Indocyanine green (ICG) fluorescence technology in pediatric robotic surgery.

This study aimed to report our experience in indocyanine green (ICG) fluorescence-guided surgery (FGS) in pediatric robotics. The data of 55 patients (35 boys and 20 girls), who underwent robotic surgery using ICG fluorescence in three institutions over the last 7 years, were retrospectively reviewed. The following robotic procedures were included: pyeloplasty (n = 21), complex Lich-Gregoir ureteral reimplantation (n = 8), varicocelectomy (n = 7), adnexal pathology resection (n = 8), partial nephrectomy (n = 4), nephrectomy (n = 4), renal cyst removal (n = 2), and excision of prostatic utricle (n = 1). The ICG was injected intravenously in all indications except for varicocele where intratesticular injection was done, and prostatic utricle or paraureteral diverticulum where trans-catheter injection was done. The ICG dosage was 0.2-0.3 mg/mL/kg. All the procedures were performed using da Vinci Xi platform. Firefly® allowed to switch form bright light to ICG-NIRF view and vice versa. All the procedures were accomplished in robotics without conversions to laparoscopy or open surgery. No episodes of allergy or anaphylaxis to ICG were recorded. An excellent ICG-NIRF view of target organs was obtained in all procedures. Based on our experience, we believe that application of ICG FGS in pediatric robotics enhances the identification of critical anatomical elements and pathological structures, thereby positively impacting both oncological and functional outcomes. This technique is safe, feasible, and versatile. We advocate the consideration of ICG as the standard of care in certain procedures such as partial nephrectomy, varicocele repair, tumor resection, and ovarian torsion. Nonetheless, further investigations are warranted to explore its potential broader applications in pediatric urology.

Endoscopic Treatment of Pilonidal Sinus Disease in Children: A Systematic Review.

Background: Pilonidal sinus disease (PSD) is a common inflammatory disease. PSD management in pediatric patients changed dramatically in the last few years especially when concerning the latest minimally invasive techniques. This article aims to identify clinical evidence about the reliability of the different techniques in managing PSD in children. Materials and Methods: We performed a PubMed search for articles published during the last 10 years, using the keywords "pilonidal," "sinus," "disease," "pediatric," "surgery," and "children." Results: We pooled 38 studies, 18 of these were excluded because they were either not relevant or concerned an adult population. Conclusions: Literature analysis shows that endoscopic techniques for PSD are superior to excision and primary closure (EPC) in terms of tolerance and postoperative conditions and, with the growing number of studies in the matter, important endpoints such as wound healing time and length of hospital stay will be proved to be superior. Pediatric Endoscopic pilonidal disease treatment showed to be a very promising alternative even from a statistical point of view, especially when considered that in this group, studies seemed to be more solid. Literature analysis showed that minimally invasive techniques were statistically superior to EPC in terms of recurrence and complications.

Robotic-assisted pyeloplasty in children: a systematic review of the literature.

Robotic pyeloplasty has become a natural progression from the development of open, then laparoscopic procedures to treat pediatric patients with ureteropelvic junction obstruction (UPJO). Robotic-assisted pyeloplasty (RALP) is now considered a new gold standard in pediatric MIS. A systematic review of the literature retrieved from PubMed and published in the last 10 years (2012-2022) was performed. This review underlines that in all children except the smallest infants, where the open procedure has benefits in terms of duration of general anesthetic and there are limitations in the size of instruments, robotic pyeloplasty is becoming the preferred procedure to perform in patients with UPJO. Results for the robotic approach are extremely promising, with shorter operative times than laparoscopy and equal success rates, length of stay and complications. In case of redo pyeloplasty, RALP is easier to perform than other open or MIS procedures. By 2009, robotic surgery became the most used modality to treat all UPJO and continues to grow in popularity. Robot-assisted laparoscopic pyeloplasty in children is safe and effective with excellent outcomes, even in redo pyeloplasty or challenging anatomical cases. Moreover, robotic approach shortens the learning curve for junior surgeons, who can readily achieve levels of expertise comparable to senior practitioners. However, there are still concerns regarding the cost associated with this procedure. Further high-quality prospective observational studies and clinical trials, as well as new technologies specific for the pediatric population, are advisable for RALP to reach the level of gold standard.

Quality of life of pediatric patients operated for pilonidal sinus disease.

