical mosaic distribution."
    explanation: >-
      This later review confirms that CLOVES and related PROS disorders remain
      sporadic mosaic conditions without established population prevalence.
pathophysiology:
- name: Constitutive PI3K Activation
  description: >
    Somatic gain-of-function mutations in PIK3CA (encoding the p110alpha
    catalytic subunit of PI3K) increase enzymatic activity, resulting in
    elevated PIP3 production in affected cells.
  genes:
  - preferred_term: PIK3CA
    term:
      id: hgnc:8975
      label: PIK3CA
  molecular_functions:
  - preferred_term: phosphatidylinositol 3-kinase activity
    term:
      id: GO:0046934
      label: 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity
  biological_processes:
  - preferred_term: PI3K Signaling
    term:
      id: GO:0043491
      label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
  evidence:
  - reference: PMID:34568242
    reference_title: "PIK3CA-Related Overgrowth Spectrum From Diagnosis to Targeted Therapy: A Case of CLOVES Syndrome Treated With Alpelisib."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These conditions are caused by somatic gain-of-function mutations in PIK3CA,
      which encodes the 110-kD catalytic alpha subunit of PI3K (p110alpha). These
      PIK3CA mutations occur as post-zygotic events and lead to a gain of function
      of PI3K, with consequent constitutional activation of the downstream cascades
      (e.g., AKT/mTOR pathway), involved in cellular proliferation, survival and
      growth, as well as in vascular development in the embryonic stage.
    explanation: >-
      Establishes that PIK3CA gain-of-function mutations constitutively activate
      PI3K enzymatic activity.
  downstream:
  - target: AKT/mTOR Pathway Hyperactivation
    description: >-
      Elevated PIP3 recruits and activates AKT, which in turn activates
      mTOR signaling.
- name: AKT/mTOR Pathway Hyperactivation
  description: >
    Constitutive PI3K activation leads to enhanced AKT phosphorylation and
    downstream mTOR signaling. This results in increased cell proliferation,
    growth, and survival in affected tissues, driving the overgrowth phenotype.
  cell_types:
  - preferred_term: Endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  - preferred_term: Adipocyte
    term:
      id: CL:0000136
      label: adipocyte
  biological_processes:
  - preferred_term: Cell Proliferation
    term:
      id: GO:0008283
      label: cell population proliferation
  evidence:
  - reference: PMID:34074347
    reference_title: "Somatic frameshift mutation in PIK3CA causes CLOVES syndrome by provoking PI3K/AKT/mTOR pathway."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vitro studies revealed that p.X1069Trpfs*4 mutant exhibited increased
      AKT phosphorylation significantly to that of the wildtype, which could be
      inhibited by PI3K/AKT/mTOR pathway inhibitors.
    explanation: >-
      In vitro functional studies confirm that CLOVES-associated PIK3CA mutations
      significantly increase AKT phosphorylation, demonstrating constitutive
      pathway activation.
  downstream:
  - target: Aberrant Vascular Development
    description: >-
      Hyperactive AKT/mTOR signaling in endothelial cells drives abnormal
      vascular morphogenesis.
  - target: Lipomatous Overgrowth
    description: >-
      Hyperactive AKT/mTOR signaling in adipose precursors promotes
      excessive adipogenesis and lipomatous expansion.
- name: Aberrant Vascular Development
  description: >
    PIK3CA gain-of-function mutations in endothelial and lymphatic endothelial
    cells drive abnormal vascular morphogenesis, resulting in complex combined
    vascular malformations. These include slow-flow lymphatic, capillary, and
    venous malformations that are progressive and can cause significant morbidity
    through mass effect, coagulopathy, and infection risk.
  cell_types:
  - preferred_term: Endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: Angiogenesis
    term:
      id: GO:0001525
      label: angiogenesis
  - preferred_term: Lymphangiogenesis
    term:
      id: GO:0001946
      label: lymphangiogenesis
  evidence:
  - reference: PMID:27426476
    reference_title: "CLOVES syndrome: review of a PIK3CA-related overgrowth spectrum (PROS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These mutations are responsible for the clinical manifestations of the
      syndrome, which include low- and high-flow vascular malformations, thoracic
      lipomatous hyperplasia, asymmetric growth, and visceral and neurological
      disorders.
    explanation: >-
      Review confirms that PIK3CA mutations drive the full spectrum of CLOVES
      vascular malformations including low- and high-flow types.
  - reference: PMID:29899452
    reference_title: "Targeted therapy in patients with PIK3CA-related overgrowth syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Previously intractable vascular tumours became smaller, congestive heart
      failure was improved, hemihypertrophy was reduced, and scoliosis was
      attenuated.
    explanation: >-
      Demonstrates that vascular malformations are a key clinical feature that
      responds to targeted PIK3CA inhibition therapy.
- name: Lipomatous Overgrowth
  description: >
    Constitutive PI3K activation in adipose precursor cells promotes excessive
    adipogenesis and lipomatous tissue expansion. The overgrowth is typically
    truncal, asymmetric, and progressive, and can involve both subcutaneous and
    visceral compartments.
  cell_types:
  - preferred_term: Adipocyte
    term:
      id: CL:0000136
      label: adipocyte
  biological_processes:
  - preferred_term: Adipogenesis
    term:
      id: GO:0045444
      label: fat cell differentiation
  evidence:
  - reference: PMID:22658544
    reference_title: "Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congenital lipomatous overgrowth with vascular, epidermal, and skeletal
      anomalies (CLOVES) is a sporadically occurring, nonhereditary disorder
      characterized by asymmetric somatic hypertrophy and anomalies in multiple
      organs.
    explanation: >-
      Confirms lipomatous overgrowth as a defining feature of CLOVES syndrome.
genetic:
- name: PIK3CA Somatic Mutations
  association: Causative
  gene_term:
    preferred_term: PIK3CA
    term:
      id: hgnc:8975
      label: PIK3CA
  notes: >
    Somatic activating mutations in PIK3CA (encoding the p110alpha catalytic
    subunit of PI3K) are found in affected tissues. Common hotspot mutations
    include E542K, E545K, H1047R, H1047L, and C420R. The mutations are mosaic
    and often detectable only in affected tissue rather than blood. The specific
    mutation and its tissue distribution determine the clinical phenotype and
    severity.
  evidence:
  - reference: PMID:22658544
    reference_title: "Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified mutations in PIK3CA in all six individuals, and mutant allele
      frequencies ranged from 3% to 30% in affected tissue from multiple
      embryonic lineages. Interestingly, these same mutations have been identified
      in cancer cells, in which they increase phosphoinositide-3-kinase activity.
