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Lateralized Overgrowth (LO) in patients within the PIK3CA-related Overgrowth Spectrum (PROS). The latter include cases with megalencephaly-capillary malformation syndrome (MCAP, (A,B)), fibroadipose overgrowth with vascular anomalies (FAVA, (C,D,J-L)), Klippel-Trenaunay syndrome (KTS, (E-H)), congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/skeletal and spinal syndrome (CLOVES, (I)), hemihyperplasia multiple lipomatosis (HHML, (M)).
Source publication
Congenital disorders of lateralized or segmental overgrowth (LO) are heterogeneous conditions with increased tissue growth in a body region. LO can affect every region, be localized or extensive, involve one or several embryonic tissues, showing variable severity, from mild forms with minor body asymmetry to severe ones with progressive tissue grow...
Context in source publication
Context 1
... pathogenic variants at the base of the clinical pictures of PROS are commonly postzygotic, coming to configure a picture of tissue mosaicism [41]. The extension of the mosaicism and, to a lesser extent, the genotype is responsible for the different phenotypes of the PROS [39,40,42] (Figure 4). The degree of mosaicism is determined by the timing of embryonic development in which the DNA mutates, determining the body extension and the kind of tissues involved. ...
Citations
... Hemihypertrophy is defined as an increase in length or circumference of one side of the body or limb compared to the contralateral part. It can be part of a syndrome, such as in BWS, or isolated, hence the new term ILO (32). On the other hand, BWS is a growth disorder commonly associated with WT. ...
Fetal Wilms tumor (WT) is extremely rare, but with advances in fetal imaging, more cases are being reported. The management of these cases remains challenging. Herein, we present the case of a full-term female infant diagnosed antenatally at 32 weeks of gestation with a right solid renal mass detected on routine prenatal ultrasound without polyhydramnios. At birth, the infant was healthy, with no evidence of dysmorphic features or abnormal laboratory tests to suggest a predisposition syndrome. Her family history was also unremarkable. A successful radical right nephrectomy was performed on day 2 of life revealing a classic WT. She received vincristine as adjuvant chemotherapy without any complications. At the age of 1 month, the infant developed isolated lateralized overgrowth of the right lower limb suspicious of Beckwith–Wiedemann syndrome. At the latest follow-up of 4 years, the child is healthy and disease-free with conserved asymmetry of lower limbs. The case provides insights into the challenging diagnosis and treatment of fetal WT. A review of the literature suggests that the presence of polyhydramnios is a worse prognostic factor while the combination of best supportive care and surgery remains the best management. Fetal WT can be associated with predisposition syndromes; however, their first manifestations can develop after the diagnosis of cancer has been made, as in our patient. We propose starting active surveillance programs and genetic testing for any case of fetal WT.
... Resection is used to treat hamartomas. mTor inhibitors such as sirolimus and everolimus have been shown in clinical trials to be useful to treat symptoms [6]. SOLAMEN syndrome is the germline mutation of PTEN, as such cancer surveillance is recommended due to the high risk of breast, thyroid, kidney, and endometrial cancer. ...
Background
Segmental overgrowth, lipomatosis, arteriovenous malformation, and epidermal nevus (SOLAMEN) syndrome is a segmental overgrowth syndrome that is part of Cowden’s Syndrome, a subset of the PTEN hamartoma tumor syndrome cluster. Due to SOLAMEN disease’s rarity, clinical suspicion should arise if multiple small nonspecific variably low-attenuated nodular lesions in the back, shoulders, and upper arms are present on CT, which are associated with mucocutaneous lesions. We present a rare case of SOLAMEN syndrome with widespread lipomatous growth, greater than reported in literature, with confirmed PTEN genetic testing.
Case presentation
We describe a case of a 2-year-old boy with a slowly growing left neck mass since birth. Physical exam revealed macrocephaly and epidermal nevi on left axilla, arm, and fingers, appearing as pink verrucous and has visible veins on chest wall/abdomen. CT and MRI imaging showed a lipomatous hibernoma extending from the leftward neck to the abdominal cavity, encasing vascular structures form the left carotid and subclavian arteries to the diaphragmatic hiatus, in addition to the spleen and kidney. Biopsy of the left shoulder revealed hibernoma, a fatty neoplasm of benign brown fat. Patient had a resection of his left shoulder hibernoma and is currently asymptomatic, undergoing surveillance.