Quality of life (QOL) outcome is an ideal method for determining the efficacy of a surgical treatment. In children operated for pilonidal sinus disease (PSD), open procedures imply prolonged wound care, significant morbidity, and high recurrence rates. Endoscopic treatment (PEPSIT) overcomes these limitations. We report our experience in the management of PSD to evaluate the QOL of patients undergoing open and endoscopic treatment. The records of 177 patients undergoing surgery for PSD from 2008 to 2021 were retrospectively reviewed. Twenty patients were operated with open surgery (G1) and 157 with PEPSIT (G2). We analyzed QOL through the following criteria: hospital stay (HS), healing time (HT), return to sport (RTSp), return to school (RTSc), resumption of social life (RSL), and recurrence rate and reoperation (RRR). Moreover, we used Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) for a more subjective evaluation of life satisfaction. We found significant differences in all the analyzed criteria: HS varied from 3 to 7 days in G1 and from 1 to 2 days in G2; HT from 40 to 75 days in G1 while from 20 to 41 days in G2; RTSp from 50 to 80 days in G1 while from 7 to 21 days in G2; RTSc from 9 to 15 days in G1 while from 2 to 4 days in G2; RSL from 13 to 20 days in G1 while from 2 to 5 days in G2; RRR was 25% in G1 and 4.4% in G2. CONCLUSION: Endoscopic treatment (PEPSIT) significantly improves the quality of life of patients operated for PSD. Compared to open surgery, PEPSIT presents shorter hospital stay, faster healing time, return to sport activities, return to school and resumption of a normal social life, and lower rates of recurrence and reoperation. In addition, PQ-LES-Q demonstrated a good overall quality of life and life satisfaction. Further prospective studies should be obtained to consider PEPSIT as the gold standard for the treatment of PSD in pediatric patients. WHAT IS KNOWN: • Many techniques have been proposed in the last 20 years for the surgical treatment of PSD. • PEPSIT is showing promising results in terms of safety and long-term efficacy. WHAT IS NEW: • The main impact in QOL of patients operated with PEPSIT is on their daily activity, including a shorter hospital stay, faster healing time, return to sport activities, return to school and resumption of a normal social life, lower rates of recurrence and reoperation. • After PEPSIT, children maintain a satisfactory quality of life according to the analysis of PQ-LES-Q.

Repurposing Histaminergic Drugs in Multiple Sclerosis.

Multiple sclerosis is an autoimmune disease with a strong neuroinflammatory component that contributes to severe demyelination, neurodegeneration and lesions formation in white and grey matter of the spinal cord and brain. Increasing attention is being paid to the signaling of the biogenic amine histamine in the context of several pathological conditions. In multiple sclerosis, histamine regulates the differentiation of oligodendrocyte precursors, reduces demyelination, and improves the remyelination process. However, the concomitant activation of histamine H1-H4 receptors can sustain either damaging or favorable effects, depending on the specifically activated receptor subtype/s, the timing of receptor engagement, and the central versus peripheral target district. Conventional drug development has failed so far to identify curative drugs for multiple sclerosis, thus causing a severe delay in therapeutic options available to patients. In this perspective, drug repurposing offers an exciting and complementary alternative for rapidly approving some medicines already approved for other indications. In the present work, we have adopted a new network-medicine-based algorithm for drug repurposing called SAveRUNNER, for quantifying the interplay between multiple sclerosis-associated genes and drug targets in the human interactome. We have identified new histamine drug-disease associations and predicted off-label novel use of the histaminergic drugs amodiaquine, rupatadine, and diphenhydramine among others, for multiple sclerosis. Our work suggests that selected histamine-related molecules might get to the root causes of multiple sclerosis and emerge as new potential therapeutic strategies for the disease.

Laparoscopic Partial Nephrectomy for Duplex Kidneys in Infants and Children: How We Do It.

Duplication anomalies of the kidney represent common congenital malformations of the urinary tract. A duplex kidney has often one pole that is poorly or nonfunctioning. In this last case, surgery may be indicated to remove the nonfunctioning pole. The most common indications for partial nephrectomy in pediatrics include symptomatic vesicoureteral reflux to the nonfunctioning pole and/or ectopic ureter or ureterocele causing urinary incontinence. In this article, we describe the technique of laparoscopic partial nephrectomy in infants and children with duplex kidney. A surgical procedure properly executed following critical technical steps is the key factor for the success of surgery.

Robotics and future technical developments in pediatric urology.

