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BACKGROUND: Lymphatic malformations are vascular developmental anomalies varying from local superficial masses to diffuse infiltrating lesions, resulting in disfigurement. Patients' outcomes range from spontaneous regression to severe sequelae notwithstanding appropriate treatment. The current classification guides, in part, clinicians through the decision-making process, prognosis prediction and choice of therapeutic strategies. Even though the understanding of molecular basis of the disease has been recently improved, a standardized management algorithm has not been reached yet. RESULTS: Here, we report our experience on five children with different lymphatic anomalies of the head and neck region treated by applying a multidisciplinary approach reaching a consensus among specialists on problem-solving and setting priorities. CONCLUSIONS: Although restitutio ad integrum was rarely achieved and the burden of care is challenging for patients, caregivers and healthcare providers, this study demonstrates how the referral to expert centres can significantly improve outcomes by alleviating parental stress and ameliorating patients' quality of life. A flow-chart is proposed to guide the multidisciplinary care of children with LMs and to encourage multidisciplinary collaborative initiatives to implement dedicated patients' pathways.
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Anomalías Linfáticas , Humanos , Anomalías Linfáticas/terapia , Anomalías Linfáticas/patología , Femenino , Masculino , Niño , Cuello/patología , Cabeza , Preescolar , Lactante , Calidad de VidaRESUMEN
FBRSL1, together with FBRS and AUTS2 (Activator of Transcription and Developmental Regulator; OMIM 607270), constitutes a tripartite AUTS2 gene family. AUTS2 and FBRSL1 are evolutionarily more closely related to each other than to FBRS (Fibrosin 1; OMIM 608601). Despite its paralogous relation to AUTS2, FBRSL1's precise role remains unclear, though it likely shares functions in neurogenesis and transcriptional regulation. Herein, we report the clinical presentation with therapeutic approaches and the molecular etiology of a patient harboring a de novo truncating variant (c.371dupC) in FBRSL1, leading to a premature stop codon (p.Cys125Leufs*7). Our study extends previous knowledge by highlighting potential interactions and implications of this variant, alongside maternal and paternal duplications, for the patient's phenotype. Using sequence conservation data and in silico analysis of the truncated protein, we generated a predicted domain structure. Furthermore, our in silico analysis was extended by taking into account SNP array results. The extension of in silico analysis was performed due to the possibility that the coexistence of FBRSL1 truncating variant contemporary with maternal and paternal duplication could be a modifier of proband's phenotype and/or influence the novel syndrome clinical characteristics. FBRSL1 protein may be involved in neurodevelopment due to its homology with AUTS2, together with distinctive neuronal expression profiles, and thus should be considered as a potential modulation of clinical characteristics in a novel syndrome. Finally, considering that FBRSL1 is apparently involved in neurogenesis and in transcriptional regulatory networks that orchestrate gene expression, together with the observation that different genetic syndromes are associated with distinct genomic DNA methylation patterns, the specific episignature has been explored.
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Proteínas del Citoesqueleto , Discapacidad Intelectual , Factores de Transcripción , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Factores de Transcripción/genética , Proteínas del Citoesqueleto/genética , Masculino , Femenino , Síndrome , Fenotipo , Codón sin Sentido/genéticaRESUMEN
Arrhythmic risk stratification in patients with Lamin A/C gene (LMNA)-related cardiomyopathy influences clinical decisions. An implantable cardioverter defibrillator (ICD) should be considered in patients with an estimated 5-year risk of malignant ventricular arrhythmia (MVA) of ≥10%. The risk prediction score for MVA includes non-missense LMNA mutations, despite their role as an established risk factor for sudden cardiac death (SCD) has been questioned in several studies. The purpose of this study is to investigate cardiac features and find gene-phenotype correlations that would contribute to the evidence on the prognostic implications of non-missense vs. missense mutations in a cohort of LMNA mutant patients. An observational, prospective study was conducted in which 54 patients positive for a Lamin A/C mutation were enrolled, and 20 probands (37%) were included. The median age at first clinical manifestation was 41 (IQR 19) years. The median follow-up was 8 years (IQR 8). The type of LMNA gene mutation was distributed as follows: missense in 26 patients (48%), non-frameshift insertions in 16 (30%), frameshift deletions in 5 (9%), and nonsense in 7 (13%). Among the missense mutation carriers, two (8%) died and four (15%) were admitted onto the heart transplant list or underwent transplantation, with a major adverse cardiovascular event (MACE) rate of 35%. No statistically significant differences in MACE prevalence were identified according to the missense and non-missense mutation groups (p value = 0.847). Our data shift the spotlight on this considerable topic and could suggest that some missense mutations may deserve attention regarding SCD risk stratification in real-world clinical settings.
