Imatinib, a New Adjuvant Medical Treatment for Multifocal Villonodular Synovitis Associated to Noonan Syndrome: A Case Report and Literature Review

Noonan syndrome (NS) is an autosomal dominant multisystem disorder caused by the dysregulation of the Rat Sarcoma/Mitogen-activated protein kinase (RAS/MAPK) pathway and characterized by short stature, heart defects, pectus excavatum, webbed neck, learning disabilities, cryptorchidism, and facial dysmorphia. Villonodular synovitis is a joint disorder most common in young adults characterized by an abnormal proliferation of the synovial membrane. Multifocal Villonodular synovitis is a rare disease whose recurrent nature can make its management particularly difficult. Currently, there is no systemic therapy recommended in diffuse and recurrent forms, especially because of the fear of long-term side effects in patients, who are usually young. Yet, tyrosine kinase inhibitors seem promising to reduce the effects of an aberrant colony stimulating factor-1 (CSF-1) production at the origin of the synovial nodule proliferation. We present here the case of a 21-year-old woman with NS associated to diffuse multifocal villonodular synovitis (DMVS). Our clinical case provides therapeutic experience in this very rare association. Indeed, in association with surgery, the patient improved considerably: she had complete daily life autonomy, knee joint amplitudes of 100° in flexion and 0° in extension and was able to walk for 10 min without any technical assistance. To our knowledge, this is the first case of a patient suffering from DMVS associated with a Noonan syndrome treated with Glivec® (oral administration at a dosage of 340 mg/m2 in children, until disease regression) on a long-term basis.

Noonan syndrome and pregnancy outcomes

Background: Noonan syndrome is a genetic disorder with high prevalence of congenital heart defects, such as pulmonary stenosis, atrial septal defect and hypertrophic cardiomyopathy. Scarce data exists regarding the safety of pregnancy in patients with Noonan syndrome, particularly in the context of maternal cardiac disease. Study design: We performed a retrospective chart review of patients at Yale-New Haven Hospital from 2012 to 2020 with diagnoses of Noonan syndrome and pregnancy. We analysed medical records for pregnancy details and cardiac health, including echocardiograms to quantify maternal cardiac dysfunction through measurements of pulmonary valve peak gradient, structural heart defects and interventricular septal thickness. Results: We identified five women with Noonan syndrome (10 pregnancies). Three of five patients had pulmonary valve stenosis at the time of pregnancy, two of which had undergone cardiac procedures. 50% of pregnancies (5/10) resulted in pre-term birth. 80% (8/10) of all deliveries were converted to caesarean section after a trial of labour. One pregnancy resulted in intra-uterine fetal demise while nine pregnancies resulted in the birth of a living infant. 60% (6/10) of livebirths required care in the neonatal intensive care unit. One infant passed away at 5 weeks of age. Conclusions: The majority of mothers had pre-existing, though mild, heart disease. We found high rates of prematurity, conversion to caesarean section, and elevated level of care. No maternal complications resulted in long-term morbidity. Our study suggests that women with Noonan syndrome and low-risk cardiac lesions can become pregnant and deliver a healthy infant with counselling and risk evaluation.

Postoperative Pulmonary Hemodynamics and Systemic Inflammatory Response in Pediatric Patients Undergoing Surgery for Congenital Heart Defects

There is scarce information about the relationships between postoperative pulmonary hemodynamics, inflammation, and outcomes in pediatric patients with congenital cardiac communications undergoing surgery. We prospectively studied 40 patients aged 11 (8–17) months (median with interquartile range) with a preoperative mean pulmonary arterial pressure of 48 (34–54) mmHg who were considered to be at risk for postoperative pulmonary hypertension. The immediate postoperative pulmonary/systemic mean arterial pressure ratio (PAP/SAPIPO, mean of first 4 values obtained in the intensive care unit, readings at 2-hour intervals) was correlated directly with PAP/SAP registered in the surgical room just after cardiopulmonary bypass ( r = 0.68 , p < 0.001 ). For the entire cohort, circulating levels of 15 inflammatory markers changed after surgery. Compared with patients with PAP / SA P IPO ≤ 0.40 ( n = 22 ), those above this level ( n = 18 ) had increased pre- and postoperative serum levels of granulocyte colony-stimulating factor ( p = 0.040 ), interleukin-1 receptor antagonist ( p = 0.020 ), interleukin-6 ( p = 0.003 ), and interleukin-21 ( p = 0.047 ) (panel for 36 human cytokines) and increased mean platelet volume ( p = 0.018 ). Using logistic regression analysis, a PAP / SA P IPO > 0.40 and a heightened immediate postoperative serum level of macrophage migration inhibitory factor (quartile analysis) were shown to be predictive of significant postoperative cardiopulmonary events (respective hazard ratios with 95% CIs, 5.07 (1.10–23.45), and 3.29 (1.38–7.88)). Thus, the early postoperative behavior of the pulmonary circulation and systemic inflammatory response are closely related and can be used to predict outcomes in this population.

