PIK3CA vascular overgrowth syndromes: an update
Meagan Hughesa, Michelle Haob, and Minnelly Luua
INTRODUCTION
Vascular malformations may be associated with a range of coexisting anomalies including segmental overgrowth and abnormalities of the musculoskele- tal, cutaneous, and neurologic systems. Historically, various monikers were used to describe these syn- dromes despite overlapping clinical features. Recently, somatic activating mutations in the phos- phatidylinositol-4,5-bisphosphate 3-kinase, cata- lytic subunit alpha (PIK3CA) gene have been identified as the underlying cause of multiple syn- dromes involving vascular malformations and seg- mental overgrowth, giving rise to the umbrella term PIK3CA-related overgrowth spectrum (PROS) [1]. Diagnostic criteria for PROS were proposed by Kep- pler-Noreuil et al. [2] in 2015, highlighting the over- lapping clinical features seen across multiple syndromes due to PIK3CA mutations.
Herein, we review and provide updates on the pathogenesis, clinical features, and management of syndromes belonging to the spectrum of PIK3CA- related overgrowth disorders. Recognition of these syndromes and their potential complications is
vital to proper diagnosis, risk stratification, and man- agement, thus decreasing morbidity and mortality in affected patients. Traditional management of over- growth syndromes has been conservative and limited to addressing complications as they arise, however, the identification of the PIK3CA-mTOR pathway has opened doors for therapeutic advancement.
PATHOGENESIS
Postzygotic somatic activating mutations in PIK3CA are responsible for the PIK3CA-related overgrowth clinical spectrum. PIK3CA encodes p110a, a critical
aDepartment of Dermatology, USC Keck School of Medicine and Child- ren’s Hospital Los Angeles and bUSC Keck School of Medicine, Los Angeles, California, USA
Correspondence to Minnelly Luu, MD, Department of Dermatology, USC Keck School of Medicine and Children’s Hospital Los Angeles, Los Angeles, California, USA. Tel: +1 323 361 4191; fax: +1 323 361 7257; e-mail: [email protected]
Curr Opin Pediatr 2020, 32:539–546 DOI:10.1097/MOP.0000000000000923
1040-8703 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. www.co-pediatrics.com
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
component of the PI3-kinase enzyme, which acti- vates signaling pathways involved in cellular prolif- eration, survival, and growth. One of the key downstream effectors of this pathway is mTOR1 via phosphorylation of AKT. Activating hotspot mutations in PIK3CA were first identified in adult tumors [3]. More recently, a growing number of vascular malformation and overgrowth disorders have been linked to somatic PIK3CA mutations in a mosaic pattern. The majority of cases are due to oncogenic hotspot mutations; however, nonhot- spot mutations have been identified and seem to correlate with a less severe but more extensive dis- ease phenotype [4]. The wide phenotypic spectrum, ranging from an isolated digit to diffuse multisystem involvement, is likely related to the type and timing of mutation development during embryogenesis. It is speculated that germline mutations in PIK3CA are not compatible with life, highlighting the vital role this enzyme plays in cellular function [5].
KLIPPEL–TRENAUNAY SYNDROME
Klippel–Trenaunay syndrome (KTS) is traditionally defined by the presence of a capillary malformation, venous malformation, and limb overgrowth with or without a lymphatic malformation (International Society for the Study of Vascular Anomalies (ISSVA)). However, other specific clinical features are generally recognized as part of this syndrome. Classically, the findings in KTS are isolated to a lower extremity, with extension onto the lower trunk. The capillary malfor- mation is often sharply circumscribed, violaceous in color, and localized to the lateral aspect of the affected
FIGURE 1. Overgrowth of the right lower extremity and buttock with an overlying violaceous geographic vascular stain studded with hemorrhagic vesicles consistent with Klippel–Trenaunay syndrome.
extremity. It has been described as geographic [6], and, over time, it develops hemorrhagic and clear vesicles on its surface, the latter suggestive of an underlying lymphatic malformation [7], Fig. 1. The underlying vascular malformation is generally a complex com- bined venous-lymphatic malformation extending deep to muscular fascia. A characteristic venous anom- aly is the presence of a persistent embryonic vein. The lateral marginal vein (LMV), also known as the vein of Servelle, is seen in up to 70% of patients [8].
