Juvenile myelomonocytic leukaemia and Noonan syndrome.

BACKGROUND: Infants with Noonan syndrome (NS) are predisposed to developing juvenile myelomonocytic leukaemia (JMML) or JMML-like myeloproliferative disorders (MPD). Whereas sporadic JMML is known to be aggressive, JMML occurring in patients with NS is often considered as benign and transitory. However, little information is available regarding the occurrence and characteristics of JMML in NS. METHODS AND RESULTS: Within a large prospective cohort of 641 patients with a germline PTPN11 mutation, we identified MPD features in 36 (5.6%) patients, including 20 patients (3%) who fully met the consensus diagnostic criteria for JMML. Sixty percent of the latter (12/20) had severe neonatal manifestations, and 10/20 died in the first month of life. Almost all (11/12) patients with severe neonatal JMML were males. Two females who survived MPD/JMML subsequently developed another malignancy during childhood. Although the risk of developing MPD/JMML could not be fully predicted by the underlying PTPN11 mutation, some germline PTPN11 mutations were preferentially associated with myeloproliferation: 10/48 patients with NS (20.8%) with a mutation in codon Asp61 developed MPD/JMML in infancy. Patients with a p.Thr73Ile mutation also had more chances of developing MPD/JMML but with a milder clinical course. SNP array and whole exome sequencing in paired tumoral and constitutional samples identified no second acquired somatic mutation to explain the occurrence of myeloproliferation. CONCLUSIONS: JMML represents the first cause of death in PTPN11-associated NS. Few patients have been reported so far, suggesting that JMML may sometimes be overlooked due to early death, comorbidities or lack of confirmatory tests.

Outcomes in children with Noonan syndrome and hypertrophic cardiomyopathy: a study from the Pediatric Cardiomyopathy Registry.

BACKGROUND: Studies of cardiomyopathy in children with Noonan syndrome (NS) have been primarily small case series or cross-sectional studies with small or no comparison groups. METHODS: We used the Pediatric Cardiomyopathy Registry database to compare the survival experience of children with NS and hypertrophic cardiomyopathy (HCM) with children with idiopathic or familial HCM and to identify clinical and echocardiographic predictors of clinical outcomes. RESULTS: Longitudinal data in 74 children with NS and HCM and 792 children with idiopathic or familial isolated HCM were compared. Children with NS were diagnosed with HCM before 6 months old more often (51%) than children with HCM (28%) and were more likely to present with congestive heart failure (CHF) (24% vs 9%). The NS cohort had lower crude survival than the group with other HCM (P = .03), but survival did not differ after adjustment for CHF and age at diagnosis. Within the NS cohort (1-year survival 78%), a diagnosis of HCM before age 6 months with CHF resulted in 31% 1-year survival. Lower height-for-age z score (hazard ratio 0.26, P = .005) in place of CHF and lower left ventricular fractional shortening z score (hazard ratio 0.79, P = .04) also independently predicted mortality. CONCLUSIONS: Patients with NS with HCM have a worse risk profile at presentation compared with other children with HCM, resulting in significant early mortality (22% at 1 year). Decreased height-for-age and lower, although still supranormal, left ventricular fractional shortening z score are independent predictors of mortality in patients with NS with HCM. Such patients should have an aggressive therapeutic approach including potential listing for cardiac transplantation.

Early Outcomes of Cardiac Surgery in Patients with Noonan Syndrome.