Conclusion
Due to SOMAMEN syndrome’s rarity, clinical suspicion should arise if a patient presents with multiple small-nonspecific variably low-attenuated nodular lesions on CT and mucocutaneous lesions. Ongoing monitoring should be done as there is an increased risk of cancer.
... "Personalized follow-up strategy to be tailored according to the clinical and radiological features of patients with PIK3CA-related disorders. When the clinician is involved in the care of a patient showing an asymmetric overgrowth involving more than one body segment, they need to accurately check the following body district in order to speculate about a diagnosis of syndromic PROS: head and neck, trunk, four limbs [14]. The present flowchart provides general information about the different tissues and organs (see letters (A-E)) that can be affected and other possible issues (F) in a syndromic PROS. ...
... The present flowchart provides general information about the different tissues and organs (see letters (A-E)) that can be affected and other possible issues (F) in a syndromic PROS. Moreover, in the boxes below, clinicians can find a detailed checklist showing an asymmetric overgrowth involving more than one body segment, they need to accurately check the following body district in order to speculate about a diagnosis of syndromic PROS: head and neck, trunk, four limbs [14]. The present flowchart provides general information about the different tissues and organs (see letters (A-E)) that can be affected and other possible issues (F) in a syndromic PROS. ...
PIK3CA-related disorders encompass many rare and ultra-rare conditions caused by somatic genetic variants that hyperactivate the PI3K-AKT-mTOR signaling pathway, which is essential for cell cycle control. PIK3CA-related disorders include PIK3CA-related overgrowth spectrum (PROS), PIK3CA-related vascular malformations and PIK3CA-related non-vascular lesions. Phenotypes are extremely heterogeneous and overlapping. Therefore, diagnosis and management frequently involve various health specialists. Given the rarity of these disorders and the limited number of centers offering optimal care, the Scientific Committee of the Italian Macrodactyly and PROS Association has proposed a revision of the most recent recommendations for the diagnosis, molecular testing, clinical management, follow-up, and treatment strategies. These recommendations give insight on molecular diagnosis, eligible samples, preferable sequencing, and validation methods and management of negative results. The purpose of this paper is to promote collaboration between health care centers and clinicians with a joint shared approach. Finally, we suggest the direction of present and future research studies, including new systemic target therapies, which are currently under evaluation in several clinical trials, such as specific inhibitors that can be employed to downregulate the signaling pathway.
... In spite of the advances in the knowledge of the PROS across the last decade, a consistent fraction of these phenotypes still remains orphan of a molecular diagnosis due to several factors: these include inappropriate tissue DNA sampling, very low-level mosaicism difficult to be detected, molecular mechanisms still to be unraveled. Some of the cases with PROS-like or overlapping phenotypes have recently shown to be caused by variants in genes of the same signal cascade (i.e., AKT1, AKT3, mTOR [9,[12][13][14][15]) or crosstalking molecular pathways (i.e., RAS/MAPK [16,17], or vascular proliferation pathway [18,19],). However, still nearly 30% of cases remain undiagnosed [9]. ...
PIK3CA pathogenic variants are responsible for a group of overgrowth syndromes, collectively known as PIK3CA-Related Overgrowth Spectrum (PROS). These gain-of-function variants arise postzygotically, and, according to time of onset, kind of embryonal tissue affected and regional body extension, give rise to heterogeneous phenotypes. PROS rarity and heterogeneity hamper the correct estimation of its epidemiology. Our work represents the first attempt to define the prevalence of PROS according to the established diagnostic criteria and molecular analysis and based on solid demographic data. We assessed the prevalence in Piedmont Region (Italy), including in the study all participants diagnosed with PROS born there from 1998 to 2021. The search identified 37 cases of PROS born across the 25-year period, providing a prevalence of 1:22,313 live births. Molecular analysis was positive in 81.0% of participants. Taking into account the cases with a detected variant in PIK3CA (n = 30), prevalence of molecularly positive PROS was 1:27,519.