      We conclude that CLOVES is caused by postzygotic activating mutations in
      PIK3CA.
    explanation: >-
      Landmark study identifying PIK3CA somatic mosaic mutations as the cause of
      CLOVES syndrome in all six patients studied, with mutant allele frequencies
      of 3-30% in affected tissues.
  - reference: PMID:34568242
    reference_title: "PIK3CA-Related Overgrowth Spectrum From Diagnosis to Targeted Therapy: A Case of CLOVES Syndrome Treated With Alpelisib."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PIK3CA-related cancers and PROS share almost the same PIK3CA mutational
      profile, with about 80% of mutations occurring at three hotspots, E542,
      E545, and H1047. These hotspot mutations show the most potent effect on
      enzymatic activation of PI3K and consequent downstream biological responses.
    explanation: >-
      Confirms the three major hotspot mutations (E542, E545, H1047) account for
      about 80% of PIK3CA mutations in PROS/CLOVES.
  - reference: PMID:34074347
    reference_title: "Somatic frameshift mutation in PIK3CA causes CLOVES syndrome by provoking PI3K/AKT/mTOR pathway."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We have identified the first frameshift mutation in PIK3CA that causes
      CLOVES syndrome, which was confirmed to overactive PI3K/AKT/mTOR pathway
      by transient transfection assays.
    explanation: >-
      Expands the mutational spectrum beyond missense mutations, demonstrating
      that frameshift mutations affecting the PIK3CA stop codon can also cause
      CLOVES syndrome through PI3K/AKT/mTOR pathway overactivation.
phenotypes:
- name: Lipomatous Overgrowth
  description: >
    Congenital truncal lipomatous masses that are typically asymmetric and
    progressive. These soft, fatty masses can be massive and may involve the
    chest, abdomen, or back.
  phenotype_term:
    preferred_term: Lipomatous overgrowth
    term:
      id: HP:0001012
      label: Multiple lipomas
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:27426476
    reference_title: "CLOVES syndrome: review of a PIK3CA-related overgrowth spectrum (PROS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CLOVES (Congenital Lipomatous asymmetric Overgrowth of the trunk with
      lymphatic, capillary, venous, and combined-type Vascular malformations,
      Epidermal naevi, Scoliosis/Skeletal and spinal anomalies) is an overgrowth
      syndrome caused by mosaic activating mutation in gene PIK3CA
    explanation: >-
      Lipomatous overgrowth is a defining feature of CLOVES syndrome, forming
      part of the acronym itself.
- name: Venous Malformation
  description: >
    Slow-flow venous malformations are a core vascular component of CLOVES
    syndrome. They frequently co-occur with lymphatic and capillary
    malformations as part of the combined vascular phenotype.
  phenotype_term:
    preferred_term: Venous malformation
    term:
      id: HP:0012721
      label: Venous malformation
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:29899452
    reference_title: "Targeted therapy in patients with PIK3CA-related overgrowth syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations,
      epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic
      disorder that results from somatic, mosaic gain-of-function mutations of
      the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth
      syndromes (PROS).
    explanation: >-
      Confirms vascular malformations as a defining clinical feature of CLOVES
      syndrome.
- name: Epidermal Nevus
  description: >
    Linear verrucous epidermal nevi occur in a subset of patients,
    found in 4/35 (11%) in the largest PROS clinical delineation study.
  phenotype_term:
    preferred_term: Epidermal nevus
    term:
      id: HP:0010816
      label: Epidermal nevus
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:24782230
    reference_title: "Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Vascular malformations were found in 15/35 (43%) and epidermal nevi in
      4/35 (11%) patients, lower than in Proteus syndrome.
    explanation: >-
      Largest clinical delineation study documents epidermal nevi in 11% of
      PROS patients, confirming OCCASIONAL frequency.
- name: Scoliosis
  description: >
    Progressive scoliosis is a common skeletal anomaly, often severe and
    requiring surgical intervention.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  frequency: FREQUENT
  evidence:
  - reference: PMID:34568242
    reference_title: "PIK3CA-Related Overgrowth Spectrum From Diagnosis to Targeted Therapy: A Case of CLOVES Syndrome Treated With Alpelisib."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present an 8-year-old girl with CLOVES syndrome, born with a large
      cystic lymphangioma involving the left hemithorax and flank, multiple
      lipomas, and hypertrophy of the left foot and leg. She developed severe
      scoliosis.
    explanation: >-
      Case report of a CLOVES patient demonstrating severe scoliosis as a
      significant clinical feature.