There is a paucity of cardiac surgery outcomes data for patients with Noonan syndrome (NS). Our objective was to evaluate early results in these patients. Between January 1999 and December 2015, 29 patients (18 males, 62%) with NS underwent cardiac surgery at our institution. Mean age was 23 ± 17.9 years; 12 (41%) were under 18 years of age. Fourteen patients (48%) had prior sternotomies. The primary operations for the main diagnosis were pulmonary valve/conduit replacement/repair (n = 14, 48%), septal myectomy for obstructive hypertrophic cardiomyopathy (n = 7, 24%), aortic valve replacement/repair (n = 4, 14%), atrial septal defect (ASD) repair (n = 2, 7%), and cardiac transplantation (n = 2, 7%). Concomitant procedures were performed in 24 patients (83%), most commonly right ventricular outflow tract reconstruction (n = 13, 45%), mitral valve repair/replacement (n = 7, 24%), and ASD repair (n = 6, 21%). Mean bypass and cross-clamp times were 88.8 ± 51 minutes and 54.7 ± 67 minutes, respectively. There was 1 early death (3%). Postoperative morbidity occurred in 18 patients (62%), most commonly arrhythmias (n = 14, 48%) or respiratory insufficiency/pneumonia (n = 6, 21%). There were 2 early reoperations and 4 early readmissions. Univariate factors associated with morbidity included male gender (P = 0.03) and longer cross-clamp time (P = 0.02). Median length of hospital stay was 6 days (interquartile range 5-10.5 days). Patients with NS frequently have multiple cardiac lesions requiring a broad spectrum of operations. Early mortality is low despite procedure complexity. Although early postoperative morbidity is common, patients overall do well with reasonable hospital lengths of stay. Additional studies are needed to evaluate long-term outcomes and quality of life.

New Noonan syndrome model mice with RIT1 mutation exhibit cardiac hypertrophy and susceptibility to ß-adrenergic stimulation-induced cardiac fibrosis.

BACKGROUND: Noonan syndrome (NS) is a genetic disorder characterized by short stature, a distinctive facial appearance, and heart defects. We recently discovered a novel NS gene, RIT1, which is a member of the RAS subfamily of small GTPases. NS patients with RIT1 mutations have a high incidence of hypertrophic cardiomyopathy and edematous phenotype, but the specific role of RIT1 remains unclear. METHODS: To investigate how germline RIT1 mutations cause NS, we generated knock-in mice that carried a NS-associated Rit1 A57G mutation (Rit1A57G/+). We investigated the phenotypes of Rit1A57G/+ mice in fetal and adult stages as well as the effects of isoproterenol on cardiac function in Rit1A57G/+ mice. FINDINGS: Rit1A57G/+ embryos exhibited decreased viability, edema, subcutaneous hemorrhage and AKT activation. Surviving Rit1A57G/+ mice had a short stature, craniofacial abnormalities and splenomegaly. Cardiac hypertrophy and cardiac fibrosis with increased expression of S100A4, vimentin and periostin were observed in Rit1A57G/+ mice compared to Rit1+/+ mice. Upon isoproterenol stimulation, cardiac fibrosis was drastically increased in Rit1A57G/+ mice. Phosphorylated (at Thr308) AKT levels were also elevated in isoproterenol-treated Rit1A57G/+ hearts. INTERPRETATION: The A57G mutation in Rit1 causes cardiac hypertrophy, fibrosis and other NS-associated features. Biochemical analysis indicates that the AKT signaling pathway might be related to downstream signaling in the RIT1 A57G mutant at a developmental stage and under ß-adrenergic stimulation in the heart. FUND: The Grants-in-Aid were provided by the Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development, the Japan Society for the Promotion of Science KAKENHI Grant.

Long-term results of the modified Konno procedure in high-risk children with obstructive hypertrophic cardiomyopathy.

OBJECTIVE: Transaortic septal myectomy is the gold standard surgery in obstructive hypertrophic cardiomyopathy, but it is not optimal for children aged less than 5 years and with right ventricular outflow tract obstruction. We evaluated outcomes with the modified Konno procedure in children with severe forms of obstructive hypertrophic cardiomyopathy. METHODS: A total of 79 consecutive children who underwent the modified Konno procedure in our center between 1991 and 2016 were included. RESULTS: Clinical features included age less than 5 years (38%), maximal septal thickness 25 mm or more (32%), extension to the left ventricular apex (29%), and right ventricular outflow tract obstruction (28%). In total, 25% of patients had Noonan syndrome. Five children (6%) aged less than 15 months with Noonan syndrome and biventricular obstruction died in the hospital. Mean follow-up was 6 ± 5.7 years. Survival without death and heart transplantation was 82% at 20 years. Atrioventricular block occurred in 9 patients (11%) and was associated with right ventricular outflow tract obstruction and surgery before 2010. Death, resuscitated sudden cardiac death, and appropriate implantable defibrillator shock were associated with maximal septal thickness before surgery (adjusted odds ratio, 1.20; 95% confidence interval, 1.07-1.35; P = .002) and need for an associated procedure (adjusted odds ratio, 8.84; 95% confidence interval, 2.01-38.93; P = .004). There was no case of recurrent obstruction. Reoperation was required in 4 patients (5%) for other reasons. CONCLUSIONS: The modified Konno procedure provided durable obstruction relief and good long-term survival in children with severe forms of obstructive hypertrophic cardiomyopathy. Children with Noonan syndrome undergoing surgery early in life were at higher risk of early mortality.