Complications in KTS frequently include infec- tion, which may present as cellulitis, abscess, or bacteremia. Patients are also prone to hemorrhage into their lymphatic cysts, which leads to erythema,
swelling, and pain mimicking infection. Chronic pain can be debilitating and is found at higher rates in patients with a history of cellulitis, superficial thrombophlebitis, and thrombotic events [9].
One of the more significant complications seen in KTS and other PROS syndromes, most nota- bly Congenital Lipomatous Overgrowth Vascular malformations Epidermal nevi and Skeletal abnor- malities (CLOVES), is the increased risk of thrombo- embolic complications, including deep vein thromboses (DVT) and pulmonary embolism. Risk factors are multifactorial. Disorganized channels within venous malformations result in stasis and localized intravascular coagulation with consump- tion of coagulation factors. Patients with pain or asymmetric overgrowth may have limited mobility, which is accentuated postprocedurally. In fact, a recent study looking at thromboembolic events in PROS patients, including those with KTS, reported that 64% of pulmonary embolisms occurred after surgery or sclerotherapy [10]. Endothelial activation is an additional risk factor for thrombosis. Soluble markers of endothelial cell activation such as throm- bomodulin and E-selectin are known to be signifi- cantly elevated in PROS patients when compared with controls, possibly secondary to chronic inflam- mation though activation of endothelial cells and abnormal vascular morphogenesis due to PIK3CA mutation may confer an additional biologic predis- position to endothelial activation [11]. To date, no clinical or laboratory markers have been found to correlate with risk for thrombosis in PROS patients [11].
Pulmonary embolisms have been reported in 12.5 and 9% of patients studied with KTS and CLOVES, respectively [10]. In KTS, connection of persistent embryonic veins to the deep venous system creates a direct conduit for clots to the lungs. Chronic throm- boembolic pulmonary hypertension, which is a severe complication of recurrent pulmonary embolism, was reported in five patients with KTS [12].
Given elevated risk for DVT and pulmonary embolism, Keppler-Noreuil et al. suggest that PROS patients with a vascular anomaly may benefit from baseline coagulation laboratory studies including D- dimer level, thus allowing comparison when DVT/ pulmonary embolism is suspected or when vigilance is heightened, that is postoperatively. To reduce postoperative DVT risk the authors recommend
0.5 mg/kg enoxaparin, sequential compression devi- ces, and early mobilization following surgery [11]. Traditionally, the management of persistent embry- onic veins in the setting of KTS has been conserva- tive with compression stockings and pain control, however, closure of the LMV results in improvement in symptoms and decreased risk of thrombosis [8].
There have been 17 cases to date reporting endove- nous laser ablation of a persistent embryonic vein with good results [13,14]. Two additional cases were successfully treated with n-butyl cyanoacrylate for small marginal veins [13]. Due to risk of thrombosis and pulmonary embolism, some are advocating early closure of persistent embryonic veins [8].
The presence of limb overgrowth, one of the diagnostic features of KTS, predisposes patients to orthopedic complications. In a recent review, 84% of patients had documented leg length discrepancy, the most common orthopedic finding [15]. Ortho- pedic evaluation was required in 64% of patients, with 50% of patients requiring surgical interven- tion. Surgical intervention in affected limbs has traditionally drawn hesitance due to the associated vascular malformation. However, 12 patients who underwent total knee arthroplasty were reported to have clinical improvement and tolerable adverse effects [16].
CONGENITAL LIPOMATOUS OVERGROWTH VASCULAR MALFORMATIONS EPIDERMAL NEVI AND SKELETAL ABNORMALITIES
CLOVES represent a severe phenotype in the PIK3CA spectrum characterized by progressive asymmetric overgrowth, combined vascular anom- alies, musculoskeletal abnormalities, and cutaneous lesions. A defining feature of CLOVES syndrome is the complex lipomatous overgrowth involving the trunk. Infiltration into adjacent tissue leads to pro- gressive scoliosis, and, if paraspinal or intraspinal spaces are involved, subsequent compression of the cord, thecal sac, or nerve roots can occur [17]. Vascular malformations are usually combined, slow-flow (lymphatic-venous-capillary) that may infiltrate the lipomatous overgrowth, Fig. 2a [18]. Although fast-flow lesions are less common, spinal and paraspinal arteriovenous malformations have been described in CLOVES and are a cause of mye- lopathy [19].
