Generation of the CSSi020-A (14437) iPSC line from a patient carrying a copy number variation (CNV) in the 17p11.2 chromosome region.

Smith-Magenis syndrome (SMS) is a complex neurodevelopmental disorder with a birth incidence of 1:25,000. SMS is caused by haploinsufficiency of the retinoic acid-induced retinoic acid1 (RAI1) gene, determined by an interstitial deletion of âˆ¼ 3.7 Mb (17p11.2, including the RAI1 gene) in 90 % of cases and a mutation on the RAI1 gene in only 10 % of cases. We generated and characterized a human pluripotent stem cell line (hIPSCs) derived from primary fibroblasts of a 17-year-old woman carrying a 17p11.2 deletion including the RAI1 gene.

Breast cancer patients' postoperative outcomes in nipple-sparing mastectomy and reconstruction with subpectoral implant placement: a single center experience.

Background: The continuous increase in the rate of nipple sparing mastectomy (NSM), the development of several reconstructive techniques and the following introduction of acellular derma matrix (ADM) has revolutionized implant-based breast reconstruction. This study aimed to investigate postoperative complications, health-related quality of life (HRQoL) and patients' satisfaction in patients undergoing NSM and breast reconstruction with or without ADM. Methods: Enrolled patients were divided into three groups: immediate breast reconstruction (IBR) with definitive implant and ADM (Group A), IBR only with definitive prosthesis (Group B), and two-stage breast reconstruction (Group C). The postoperative complications, BREAST-Q outcomes and reoperations were compared. Results: A total of 105 BC patients were enrolled and a total of 139 post-mastectomy breast reconstructions were performed. Seroma was the most prevalent complication observed: 8.3% in Group A, 2.9% in Group B and 5.7% in Group C. Postoperative infection occurred in two patients of Group A (5.6%), one patient of Group B (2.9%) and one of Group C (2.9%). Group A reported larger drain volume (1,125±243.5 cc), longer drain period (13.2±2.8 days), and the lowest incidence of capsular contracture (5.6%). The BREAST-Q patient-reported outcome measures document that all patients aged ≥50 years presented a higher score in "Satisfaction with breast" (P<0.001) and "Satisfaction with outcome" domains (P<0.05). Performing a bilateral breast reconstruction was associated to higher scores in "Physical wellbeing chest domain" (P<0.05). In addition, patients in Group A and Group B reported higher score in "Satisfaction with the breast" domain (P<0.001) but only in Group B we reported a higher score in "Satisfaction with outcome" (P<0.001). Conclusions: Subpectoral IBR results in manageable complications and greater personal satisfaction. The ADM could improve breast reconstruction reducing the rate of capsular contracture. The prepectoral placement of ADM could minimize complications and optimize aesthetic results.

Heterozygosity for loss-of-function variants in LZTR1 is associated with isolated multiple café-au-lait macules.

PURPOSE: Pathogenic LZTR1 variants cause schwannomatosis and dominant/recessive Noonan syndrome (NS). We aim to establish an association between heterozygous loss-of-function LZTR1 alleles and isolated multiple café-au-lait macules (CaLMs). METHODS: A total of 849 unrelated participants with multiple CaLMs, lacking pathogenic/likely pathogenic NF1 and SPRED1 variants, underwent RASopathy gene panel sequencing. Data on 125 individuals with heterozygous LZTR1 variants were collected for characterizing their clinical features and the associated molecular spectrum. In vitro functional assessment was performed on a representative panel of missense variants and small in-frame deletions. RESULTS: Analysis revealed heterozygous LZTR1 variants in 6.0% (51/849) of participants, exceeding the general population prevalence. LZTR1-related CaLMs varied in number, displayed sharp or irregular borders, and were generally isolated but occasionally associated with features recurring in RASopathies. In 2 families, CaLMs and schwannomas co-occurred. The molecular spectrum mainly consisted of truncating variants, indicating loss-of-function. These variants substantially overlapped with those occurring in schwannomatosis and recessive NS. Functional characterization showed accelerated protein degradation or mislocalization, and failure to downregulate mitogen-activated protein kinase signaling. CONCLUSION: Our findings expand the phenotypic variability associated with LZTR1 variants, which, in addition to conferring susceptibility to schwannomatosis and causing dominant and recessive NS, occur in individuals with isolated multiple CaLMs.

