Further Evaluation
Whole-exome sequencing conducted on genomic DNA extracted from the resected lymphangioma tissue revealed the presence of a PIK3CA (NM_006218) c.3140A>G (H1047R) gain-of-function mutation with 11% mosaicism. This finding led to the diagnosis of CLOVES syndrome, a phenotype in the PIK3CA-related overgrowth spectrum (PROS). The patient's treatment regimen included alpelisib, which significantly reduced the size of the dorsal lipomas and the residual, unresectable thoracic lymphatic malformation. This intervention also enhanced the patient's mobility and overall functional status.
Discussion
PROS is a complex and heterogeneous condition caused by somatic variations in the PIK3CA gene. PROS is characterized by a wide range of clinical presentations, reflecting the diversity of affected tissues and the extent of overgrowth. Phenotypes within PROS are diverse and can range from a single lesion (eg, solitary macrodactyly) to systemic diseases (eg, Klippel-Trenaunay syndrome and CLOVES syndrome). CLOVES (syndrome is a recently described overgrowth syndrome. The phenotypes included in PROS, all of which are caused by a pathogenic PIK3CA variant, are:
Fibroadipose hyperplasia (also called fibroadipose overgrowth)
CLOVES syndrome
Klippel-Trenaunay syndrome
Megalencephaly-capillary malformation syndrome
Hemihyperplasia-multiple lipomatosis syndrome
Dysplastic megalencephaly, hemimegalencephaly, and focal cortical dysplasia
Facial infiltrating lipomatosis (a congenital disorder that causes overgrowth of one side of the face)
CLAPO syndrome (capillary malformation of the lower lip, lymphatic malformation of the face and neck, asymmetry and partial/generalized overgrowth)
This heterogeneity is primarily due to the timing of the onset of the somatic causative PIK3CA pathogenic variants during embryonic and fetal development, influencing the degree of mosaicism and the combination of tissues involved (eg, neural progenitor cell pathogenic variants can lead to postnatal megalencephaly and hydrocephalus). Moreover, different gain-of-function variants in PIK3CA lead to varying levels of hyperactivation of the PI3K/AKT/mTOR pathway, resulting in diverse severity of abnormal proliferation of mesodermal and ectodermal tissues from embryogenesis onwards. The pathogenesis of CLOVES syndrome has been attributed to somatic (postzygotic) mutations in the PIK3CA gene that result in increased AKT cell signaling and excess cell proliferation.
In general, PROS is marked by segmental overgrowth of multiple tissues, including:
Lipomatosis overgrowth: with or without regional reduction of adipose tissue on the trunk and limbs.
Vascular malformations: Capillary, venous, arteriovenous, or lymphatic types, which are common and occur in about 43% of patients. These abnormalities can contribute to additional complications, including swelling, pain, and increased risk for bleeding.
Skeletal findings: Polydactyly, macrodactyly, macrodontia, and scoliosis or other spinal abnormalities.
Overgrowth of tissues and organs: Excessive and asymmetric overgrowth can affect the skin, bones, muscles, and other structures, leading to disfigurement and functional impairments. The overgrowth typically follows a distal-to-proximal pattern, mostly unilateral and affecting the lower limbs.
Isolated lymphatic malformation: Dilated vascular channels lined by lymphatic endothelial cells may lead to fluid-filled cysts that usually grow proportionally with the growth of the affected person and may cause pain or significant morbidity if they are infiltrative.
Epidermal nevi and pigmentary anomalies: These are common and include thickened epidermal nevi or pigmentary anomalies, such as hyperpigmentation or hypopigmentation. These skin manifestations can be early signs of PROS and aid in diagnosis.
It is estimated that each of these conditions has a prevalence rate of less than 1 in 1,000,000.
Differential Diagnosis
Several syndromes may be considered when diagnosing PROS. These syndromes share common clinical features such as overgrowth, hemihyperplasia, vascular anomalies, skin abnormalities, scoliosis, tumors and others. However, these other overgrowth syndromes have more distinctive features and specific genetic causes that set them apart from PROS. These syndromes include:
Proteus syndrome (somatic AKT1 gene variant);
Linear sebaceous nevus syndrome (somatic HRAS, NRAS, KRAS gene variants);
Mosaic KRAS-related disorder;
PTEN-hamartoma tumor syndrome (somatic and germline PTEN gene variant); and
Neurofibromatosis type 1 (somatic and germline NF1 gene variant).
Diagnostic Testing
Testing for PROS generally requires genetic testing of affected tissue with either tissue or skin biopsy to look for a somatic PIK3CA mutation in patients with high clinical suspicion. It is difficult to identify the tissue with the highest probability of carrying the mutation because biopsies from PROS patients often show low levels of mosaicism, as is seen in this patient. Molecular genetic testing for diagnosing PROS requires a tissue sample from an affected area, preferably obtained through dermal biopsy or surgical procedures. PIK3CA mutations can be detected in affected tissues or cultured cells at varying levels; however, testing blood or DNA isolated from blood is not yet recommended because PIK3CA mutations have not been detected in blood samples.