... Although LO is the main feature of ILO patients, it also occurs in the classic phenotype and more frequently in the atypical phenotype. It may be associated with any molecular subtype, although it is most common in patients with pUPD11 (60-85%) [7][8][9][10]. BWSp is a disease with mosaicism; some patients are diagnosed molecularly by secondary tissue testing. ...
Simple Summary
Lateralized overgrowth may be isolated or accompany syndromes. Recently, international BWS consensus proposed that the patients with isolated lateralized overgrowth and epigenetic change related to this syndrome should be evaluated within the Beckwith–Wiedemann spectrum. The risk of cancer is high in patients with lateralized overgrowth, some patients also may be admitted presenting with a tumor. The aim of this study was to classify patients with lateralized overgrowth into isolated, atypical, and classic phenotypes according to consensus scoring, to investigate epigenetic alterations on chromosome 11p15.5, and to raise awareness for early detection and prevention of cancer.
Abstract
The Beckwith–Wiedemann spectrum (BWSp) ranges from isolated lateralized overgrowth (ILO) to classic phenotypes. In this broad clinical spectrum, an epigenetic alteration on chromosome 11p15.5 can be detected. The risk for embryonal tumors is high, especially in patients with lateralized overgrowth (LO). The aim of this study is to investigate epigenetic alterations in 11p15.5 and tumor risk in 87 children with LO. The methylation level of 11p15.5 was examined in the blood of all patients and in skin samples or buccal swabs from 40 patients with negative blood tests; 63.2% of patients were compatible with the ILO phenotype, 18.4% were atypical, and 18.4% were classic. The molecular diagnosis rate was 81.2% for the atypical and classic phenotypes, and 10.9% for the ILO phenotype. In patients with epigenetic alterations, LO was statistically significantly more severe than in test negatives. Tumors developed in six (6.9%) of the total 87 patients with LO; four belonged to the atypical or classical phenotype (12.5%) and two to ILO (3.5%). Three of the four patients with atypical/classical phenotypes had pUPD11, one had IC1-GOM alteration, and two ILO patients were negative. We conclude that LO patients should be monitored for tumor risk even if their epigenetic tests are negative.
... Given the considerable share of negative cases below 4 points, a molecular approach from tissue-extracted DNA instead of blood could be advisable in patients with the possibility to define a regional involvement (e.g., tumor, ILO, pancreatic hyperplasia . . . ), a testing approach which is commonly used in other conditions characterized by overgrowth and localized mosaicism [35]. In fact, an improvement in diagnostic performance has been documented by analyzing DNA from overgrowth tissue in these conditions, and the greater level of invasiveness in this situation would not only be justified by allowing a differential diagnosis towards other forms of overgrowth (e.g., PIK3CA-related overgrowth spectrum, vascular phenotype overlapping PIK3CA-related overgrowth spectrum with mutations in other genes) or body asymmetry (e.g., Silver-Russell syndrome) [35][36][37], but also by the opportunity to apply more precisely a targeted cancer screening [31] or management [38,39] based on the molecular lesion found within the BWSp. ...
... ), a testing approach which is commonly used in other conditions characterized by overgrowth and localized mosaicism [35]. In fact, an improvement in diagnostic performance has been documented by analyzing DNA from overgrowth tissue in these conditions, and the greater level of invasiveness in this situation would not only be justified by allowing a differential diagnosis towards other forms of overgrowth (e.g., PIK3CA-related overgrowth spectrum, vascular phenotype overlapping PIK3CA-related overgrowth spectrum with mutations in other genes) or body asymmetry (e.g., Silver-Russell syndrome) [35][36][37], but also by the opportunity to apply more precisely a targeted cancer screening [31] or management [38,39] based on the molecular lesion found within the BWSp. Further studies are needed to test this hypothesis and assess the best approach in such a condition, as well as the increase in the diagnostic yield by this approach. ...