Minimally invasive surgery (MIS) has represented the main innovation in the field of pediatric surgery and urology over the last 30 years. Pediatric MIS is a wide field, ranging from the standard laparoscopic surgery using 3-mm ports to robotics mainly adopted for pediatric urology indications. The aim of this paper was to summarize the current status of robotic surgery in pediatric urology and to evaluate possible future technical developments for this technique. In pediatric urology, many procedures are challenged by the narrow working space available in smaller children, the difficulty to perform complex and long suture lines to repair complex urinary malformations, and the challenge to remove renal or adrenal tumors. The main characteristic of robotic surgery is that the robotic instruments inserted into the abdominal cavity are remotely controlled by the surgeon, who is sitting at a console next to the patient or even far away, avoiding human tremor during complex suturing. Due to the magnification of the operative field view and the six degrees of freedom of the robotic instruments compared to conventional laparoscopic instruments, providing enhanced 3D vision and improved surgeon ergonomics, robot-assisted surgery appears to be beneficial over conventional MIS, especially in complex reconstructive procedures. Currently, there are two robotic systems available on the market and certified for robotic surgery in children: the DaVinci (Intuitive Surgical, since 2001) and Senhance (Transenterix, since 2020). However, almost the totality of papers published in the international literature are focused on robotic procedures using the DaVinci platform. Analyzing the current literature, there is no evidence about the indications where robotics are preferable to conventional MIS approaches. Currently, the main indications of robotic surgery in pediatric urology are: pyeloplasty for ureteropelvic junction obstruction (UPJO), ureteral reimplantation according to Lich Gregoire technique, Mitrofanoff procedure, nephrectomy or partial nephrectomy for oncological indications, removal of renal cysts, bladder neck reconstruction or removal of urinary tract stones. The future developments in this field are certainly represented by intraoperative use of indocyanine green (ICG) fluorescence imaging that permits to have a better vision of vascular anatomy or clearly identify nodes in case of tumors, and by development of 5G technology. The main limitation of robotic surgery today remains the excessive cost of the machine itself and the limited lifespan of robotic instruments. We believe that robotic surgery will surely represent the new field of development in pediatric surgery, but its widespread application will depend on the introduction of new robotic platforms in the market, that will certainly low the costs, and also to the development of smaller size instruments more suitable for pediatric use.

Robot­Assisted Laparoscopic Extra-Vesical Ureteral Reimplantation (Ralur/Revur) for Pediatric Vesicoureteral Reflux: A Systematic Review of Literature.

This literature review aimed to assess the outcomes of robot-assisted laparoscopic extra-vesical ureteral reimplantation (RALUR/REVUR) in standard, complex and re-operative cases. Twenty-two studies (period 2008-2019) containing 1362 children receiving RALUR/REVUR, were included. Unilateral repair was faster compared to bilateral (P = .0000). The overall patient success rate was 92%. The mean post-operative complications rate was 10.7%. The mean re-operations rate was 3.9%. The available data show that RALUR/REVUR can be a first line surgical approach for pediatric vesicoureteral reflux at most centers with the caveat that learning curves for the surgeons are expected as with most new surgical procedures.

Technical standardization of ICG near-infrared fluorescence (NIRF) laparoscopic partial nephrectomy for duplex kidney in pediatric patients.

PURPOSE: This study aimed to standardize the operative technique of indocyanine green (ICG) near-infrared fluorescence (NIRF) laparoscopic partial nephrectomy (LPN) and compare it with the standard technique. METHODS: In the last 4 years, we performed 22 LPN (14 right-sided, 8 left-sided) in children with non-functioning moiety of duplex kidney. Patients included 12 girls and 10 boys with a median age of 3.9 years (range 1-10). Patients were grouped according to the use of ICG-NIRF: G1 included 12 patients operated using ICG-NIRF and G2 included 10 patients receiving the standard technique. We standardized the technique of injection of ICG in three different steps. RESULTS: The median operative time was significantly lower in G1 [87 min (range 68-110)] compared with G2 [140 min (range 70-220)] (p = 0.001). One intra-operative complication occurred in G2. At post-operative ultrasound (US), the residual moiety was normal in all patients. An asymptomatic renal cyst related to the site of surgery was visualized at US in 8/22 (36%), with a significantly higher incidence in G2 (6/10, 60%) compared with G1 (2/12, 16.6%) (p = 0.001). Renogram demonstrated no loss of function of residual moiety. No allergic reactions to ICG occurred. CONCLUSION: ICG-NIRF LPN is technically easier, quicker, and safer compared with the standard technique. The main advantages of using ICG-NIRF during LPN are the clear identification of normal ureter, vasculature of non-functioning pole, and demarcation line between the avascular and the perfused pole. The main limitation of ICG technology remains the need for specific laparoscopic equipment that is not always available.