The types of assays and their respective sensitivities are shown in the Table.
MALDI-TOF = matrix-assisted laser desorption/ionization time-of-flight; NA = not applicable; PCR = polymerase chain reaction; RFLP = restriction fragment length polymorphism
It is essential to interpret the findings of a particular assay and the tissue sampled. A mosaic mutation can help diagnose a PROS disorder; however, there is no direct correlation between the mutation level and disease manifestation or severity of the patient's symptoms.
Management
The available management strategies for PROS-related complications includes debulking of lipomatous lesions; scoliosis and leg-length discrepancy may require orthopedic care and surgical intervention. Neurologic complications (eg, obstructive hydrocephalus, increased intracranial pressure, progressive and/or symptomatic cerebellar tonsillar ectopia or Chiari malformation, and epilepsy in those with brain overgrowth or malformations) may warrant neurosurgical intervention. Depending on the type of vascular malformation, sclerotherapy, laser therapy, or oral medications such as sirolimus may be used. Similarly, lymphatic malformations may be treated with oral medications or careful surgical debulking, preferably by a vascular anomalies team. For patients experiencing pain, evaluation for the source of pain and treatment of the underlying cause is recommended.
Sirolimus, an mTOR inhibitor, has been used with modest success to reduce overgrowth and symptoms in patients with PROS. However, patients do not always respond to this treatment and sometimes experience disease progression while on it.
Miransertib, a pan-protein kinase B (AKT) inhibitor, was clinically evaluated and was available under expanded access. However, it is no longer available because efficacy was not demonstrated in the MOSAIC trial.
Taselisib, a beta-sparing PI3K inhibitor evaluated for PROS in the TOTEM trial, was discontinued from further clinical development owing to an unfavorable safety profile that precluded long-term use, despite providing functional improvements.
Alpelisib, an orally bioavailable alpha-selective PI3K inhibitor, directly targets the molecular driver of PROS pathology. Efficacy was evaluated using real-world data from EPIK-P1, a single-arm clinical study in patients aged 2 years or older with PROS who received alpelisib as part of an expanded access program for compassionate use. In primary findings from EPIK-P1, 37.5% of patients(n = 12/32) showed at least a 20% reduction in target lesion volume after 24 weeks. As a result, alpelisib received accelerated approval from the FDA US Food and Drug Administration on April 6, 2022, for the treatment of adult and pediatric patients at least 2 years of age with severe manifestations of PROS who require systemic therapy.
Prognosis
The prognosis for individuals with PROS varies widely, depending on the areas of the body affected and the severity of the symptoms. The condition can lead to significant morbidity and disability, particularly in those with extensive neurologic involvement or complex lymphatic anomalies, who tend to have a poorer prognosis. Patients with severe cases of PROS, especially those with critical functional impairments, often do not survive into adulthood, highlighting the spectrum's potential impact on lifespan and quality of life.
Comprehensive and regular monitoring is essential to address the diverse and evolving clinical manifestations of PROS. During each medical visit, it is essential to measure growth parameters, including head circumference and the length of arms, hands, legs, and feet. This assessment helps identify any new neurologic symptoms, such as seizures, changes in muscle tone, or signs of Chiari malformation. Monitoring the patient's developmental progress, behavior, and motor skills is similarly recommended.
Clinical Takeaways
It is crucial to ensure an early and accurate diagnosis of PROS (CLOVES and other component syndromes) to allow the initiation of appropriate treatments that have been shown to significantly affect overall functional status. Identifying the PIK3CA mutation through genetic testing from the affected tissue is essential for confirming the diagnosis, as seen in this case with the discovery of a PIK3CA gain-of-function mutation. Confirming diagnosis is important because CLOVES syndrome and other PROS can present with a wide range of symptoms and complications that require tailored management strategies to prevent further complications and improve quality of life.
Management of CLOVES and other PROS syndromes requires a multidisciplinary approach owing to their systemic and diverse manifestations, including overgrowths, vascular malformations, and potential for recurrent infections. Surgical interventions may be necessary to remove or reduce overgrowth and alleviate comorbidities; however, they are not curative and regrowth is common. Thus, systemic therapies such as alpelisib that target the molecular basis of the disease offer a promising addition to the management strategies.
https://www.medscape.com/viewarticle/1000430?src=flex_916_medscape.com
Gerasimenko A, Baldassari S, Baulac S. mTOR pathway: Insights into an established pathway for brain mosaicism in epilepsy. Neurobiol Dis. 2023 Jun 15;182:106144. doi: 10.1016/j.nbd.2023.106144. Epub 2023 May 4. PMID: 37149062.