Cardiac defects, morbidity and mortality in patients affected by RASopathies. CARNET study results.

BACKGROUND: RASopathies are developmental disease caused by mutations in genes encoding for signal transducers of the RAS-MAPK cascade. The aim of the present study was to provide a comprehensive description of morbidity and mortality in patients with molecularly confirmed RASopathy. METHODS: A multicentric, observational, retrospective study was conducted in seven European cardiac centres participating to the CArdiac Rasopathy NETwork (CARNET). Clinical records of 371 patients with confirmed molecular diagnosis of RASopathy were reviewed. Mortality was described as crude mortality, cumulative survival and restricted estimated mean survival. Multivariable regression analysis was used to assess the impact of mutated genes on number of interventions and overall prognosis. RESULTS: Cardiac defects occurred in 80.3% of cases, almost half of them underwent at least one intervention. Overall, crude mortality was 0.29/100 patients-year. Cumulative survival was 98.8%, 98.2%, 97.7%, 94.3%, at 1, 5, 10, and 20years, respectively. Restricted estimated mean survival at 20years follow-up was 19.6years. Ten patients died (2.7% of the entire cohort; 3.4% of patients with cardiac defect). Patients with hypertrophic cardiomyopathy (HCM) and age <2years or young adults, as well as subjects with biventricular obstruction and PTPN11 mutations had a higher risk of cardiac death. CONCLUSIONS: The risk of intervention was higher in individuals with Noonan syndrome and pulmonary stenosis carrying PTPN11 mutations. Overall, mortality was relatively low, even though the specific association between HCM, biventricular outflow tract obstructions and PTPN11 mutations appeared to be associated with early mortality, including immediate post-operative events and sudden death.

A regional study of presentation and outcome of hypertrophic cardiomyopathy in infants.

OBJECTIVE: To describe regional incidence, presentation, and outcome of idiopathic (familial) and Noonan syndrome related infant hypertrophic cardiomyopathy (HCM) between 1969 and 1994. DESIGN: Case series. SETTING: Regional cardiac referral unit of the South West Region of England and south Wales, population approximately four million. PATIENTS: 21 cases of idiopathic (or familial) HCM, and eight infants with Noonan syndrome. MAIN OUTCOME MEASURES: Survival and persistence or resolution of symptoms or cardiac hypertrophy. RESULTS: Incidence: eight cases between 1969 and 1982 (idiopathic 6, Noonan 2), 21 cases between 1982 to 1994 (idiopathic 15, Noonan 6). Mode of presentation: cardiac failure, 17 (59%); murmur, 9 (30%); cyanosis, 2 (7%); family history, 1 (7%). Age at presentation: 0-7 days, 16 (55%); 8 days-4 months, 9 (31%); 5-12 months, 4 (14%). OUTCOME: five deaths (17%), all < 1 year, all from progressive cardiac failure (idiopathic 3, Noonan 2). Four of these five had not received beta blockade. Among the 24 survivors (follow up 1.3-23.2 years, median 5.5 years) hypertrophy had resolved in nine (38%) (idiopathic 8, Noonan 1), was mild and asymptomatic in seven (29%), and was symptomatic or severe in eight (33%). All 10 infants presenting with septal thickness > 1.3 cm have persistent cardiac hypertrophy. CONCLUSIONS: Mortality in infant HCM is much lower than previously reported and resolution is more frequent. This may reflect increased detection of less severe forms in addition to the success of aggressive medical management including beta blockade.