Simple Summary
Beckwith-Wiedemann syndrome (BWSp) has recently been renamed to spectrum to reflect its diverse presentation and clinical features. In 2018, an international consensus developed a diagnostic approach and redefined clinical criteria, establishing a score above which a diagnosis can be made in case of a negative genetic test. We described a cohort of 831 patients to validate the efficacy of the 2018 consensus score for BWSp diagnosis, and to gather data on the performance of previous and current scoring systems, as well as the relationship between BWSp features, molecular tests, and the risk of cancer development.
Abstract
Different scoring systems for the clinical diagnosis of the Beckwith–Wiedemann spectrum (BWSp) have been developed over time, the most recent being the international consensus score. Here we try to validate and provide data on the performance metrics of these scoring systems of the 2018 international consensus and the previous ones, relating them to BWSp features, molecular tests, and the probability of cancer development in a cohort of 831 patients. The consensus scoring system had the best performance (sensitivity 0.85 and specificity 0.43). In our cohort, the diagnostic yield of tests on blood-extracted DNA was low in patients with a low consensus score (~20% with a score = 2), and the score did not correlate with cancer development. We observed hepatoblastoma (HB) in 4.3% of patients with UPD(11)pat and Wilms tumor in 1.9% of patients with isolated lateralized overgrowth (ILO). We validated the efficacy of the currently used consensus score for BWSp clinical diagnosis. Based on our observation, a first-tier analysis of tissue-extracted DNA in patients with <4 points may be considered. We discourage the use of the consensus score value as an indicator of the probability of cancer development. Moreover, we suggest considering cancer screening for negative patients with ILO (risk ~2%) and HB screening for patients with UPD(11)pat (risk ~4%).
... In this setting, phenotypes associated with somatic variants of the RASopathy genes continue to emerge showing extreme clinical variability, reflecting the specific variant effects, the location of the mosaic, and timing of the DNA change during embryonic life. 3 Schimmelpenning-Feuerstein-Mims syndrome (SFMS, OMIM #163200), also known as linear sebaceous nevus syndrome, is a neurooculocutaneous condition caused by somatic gain-of-function variants in the HRAS, NRAS, or KRAS genes. SFMS is characterized by congenital linear nevus sebaceous on the face associated with brain anomalies and dysfunction, epidermal nevi, ocular malformations, and vascular abnormalities. ...
Cutaneous skeletal hypophosphatemia syndrome (CSHS) is caused by somatic mosaic NRAS variants and characterized by melanocytic/sebaceous naevi, eye, and brain malformations, and FGF23‐mediated hypophosphatemic rickets. The MEK inhibitor Trametinib, acting on the RAS/MAPK pathway, is a candidate for CSHS therapy. A 4‐year‐old boy with seborrheic nevus, eye choristoma, multiple hamartomas, brain malformation, pleural lymphangioma and chylothorax developed severe hypophosphatemic rickets unresponsive to phosphate supplementation. The c.182A>G;p.(Gln61Arg) somatic NRAS variant found in DNA from nevus biopsy allowed diagnosing CSHS. We administered Trametinib for 15 months investigating the transcriptional effects at different time points by whole blood RNA‐seq. Treatment resulted in prompt normalization of phosphatemia and phosphaturia, catch‐up growth, chylothorax regression, improvement of bone mineral density, reduction of epidermal nevus and hamartomas. Global RNA sequencing on peripheral blood mononucleate cells showed transcriptional changes under MEK inhibition consisting in a strong sustained downregulation of signatures related to RAS/MAPK, PI3 kinase, WNT and YAP/TAZ pathways, reverting previously defined transcriptomic signatures. CSHS was effectively treated with a MEK inhibitor with almost complete recovery of rickets and partial regression of the phenotype. We identified “core” genes modulated by MEK inhibition potentially serving as surrogate markers of Trametinib action. This article is protected by copyright. All rights reserved.
Mosaic RASopathies are a heterogeneous group of diseases characterized by the presence at birth or early onset of congenital anomalies, cutaneous and vascular anomalies, segmental overgrowth, and increased cancer risk. They are caused by somatic pathogenic variants of the genes belonging the RAt Sarcoma Mitogen‐activated protein kinase (RAS/MAPK) pathway causing its hyperactivation. Here, we review the clinical and molecular characteristics of this heterogeneous group of diseases, including the possibilities of molecular diagnosis and new therapeutic perspectives.