Loss-of-function variants in ERF are associated with a Noonan syndrome-like phenotype with or without craniosynostosis.

Pathogenic, largely truncating variants in the ETS2 repressor factor (ERF) gene, encoding a transcriptional regulator negatively controlling RAS-MAPK signaling, have been associated with syndromic craniosynostosis involving various cranial sutures and Chitayat syndrome, an ultrarare condition with respiratory distress, skeletal anomalies, and facial dysmorphism. Recently, a single patient with craniosynostosis and a phenotype resembling Noonan syndrome (NS), the most common disorder among the RASopathies, was reported to carry a de novo loss-of-function variant in ERF. Here, we clinically profile 26 individuals from 15 unrelated families carrying different germline heterozygous variants in ERF and showing a phenotype reminiscent of NS. The majority of subjects presented with a variable degree of global developmental and/or language delay. Their shared facial features included absolute/relative macrocephaly, high forehead, hypertelorism, palpebral ptosis, wide nasal bridge, and low-set/posteriorly angulated ears. Stature was below the 3rd centile in two-third of the individuals, while no subject showed typical NS cardiac involvement. Notably, craniosynostosis was documented only in three unrelated individuals, while a dolichocephalic aspect of the skull in absence of any other evidence supporting a premature closing of sutures was observed in other 10 subjects. Unilateral Wilms tumor was diagnosed in one individual. Most cases were familial, indicating an overall low impact on fitness. Variants were nonsense and frameshift changes, supporting ERF haploinsufficiency. These findings provide evidence that heterozygous loss-of-function variants in ERF cause a "RASopathy" resembling NS with or without craniosynostosis, and allow a first dissection of the molecular circuits contributing to MAPK signaling pleiotropy.

Defining the variant-phenotype correlation in patients affected by Noonan syndrome with the RAF1:c.770C>T p.(Ser257Leu) variant.

Hypertrophic cardiomyopathy (HCM) is the major contributor to morbidity and mortality in Noonan syndrome (NS). Gain-of-function variants in RAF1 are associated with high prevalence of HCM. Among these, NM_002880.4:c.770C > T, NP_002871.1:p.(Ser257Leu) accounts for approximately half of cases and has been reported as associated with a particularly severe outcome. Nevertheless, comprehensive studies on cases harboring this variant are missing. To precisely define the phenotype associated to the RAF1:c.770C > T, variant, an observational retrospective analysis on patients carrying the c.770C > T variant was conducted merging 17 unpublished patients and literature-derived ones. Data regarding prenatal findings, clinical features and cardiac phenotypes were collected to provide an exhaustive description of the associated phenotype. Clinical information was collected in 107 patients. Among them, 92% had HCM, mostly diagnosed within the first year of life. Thirty percent of patients were preterm and 47% of the newborns was admitted in a neonatal intensive care unit, mainly due to respiratory complications of HCM and/or pulmonary arterial hypertension. Mortality rate was 13%, mainly secondary to HCM-related complications (62%) at the average age of 7.5 months. Short stature had a prevalence of 91%, while seizures and ID of 6% and 12%, respectively. Two cases out of 75 (3%) developed neoplasms. In conclusion, patients with the RAF1:c.770C > T pathogenic variant show a particularly severe phenotype characterized by rapidly progressive neonatal HCM and high mortality rate suggesting the necessity of careful monitoring and early intervention to prevent or slow down the progression of HCM.

A Nutraceutical Combination of Bromelain and Boswellia Serrata Casperome® in Siben®: Effects on the Postoperative Course of Inguinal Hernioplasty with Mesh at One Year Follow up. A Randomized Multicentric Study.