- name: Spinal Anomalies
  description: >
    Spinal abnormalities including tethered cord, fatty filum terminale,
    vertebral anomalies, and spinal-paraspinal fast-flow vascular lesions.
  phenotype_term:
    preferred_term: Spinal dysraphism
    term:
      id: HP:0010301
      label: Spinal dysraphism
  frequency: FREQUENT
  evidence:
  - reference: PMID:21310861
    reference_title: "Complex spinal-paraspinal fast-flow lesions in CLOVES syndrome: analysis of clinical and imaging findings in 6 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CLOVES syndrome is a complex disorder of congenital lipomatous overgrowth,
      vascular malformations, epidermal nevi, and skeletal/scoliosis/spinal
      anomalies. We report the occurrence of spinal-paraspinal fast-flow lesions
      within or adjacent to the truncal overgrowth or a cutaneous birthmark in 6
      patients with CLOVES syndrome.
    explanation: >-
      Documents spinal-paraspinal fast-flow vascular lesions as a recognized
      feature of CLOVES syndrome in 6 patients from a cohort study.
  - reference: PMID:31334068
    reference_title: "Cloves Syndrome: A Rare Disorder of Overgrowth with Unusual Features - An Uncommon Phenotype?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Central nervous system (CNS) manifestations include polymicrogyria,
      noncontiguous abnormalities of the gray and white matter, a four-layered
      cortex, ventriculomegaly, hemimegalencephaly, dysgenesis of the corpus
      callosum, neuronal migration defects and consequent seizures, tethered
      spinal cord, and neural tube defects.
    explanation: >-
      Comprehensive review listing tethered spinal cord and neural tube defects
      among the CNS manifestations of CLOVES syndrome.
- name: Macrodactyly
  description: >
    Enlarged digits due to overgrowth of bone and soft tissue, particularly
    affecting the feet.
  phenotype_term:
    preferred_term: Macrodactyly
    term:
      id: HP:0004099
      label: Macrodactyly
  frequency: FREQUENT
  evidence:
  - reference: PMID:34074347
    reference_title: "Somatic frameshift mutation in PIK3CA causes CLOVES syndrome by provoking PI3K/AKT/mTOR pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sandal gap toe and wide foot with second and third toes macrodactyly
      caused by skeletal elongation and adipose overgrowth.
    explanation: >-
      Case report documenting macrodactyly of toes caused by skeletal elongation
      and adipose overgrowth in a CLOVES patient.
- name: Capillary Malformation
  description: >
    Capillary malformations presenting as port-wine stain-like birthmarks,
    often with geographic or patchy distribution.
  phenotype_term:
    preferred_term: Capillary malformation
    term:
      id: HP:0025104
      label: Capillary malformation
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:27426476
    reference_title: "CLOVES syndrome: review of a PIK3CA-related overgrowth spectrum (PROS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CLOVES (Congenital Lipomatous asymmetric Overgrowth of the trunk with
      lymphatic, capillary, venous, and combined-type Vascular malformations,
      Epidermal naevi, Scoliosis/Skeletal and spinal anomalies)
    explanation: >-
      Capillary malformations are explicitly part of the CLOVES phenotypic
      definition.
- name: Sandal Gap
  description: >
    Wide gap between the first and second toes, a classic acral finding
    in CLOVES syndrome.
  phenotype_term:
    preferred_term: Sandal gap
    term:
      id: HP:0001852
      label: Sandal gap
  frequency: FREQUENT
  evidence:
  - reference: PMID:31334068
    reference_title: "Cloves Syndrome: A Rare Disorder of Overgrowth with Unusual Features - An Uncommon Phenotype?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the lower limbs show soft tissue overgrowth of feet and broad forefoot,
      large bulbous toes, wide first toe web (sandal gap), plantar creases,
      lipomatous masses on plantar and dorsal feet, and wide gaps between
      metatarsal heads in 50% of 18 cases reviewed.
    explanation: >-
      Sandal gap (wide first toe web) documented in 50% of reviewed CLOVES cases.
- name: Hemihypertrophy
  description: >
    Asymmetric overgrowth of one side of the body (hemihyperplasia),
    involving soft tissues and/or skeletal structures.
  phenotype_term:
    preferred_term: Hemihypertrophy
    term:
      id: HP:0001528
      label: Hemihypertrophy
  frequency: FREQUENT
  evidence:
  - reference: PMID:29899452
    reference_title: "Targeted therapy in patients with PIK3CA-related overgrowth syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Previously intractable vascular tumours became smaller, congestive heart
      failure was improved, hemihypertrophy was reduced, and scoliosis was
      attenuated.
    explanation: >-
      Hemihypertrophy documented as a major feature that responded to alpelisib
      treatment in PROS patients.
- name: Tethered Cord
  description: >
    Tethered spinal cord due to abnormal fixation, which can cause
    progressive neurological deficits if untreated.
  phenotype_term:
    preferred_term: Tethered cord
    term:
      id: HP:0002144
      label: Tethered cord
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:31334068
    reference_title: "Cloves Syndrome: A Rare Disorder of Overgrowth with Unusual Features - An Uncommon Phenotype?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Central nervous system (CNS) manifestations include polymicrogyria,
      noncontiguous abnormalities of the gray and white matter, a four-layered
      cortex, ventriculomegaly, hemimegalencephaly, dysgenesis of the corpus
      callosum, neuronal migration defects and consequent seizures, tethered
      spinal cord, and neural tube defects.
    explanation: >-
      Tethered spinal cord listed among recognized CNS manifestations of CLOVES
      syndrome in comprehensive review.
- name: Thromboembolism
  description: >
    Risk of deep vein thrombosis and pulmonary embolism from anomalous
    marginal veins and persistent embryonic veins. May require prophylactic
    anticoagulation.
  phenotype_term:
    preferred_term: Thromboembolism
    term:
      id: HP:0001907
      label: Thromboembolism
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:31334068
    reference_title: "Cloves Syndrome: A Rare Disorder of Overgrowth with Unusual Features - An Uncommon Phenotype?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      central phlebectasia/thromboembolism in CLOVES syndrome need active or
      prophylactic surgical/medical interventions to improve quality of life.
    explanation: >-
      Thromboembolism recognized as a complication of CLOVES syndrome requiring
      active or prophylactic intervention.