Skeletal anomalies, the most common being scoliosis, can be progressive and deforming. The severity of scoliosis varies from mild to severe and is related to the extent and progression of the adja- cent lipomatous mass. Acral deformities include broad, spade-like hands with ulnar deviation of the digits, Fig. 2b, and furrowing of the palms and soles secondary to fatty deposition, which is distinct from the characteristic connective tissue nevus seen in Proteus syndrome [17]. Skeletal anomalies often manifest distally and become more pronounced proximally with time [1]. Epidermal nevi can be present and are usually in a blaschkoid pattern.
FIGURE 2. Characteristic clinical findings seen in Congenital Lipomatous Overgrowth Vascular malformations Epidermal nevi and Skeletal abnormalities syndrome: (a) lipomatous overgrowth of the low back with an overlying capillary malformation, (b) overgrowth of the right foot with wide spacing between digits.
The clinical phenotype of CLOVES continues to expand. Recently, a pediatric CLOVES patient with pancreatic steatosis complicated by elevated HgbA1c was reported. The authors postulate that PIK3CA mutation predisposes patients to fatty over- growth of the pancreas, and they suggest that PROS patients should be assessed for pancreatic abnormal- ities given association of pancreatic steatosis with diabetes and pancreatic cancer [20].
Overgrowth disorders, most characteristically hemihyperplasia and Beckwith– Wiedemann syn- drome, have been associated with an increased risk of Wilms tumor, a malignant embryonal renal neo- plasm. Precursor lesions, such as nephrogenic rests or early tumors, may be detected by screening ultra- sounds; thus surveillance recommendations, including abdominal ultrasound every 3 months through age 7, were implemented [21]. The applica- bility of these screening recommendations to PROS patients continues to come into question. A recent retrospective review of CLOVES patients demon- strated a 3.3% risk of Wilms tumor, significantly greater than the 0.0001% risk of the general popu- lation, therefore, continued surveillance has been recommended in CLOVES [22]. Separate evaluations of KTS have been performed showing either no risk or a modestly increased risk for Wilms tumor, thus routine screenings are not currently advised for KTS [23,24]. The utility of Wilms tumor screening for other phenotypes within the PROS spectrum remains unclear.
PIK3CA has now been identified as one of the most common oncogenes in human cancer; how- ever, there has been no evidence of increased risk of PIK3CA-associated cancers in PROS [4]. Although there was not an overall increased risk of skin cancer, skin cancers were found in capillary malformations and chronic ulcers in patients with PROS, thus cutaneous monitoring is recommended [23].
MEGALENCEPHALY CAPILLARY MALFORMATION
Brain overgrowth, or megalencephaly, with associ- ated neurologic manifestations has been identified as part of the PROS spectrum, which may present as part of a syndrome, as in megalencephaly capillary malformation (MCAP), or as a more isolated finding, as in dysplastic megalencephaly (DMEG). Patients with MCAP, also known as macrocephaly capillary malformation (M-CM), present with congenital or early postnatal megalencephaly, segmental over- growth, and reticulated or confluent capillary mal- formations [25]. Other neurologic manifestations include ventriculomegaly and cerebellar tonsillar ectopia, which may be complicated by hydrocepha- lus and Chiari malformation, respectively [26,27].
Several endocrinopathies are now recognized to be potential complications in PROS. Severe hypo- glycemia was reported in six patients with MCAP [28]. Insulin activates PI3K-AKT signaling, leading to further insulin secretion. The authors postulate that activating mutations in PIK3CA lead to hyper- secretion of insulin [28]. Thus, screening for hypo- glycemia during childhood is recommended for
patients with PROS. In addition, growth hormone (GH) deficiency has been described in a series of 11 patients with MCAP. Hypoglycemia and other pitu- itary deficiencies were also identified in the majority of these patients [29]. Central gain-of-function PIK3CA mutations may mimic negative feedback on the hypothalamus and pituitary. Conservative doses of GH showed reversal of hypoglycemia and normalization of linear growth velocities without an increase in overgrowth [29]. Consequently, Davis et al. recommend evaluation for GH deficiency in MCAP patients presenting with hypoglycemia and/ or growth failure. Furthermore, the possibility of comorbid endocrinopathies should be considered [28,29].