AIM: We investigated the potential benefits of administering a nutraceutical combination of Bromelain (200 mg) and Boswellia serrata Casperome® (200 mg) on post-operative outcomes of hernioplasty with mesh. METHODS: One hundred eighty patients (27 females, 153 males) were enrolled to undergo open tension-free hernioplasty with the use of Progrip®. Patients were randomized to receive either one tablet of Siben® (study group) or placebo (control group) on an empty stomach, every twelve hours for eleven postoperative days. All patients filled out a medical questionnaire focused on postoperative pain, based on the Visual Analogue Scale (VAS) scale and the Short Form-36 (SF-36) questionnaire, at time T0 (day of surgery) and T28 (28th day after surgery). RESULTS: One-year results showed a significant improvement in the primary postoperative outcome in the study group. Perception of pain was significantly reduced in the Siben® group compared with controls, both on the seventh (p < 0.05) and the twenty-first (p < 0.05) postoperative day. Patients included in the Siben® group also resumed daily activities and returned to work earlier than the controls. Moreover, results of the SF-36 indicated better Quality of Life (QoL) scores in the study group compared to the placebo group. CONCLUSIONS: Our analysis effectively demonstrates that the use of Siben® in open inguinal hernia mesh repair may improve short- and long-term surgical outcomes, contributing to a better QoL.

Novel ATP2A2 Gene Mutation c.118G>A Causing Keratinocyte and Cardiomyocyte Disconnection in Darier Disease.

Darier disease (DD) is an autosomal dominant disorder due to pathogenic variants of the ATP2A2 gene that causes an isolated skin manifestation based on keratinocyte disconnection and apoptosis. Systemic manifestations of DD have not been demonstrated so far, although a high incidence of neuropsychiatric syndromes suggests an involvement of the central nervous system. We report that the pathogenic ATP2A2 gene variant c.118G>A may cause cardiac involvement in patients with DD, consisting of keratinocyte and cardiomyocyte disconnection. Their common pathologic pathway, still unreported, was documented by both skin and left ventricular endomyocardial biopsies because cardiac dilatation and dysfunction appeared several decades after skin manifestations. Keratinocyte disconnection was paralleled by cardiomyocyte separation at the lateral junction. Cardiomyocyte separation was associated with cell disarray, sarcoplasmic reticulum dilatation, and increased myocyte apoptosis. Clinically, hyperkeratotic skin papules are associated with chest pain, severe muscle exhaustion, and ventricular arrhythmias that improved following administration of aminophylline, a phosphodiesterase inhibitor enhancing SERCA2 protein phosphorylation. Cardiac pathologic changes are similar to those documented in the skin, including cardiomyocyte disconnection that promotes precordial pain and cardiac arrhythmias. Phosphodiesterase inhibitors that enhance SERCA2 protein phosphorylation may substantially attenuate the symptoms.

SPREAD: Spatiotemporal Pathogen Relationships and Epidemiological Analysis Dashboard.

In the scope of public health, the rapid identification and control of infectious disease outbreaks are a paramount concern. Traditional surveillance methods often face challenges in effectively combining genetic, geographical, and temporal data, which is crucial for a comprehensive understanding of disease transmission dynamics. Addressing this critical need, the Spatiotemporal Phylogenomic Research and Epidemiological Analysis Dashboard (SPREAD) emerges as an innovative standalone web-based application. SPREAD integrates several modules for detailed genomic relationships, pinpointing genetically close pathogens, and spatial mapping, providing in-depth views of how diseases spread across populations and territories, with significant advantage to manage both bacteria and viruses based on allele and variant calling, respectively. Designed for broad accessibility, SPREAD operates seamlessly within web browsers, eliminating the need for sophisticated IT infrastructure and facilitating its use across various public health contexts. Its intuitive interface ensures that users can effortlessly navigate complex datasets, facilitating widespread access to advanced surveillance capabilities. Through its initial deployments, SPREAD has proven instrumental in quickly identifying transmission clusters, significantly aiding in the formulation of prompt and targeted public health responses. Through the integration of state-of-the-art technology with a focus on user-centered design, SPREAD offers a promising solution that highlights the potential of digital health innovations.