- name: Nephroblastoma (Wilms Tumor)
  description: >
    Wilms tumor occurs in approximately 3.3% of CLOVES patients. Quarterly
    abdominal ultrasonography screening is recommended until age 7 years.
  phenotype_term:
    preferred_term: Nephroblastoma (Wilms tumor)
    term:
      id: HP:0002667
      label: Nephroblastoma
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:28627003
    reference_title: "Sonographic screening for Wilms tumor in children with CLOVES syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 122 patients with CLOVES syndrome were found in our database
      (mean age 7.7 years, range 0-53 years). Four patients developed WT; all were
      diagnosed by 2 years of age. The incidence of WT in our CLOVES patient
      population (3.3%) was significantly greater than the incidence of WT in the
      general population (1/10,000) (P < 0.001).
    explanation: >-
      Large cohort study at Boston Children's Hospital documenting 3.3% Wilms
      tumor incidence in 122 CLOVES patients, significantly above general
      population risk, supporting screening recommendations.
  - reference: PMID:36804444
    reference_title: "Bilateral Wilms Tumor in CLOVES Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Wilms tumor is the most common pediatric renal mass and occurs in up to 10%
      of predisposition syndromes. One such syndrome is CLOVES syndrome, an
      extremely rare disorder within the umbrella of PIK3CA-related overgrowth
      spectrum disorders.
    explanation: >-
      Case report of bilateral Wilms tumor in a CLOVES patient, confirming
      the association and highlighting management complexity.
- name: Spinal Arteriovenous Malformation
  description: >
    High-flow arteriovenous malformations in or around the spinal cord that
    can cause spinal cord ischemia, myelopathy, and progressive neurological
    deficits including paralysis.
  phenotype_term:
    preferred_term: Spinal arteriovenous malformation
    term:
      id: HP:0002390
      label: Spinal arteriovenous malformation
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:21310861
    reference_title: "Complex spinal-paraspinal fast-flow lesions in CLOVES syndrome: analysis of clinical and imaging findings in 6 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CLOVES syndrome is a complex disorder of congenital lipomatous overgrowth,
      vascular malformations, epidermal nevi, and skeletal/scoliosis/spinal
      anomalies. We report the occurrence of spinal-paraspinal fast-flow lesions
      within or adjacent to the truncal overgrowth or a cutaneous birthmark in 6
      patients with CLOVES syndrome.
    explanation: >-
      Documents spinal-paraspinal fast-flow (arteriovenous) lesions in 6 CLOVES
      patients, establishing this as a recognized complication.
- name: Seizures
  description: >
    Seizures secondary to cortical malformations such as hemimegalencephaly,
    polymicrogyria, and neuronal migration defects. Reported in up to 50%
    of CLOVES patients with CNS involvement.
  phenotype_term:
    preferred_term: Seizures
    term:
      id: HP:0001250
      label: Seizure
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:31334068
    reference_title: "Cloves Syndrome: A Rare Disorder of Overgrowth with Unusual Features - An Uncommon Phenotype?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Central nervous system (CNS) manifestations include polymicrogyria,
      noncontiguous abnormalities of the gray and white matter, a four-layered
      cortex, ventriculomegaly, hemimegalencephaly, dysgenesis of the corpus
      callosum, neuronal migration defects and consequent seizures, tethered
      spinal cord, and neural tube defects.
    explanation: >-
      Seizures documented as a CNS manifestation of CLOVES syndrome, consequent
      to cortical malformations.
  - reference: PMID:31334068
    reference_title: "Cloves Syndrome: A Rare Disorder of Overgrowth with Unusual Features - An Uncommon Phenotype?"
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Some degree of neuorologic impairment has been reported in almost 50%
      cases in a large series.
    explanation: >-
      Neurological impairment reported in approximately 50% of CLOVES cases,
      though this includes motor deficits and developmental delay, not
      exclusively seizures.
- name: Hemimegalencephaly
  description: >
    Asymmetric enlargement of one cerebral hemisphere, a CNS manifestation
    occurring in a subset of patients with CLOVES syndrome.
  phenotype_term:
    preferred_term: Hemimegalencephaly
    term:
      id: HP:0007206
      label: Hemimegalencephaly
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:31334068
    reference_title: "Cloves Syndrome: A Rare Disorder of Overgrowth with Unusual Features - An Uncommon Phenotype?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Central nervous system (CNS) manifestations include polymicrogyria,
      noncontiguous abnormalities of the gray and white matter, a four-layered
      cortex, ventriculomegaly, hemimegalencephaly, dysgenesis of the corpus
      callosum, neuronal migration defects and consequent seizures, tethered
      spinal cord, and neural tube defects.
    explanation: >-
      Hemimegalencephaly explicitly listed among CNS manifestations of CLOVES.
- name: Polymicrogyria
  description: >
    Cortical malformation with excessive small gyri, contributing to
    seizures and developmental delay in a subset of CLOVES patients.
  phenotype_term:
    preferred_term: Polymicrogyria
    term:
      id: HP:0002126
      label: Polymicrogyria
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:31334068
    reference_title: "Cloves Syndrome: A Rare Disorder of Overgrowth with Unusual Features - An Uncommon Phenotype?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Central nervous system (CNS) manifestations include polymicrogyria,
      noncontiguous abnormalities of the gray and white matter, a four-layered
      cortex, ventriculomegaly, hemimegalencephaly, dysgenesis of the corpus
      callosum, neuronal migration defects and consequent seizures, tethered
      spinal cord, and neural tube defects.
    explanation: >-
      Polymicrogyria listed among CNS manifestations of CLOVES syndrome.
- name: Ventriculomegaly
  description: >
    Enlarged cerebral ventricles, often ipsilateral to hemimegalencephaly.