DYSPLASTIC MEGALENCEPHALY
DMEG is characterized by bilateral brain overgrowth that may occur in isolation or as part of a mega- lencephaly syndrome. DMEG and other brain over- growth disorders, namely hemimegalencephaly and focal cortical dysplasia (FCD), are thought to repre- sent a phenotypic spectrum [26]. Intractable epi- lepsy, global development delay, and complex neurologic deficits are linked to these brain malfor- mation syndromes. Everolimus, an mTOR inhibitor, is FDA-approved for partial-onset seizures in patients with tuberous sclerosis complex. Two clini- cal trials (NCT02451696, NCT03198949) assessing everolimus in patients with FCD are underway.
GENERALIZED LYMPHATIC ANOMALY
Previously referred to as lymphangiomatosis, gener- alized lymphatic anomaly (GLA) was recently added to the PIK3CA spectrum. GLA presents in infancy or early childhood and is characterized by diffuse or multifocal lymphatic malformations. Skin, soft tis- sue, abdominal, and thoracic viscera are the most common sites of involvement [30]. Disease severity is usually dictated by presence of visceral involve- ment. Recurrent effusions, particularly if pericardial, pleural, or peritoneal, can cause significant morbid- ity and mortality. Multifocal lytic bone lesions, more frequently affecting the appendicular skele- ton, are complicated by pain, increased risk of frac- ture, and immobility [31].
DIFFUSE CAPILLARY MALFORMATION WITH OVERGROWTH
Diffuse capillary malformation with overgrowth (DCMO) is characterized by extensive capillary mal- formations, usually pale pink, reticulate, and involving contiguous anatomic locations, Fig. 3. Overgrowth,
FIGURE 3. Reticulate capillary malformation characteristic of diffuse capillary malformation with overgrowth.
typically of an extremity, can involve the soft tissue or bone, and does not necessarily correlate with the location or severity of the capillary malformations. Variable prominent draining veins in DCMO should be distinguished from deep venous anomalies and complex vascular malformations, the latter two of which are characteristic of KTS but lacking in DCMO. Therefore, MRI is not required in DCMO if there is no obvious clinical sign ofadeeper vascular malformation [32]. Apart from leg length discrepancy secondary to overgrowth, complications seen in KTS are not seen in DCMO.
Similar to other PROS phenotypes, the associa- tion with Wilms tumor continues to be under inves- tigation. A recent retrospective review of 89 patients with DCMO or M-CM did not identify any cases of Wilms tumor [33].
OTHER
As genetic testing improves and clinical features associated with PIK3CA become more defined, the number of syndromes being identified within this spectrum continues to expand. Lipomatosis or dif- fuse fatty deposits has been implicated in multiple PROS syndromes including CLOVES as described above, as well as hemihyperplasia multiple lipoma- tosis, fibroadipose infiltrating lipomatosis, and mac- rodactyly/lipomatosis of nerve. These are described further in Table 1 along with other newly recognized syndromes associated with PIK3CA [34– 43].
DIAGNOSIS
Challenges continue to exist when confirming a diagnosis of PROS. Mutations are usually undetect- able in blood and observed only in the affected tissue, which carry variable mutational burdens ranging from 33 to 67% [44]. Traditional Sanger sequencing misses up to 65% of mutations due to low-level mosaicism [45]. More sensitive techniques such as digital droplet PCR and targeted ultradeep sequenc- ing have increased diagnostic yield [45,46]; however,
Table 1. Additional phenotypes associated with mutations in PIK3CA
Fibroadipose hyperplasia [34] Fibroadipose overgrowth (SC, muscular, visceral)
Skeletal overgrowth Frequently progressive
HHML [35–37] Congenital asymmetry and overgrowth Cutaneous vascular anomalies Recurrent subcutaneous lipomata Static or slowly progressive
Lipoatrophy
Skeletal complications such as leg length discrepancy
Lipomatous compression of the spinal cord
Nonlipomatous hydrocephalus
Facial infiltrating lipomatosis [38,39]
Mature adipose tissue infiltrating hemifacial soft tissues Facial asymmetry and adjacent skeletal overgrowth Precocious dental development
Macrodontia Hemimacroglossia Mucosal neuromas
Cerebral abnormalities
LON [40,41] Fibroadipose proliferation within a peripheral nerve, more rarely an axial nerve
Territory overgrowth (i.e., macrodactyly)
CLAPO [42] Capillary malformation of the lower lip Lymphatic malformation of the face and neck Asymmetry with partial/generalized overgrowth
Compressive neuropathies
Upper limb muscle overgrowth with hypoplasia of the index finger [43]
Unilateral isolated upper limb muscle overgrowth Hypoplasia ulnar drift of index finger
Orthopedic complications
HHML, hemihyperplasia multiple lipomatosis; LON, lipomatosis of nerve; SC, subcutaneous.