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OBJECTIVE: To demonstrate a high-yield molecular diagnostic workflow for lateralized overgrowth (LO), a congenital condition with abnormal enlargement of body parts, and to classify it by molecular genetics. STUDY DESIGN: We categorized 186 retrospective cases of LO diagnosed between 2003 and 2023 into suspected Beckwith-Wiedemann spectrum, PIK3CA-related overgrowth spectrum (PROS), vascular overgrowth, or isolated LO, based on initial clinical assessments, to determine the appropriate first-tier molecular tests and tissue for analysis. Patients underwent testing for 11p15 epigenetic abnormalities or somatic variants in genes related to PI3K/AKT/mTOR, vascular proliferation, and RAS-MAPK cascades using blood or skin DNA. For cases with negative initial tests, a sequential cascade molecular approach was employed to improve diagnostic yield. RESULTS: This approach led to a molecular diagnosis in 54% of cases, 89% of cases consistent with initial clinical suspicions, and 11% reclassified. Beckwith-Wiedemann spectrum was the most common cause, with 43% of cases exhibiting 11p15 abnormalities. PIK3CA-related overgrowth spectrum had the highest confirmation rate, with 74% of clinically diagnosed patients showing a PIK3CA variant. Vascular overgrowth demonstrated significant clinical overlap with other syndromes. A molecular diagnosis of isolated LO proved challenging, with only 21% of cases classifiable into a specific condition. CONCLUSIONS: LO is underdiagnosed from a molecular viewpoint and to date has had no diagnostic guidelines, which is crucial for addressing potential cancer predisposition, enabling precision medicine treatments, and guiding management. This study sheds light on the molecular etiology of LO, highlighting the importance of a tailored diagnostic approach and of selecting appropriate testing to achieve the highest diagnostic yield.
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Cystic fibrosis (CF) is the most common severe autosomal recessive genetic disorder among Caucasians. The improvement of genetic techniques has allowed the identification of an increasing number of genetic variants, including large rearrangements such as duplications. We report the first case of a whole CFTR gene duplication in a healthy newborn, who had normal sweat test, also carrying R74W and V855I variants on the same allele. Familial segregation analysis and the observed frequencies of all the CFTR gene variants, revealed that R74W and V855I were probably both present in a cis arrangement on the allele also containing the duplication (i.e., in a double complex allele). Since R74W is a "variant of varying clinical consequence" its arrangement in trans with one pathogenic variant may not be sufficient to cause a classic CF disease phenotype. Moreover, its duplication could even be an advantage that could compensate for the effect of the alteration.
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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.
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Fosfatidilinositol 3-Quinasas , Humanos , Fosfatidilinositol 3-Quinasas/genética , Consenso , Mutación , Fosfatidilinositol 3-Quinasa Clase I/genética , ItaliaRESUMEN
Breast cancer (BC) is the most common cancer and the leading cause of cancer death in women worldwide. Since the discovery of the highly penetrant susceptibility genes BRCA1 and BRCA2, many other predisposition genes that confer a moderate risk of BC have been identified. Advances in multigene panel testing have allowed the simultaneous sequencing of BRCA1/2 with these genes in a cost-effective way. Germline DNA from 521 cases with BC fulfilling diagnostic criteria for hereditary BC were screened with multigene NGS testing. Pathogenic (PVs) and likely pathogenic (LPVs) variants in moderate penetrance genes were identified in 15 out of 521 patients (2.9%), including 2 missense, 7 non-sense, 1 indel, and 3 splice variants, as well as two different exon deletions, as follows: ATM (n = 4), CHEK2 (n = 5), PALB2 (n = 2), RAD51C (n = 1), and RAD51D (n = 3). Moreover, the segregation analysis of PVs and LPVs into first-degree relatives allowed the detection of CHEK2 variant carriers diagnosed with in situ melanoma and clear cell renal cell carcinoma (ccRCC), respectively. Extended testing beyond BRCA1/2 identified PVs and LPVs in a further 2.9% of BC patients. In conclusion, panel testing yields more accurate genetic information for appropriate counselling, risk management, and preventive options than assessing BRCA1/2 alone.