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:31334068
    reference_title: "Cloves Syndrome: A Rare Disorder of Overgrowth with Unusual Features - An Uncommon Phenotype?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      large left cerebral hemisphere with mild ipsilateral ventriculomegaly
      were peculiar to him denoting an uncommon phenotype.
    explanation: >-
      Ventriculomegaly documented in a CLOVES patient with hemimegalencephaly.
- name: Facial Asymmetry
  description: >
    Asymmetric facial features due to unilateral overgrowth, which may
    include cranial asymmetry and maxillary hyperplasia.
  phenotype_term:
    preferred_term: Facial asymmetry
    term:
      id: HP:0000324
      label: Facial asymmetry
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:31334068
    reference_title: "Cloves Syndrome: A Rare Disorder of Overgrowth with Unusual Features - An Uncommon Phenotype?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ipsilateral asymmetrical deformity of skull, and large left cerebral
      hemisphere with mild ipsilateral ventriculomegaly were peculiar to him
      denoting an uncommon phenotype.
    explanation: >-
      Ipsilateral skull/facial asymmetry documented in a CLOVES patient,
      consistent with mosaic overgrowth pattern.
- name: Renal Anomalies
  description: >
    Renal abnormalities including hypoplasia, agenesis, and cysts.
  phenotype_term:
    preferred_term: Renal anomalies
    term:
      id: HP:0000077
      label: Abnormality of the kidney
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:31334068
    reference_title: "Cloves Syndrome: A Rare Disorder of Overgrowth with Unusual Features - An Uncommon Phenotype?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Visceral anomalies occur in the form of renal agenesis/hypoplasia, Wilms
      tumor, splenic lesions, and extensive deep retroperitoneal and pelvic
      fatty and lymphatic malformation.
    explanation: >-
      Renal agenesis/hypoplasia documented as visceral anomalies in CLOVES.
- name: Lymphatic Malformation
  description: >
    Lymphatic malformations presenting as macrocystic or microcystic
    lymphangiomas, often in the trunk, chest, and abdomen. Lymphatic
    complications include chylothorax and chylous ascites.
  phenotype_term:
    preferred_term: Lymphangioma
    term:
      id: HP:0100764
      label: Lymphangioma
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:34568242
    reference_title: "PIK3CA-Related Overgrowth Spectrum From Diagnosis to Targeted Therapy: A Case of CLOVES Syndrome Treated With Alpelisib."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present an 8-year-old girl with CLOVES syndrome, born with a large
      cystic lymphangioma involving the left hemithorax and flank, multiple
      lipomas, and hypertrophy of the left foot and leg. She developed severe
      scoliosis.
    explanation: >-
      Case report documenting a large cystic lymphangioma as a presenting
      feature of CLOVES syndrome.
- name: Lower Limb Asymmetry
  description: >
    Asymmetric leg length or girth due to unilateral soft tissue and/or
    skeletal overgrowth. A hallmark feature of CLOVES syndrome.
  phenotype_term:
    preferred_term: Lower limb asymmetry
    term:
      id: HP:0100559
      label: Lower limb asymmetry
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:31334068
    reference_title: "Cloves Syndrome: A Rare Disorder of Overgrowth with Unusual Features - An Uncommon Phenotype?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had bilateral genu valgum, and his left lower limb was longer by 2
      cm than the right one but showed no deformity of hands and feet.
    explanation: >-
      Case report documenting lower limb length discrepancy in a CLOVES
      patient, consistent with asymmetric overgrowth.
  - reference: PMID:24782230
    reference_title: "Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      More individuals had involvement of the lower extremities (24/35) than
      upper extremities (6/35, P = 0.041), and three of 35 had overgrowth of
      both upper and lower extremities.
    explanation: >-
      In the largest PROS cohort (n=35), 24/35 (69%) had lower extremity
      involvement, supporting VERY_FREQUENT designation for lower limb
      asymmetry.
- name: Asymmetric Growth
  description: >
    Disproportionate growth affecting one side of the body more than the
    other, reflecting the mosaic distribution of the PIK3CA mutation.
  phenotype_term:
    preferred_term: Asymmetric growth
    term:
      id: HP:0100555
      label: Asymmetric growth
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:27426476
    reference_title: "CLOVES syndrome: review of a PIK3CA-related overgrowth spectrum (PROS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These mutations are responsible for the clinical manifestations of the
      syndrome, which include low- and high-flow vascular malformations,
      thoracic lipomatous hyperplasia, asymmetric growth, and visceral and
      neurological disorders.
    explanation: >-
      Asymmetric growth explicitly listed as a clinical manifestation of
      CLOVES syndrome in this review.
- name: Increased Adipose Tissue
  description: >
    Excessive adipose tissue deposition in trunk, extremities, and other
    body regions driven by constitutive PI3K pathway activation in
    adipocyte precursors.
  phenotype_term:
    preferred_term: Increased adipose tissue
    term:
      id: HP:0009126
      label: Increased adipose tissue
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:31334068
    reference_title: "Cloves Syndrome: A Rare Disorder of Overgrowth with Unusual Features - An Uncommon Phenotype?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The major deformities invariably include deposition of adipose tissue
      in all body regions and tissue spaces including face, scrotum,
      paraspinal musculature, epidural spaces, mediastinum, and pleura.
    explanation: >-
      Confirms widespread adipose tissue deposition as a major invariable
      feature of CLOVES syndrome.
  - reference: PMID:24782230
    reference_title: "Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dysregulated adipose tissue (either lipomatous lesions or regional
      lipohypoplasia) was seen in all patients
    explanation: >-
      In the largest PROS cohort (n=35), dysregulated adipose tissue was
      present in all 35 patients (100%), confirming VERY_FREQUENT designation.