Abdominoplasty after massive weight loss. Safety preservation fascia technique and clinical outcomes in a large single series-comparative study.

Introduction: Weight loss after bariatric surgery causes very important modifications to the patient's silhouette. Abdominal fat and skin excess reduction are associated with several complications. The most frequent are seroma and hematoma whereas major complications, such as pulmonary embolism, are less frequent. This study aimed to describe our technical procedure for abdominoplasty in patients with massive weight loss after bariatric surgery. Methods: In total, 196 patients were included. All patients who underwent abdominoplasty classic (group A) and abdominoplasty with the preservation and lift of Scarpa fascia (group B) and with umbilical transposition between May 2018 and May 2021 were included. Patients with concomitant correction of ventral hernia were excluded. Demographic and operative data were analyzed according to comorbidities and postoperative complications. Results: There were 160 (81.6%) women. The mean age was 43.6 years; the mean weight was 86.7 kg; and the mean BMI was 28.6 kg/m2. Five patients (2.5%) presented postoperative seroma. Four patients (2%) presented partial dehiscence/skin necrosis one of them requiring a revision. Finally, 26 patients presented a postoperative complication, with an overall incidence of 12.6%. The average postoperative hospital stay was 3.6. The rates of seroma were significantly higher in men, patients with a BMI > 30 kg/m2, and aged >50 years. Conclusion: Preserving Scarpa Fascia during surgical post-bariatric patient procedures reduces the seroma formation and the scar complication and reduces the tension of the inguinal-pubic region with correction of our deformation after weight loss. Improves reducing the drain and reducing seroma incidence suction and hospital stay.

The unexpected social cost of inguinal hernioplasty procedures derived from the COVID-19 pandemic: Surgical trend analysis based on an Italian hospital series.

BACKGROUND: The majority of inguinal hernias are usually paucisymptomatic, so are restored electively. The main purpose of this study is to assess the trends in hernia repair surgery before and during the pandemic period, analyzing an Italian hospital series of 390 patients, in an attempt to quantify the negative impact regarding social costs derived from the Covid-19 outbreak. Moreover, we want to focus on the concept of apparently minor pathology as hernioplasty which could represent a life-threatening condition for patients. METHODS: The study population consisted of all patients operated for inguinal hernia in a General Surgery Unit from 2019 to 2021, divided into a pre-pandemic and a pandemic period. RESULTS: The Covid-19 pandemic increased urgent operations in a complicated setting. A statistically significant difference was found regarding the trend of hospitalization length as well as a strong positive correlation between the severity of hernia and the hospitalization length. CONCLUSIONS: During the pandemic, it has been registered a mishandling of inguinal hernias to the detriment of both the healthcare system and patients, due to multifactorial issues and, in particular, to the restrictions imposed by the regional government that erroneously declassed hernia pathology as a minor problem for public health. We do believe that patients, after diagnosis of inguinal hernia, should learn the Taxis maneuver for its feasibility and ease of execution, in order to reduce access to emergencies in many cases and likewise to better pain and discomfort perceived, even in the event of unexpected worldwide healthcare scenario.

Evaluating the Quality of Online Patient Information for Prepectoral Breast Reconstruction Using Polyurethane-Coated Breast Implants.