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Neoplasias de la Mama , Neoplasias Renales , Humanos , Femenino , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Proteína BRCA1/genética , Penetrancia , Proteína BRCA2/genéticaRESUMEN
The autophagy process recycles dysfunctional cellular components and protein aggregates by sequestering them in autophagosomes directed to lysosomes for enzymatic degradation. A basal level of autophagy is essential for skeletal muscle maintenance. Increased autophagy occurs in several forms of muscular dystrophy and in the merosin-deficient congenital muscular dystrophy 1A mouse model (dy3k/dy3k) lacking the laminin-α2 chain. This pilot study aimed to compare autophagy marker expression and autophagosomes presence using light and electron microscopes and western blotting in diagnostic muscle biopsies from newborns affected by different congenital muscular myopathies and dystrophies. Morphological examination showed dystrophic muscle features, predominance of type 2A myofibers, accumulation of autophagosomes in the subsarcolemmal areas, increased number of autophagosomes overexpressing LC3b, Beclin-1 and ATG5, in the merosin-deficient newborn suggesting an increased autophagy. In Duchenne muscular dystrophy, nemaline myopathy, and spinal muscular atrophy the predominant accumulation of p62+ puncta rather suggests an autophagy impairment.
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Heterozygous germline or somatic variants in AKT3 gene can cause isolated malformations of cortical development (MCDs) such as focal cortical dysplasia, megalencephaly (MEG), Hemimegalencephaly (HME), dysplastic megalencephaly, and syndromic forms like megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome, and megalencephaly-capillary malformation syndrome. This report describes a new case of HME and capillary malformation caused by a somatic AKT3 variant that differs from the common p.E17K variant described in literature. The patient's skin biopsy from the angiomatous region revealed an heterozygous likely pathogenic variant AKT3:c.241_243dup, p.(T81dup) that may affect the binding domain and downstream pathways. Compared to previously reported cases with a common E17K mosaic variant, the phenotype is milder and patients showed segmental overgrowth, an uncommon characteristic in AKT3 variant cases. These findings suggest that the severity of the disease may be influenced not only by the level of mosaicism but also by the type of variant. This report expands the phenotypic spectrum associated with AKT3 variants and highlights the importance of genomic analysis in patients with capillary malformation and MCDs.
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Megalencefalia , Malformaciones Vasculares , Humanos , Mutación , Megalencefalia/genética , Megalencefalia/patología , Malformaciones Vasculares/genética , Fenotipo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
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.
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Trastornos del Crecimiento , Humanos , Mutación , Trastornos del Crecimiento/epidemiología , Trastornos del Crecimiento/genética , Trastornos del Crecimiento/diagnóstico , Fenotipo , Fosfatidilinositol 3-Quinasa Clase I/genética , SíndromeRESUMEN
Familial Mediterranean Fever (FMF) is linked with the MEFV gene and is the commonest among monogenic autoinflammatory diseases, with high prevalence in the Mediterranean basin. Although the clinical presentation of FMF has a major role in diagnosis, genotype/phenotype correlations and the role of "benign" gene variants (as R202Q) appear highly variable and incompletely clear, making difficult to select the most effective strategy in the management of patients. Aim of the present study was to investigate the clinical presentation and the genetic background in a homogenous cohort of patients from Apulia (south eastern Italy). We investigated 217 patients with a clinical suspect of autoinflammatory diseases, who were characterized for the occurrence of specific symptoms and with next generation sequencing by a 4-gene panel including MEFV, MVK, NLRP3 and TNFRSF1A. A genetic change was identified in 122 (53.7%) patients, with 161 different MEFV variants recorded in 100 individuals, 10 variants in NLRP3, and 6 each in TNFRSF1A and MVK. The benign variant R202Q was largely prevalent (41.6% of all MEFV variants). When patients were selected according the number of pathogenic MEFV variants (0, 1, or 2 pathogenic variants), results failed to show significant links between the frequency of symptoms and the number of pathogenic variants. Only family history and Pras score (indicative for severity of disease) predicted the presence of pathogenic variants, as compared with carriers of variants considered of uncertain significance or benign. Fever >38 °C and arthralgias appeared more frequently in R202Q-positive patients than in non-R202Q carriers. These two subgroups showed comparable duration of fever, occurrence of myalgia, abdominal and chest pain, Pras, and IFFS scores. In conclusion, results confirm that FMF manifests in mild form in non-middle eastern patients. This possibility partly affects the reliability of clinical criteria/scores. Furthermore, the presence of the R202Q variant might not be completely neutral in selected groups of patients.