Abstract
The mechanistic target of rapamycin (mTOR) signaling pathway is an essential regulator of numerous cellular activities such as metabolism, growth, proliferation, and survival. The mTOR cascade recently emerged as a critical player in the pathogenesis of focal epilepsies and cortical malformations. The 'mTORopathies' comprise a spectrum of cortical malformations that range from whole brain (megalencephaly) and hemispheric (hemimegalencephaly) abnormalities to focal abnormalities, such as focal cortical dysplasia type II (FCDII), which manifest with drug-resistant epilepsies. The spectrum of cortical dysplasia results from somatic brain mutations in the mTOR pathway activators AKT3, MTOR, PIK3CA, and RHEB and from germline and somatic mutations in mTOR pathway repressors, DEPDC5, NPRL2, NPRL3, TSC1 and TSC2. The mTORopathies are characterized by excessive mTOR pathway activation, leading to a broad range of structural and functional impairments. Here, we provide a comprehensive literature review of somatic mTOR-activating mutations linked to epilepsy and cortical malformations in 292 patients and discuss the perspectives of targeted therapeutics for personalized medicine.
Dobyns WB, Mirzaa GM. Megalencephaly syndromes associated with mutations of core components of the PI3K-AKT-MTOR pathway: PIK3CA, PIK3R2, AKT3, and MTOR. Am J Med Genet C Semin Med Genet. 2019 Dec;181(4):582-590. doi: 10.1002/ajmg.c.31736. Epub 2019 Aug 23. PMID: 31441589.
Abstract
Megalencephaly (MEG) is a developmental abnormality of brain growth characterized by early onset, often progressive, brain overgrowth. Focal forms of megalencephaly associated with cortical dysplasia, such as hemimegalencephaly and focal cortical dysplasia, are common causes of focal intractable epilepsy in children. The increasing use of high throughput sequencing methods, including high depth sequencing to more accurately detect and quantify mosaic mutations, has allowed us to identify the molecular etiologies of many MEG syndromes, including most notably the PI3K-AKT-MTOR related MEG disorders. Thorough molecular and clinical characterization of affected individuals further allow us to derive preliminary genotype-phenotype correlations depending on the gene, mutation, level of mosaicism, and tissue distribution. Our review of published data on these disorders so far shows that mildly activating variants (that are typically constitutional or germline) are associated with diffuse megalencephaly with intellectual disability and/or autism spectrum disorder; moderately activating variants (that are typically high-level mosaic) are associated with megalencephaly with pigmentary abnormalities of the skin; and strongly activating variants (that are usually very low-level mosaic) are associated with focal brain malformations including hemimegalencephaly and focal cortical dysplasia. Accurate molecular diagnosis of these disorders is undoubtedly crucial to more optimally treat children with these disorders using PI3K-AKT-MTOR pathway inhibitors.
Moloney PB, Cavalleri GL, Delanty N. Epilepsy in the mTORopathies: opportunities for precision medicine. Brain Commun. 2021 Sep 25;3(4):fcab222. doi: 10.1093/braincomms/fcab222. PMID: 34632383; PMCID: PMC8495134.
Abstract
The mechanistic target of rapamycin signalling pathway serves as a ubiquitous regulator of cell metabolism, growth, proliferation and survival. The main cellular activity of the mechanistic target of rapamycin cascade funnels through mechanistic target of rapamycin complex 1, which is inhibited by rapamycin, a macrolide compound produced by the bacterium Streptomyces hygroscopicus. Pathogenic variants in genes encoding upstream regulators of mechanistic target of rapamycin complex 1 cause epilepsies and neurodevelopmental disorders. Tuberous sclerosis complex is a multisystem disorder caused by mutations in mechanistic target of rapamycin regulators TSC1 or TSC2, with prominent neurological manifestations including epilepsy, focal cortical dysplasia and neuropsychiatric disorders. Focal cortical dysplasia type II results from somatic brain mutations in mechanistic target of rapamycin pathway activators MTOR, AKT3, PIK3CA and RHEB and is a major cause of drug-resistant epilepsy. DEPDC5, NPRL2 and NPRL3 code for subunits of the GTPase-activating protein (GAP) activity towards Rags 1 complex (GATOR1), the principal amino acid-sensing regulator of mechanistic target of rapamycin complex 1. Germline pathogenic variants in GATOR1 genes cause non-lesional focal epilepsies and epilepsies associated with malformations of cortical development. Collectively, the mTORopathies are characterized by excessive mechanistic target of rapamycin pathway activation and drug-resistant epilepsy. In the first large-scale precision medicine trial in a genetically mediated epilepsy, everolimus (a synthetic analogue of rapamycin) was effective at reducing seizure frequency in people with tuberous sclerosis complex. Rapamycin reduced seizures in rodent models of DEPDC5-related epilepsy and focal cortical dysplasia type II. This review outlines a personalized medicine approach to the management of epilepsies in the mTORopathies. We advocate for early diagnostic sequencing of mechanistic target of rapamycin pathway genes in drug-resistant epilepsy, as identification of a pathogenic variant may point to an occult dysplasia in apparently non-lesional epilepsy or may uncover important prognostic information including, an increased risk of sudden unexpected death in epilepsy in the GATORopathies or favourable epilepsy surgery outcomes in focal cortical dysplasia type II due to somatic brain mutations. Lastly, we discuss the potential therapeutic application of mechanistic target of rapamycin inhibitors for drug-resistant seizures in GATOR1-related epilepsies and focal cortical dysplasia type II.
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