Cardiac findings in Noonan syndrome on long-term follow-up.

OBJECTIVE: Noonan syndrome (NS) is the second most common genetic syndrome associated with cardiac abnormalities, including, most notably, pulmonary stenosis (PS) and hypertrophic cardiomyopathy (HCM). Little is known about the natural history of heart disease in this unique subset of patients. We sought to contribute information on the natural history of NS by looking at how the cardiac disease progresses with time. DESIGN: This is a retrospective review of the medical records of patients with NS seen at our institution between 1963 and 2011. RESULTS: Records were available for 113 patients. Average length of follow-up was 14.16 years (2 months to 44 years, median 12.5 years). Sixty-six percent (75/113) of our patients had PS; within this subset, 57% (43) were classified as mild, 9% (7) moderate, and 33% (25) severe. None of the cases of mild PS worsened with time. All of the severe cases had an intervention, as did some moderate cases. Fourteen percent (16/113) of our patients had HCM; 56% (9/16) were mild, diagnosed at an average age of 3.8 years. Seven of these were stable with time, while one did progress. Forty-four percent (7/16) of cases were classified as severe, diagnosed at an average age of 4.2 months, and all were managed medically, surgically, or both. Our cohort had seven deaths (ages 6 months and 6, 10, 20, 40, 49, and 50 years). CONCLUSION: Mild PS in patients with NS is nonprogressive. Severe, and in some cases moderate, PS will invariably require a therapeutic intervention. It is uncommon for HCM to progress or have new onset beyond early childhood. Prognosis of heart disease in NS is influenced most by the findings on presentation.

Survival implications: hypertrophic cardiomyopathy in Noonan syndrome.

OBJECTIVES: To understand relationships and survival implications between structural heart disease and hypertrophic cardiomyopathy in Noonan syndrome (Noonan syndrome-HCM), we reviewed the clinical course of 138 children with Noonan syndrome diagnosed with cardiovascular abnormalities and compared survival with the 30 children with Noonan syndrome-HCM with 120 contemporaneous children with nonsyndromic HCM. METHODS: Study cohorts represent consecutive cases diagnosed at our institution 1966 through 2006. Outcomes were modeled using multiphase parametric techniques followed by multivariable regression with bagging. RESULTS: Cardiac abnormalities in Noonan syndrome: Cardiac abnormalities in the 138 Noonan syndrome children included pulmonary valve dysplasia (52%), hypertrophic cardiomyopathy (22%), atrial septal defect (20%), ventricular septal defect (10%), mitral valve dysplasia (6%), coarctation (3%), and Fallot's tetralogy (2%). Need for surgery was high but not different from children with structural defects coexisting with HCM. Overall, late survival in children with Noonan syndrome and cardiac defects was good (91 ± 3% at 15 years), although significantly worse for those with Noonan syndrome-HCM (P < .01). Noonan syndrome-HCM vs. nonsyndromic HCM: In the 30 children with Noonan syndrome-HCM, structural cardiac malformations coexisted in 18 (57%). The incidence of structural cardiac malformations in nonsyndromic HCM was instead 3/120 (2.5%, P < .001). Risk-adjusted late survival was significantly worse for Noonan syndrome-HCM than for nonsyndromic HCM (P= .02). CONCLUSIONS: Noonan syndrome-HCM frequently coexists with structural cardiac malformations, whereas nonsyndromic HCM does not; their natural histories may therefore be different. Late survival is significantly worse for Noonan syndrome-HCM than nonsyndromic HCM.

Use of terbutaline in the treatment of complete heart block in the fetus.

Between 1989 and 2000, 21 fetuses were diagnosed with complete atrioventricular block. Seven women with fetal ventricular rates of less than 60 were given oral terbutaline, and 6 of these had an initial increase in the fetal ventricular rate. Four fetuses (57%) maintained an increased average rate of 60 beats per minute and survived. Two fetuses returned to rates below 55 and died. The final fetus, with hypertrophic cardiomyopathy, was unresponsive. Terbutaline, therefore, is initially effective in raising the fetal ventricular rate, but this effect may be transient.