Near-Infrared fluorescence imaging using indocyanine green (ICG): Emerging applications in pediatric urology.

BACKGROUND: Near-infrared fluorescence (NIRF) imaging with indocyanine green (ICG) has been recently adopted in pediatric minimally invasive surgery (MIS) in order to improve intra-operative visualization of anatomic structures and facilitate surgery. OBJECTIVE: This study aimed to report our preliminary experience using ICG technology in pediatric urology using laparoscopy and robotics. STUDY DESIGN: ICG technology was adopted in 57 laparoscopic or robotic urological procedures performed in our unit over a 24-month period: 41 (38 laparoscopic - 3 robotic) left varicocele repairs with intra-operative lymphography and 16 renal procedures (12 laparoscopic - 4 robotic) including 9 partial nephrectomies, 3 nephrectomies and 4 renal cyst deroofings. RESULTS: The ICG solution was injected intravenously in renal procedures or into the testis body in case of varicocele repair. Regarding the timing of the administration, the ICG injection was performed intra-operatively in all cases and allowed the visualization of the anatomic structures in a matter of 30-60 s. The dosage of ICG was 0.3 mg/mL/kg in all indications. All procedures were completed laparoscopically or robotically without conversions. No adverse and allergic reactions to ICG and other complications occurred postoperatively. DISCUSSION: This paper describes for the first time in pediatric urology that ICG-guided NIRF imaging may be helpful in laparoscopic and robotic procedures. In case of varicocele repair, ICG-enhanced fluorescence allowed to perform a lymphatic-sparing procedure and avoid the risk of postoperative hydrocele. In case of partial nephrectomy, ICG-guided NIRF was helpful to visualize the vascularization of the non-functioning moiety, identify the dissection plane between the two moieties (Fig. 1) and check the perfusion of the residual parenchyma after resection of the non-functioning pole. In case of renal cyst deroofing, ICG-guided NIRF aided to identify the avascular cyst dome and to guide its resection. No real benefits of using ICG-enhanced fluorescence were observed during nephrectomy. CONCLUSION: Our preliminary experience confirmed the safety and efficacy of ICG technology in pediatric urology and highlighted its potential advantages as adjunctive surgical technology in patients undergoing laparoscopic or robotic urological procedures. Use of NIRF was also cost-effective as no added costs were required except for the ICG dye (cost 40 eur per bottle). The most common and useful applications in pediatric urology included varicocele repair, partial nephrectomy ad renal cyst deroofing. The main limitation is the specific equipment needed in laparoscopy, that is not available in all centers whereas the robot is equipped with the Firefly® software for NIRF.

Technical standardization of MIS management of children with pilonidal sinus disease using pediatric endoscopic pilonidal sinus treatment (PEPSiT) and laser epilation.

PURPOSE: This study aimed to standardize the technique of pediatric endoscopic pilonidal sinus treatment (PEPSiT) associated with laser epilation. METHODS: All pediatric patients presenting with acute or chronic pilonidal sinus disease (PSD) who underwent PEPSiT in our institution over a 36-month period (July 2015-July 2018), were included in the study. Pre- and postoperative management, recurrence rate, postoperative pain, hospital stay, analgesic requirements, and patient satisfaction levels were evaluated. RESULTS: A total of 59 patients (23 girls and 36 boys) underwent PEPSiT during the study period. Ten/59 patients (16.9%) had recurrent PSD after open repair, and 4/59 (6.7%) presented a concomitant pilonidal cyst. All children underwent laser epilation pre- and postoperatively over the last 15 months. The average length of surgery was 27.5 min (range 20-45). The average pain score during the first 48 postoperative hours was 2.7 (range 2-5), and the average analgesic requirement was 20 h (range 16-24). The average hospitalization was 22.4 h (range 18-36). At 1 month postoperatively, external openings were healed in all patients. During follow-up, 1 recurrence (1.6%) was recorded and successfully re-treated with PEPSiT. CONCLUSIONS: We believe that PEPSiT represents the technique of choice for treatment of PSD in the pediatric population. It is crucial to standardize the technique consisting of pre- and postoperative laser epilation, PEPSiT, and accurate postoperative wound management with eosin and sulfadiazine spray. LEVEL OF EVIDENCE: Treatment study - Level IV.