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Fiebre Mediterránea Familiar , Humanos , Fiebre Mediterránea Familiar/diagnóstico , Fiebre Mediterránea Familiar/epidemiología , Fiebre Mediterránea Familiar/genética , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Reproducibilidad de los Resultados , Pirina/genética , Estudios de Asociación Genética , Fiebre , MutaciónRESUMEN
Sigma-2 receptor (S2R) is a S2R ligand-binding site historically associated with reportedly 21.5 kDa proteins that have been linked to several diseases, such as cancer, Alzheimer's disease, and schizophrenia. The S2R is highly expressed in various tumors, where it correlates with the proliferative status of the malignant cells. Recently, S2R was reported to be the transmembrane protein TMEM97. Prior to that, we had been investigating the translocator protein (TSPO) as a potential 21.5 kDa S2R candidate protein with reported heme and sterol associations. Here, we investigate the contributions of TMEM97 and TSPO to S2R activity in MCF7 breast adenocarcinoma and MIA PaCa-2 (MP) pancreatic carcinoma cells. Additionally, the role of the reported S2R-interacting partner PGRMC1 was also elucidated. Proximity ligation assays and co-immunoprecipitation show a functional association between S2R and TSPO. Moreover, a close physical colocalization of TMEM97 and TSPO was found in MP cells. In MCF7 cells, co-immunoprecipitation only occurred with TMEM97 but not with PGRMC1, which was further confirmed by confocal microscopy experiments. Treatment with the TMEM97 ligand 20-(S)-hydroxycholesterol reduced co-immunoprecipitation of both TMEM97 and PGRMC1 in immune pellets of immunoprecipitated TSPO in MP cells. To the best of our knowledge, this is the first suggestion of a (functional) interaction between TSPO and TMEM97 that can be affected by S2R ligands.
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Receptores sigma , Humanos , Ligandos , Unión Proteica , Receptores sigma/metabolismo , Sitios de Unión , Receptores de GABA/metabolismo , Proteínas de la Membrana/metabolismo , Receptores de Progesterona/metabolismoRESUMEN
Pathogenic variants in genes are involved in histone acetylation and deacetylation resulting in congenital anomalies, with most patients displaying a neurodevelopmental disorder and dysmorphism. Arboleda-Tham syndrome caused by pathogenic variants in KAT6A (Lysine Acetyltransferase 6A; OMIM 601408) has been recently described as a new neurodevelopmental disorder. Herein, we describe a patient characterized by complex phenotype subsequently diagnosed using the clinical exome sequencing (CES) with Arboleda-Tham syndrome (ARTHS; OMIM 616268). The analysis revealed the presence of de novo pathogenic variant in KAT6A gene, a nucleotide c.3385C>T substitution that introduces a premature termination codon (p.Arg1129*). The need for straight multidisciplinary collaboration and accurate clinical description findings (bowel obstruction/megacolon/intestinal malrotation) was emphasized, together with the utility of CES in establishing an etiological basis in clinical and genetical heterogeneous conditions. Therefore, considering the phenotypic characteristics, the condition's rarity and the reviewed literature, we propose additional diagnostic criteria that could help in the development of future clinical diagnostic guidelines. This was possible thanks to objective examinations performed during the long follow-up period, which permitted scrupulous registration of phenotypic changes over time to further assess this rare disorder. Finally, given that different genetic syndromes are associated with distinct genomic DNA methylation patterns used for diagnostic testing and/or as biomarker of disease, a specific episignature for ARTHS has been identified.