Background: An increasing number of patients are using online information regarding medical issues; however, the Internet is not subject to content ratings or filters. Unreliable information found on the web can heavily influence patients to the extent that it can lead to wrong decisions in the choice of treatment. In our daily experience we meet more informed patients and given the increasing use of polyurethane-coated implants in breast reconstruction in Europe, we wondered about the level of information available online. Our study aims to assess the quality of information available online on breast reconstruction with polyurethane-coated implants. Materials and Methods: Assuming that the most used search engines are Google and Yahoo, we used a search strategy to identify online information regarding prepectoral breast reconstruction with polyurethane-coated implants. The selected websites were divided into 5 groups (practitioners, hospitals, healthcare portals, professional societies, and encyclopedias), and the quality of information was assessed by using an expanded version of the Ensuring Quality Information for Patients (EQIP) tool, which is a checklist applicable to all existing types of information. Results: Fifty-six websites were selected and were categorized into 5 groups: 17 practitioners, 9 hospitals, 13 healthcare portals, 7 professional societies, 10 encyclopedias. The average score was 17 points (range: 12 - 25). We found 13 reliable websites with a score higher than 20 using the expanded version of the EQIP tool, whereas 43 were deemed unreliable, as they scored lower. Conclusion: Proper communication between surgeon and patient is crucial in the therapeutic choice, as the available online information presently is scarce and can lead to wrong decisions if not properly verified.

Novel Genetic Microvascular Dysplasia Causing Hypoperfusion of Cardiac, Renal, and Cerebral Circulation.

BACKGROUND: Microvascular disorders represent an uncommon site of tissue hypo-perfusion and damage. Various genetic and acquired causes can be involved. A 65-year-old man was admitted because of refractory angina, which he had had since the age of 30 years, micro-hematuria, and recurrent transitory ischemic attacks from the age of 64. METHODS: Hematochemical studies, ECG, Holter monitoring, 2D-echo, cardiac magnetic resonance (CMR), CTA of cerebral vessels, endomyocardial coronary angiography, and kidney biopsy processes were undertaken. Gene mutation analysis was conducted using next-generation sequencing, which included more than 5000 genes associated with inherited diseases. RESULTS: Hematochemical findings were unremarkable. The ECG, Holter, 2D-echo, and CTA of brain vessels were normal. Cerebral magnetic resonance showed the presence of multiple small foci of ischemia. Coronary and ventricular angiography showed normal arteries with remarkably slow flow and multiple biventricular micro-aneurysms. At the endomyocardial biopsy, five of seven arterioles presented severe lumen obstruction due to hypertrophy and disarray of the muscular coat. Similarly, obstructed pre-glomerular arteries with glomerular sclerosis were seen at the renal biopsy. Genetics identified mutations in the ABCC6, MMP2, and XYLT1 genes, which play pivotal roles in the extracellular matrix. CONCLUSION: This study described a new genetic microvascular obstructive disease causing progressive hypo-perfusion of the human brain, heart, and kidney.

Portable Negative Pressure Wound Dressing in Oncoplastic Conservative Surgery for Breast Cancer: A Valid Ally.

Background and Objectives: The use of oncoplastic techniques has spread widely in the last decade, with an expansion of the indications and demonstration of excellent oncological safety profiles. A potential downside may be the increased complication rates, which could influence the timing of adjuvant therapy. To date, there is increasing evidence that negative pressure therapy on closed wounds can reduce complication rates after surgery. From this perspective, we tested the use of portable negative pressure wound dressings (NPWDs) in oncoplastic surgery to minimize early post-operative admissions to the outpatient clinic and prevent surgical complications. Materials and Methods: An observational prospective cohort study was conducted on a population of patients who underwent quadrantectomy and wise-pattern reduction mammoplasty for breast cancer. The primary objective of the study is represented by the evaluation of the impact of NPWD on post-operative outcomes in an oncoplastic surgery setting. Patients enrolled between January 2021 and January 2023 were divided into two groups, the conventional dressing (CD) group and the NPWD group, by a simple randomization list. Results: A total of 100 patients were enrolled, with 52 in the CD group and 48 in the NPWD group. The use of NPWD significantly reduced the wound dehiscence rate (2.0% vs. 7.7% p = 0.002) and the number of one-month postoperative admissions to our clinic (3.8 ± 1.1 vs. 5.7 ± 1.3 p = 0.0009). Although not significant, it is possible to note a trend of reduction of clinically relevant postoperative total complications in patients treated with NPWDs. Conclusions: NPWDs may represent a useful tool in the post-surgical management of complex oncoplastic procedures, ensuring less wound dehiscence. Furthermore, the use of these dressings led to a significant reduction in admissions to the clinic, promoting a lower use of resources by hospitals and effective prevention of possible complications.