- name: Cutis Marmorata
  description: >
    Reticular mottled skin discoloration with cyanotic areas surrounding
    pale central areas, reflecting vascular dysregulation.
  phenotype_term:
    preferred_term: Cutis marmorata
    term:
      id: HP:0000965
      label: Cutis marmorata
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:24782230
    reference_title: "Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other skin abnormalities included a dermal melanocytic nevus,
      café-au-lait macules, hypopigmented macules, cutis marmorata,
      pigmented nevi, and patchy hyperpigmentation in 12/33 (36%) patients.
    explanation: >-
      Cutis marmorata documented in 36% of patients in the largest
      clinical delineation study of PIK3CA-related overgrowth spectrum.
- name: Arteriovenous Malformation
  description: >
    Anomalous high-flow connections between arteries and veins without
    intervening capillary beds. Can occur in trunk, extremities, and
    spinal-paraspinal regions.
  phenotype_term:
    preferred_term: Arteriovenous malformation
    term:
      id: HP:0100026
      label: Arteriovenous malformation
  frequency: FREQUENT
  evidence:
  - reference: PMID:31334068
    reference_title: "Cloves Syndrome: A Rare Disorder of Overgrowth with Unusual Features - An Uncommon Phenotype?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients show lymphatic, venous and capillary (low-flow), or
      arteriovenous malformations (port-wine stains) with or without
      arteriovenous fistulae (high-flow vascular anomalies) that usually
      become evident during childhood.
    explanation: >-
      Arteriovenous malformations documented as occurring in all CLOVES
      patients alongside other vascular anomalies.
  - reference: PMID:24782230
    reference_title: "Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      there were 15/35 patients (43%) with vascular malformations, including
      capillary venous or lymphatic malformations. Some of these 15
      individuals had combined venous/lymphatic malformations.
    explanation: >-
      Vascular malformations documented in 43% of PROS patients (n=35).
      The FREQUENT designation accounts for combined low- and high-flow
      vascular anomalies across the spectrum.
- name: Spina Bifida
  description: >
    Incomplete closure of the vertebral arches (neural tube defect),
    ranging from spina bifida occulta to open defects.
  phenotype_term:
    preferred_term: Spina bifida
    term:
      id: HP:0002414
      label: Spina bifida
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:31334068
    reference_title: "Cloves Syndrome: A Rare Disorder of Overgrowth with Unusual Features - An Uncommon Phenotype?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Central nervous system (CNS) manifestations include polymicrogyria,
      noncontiguous abnormalities of the gray and white matter, a four-layered
      cortex, ventriculomegaly, hemimegalencephaly, dysgenesis of the corpus
      callosum, neuronal migration defects and consequent seizures, tethered
      spinal cord, and neural tube defects.
    explanation: >-
      Neural tube defects (including spina bifida) listed among CNS
      manifestations of CLOVES syndrome.
  - reference: PMID:24782230
    reference_title: "Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hip subluxation/dislocation, spina bifida occulta, tethered cord,
      extra segments in the vertebrae, uterine fibroids, and splenic cysts
    explanation: >-
      Spina bifida occulta documented among malformations in the PROS
      cohort (n=35).
- name: Polydactyly
  description: >
    Presence of supernumerary digits, occasionally seen in CLOVES
    patients as part of the acral overgrowth spectrum.
  phenotype_term:
    preferred_term: Polydactyly
    term:
      id: HP:0010442
      label: Polydactyly
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:24782230
    reference_title: "Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other limb findings included postaxial or preaxial polydactyly and
      cutaneous syndactyly, which involved only the toes. In particular,
      four had polydactyly: two with postaxial polydactyly (one unilateral
      left foot and one bilateral feet), one central and one with preaxial
      polydactyly (of the hallux).
    explanation: >-
      Polydactyly documented in 4 of 35 PROS patients in the largest
      clinical delineation study, with both postaxial and preaxial forms.
- name: Cutaneous Syndactyly
  description: >
    Soft tissue fusion between adjacent digits, occasionally seen in
    CLOVES patients.
  phenotype_term:
    preferred_term: Cutaneous syndactyly
    term:
      id: HP:0012725
      label: Cutaneous syndactyly
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:24782230
    reference_title: "Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There were seven with cutaneous syndactyly: two with unilateral 2–3
      toes, two with unilateral 2–4 toes, one bilateral with 2–5 toes
      (Right) and 2–4 toes (Left), and two unspecified
    explanation: >-
      Cutaneous syndactyly of the toes documented in 7 of 35 PROS patients
      in the largest clinical delineation study.
- name: Broad Palm
  description: >
    Abnormally wide palms due to soft tissue and skeletal overgrowth
    of the hands.
  phenotype_term:
    preferred_term: Broad palm
    term:
      id: HP:0001169
      label: Broad palm
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:31334068
    reference_title: "Cloves Syndrome: A Rare Disorder of Overgrowth with Unusual Features - An Uncommon Phenotype?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prominent upper limb deformities include symmetrical overgrowth of
      digit(s), laxity of collateral ligaments of metacarpophalangeal and
      interphalangeal joints, and broad spade like hands with ulnar deviation
      of digits.
    explanation: >-
      Broad spade-like hands explicitly documented as a prominent upper limb
      deformity in CLOVES syndrome.
- name: Pectus Excavatum
  description: >
    Concave deformity of the chest wall (funnel chest), occasionally
    seen in CLOVES patients. Listed in Orphanet clinical synopsis
    (ORPHA:140944) as an occasional feature; no cohort-level frequency
    data available in the primary literature.
  phenotype_term:
    preferred_term: Pectus excavatum
    term:
      id: HP:0000767
      label: Pectus excavatum
  frequency: OCCASIONAL
- name: Hip Dysplasia
  description: >
    Developmental dysplasia of the hip, occasionally occurring in
    CLOVES patients as part of the skeletal anomaly spectrum.
  phenotype_term:
    preferred_term: Hip dysplasia
    term:
      id: HP:0001385
      label: Hip dysplasia
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:24782230
    reference_title: "Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hip subluxation/dislocation, spina bifida occulta, tethered cord,
      extra segments in the vertebrae, uterine fibroids, and splenic cysts
    explanation: >-
      Hip subluxation/dislocation documented among skeletal malformations
      in the largest clinical delineation study of PROS patients.