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Histona Acetiltransferasas , Trastornos del Neurodesarrollo , Humanos , Codón sin Sentido , Pruebas Genéticas , Histona Acetiltransferasas/genética , Trastornos del Neurodesarrollo/genética , FenotipoRESUMEN
BACKGROUND: Postzygotic activating PIK3CA variants cause several phenotypes within the PIK3CA-related overgrowth spectrum (PROS). Variant strength, mosaicism level, specific tissue involvement and overlapping disorders are responsible for disease heterogeneity. We explored these factors in 150 novel patients and in an expanded cohort of 1007 PIK3CA-mutated patients, analysing our new data with previous literature to give a comprehensive picture. METHODS: We performed ultradeep targeted next-generation sequencing (NGS) on DNA from skin biopsy, buccal swab or blood using a panel including phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway genes and GNAQ, GNA11, RASA1 and TEK. Additionally, 914 patients previously reported were systematically reviewed. RESULTS: 93 of our 150 patients had PIK3CA pathogenetic variants. The merged PROS cohort showed that PIK3CA variants span thorough all gene domains, some were exclusively associated with specific PROS phenotypes: weakly activating variants were associated with central nervous system (CNS) involvement, and strongly activating variants with extra-CNS phenotypes. Among the 57 with a wild-type PIK3CA allele, 11 patients with overgrowth and vascular malformations overlapping PROS had variants in GNAQ, GNA11, RASA1 or TEK. CONCLUSION: We confirm that (1) molecular diagnostic yield increases when multiple tissues are tested and by enriching NGS panels with genes of overlapping 'vascular' phenotypes; (2) strongly activating PIK3CA variants are found in affected tissue, rarely in blood: conversely, weakly activating mutations more common in blood; (3) weakly activating variants correlate with CNS involvement, strong variants are more common in cases without; (4) patients with vascular malformations overlapping those of PROS can harbour variants in genes other than PIK3CA.
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Malformaciones Vasculares , Humanos , Mutación/genética , Fenotipo , Genotipo , Fosfatidilinositol 3-Quinasa Clase I/genética , Malformaciones Vasculares/diagnóstico , Malformaciones Vasculares/genética , Proteína Activadora de GTPasa p120/genéticaRESUMEN
Sporadic intra-abdominal desmoid tumors are rare and known to potentially occur after trauma including previous surgery, although knowledge of the underlying pathogenetic mechanism is still limited. We reviewed the recent literature on sporadic intraabdominal desmoids and inflammation as we investigated the mutational and epigenetic makeup of a case of multiple synchronous mesenterial desmoids occurring after necrotizing pancreatitis. A 62-year-old man had four mesenteric masses up to 4.8 cm diameter detected on CT eighteen months after laparotomy for peripancreatic collections from necrotizing pancreatitis. All tumors were excised and diagnosed as mesenteric desmoids. DNA from peripheral blood was tested for a multigene panel. The tumour DNA was screened for three most frequent ß-catenin gene mutations T41A, S45F and S45P. Expression levels of miR-21-3p and miR-197-3-p were compared between the desmoid tumors and other wild-type sporadic desmoids. The T41A CTNNB1 mutation was present in all four desmoid tumors. miR-21-3p and miR-197-3p were respectively upregulated and down-regulated in the mutated sporadic mesenteric desmoids, with respect to wild-type lesions. The patient is free from recurrence 34 months post-surgery. The literature review did not show similar studies. To our knowledge, this is the first study to interrogate genetic and epigenetic signature of multiple intraabdominal desmoids to investigate potential association with abdominal inflammation following surgery for necrotizing pancreatitis. We found mutational and epigenetic features that hint at potential activation of inflammation pathways within the desmoid tumor.