Twenty-Five Year Experience with Laparoscopic Cholecystectomy in the Pediatric Population-From 10 mm Clips to Indocyanine Green Fluorescence Technology: Long-Term Results and Technical Considerations.

Background: This study aimed to review our 25-year experience with pediatric laparoscopic cholecystectomy (LC) to assess its long-term outcome. Materials and Methods: The records of 215 children (127 girls and 88 boys) who underwent LC for the past 25 years (1993-2018) were retrospectively reviewed. All patients had a symptomatic cholelithiasis. The cholelithiasis was idiopathic in 185 patients (86%) and secondary in 30 patients (14%). A four-trocar technique was always adopted and cystic duct and cystic artery were clipped using 10-mm clips in the first 35 cases (16.3%) and 5-mm clips in the following 180 patients (83.7%). In the last 15 cases, indocyanine green (ICG)-enhanced fluorescence was adopted intraoperatively for a better identification of the anatomy of gallbladder and biliary tree. Results: The average operative time was 69 minutes and fell down to 52 minutes after introduction of ICG fluorescence (P = .001). Fifteen anatomic anomalies (6.9%), involving bile duct in 5 cases and cystic artery in 10 cases, were recorded. Technical problems were reported intraoperatively in 6 cases (2.8%). We recorded 4 postoperative Clavien IIIb complications (1.9%): 1 bleeding from the cystic artery, 1 dislocation of the clips on the cystic duct, and 2 iatrogenic injuries to the main bile duct managed with choledojejunostomy in 1 case and suture of the choleducus over a stent in the second case. We also recorded 3 umbilical granulomas (1.4%) (Clavien II). Conclusions: LC is a standardized and effective procedure to perform in children. Our 25-year experience showed that major complications (Clavien IIIb) can occur even in experienced surgeons' hands. Age, weight, and preoperative cholecystitis were significantly associated with the risk of bile duct injury in our series. Considering its versatility and safety, we believe that ICG fluorescence technology may be adopted in every LC to ease the dissection and reduce the likelihood of complications.

Somatic mutations in NKX2­5, GATA4, and HAND1 are not a common cause of tetralogy of Fallot or hypoplastic left heart.

The majority of congenital heart disease (CHD) occurs as a sporadic finding, with a minority of cases associated with a known genetic abnormality. Combinations of genetic and environmental factors are implicated, with the recent and intriguing hypothesis that an apparently high rate of somatic mutations might explain some sporadic CHD. We used samples of right ventricular myocardium from patients undergoing surgical repair of tetralogy of Fallot (TOF) and hypoplastic left heart (HLH) to examine the incidence of somatic mutation in cardiac tissue. TOF is a common form of cyanotic CHD, occurring in 3.3 per 10,000 live births. HLH is a rare defect in which the left side of the heart is severely under-developed. Both are severe malformations whose genetic etiology is largely unknown. We carried out direct sequence analysis of the NKX2­5 and GATA4 genes from fresh frozen cardiac tissues and matched blood samples of nine TOF patients. Analysis of NKX2­5, GATA4, and HAND1 was performed from cardiac tissue of 24 HLH patients and three matched blood samples. No somatic or germline mutations were identified in the TOF or HLH patients. Although limited by sample size, our study suggests that somatic mutations in NKX2­5 and GATA4 are not a common cause of isolated TOF or HLH.

GATA4 mutations in 357 unrelated patients with congenital heart malformation.

Congenital heart disease (CHD) represents one of the most common birth defects, but the genetic causes remain largely unknown. Mutations in GATA4, encoding a zinc finger transcription factor with a pivotal role in heart development, have been associated with CHD in several familial cases and a small subset of sporadic patients. To estimate the pathogenetic role of GATA4 in CHD, we screened for mutations in 357 unrelated patients with different congenital heart malformations. In addition to nine synonymous changes, we identified two known (A411V and D425N) and two novel putative mutations (G69D and P163R) in five patients with atrial or ventricular septal defects that were not seen in control subjects. The four mutations did not show altered GATA4 transcriptional activity in synergy with the transcription factors NKX2-5 and TBX20. Our data expand the spectrum of mutations associated with cardiac septal defects but do not support GATA4 mutations as a common cause of CHD.

Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum.