Neither inguinoscrotal hernia nor hydrocele misunderstood giant testicular neoplasm. Case report and literature review.

AIM: This case experience aims to question the current know-how when a masked testicle malignancy occurs, in order to achieve the correct clinical framework and avoid mistakes during surgical procedures. in the evaluation MATERIALS AND METHODS: A 36-year-old male patient was admitted with an incorrect diagnosis of left-sided incarcerated inguinoscrotal hernia, and then discovered a seminomatous testicular neoplasm matched with a hypertensive ipsilateral hydrocele. Therefore, we performed a radical epididymo-orchiectomy and referred the patient to the oncologist for adjuvant chemotherapy after discharge. RESULTS: The surgery was perceived by the patient as the best possible treatment because the symptoms were relieved. DISCUSSION: A 36-year-old male patient was admitted to our surgical department due to an incorrect diagnosis of leftsided incarcerated inguinoscrotal hernia, consequently to a misguided scrotal ultrasound-doppler exam. During the urgent surgical operation, we realized that we were dealing with an enormous 17x10x9 cm seminomatous testicular neoplasm matched with a hypertensive ipsilateral hydrocele. Therefore, we performed a radical epididymo-orchiectomy and referred the patient to the oncologist for adjuvant chemotherapy after discharge. CONCLUSION: This case report points out that there may be a poor correlation between clinical findings and pathophysiologic processes affecting scrotal structures. Additional radiological investigations, such as CT scan, could clarify and confirm the clinical scenario, improving the preoperative planning and surgical outcomes. KEY WORDS: Inguinal Hernia, Seminoma, Testicular Neoplasm.

The HELLP syndrome: clinical issues and surgical management. A Case Experience.

AIM: This study aims to challenge the current know-how in patients with spontaneous rupture of a liver hematoma, to differentiate amongst patients requiring such specific surgical therapy and avoiding mistakes during surgical operations, in order to terminate pregnancy with beneficial effects on the mother and fetus. MATERIALS AND METHODS: In a emergency scenario we admitted a 37-year-old woman at 35+4 weeks of gestation for emergency cesarean section after the onset of right hypochondrium pain. A diagnosis of hemoperitoneum and severe preeclampsia with liver and splenic bleeding was done and managed with packing of hepatic and splenic hematomas and according to her haemo-dynamic clinical conditions, done in different time. RESULTS: A diagnosis of hemoperitoneum and severe pre-eclampsia with liver and splenic bleeding was done and managed it with 3 xypho-pubic-laparatomy in different time with haemostatic packing. DISCUSSION: In this case report, the patient underwent an emergency caesarean section and was managed with packing of hepatic and splenic hematomas and according to her haemodynamic clinical conditions was operated in different time. The choice of laparotomy and hepatic packing has proved to be a viable option in patients with unstable vital signs and is feasible even in limited resource settings. CONCLUSION: Short interval between diagnosis and management may enhance the feto-maternal survival rate and prevent further morbidity or mortality. The choice of laparotomy and hepatic packing has proved to be a viable option in patients with unstable vital signs and is feasible even in limited resource settings. KEY WORDS: HELLP syndrome, Liver hematoma rupture, Packing.

A novel ANO3 variant in two siblings with different phenotypes.

INTRODUCTION: Dystonia type 24 is due to the mutation of the ANO3 gene. It generally consists of craniocervical dystonia associated with tremor; however, other neurological manifestations may also occur. Scientific literature has been expanding on its phenotype over the past few years. CASE: Here we present two siblings affected by dystonia 24 associated to a novel missense mutation of the ANO3 gene. Description of their phenotype, with regard to motor and non-motor features, may improve the knowledge on DYT 24. Consistent with previous reports, our patients presented with cranio-cervical involvement, and they also exhibited different severity and phenotypes. However non-motor symptoms were present too. CONCLUSION: Dystonia 24 spectrum is continuously expanding. This case suggests that the ANO3 missense mutation should be sought in all cases of dystonia and isolated tremor and that non-motor symptoms are an integral part of dystonic syndromes. It also shows that clinical and treatment features may vary from patient to patient, even if they may present the same mutation.