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Fibromatosis Agresiva , MicroARNs , Pancreatitis , Masculino , Humanos , Persona de Mediana Edad , Fibromatosis Agresiva/genética , Fibromatosis Agresiva/cirugía , Fibromatosis Agresiva/diagnóstico , Mutación , Inflamación/complicaciones , beta Catenina/genética , Pancreatitis/complicaciones , MicroARNs/genéticaRESUMEN
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.
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Proteínas Quinasas Activadas por Mitógenos , Proteínas ras , Proteínas Quinasas Activadas por Mitógenos/genética , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteínas ras/genéticaRESUMEN
We report on a child with prenatal findings of increased nuchal translucency, polydramnios, ascites, and overgrowth. At birth, she presented length >97° centile, minor facial anomalies, megalencephaly, and Wolff-Parkinson-White syndrome. Whole-exome sequencing showed a pathogenic variant in the NRAS gene, but no mutations were found in PI3K/AKT/mTOR pathway genes.
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BACKGROUND AND AIM OF THE WORK: BRCA1/2 are tumour-suppressor genes involved in DNA homologous recombination and ovarian cancer development. The study evaluated the risk of tumor cancer in women presenting the BRCA mutations. METHODS: Risk-reducing surgery (RRS) was performed in 100 patients carrying BRCA1 (aged between 30-73 years, median age was 51 years) and BRCA 2 mutation (aged between 36-70 years, median age was 53 years). Fifty-eight patients had previous history of breast cancer. RESULTS: Between the 100 patients, 82 women underwent risk-reducing salpingo-oophorectomy (RRSO) through a laparoscopic minimally invasive approach, 7 (7 %) underwent laparoscopic RRSO and contextual hysterectomy, 1 woman (1 %) underwent RRSO through a laparotomic approach and 10 women (10 %) laparotomic RRSO and hysterectomy. During 5 (5 %) laparoscopic RRSO, prophylactic bilateral mastectomy was also performed. Early and late complication occurred in 3 patients (3 %). Two patients (2 %) were found to have occult Serous Tubal Intraepithelial Carcinoma (STIC) and three patients (3 %) occult cancer. CONCLUSIONS: RRSO is safe and feasible in BRCA mutation carriers. The procedure is effective for genetic prevention of ovarian cancer.
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Neoplasias de la Mama , Neoplasias Ováricas , Adulto , Anciano , Neoplasias de la Mama/genética , Neoplasias de la Mama/prevención & control , Neoplasias de la Mama/cirugía , Femenino , Genes BRCA1 , Genes BRCA2 , Humanos , Mastectomía , Persona de Mediana Edad , Mutación , Neoplasias Ováricas/genética , Neoplasias Ováricas/prevención & control , Neoplasias Ováricas/cirugía , Ovariectomía , Estudios Prospectivos , SalpingooforectomíaRESUMEN
Lateralized/segmental overgrowth disorders (LOs) encompass a heterogeneous group of congenital conditions with excessive body tissue growth. Documented molecular alterations in LOs mostly consist of somatic variants in genes of the PI3KCA/AKT/mTOR pathway or of chromosome band 11p15.5 imprinted region anomalies. In some cases, somatic pathogenic variants in genes of the RAS/MAPK pathway have been reported. We present the first case of a somatic pathogenic variant (T507K) in PTPN11 causing a LO phenotype characterized by severe lateralized overgrowth, vascular proliferation, and cerebral astrocytoma. The T507K variant was detected in DNA from overgrown tissue in a leg with capillary malformation. The astrocytoma tissue showed a higher PTPN11 variant allele frequency. A pathogenic variant in FGFR1 was also found in tumor tissue, representing a second hit on the RAS/MAPK pathway. These findings indicate that RAS/MAPK cascade overactivation can cause mosaic overgrowth phenotypes resembling PIK3CA-related overgrowth disorders (PROS) with cancer predisposition and are consistent with the hypothesis that RAS/MAPK hyperactivation can be involved in the pathogenesis of astrocytoma. This observation raises the issue of cancer predisposition in patients with RAS/MAPK pathway gene variants and expands genotype spectrum of LOs and the treatment options for similar cases through inhibition of the RAS/MAPK oversignaling.