a negative result does not exclude a diagnosis of PROS in individuals with suggestive features [3].
Mutation confirmation is important as the thera- peutic landscape shifts totargeted therapy. The highest diagnostic yield is from involved tissue, and blood testing is not recommended. Both affected and unaf- fected tissue samples should ideally be tested to increase the confidence in pathogenicity when a genetic variant is identified [44]. There are rare cases of mutation identification from uninvolved sites including blood in megalencephaly syndromes [44], urine in a set of patients with CLOVES [47], and cul- tured amniotic cells from embryos with overgrowth enabling prenatal diagnosis [44,48].
TREATMENT
Over the past decade, the paradigm shift toward molecular classification of vascular anomalies has opened the door for targeted therapeutics. Sirolimus emerged as a therapeutic option for complex vascu- lar anomalies in 2011 [49]. Since then, sirolimus has been described as an effective treatment for KTS [50], GLA [51], CLAPO [52], and has been shown to stabilize disease severity and diminish symptoms in PROS [53]. A recent open-label trial supports sirolimus’ ability to modestly reduce tissue growth at overgrown sites. However, this study also reported a significant adverse effect profile with 72% report- ing an adverse effect, 37% grade 3 or 4, and 18% withdrawing from treatment [53]. These studies
show that sirolimus targets growing tissue instead of promoting regression of prior overgrowth, sug- gesting that long-term continuation and early initi- ation of therapy would result in maximum benefit [53]. Low-dose sirolimus therapy should be consid- ered in PROS on a case-by-case basis after weighing the risks and benefits.
Severaldirect PIK3CAinhibitorsare FDA-approved for lymphoma/leukemia, and, in May 2019, Alpelisib (BYL719) – an alpha-specific PIK3CA inhibitor – was approved for breast cancer. BYL719 was recently trialed in seventeen patients with various different pheno- typic expressions across the PIK3CA spectrum, includ- ing six CLOVES, two MCAP, and nine localized overgrowthpatients. Allpatientshadnotableimprove- ments, including reduction in capillary malformations and epidermal nevi, discontinuation of chronic gas- trointestinal (GI) bleeding, improvement in scoliosis, and improved cognitive function in the two patients with MCAP [54]. In this cohort, Alpelisib was well tolerated without organ toxicity. Reported adverse effects included grade 1 oral ulcerations and mild hyperglycemia. Recently, a patient with severe exter- nal genital involvement was started on BYL719, enabling surgical reconstruction [55].
Due to the large range of potential comorbidities seen across the PROS spectrum, a multidisciplinary team, such as in a vascular anomalies clinic, would be optimal for the management of PROS patients. Subspecialties that may be involved in their care may include dermatology, interventional radiology,
hematology–oncology, orthopedics, neurology, sur- gery, and endocrinology. Baseline coagulation studies including D-dimer may be considered for patients with an underlying vascular anomaly. Further evaluation and work-up should be determined by the individual phenotype and complications as outlined above.
CONCLUSION
Recognizing the broad clinical features, complica- tions and diagnostic strategies for vascular over- growth syndromes associated with mosaic mutations in PIK3CA is important in preventing morbidity, particularly as the therapeutic landscape evolves to more targeted therapy.
Acknowledgements
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Conflicts of interest
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REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
& of special interest
&& of outstanding interest
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44. Lalonde E, Ebrahimzadeh J, Rafferty K, et al. Molecular diagnosis of somatic overgrowth conditions: a single-center experience. Mol Genet Genomic Med 2019; 7:e536.