- name: Gait Disturbance
  description: >
    Abnormal gait pattern resulting from limb length discrepancy,
    skeletal overgrowth, or neurological involvement.
  phenotype_term:
    preferred_term: Gait disturbance
    term:
      id: HP:0001288
      label: Gait disturbance
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:34074347
    reference_title: "Somatic frameshift mutation in PIK3CA causes CLOVES syndrome by provoking PI3K/AKT/mTOR pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Symptoms of claudication caused by the unilateral deformation worsened
      with age.
    explanation: >-
      Claudication (gait disturbance) documented as a progressive symptom
      caused by unilateral limb deformation in a CLOVES patient.
- name: Pain
  description: >
    Chronic or recurrent pain from vascular malformations, skeletal
    anomalies, nerve compression, or tissue overgrowth.
  phenotype_term:
    preferred_term: Pain
    term:
      id: HP:0012531
      label: Pain
  frequency: FREQUENT
  evidence:
  - reference: PMID:31334068
    reference_title: "Cloves Syndrome: A Rare Disorder of Overgrowth with Unusual Features - An Uncommon Phenotype?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This will also prevent cutaneous and visceral morbidities, neurological
      deficit, pain, breathing difficulties, and possible complications such
      as hemoptysis, gastrointestinal bleeding or obstruction, and pulmonary
      embolism arising from vascular anomalies.
    explanation: >-
      Pain explicitly mentioned as a morbidity requiring intervention
      in CLOVES syndrome management.
- name: Webbed Neck
  description: >
    Lateral skin folds along the sides of the neck (pterygium colli),
    rarely reported in CLOVES patients. Listed in HPOA annotations
    (OMIM:612918, 1/6 patients) but not documented in large cohort
    studies; literature confirmation needed.
  phenotype_term:
    preferred_term: Webbed neck
    term:
      id: HP:0000465
      label: Webbed neck
  frequency: OCCASIONAL
- name: Splenomegaly
  description: >
    Enlargement of the spleen, rarely reported in association with
    visceral involvement in CLOVES syndrome.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:31334068
    reference_title: "Cloves Syndrome: A Rare Disorder of Overgrowth with Unusual Features - An Uncommon Phenotype?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Visceral anomalies occur in the form of renal agenesis/hypoplasia,
      Wilms tumor, splenic lesions, and extensive deep retroperitoneal and
      pelvic fatty and lymphatic malformation.
    explanation: >-
      Splenic lesions documented among visceral anomalies in CLOVES
      syndrome.
  - reference: PMID:24782230
    reference_title: "Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hip subluxation/dislocation, spina bifida occulta, tethered cord,
      extra segments in the vertebrae, uterine fibroids, and splenic cysts
    explanation: >-
      Splenic cysts documented among malformations in the PROS cohort
      (n=35), consistent with splenic involvement.
- name: Skin Tags
  description: >
    Small benign cutaneous outgrowths (acrochorda), occasionally
    present in CLOVES patients. Listed in Orphanet clinical synopsis
    (ORPHA:140944) as an occasional feature; no cohort-level frequency
    data available in the primary literature.
  phenotype_term:
    preferred_term: Skin tags
    term:
      id: HP:0010609
      label: Skin tags
  frequency: OCCASIONAL
- name: Delayed Eruption of Teeth
  description: >
    Delayed eruption of teeth, observed in CLOVES patients as part of
    craniofacial involvement.
  phenotype_term:
    preferred_term: Delayed eruption of teeth
    term:
      id: HP:0000684
      label: Delayed eruption of teeth
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:31334068
    reference_title: "Cloves Syndrome: A Rare Disorder of Overgrowth with Unusual Features - An Uncommon Phenotype?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had delayed canine eruption and dental hypoplasia.
    explanation: >-
      Delayed canine eruption documented in a CLOVES patient with
      craniofacial involvement.
- name: Testicular Lipomatosis
  description: >
    Multiple foci of adipocytes within the testicular interstitium,
    presenting as hyperechoic intratesticular lesions.
  phenotype_term:
    preferred_term: Testicular lipomatosis
    term:
      id: HP:0025476
      label: Testicular lipomatosis
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:31334068
    reference_title: "Cloves Syndrome: A Rare Disorder of Overgrowth with Unusual Features - An Uncommon Phenotype?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The major deformities invariably include deposition of adipose tissue
      in all body regions and tissue spaces including face, scrotum,
      paraspinal musculature, epidural spaces, mediastinum, and pleura.
    explanation: >-
      Adipose tissue deposition in the scrotum is documented as part of
      CLOVES syndrome, consistent with testicular lipomatosis.
treatments:
- name: Alpelisib (BYL719)
  description: >
    Alpelisib is a selective PI3Kalpha inhibitor that has shown efficacy in
    reducing overgrowth and vascular malformations in patients with PROS
    including CLOVES syndrome. It was granted accelerated approval by the FDA
    on April 5, 2022 for patients with PROS aged two years and older requiring
    systemic therapy.
  treatment_term:
    preferred_term: PI3K inhibitor therapy
    term:
      id: MAXO:0000648
      label: enzyme inhibitor agent therapy
  evidence:
  - reference: PMID:29899452
    reference_title: "Targeted therapy in patients with PIK3CA-related overgrowth syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On the basis of these results, we used BYL719 to treat nineteen patients
      with PROS. The drug improved the disease symptoms in all patients.