Accuracy of Heart Auscultation Examination by General Practitioners From Various Levels of Competency in Detection of Heart Abnormality in Basic School Children

Background. Most of heart defects in children do not show typical clinical symptoms. Ten percent of the cases are late detected. Echocardiography is an examination with high sensitivity and specificity in detecting heart defects in children, but it cannot be performed by all health workers, expensive and not always available in hospitals. Auscultation is an important part of a physical examination that inexpensive, easy examination, and becomes a competency of all doctors. The aim of this study to determine the accuracy of the screening method by listening to murmurs on heart auscultation by various levels of physician competence. Methods. This is a diagnostic test of 250 elementary school children held in the pediatric ward of dr. Mohammad Hoesin Palembang from September to November 2019. The auscultation examination was performed by three pediatrics resident from three stages (i.e. junior, middle and senior), followed by echocardiography examinations by a pediatric cardiologist. Results. The highest sensitivity of auscultation was found in senior resident, 42.4%, while the lowest was found in junior resident, 12.1%. The results of the kappa analysis of the cardiac auscultation examination on the three examiners showed a poor level of agreement on junior stage compared to senior resident (k = 0.189; CI = 0.033-0.346) and the level of agreement was sufficient in junior stage compared to middle stage resident (k = 0.297; CI = 0.134 -0.461) and middle stage compared to senior resident (k = 0.301; CI = 0.147-0.456). Conclusion. Experience and length of learning will affect the accuracy of the auscultation examination in detecting heart defects in children.

Ellis van Creveld syndrome: An unusual presentation at birth

Ellis Van Creveld, a syndrome comprising of chondrodysplasia, bilateral polydactyly of the hands with skeletal abnormalities, and congenital heart defect is a rare autosomal recessive disease. The prevalence of the disease in the world is 1/6000–20,000 newborns. In the Indian population, it is difficult to estimate the exact prevalence of the disease but, it is mostly seen in the Amish population. The cardinal features are short stature, dysplastic nails and teeth, polydactyly, narrow chest, and heart defects. The crucial differentials are Jeune dystrophy, Weyers syndrome, and McKusick-Kaufman syndrome. Here, we report a neonate, born of a non-consanguineous marriage with a syndromic appearance consisting of a bell-shaped chest, polydactyly, natal teeth, and single atrium. Prognosis is related to respiratory and heart defects in the early neonatal period.

Tunable Blood Shunt for Neonates With Complex Congenital Heart Defects

Despite advancements in procedures and patient care, mortality rates for neonatal recipients of the Norwood procedure, a palliation for single ventricle congenital malformations, remain high due to the use of a fixed-diameter blood shunt. In this study, a new geometrically tunable blood shunt was investigated to address limitations of the current treatment paradigm (e.g., Modified Blalock-Taussig Shunt) by allowing for controlled modulation of blood flow through the shunt to accommodate physiological changes due to the patient’s growth. First, mathematical and computational cardiovascular models were established to investigate the hemodynamic requirements of growing neonatal patients with shunts and to inform design criteria for shunt diameter changes. Then, two stages of prototyping were performed to design, build and test responsive hydrogel systems that facilitate tuning of the shunt diameter by adjusting the hydrogel’s degree of crosslinking. We examined two mechanisms to drive crosslinking: infusion of chemical crosslinking agents and near-UV photoinitiation. The growth model showed that 15–18% increases in shunt diameter were required to accommodate growing patients’ increasing blood flow; similarly, the computational models demonstrated that blood flow magnitudes were in agreement with previous reports. These target levels of diameter increases were achieved experimentally with model hydrogel systems. We also verified that the photocrosslinkable hydrogel, composed of methacrylated dextran, was contact-nonhemolytic. These results demonstrate proof-of-concept feasibility and reflect the first steps in the development of this novel blood shunt. A tunable shunt design offers a new methodology to rebalance blood flow in this vulnerable patient population during growth and development.

Association of Alcohol Use Diagnostic Codes in Pregnancy and Offspring Conotruncal and Endocardial Cushion Heart Defects

Background The pathogenesis of congenital heart disease (CHD) remains largely unknown, with only a small percentage explained solely by genetic causes. Modifiable environmental risk factors, such as alcohol, are suggested to play an important role in CHD pathogenesis. We sought to evaluate the association between prenatal alcohol exposure and CHD to gain insight into which components of cardiac development may be most vulnerable to the teratogenic effects of alcohol. Methods and Results This was a retrospective analysis of hospital discharge records from the California Office of Statewide Health Planning and Development and linked birth certificate records restricted to singleton, live‐born infants from 2005 to 2017. Of the 5 820 961 births included, 16 953 had an alcohol‐related International Classification of Diseases , Ninth and Tenth Revisions (ICD‐9; ICD‐10 ) code during pregnancy. Log linear regression was used to calculate risk ratios (RR) for CHD among individuals with an alcohol‐related ICD ‐9 and ICD10 code during pregnancy versus those without. Three models were created: (1) unadjusted, (2) adjusted for maternal demographic factors, and (3) adjusted for maternal demographic factors and comorbidities. Maternal alcohol‐related code was associated with an increased risk for CHD in all models (RR, 1.33 to 1.84); conotruncal (RR, 1.62 to 2.11) and endocardial cushion (RR, 2.71 to 3.59) defects were individually associated with elevated risk in all models. Conclusions Alcohol‐related diagnostic codes in pregnancy were associated with an increased risk of an offspring with a CHD, with a particular risk for endocardial cushion and conotruncal defects. The mechanistic basis for this phenotypic enrichment requires further investigation.