FOXI3 pathogenic variants cause one form of craniofacial microsomia.

Craniofacial microsomia (CFM; also known as Goldenhar syndrome), is a craniofacial developmental disorder of variable expressivity and severity with a recognizable set of abnormalities. These birth defects are associated with structures derived from the first and second pharyngeal arches, can occur unilaterally and include ear dysplasia, microtia, preauricular tags and pits, facial asymmetry and other malformations. The inheritance pattern is controversial, and the molecular etiology of this syndrome is largely unknown. A total of 670 patients belonging to unrelated pedigrees with European and Chinese ancestry with CFM, are investigated. We identify 18 likely pathogenic variants in 21 probands (3.1%) in FOXI3. Biochemical experiments on transcriptional activity and subcellular localization of the likely pathogenic FOXI3 variants, and knock-in mouse studies strongly support the involvement of FOXI3 in CFM. Our findings indicate autosomal dominant inheritance with reduced penetrance, and/or autosomal recessive inheritance. The phenotypic expression of the FOXI3 variants is variable. The penetrance of the likely pathogenic variants in the seemingly dominant form is reduced, since a considerable number of such variants in affected individuals were inherited from non-affected parents. Here we provide suggestive evidence that common variation in the FOXI3 allele in trans with the pathogenic variant could modify the phenotypic severity and accounts for the incomplete penetrance.

Further case of enlarged spinal nerve roots in KRAS-related Noonan syndrome.

Noonan syndrome (NS) belongs to RASopathies, a family of disorders caused by unregulated signaling through the RAS-MAPK pathway. Herein, we report on an individual with molecularly confirmed diagnosis of NS showing asymptomatic enlarged spinal nerve roots, which are distinctive features of neurofibromatosis type 1. To date, a total of 16 patients with neurogenic tumors resembling neurofibromas/schwannomas and a molecularly confirmed diagnosis of a non-NF1 RASopathy have been reported, adding this further feature shared among RASopathies.

Mosaic genome-wide paternal uniparental disomy after discordant results from primary fetal samples and cultured cells.

Mosaic genome-wide paternal uniparental disomy (GWpUPD) is a rare condition in which two euploid cell lines coexist in the same individual, one with biparental content and one with genome-wide paternal isodisomy. We report a complex prenatal diagnosis with discordant results from cultured and uncultured samples. A pregnant woman was referred for placental mesenchymal dysplasia and fetal omphalocele. Karyotype, array-CGH and Beckwith-Wiedemann Syndrome (BWS) testing (methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) of 11p15) performed on amniocytes were negative. After intrauterine fetal demise, the clinical suspicion persisted and BWS MS-MLPA was repeated on cultured cells from umbilical cord and amniotic fluid, revealing a mosaicism for KvH19 hypermethylation/KCNQ1OT1:TSS:DMR hypomethylation. These results, along with microsatellite analysis of the BWS region, were consistent with mosaic paternal 11p15 isodisomy. A concurrent maternal contamination exclusion test, analyzing polymorphic microsatellite markers on multiple chromosomes, showed an imbalance in favor of paternal alleles at all examined loci on cultured amniocytes and umbilical cord samples. This led to suspicion of mosaic GWpUPD, later confirmed by SNP-array, identifying a mosaic genome-wide paternal isodisomy affecting 60% of fetal cells. The assessment of mosaic GWpUPD requires multiple approaches beyond the current established diagnostic processes, also entertaining possible low-rate mosaicism. Clinical acumen and an integrated testing approach are the key to a successful diagnosis.