Noonan, LEOPARD, and cardiofaciocutaneous syndromes (NS, LS, and CFCS) are developmental disorders with overlapping features including distinctive facial dysmorphia, reduced growth, cardiac defects, skeletal and ectodermal anomalies, and variable cognitive deficits. Dysregulated RAS-mitogen-activated protein kinase (MAPK) signal traffic has been established to represent the molecular pathogenic cause underlying these conditions. To investigate the phenotypic spectrum and molecular diversity of germline mutations affecting BRAF, which encodes a serine/threonine kinase functioning as a RAS effector frequently mutated in CFCS, subjects with a diagnosis of NS (N=270), LS (N=6), and CFCS (N=33), and no mutation in PTPN11, SOS1, KRAS, RAF1, MEK1, or MEK2, were screened for the entire coding sequence of the gene. Besides the expected high prevalence of mutations observed among CFCS patients (52%), a de novo heterozygous missense change was identified in one subject with LS (17%) and five individuals with NS (1.9%). Mutations mapped to multiple protein domains and largely did not overlap with cancer-associated defects. NS-causing mutations had not been documented in CFCS, suggesting that the phenotypes arising from germline BRAF defects might be allele specific. Selected mutant BRAF proteins promoted variable gain of function of the kinase, but appeared less activating compared to the recurrent cancer-associated p.Val600Glu mutant. Our findings provide evidence for a wide phenotypic diversity associated with mutations affecting BRAF, and occurrence of a clinical continuum associated with these molecular lesions.

Costello syndrome: clinical diagnosis in the first year of life.

We report on three patients with Costello syndrome (CS) diagnosed during the first year of life and try to outline the clinical characteristics facilitating early recognition of this syndrome, which can now be corroborated by testing the HRAS gene. Phenotypical overlap of CS with Noonan (NS) and cardiofaciocutaneous syndrome (CFCS), particularly in neonatal age, is well known. Diagnostic features useful for recognition of CS in the first year of life are the following: (1) fetal and neonatal macrosomia with subsequent slow growth due to severe feeding difficulties, (2) developmental delay, (3) particularly coarse facial dysmorphisms and gingival hyperplasia, (4) skeletal anomalies as osteoporosis and metaphyseal enlargement, (5) hypertrophic cardiomyopathy (HCM) with asymmetric septal thickening and systolic anterior motion of the mitral valve, and (6) specific atrial arrhythmias. Following a clinical suspect of CS based on specific features, molecular screening of HRAS gene mutations should precede analysis of the other genes in the Ras-MAPK pathway implicated in related disorders with overlapping phenotypes.

Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy.

Noonan and LEOPARD syndromes are developmental disorders with overlapping features, including cardiac abnormalities, short stature and facial dysmorphia. Increased RAS signaling owing to PTPN11, SOS1 and KRAS mutations causes approximately 60% of Noonan syndrome cases, and PTPN11 mutations cause 90% of LEOPARD syndrome cases. Here, we report that 18 of 231 individuals with Noonan syndrome without known mutations (corresponding to 3% of all affected individuals) and two of six individuals with LEOPARD syndrome without PTPN11 mutations have missense mutations in RAF1, which encodes a serine-threonine kinase that activates MEK1 and MEK2. Most mutations altered a motif flanking Ser259, a residue critical for autoinhibition of RAF1 through 14-3-3 binding. Of 19 subjects with a RAF1 mutation in two hotspots, 18 (or 95%) showed hypertrophic cardiomyopathy (HCM), compared with the 18% prevalence of HCM among individuals with Noonan syndrome in general. Ectopically expressed RAF1 mutants from the two HCM hotspots had increased kinase activity and enhanced ERK activation, whereas non-HCM-associated mutants were kinase impaired. Our findings further implicate increased RAS signaling in pathological cardiomyocyte hypertrophy.

A novel PTPN11 gene mutation bridges Noonan syndrome, multiple lentigines/LEOPARD syndrome and Noonan-like/multiple giant cell lesion syndrome.

Noonan (NS) and multiple lentigines/LEOPARD syndromes (LS) have proved to be associated with distinct PTPN11 mutations. Noonan-like/multiple giant cell lesion syndrome (NLS) is a rare disease, characterised by short stature, facial dysmorphisms, congenital heart defect (CHD) and central giant cell lesions. PTPN11 gene mutations have been reported in a single NLS family and two sporadic patients. Here we report a patient with a complex phenotype progressing throughout the years from NS at birth towards LS and NLS. PTPN11 gene analysis disclosed a novel missense mutation (Ala461Thr) in exon 12, affecting the consensus sequence of the SHP2-active site. This observation joins together NS and LS to NLS into a unique genetic defect, broadening the clinical and molecular spectrum of PTPN11-related disorders.