Researchers performed targeted next generation sequencing (NGS) using an eight-gene panel in 80 patients with somatic overgrowth; a molecular diagnosis was made in 45% of patients, 60.9% after exclusion of blood-only sample submissions. The authors recommend starting with PIK3CA analysis and reflexing to a multigene panel if needed for cases with unambiguous PROS clinical features. In addition, the authors argue that submission of both unaffected and overgrown tissues helps to confirm pathogenicity of detected variants.
45. Ten Broek RW, Eijkelenboom A, van der Vleuten CJM, et al. Comprehensive molecular and clinicopathological analysis of vascular malformations: a study of 319 cases. Genes Chromosomes Cancer 2019; 58:541–550.
A combined retro and prospective study using next generation sequencing with unique molecule identifiers, a technology with superior detection level of 1% mutant alleles, performed for frequently mutated positions in more than 21 genes on 391 patient samples. Pathogenic mutations were identified in 132/319, including 91 mutations with a variant allele frequency less than 10%, six cases with combined mutations, and six cases with variant allele frequency approaching 50% suggestive of germline mutations. The authors conclude mutational and multigene analysis of vascular malformations is of high diagnostic value and can help stratify patients for targeted therapies.
46. Rivie`re JB, Mirzaa GM, O’Roak BJ, et al. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related
megalencephaly syndromes. Nat Genet 2012; 44:934–940.
47. Michel ME, Konczyk DJ, Yeung KS, et al. Causal somatic mutations in urine DNA from persons with the CLOVES subgroup of the PIK3CA-related overgrowth spectrum. Clin Genet 2018; 93:1075 –1080.
48. Emrick LT, Murphy L, Shamshirsaz AA, et al. Prenatal diagnosis of CLOVES syndrome confirmed by detection of a mosaic PIK3CA mutation in cultured amniocytes. Am J Med Genet A 2014; 164A:2633–2637.
49. Hammill AM, Wentzel M, Gupta A, et al. Sirolimus for the treatment of complicated vascular anomalies in children. Pediatr Blood Cancer 2011; 57:1018– 1024.
50. Bessis D, Vernhet H, Bigorre M, et al. Life-threatening cutaneous bleeding in childhood Klippel–Trenaunay syndrome treated with oral sirolimus. JAMA Dermatol 2016; 152:1058–1059.
51. Ricci KW, Hammill AM, Mobberley-Schuman P, et al. Efficacy of systemic sirolimus in the treatment of generalized lymphatic anomaly and Gorham– Stout disease. Pediatr Blood Cancer 2019; 66:e27614.
A case series of 18 patients with GLA or Gorham–Stout disease treated with oral sirolimus with 83% reporting improvement in one or more aspects of their disease.
52. Gonza´lez-Hermosa MR, Guerra E, Tuduri I, et al. CLAPO syndrome: effective response to treatment with oral rapamycin. Dermatol Ther 2019; 32:e12991.
A case report of a patient with CLAPO syndrome related with oral rapamycin with successful reduction of his lymphatic malformation enabling surgical intervention.
53. Parker VER, Keppler-Noreuil KM, Faivre L, et al. Safety and efficacy of low- dose sirolimus in the PIK3CA-related overgrowth spectrum. Genet Med 2019; 21:1189 –1198.
An open-label clinical trial investigating the safety and efficacy of low-dose sirolimus therapy in reducing tissue volumes in PROS. The results indicate that sirolimus led to a modest decrease in tissue volume but was also associated with a significant rate of adverse events.
54. Venot Q, Blanc T, Rabia SH, et al. Targeted therapy in patients with PIK3CA- related overgrowth syndrome. Nature 2018; 558:540 –546.
55. Lo´pez GJC, Lizarraga R, Delgado C, et al. Alpelisib treatment for genital vascular malformation in a patient with congenital lipomatous overgrowth,
vascular malformations, epidermal nevi, and spinal/skeletal anomalies and/or scoliosis (CLOVES) syndrome. J Pediatr Adolesc Gynecol 2019; 32:648–650.
Case report describing a patient with CLOVES and genital vascular malformation with vaginal bleeding, unresponsive to oral sirolimus and who showed improve- ment with Alpelisib therapy, advancing her to surgical debulking candidacy and obviating further blood transfusions.