      Previously intractable vascular tumours became smaller, congestive heart
      failure was improved, hemihypertrophy was reduced, and scoliosis was
      attenuated. The treatment was not associated with any substantial side
      effects.
    explanation: >-
      Landmark study demonstrating that BYL719 (alpelisib) improved symptoms
      in all 19 PROS patients treated, including tumor shrinkage, improved
      heart failure, reduced hemihypertrophy, and attenuated scoliosis.
  - reference: PMID:38025143
    reference_title: "Alpelisib: A Novel Agent for PIK3CA-Related Overgrowth Spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For patients two years of age and older requiring systemic therapy,
      alpelisib is an option which was recently granted accelerated approval by
      the US Food and Drug Administration (FDA) on April 5, 2022. Alpelisib is
      an inhibitor of PI3K, slowing the progression of existing lesions and
      preventing new lesions in patients with PROS.
    explanation: >-
      Confirms FDA accelerated approval of alpelisib for PROS in patients
      aged 2 years and older.
  - reference: PMID:34568242
    reference_title: "PIK3CA-Related Overgrowth Spectrum From Diagnosis to Targeted Therapy: A Case of CLOVES Syndrome Treated With Alpelisib."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we decided to discontinue Sirolimus and start targeted therapy with
      Alpelisib (50 mg/day). We noticed a decrease in fibroadipose overgrowth
      at the dorsal level, an improvement in in posture and excellent
      tolerability.
    explanation: >-
      Case report demonstrating alpelisib efficacy in a CLOVES patient with
      decreased fibroadipose overgrowth and improved posture after switching
      from sirolimus.
- name: Sirolimus (Rapamycin)
  description: >
    mTOR inhibitor used to manage vascular malformations and lymphatic
    anomalies. May slow progression of overgrowth and reduce vascular
    malformation volume, though response is often limited compared to
    direct PI3K inhibition.
  treatment_term:
    preferred_term: mTOR inhibitor therapy
    term:
      id: MAXO:0000648
      label: enzyme inhibitor agent therapy
  evidence:
  - reference: PMID:29899452
    reference_title: "Targeted therapy in patients with PIK3CA-related overgrowth syndrome."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Eight patients had received previous rapamycin treatment for18 months
      without clinical or radiological improvement.
    explanation: >-
      Eight PROS patients treated with rapamycin for 18 months showed no
      clinical or radiological improvement, demonstrating limited efficacy
      of mTOR inhibition compared to direct PI3K inhibition.
  - reference: PMID:34568242
    reference_title: "PIK3CA-Related Overgrowth Spectrum From Diagnosis to Targeted Therapy: A Case of CLOVES Syndrome Treated With Alpelisib."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She then started treatment with Rapamycin from May 2019, without
      significant improvement in both vascular malformation and leg hypertrophy.
    explanation: >-
      Case report demonstrating limited efficacy of rapamycin/sirolimus in a
      CLOVES patient, prompting switch to alpelisib.
- name: Surgical Debulking
  description: >
    Surgical resection of lipomatous masses and overgrown tissue. Often
    requires multiple procedures and recurrence is common.
  treatment_term:
    preferred_term: Surgical debulking
    term:
      id: MAXO:0000004
      label: surgical procedure
  evidence:
  - reference: PMID:34568242
    reference_title: "PIK3CA-Related Overgrowth Spectrum From Diagnosis to Targeted Therapy: A Case of CLOVES Syndrome Treated With Alpelisib."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Traditional therapeutic approaches, such as sclerotherapy and surgical
      debulking, are often not curative in PROS patients, leading to a
      recrudescence of the overgrowth in the treated area.
    explanation: >-
      Confirms that surgical debulking is a standard approach but often not
      curative with frequent recurrence.
- name: Sclerotherapy
  description: >
    Percutaneous sclerotherapy for lymphatic and venous malformations to reduce
    mass effect and symptoms.
  treatment_term:
    preferred_term: Sclerotherapy
    term:
      id: MAXO:0000004
      label: surgical procedure
  evidence:
  - reference: PMID:34568242
    reference_title: "PIK3CA-Related Overgrowth Spectrum From Diagnosis to Targeted Therapy: A Case of CLOVES Syndrome Treated With Alpelisib."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Many therapeutic approaches have been attempted, including Sildenafil
      treatment, scleroembolization, laser therapy, and multiple debulking
      surgeries, but none of these were of benefit to our patient's clinical
      status.
    explanation: >-
      Documents sclerotherapy (scleroembolization) as an attempted treatment
      modality in CLOVES syndrome management.
- name: Wilms Tumor Screening
  description: >
    Quarterly abdominal ultrasonography recommended for children with CLOVES
    syndrome until age 7 years, given the 3.3% incidence of Wilms tumor.
    Screening may be most beneficial for patients under 3 years of age.
  treatment_term:
    preferred_term: Ultrasonographic renal screening
    term:
      id: MAXO:0000126
      label: cancer screening
  evidence:
  - reference: PMID:28627003
    reference_title: "Sonographic screening for Wilms tumor in children with CLOVES syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with CLOVES syndrome have an increased risk of WT. Given the
      benefits of early detection and treatment, children with CLOVES syndrome
      should be considered for quarterly abdominal ultrasonography until age 7
      years. Screening may be most beneficial for patients under 3 years of age.
    explanation: >-
      Evidence-based screening recommendation from a cohort of 122 CLOVES
      patients with 3.3% Wilms tumor incidence.
classifications:
  harrisons_chapter:
  - classification_value: hereditary disease
  - classification_value: vascular disease
  - classification_value: skin disorder
  - classification_value: musculoskeletal system disorder
datasets:
notes: >-
  Key database resources: OMIM  # 612918; ClinVar PIK3CA-CLOVES variants
  (RCV000024621 H1047R, RCV000024622 E542K, RCV000024623 C420R,
  RCV000032905 H1047L); COSMIC PIK3CA somatic mutations; Orphanet
  ORPHA:140944; GeneReviews NBK153722; NORD IAMRARE CLOVES Registry.