Peripheral Pulmonary Stenosis Research Articles

Congenital heart defects and postoperative follow-up of patients with Williams syndrome as a single center experience and review of the cases from Türkiye.

Cardiovascular system involvement is quite common and the leading cause of morbidity and mortality in patients with Williams syndrome (WS), most of whom need surgery. The present study aimed to provide a detailed evaluation of the features of surgical procedures and outcomes of patients with WS given as single-center experience, and additionally to make a detailed review from Türkiye. Thirty-five children with WS diagnosed between the years 1992 and 2021 were evaluated retrospectively including cardiovascular data, surgical treatment features, and outcomes. A total of six articles from Türkiye were evaluated. A total of 35 patients with Williams Syndrome (24 male) with a median age of cardiologic diagnosis of 6 months (range, 2 days-6 years) were evaluated. The cardiac defects of the patients with WS were found as supravalvular aortic stenosis (SVAS) (n=30, 85%) and peripheral pulmonary stenosis (PPS) (n=21, 65%). Additional cardiac anomalies were seen in 71% patients. The rate of SVAS and PPS surgery in all patients with WS was 77.1%. The median surgical age of the patients was 2.5 years (range, 7 months-15.5 years). No patients died due to surgery. But one patient died because of ventricular tachycardia due to anesthesia at the beginning of angiography. A total of 138 (63% male) patients with WS were evaluated from the articles published in Türkiye. Of 138 patients, 64.4% had SVAS, 52.1% had PPS, and 39.8% had additional cardiac anomaly. The median follow-up period ranged from 17 months to 18 years, and six (4.3%) patients died in the early postoperative period. Cardiovascular system involvement is extremely common and is the leading cause of morbidity and mortality in patients with WS, often requiring surgical intervention. As seen in our study including 35 patients with WS and in publications from Türkiye, SVAS in patients with WS generally requires surgery, especially in the first year of life. PPS, on the other hand, requires surgery less frequently than SVAS, and pulmonary stenosis appears to decrease over time.

Identification of Prostaglandin I2 Synthase Rare Variants in Patients With Williams Syndrome and Severe Peripheral Pulmonary Stenosis.

Peripheral pulmonary stenosis (PPS) is a condition characterized by the narrowing of the pulmonary arteries, which impairs blood flow to the lung. The mechanisms underlying PPS pathogenesis remain unclear. Thus, the aim of this study was to investigate the genetic background of patients with severe PPS to elucidate the pathogenesis of this condition. We performed genetic testing and functional analyses on a pediatric patient with PPS and Williams syndrome (WS), followed by genetic testing on 12 patients with WS and mild-to-severe PPS, 50 patients with WS but not PPS, and 21 patients with severe PPS but not WS. Whole-exome sequencing identified a rare PTGIS nonsense variant (p.E314X) in a patient with WS and severe PPS. Prostaglandin I2 synthase (PTGIS) expression was significantly downregulated and cell proliferation and migration rates were significantly increased in cells transfected with the PTGIS p.E314X variant-encoding construct when compared with that in cells transfected with the wild-type PTGIS-encoding construct. p.E314X reduced the tube formation ability in human pulmonary artery endothelial cells and caspase 3/7 activity in both human pulmonary artery endothelial cells and human pulmonary artery smooth muscle cells. Compared with healthy controls, patients with PPS exhibited downregulated pulmonary artery endothelial prostaglandin I2 synthase levels and urinary prostaglandin I metabolite levels. We identified another PTGIS rare splice-site variant (c.1358+2T>C) in another pediatric patient with WS and severe PPS. In total, 2 rare nonsense/splice-site PTGIS variants were identified in 2 pediatric patients with WS and severe PPS. PTGIS variants may be involved in PPS pathogenesis, and PTGIS represents an effective therapeutic target.

Alagille Syndrome: Challenging Diagnosis and Prognostic Factors, A Case Report

Alagille syndrome (AS) commonly presents with cholestasis, much like other liver diseases, making the diagnosis challenging. We report a case of a patient with AS mimicking biliary atresia (BA) with a poor outcome. The infant, a product of a non-consanguineous marriage, presented with jaundice, clay stools, peripheral pulmonary stenosis, atrial septal defect, and butterfly vertebrae. Cholescintigraphy showed an absence of radiotracer excretion. Surgical exploration revealed the presence of a hypoplastic hepatic duct but a normal gallbladder, cystic, and common bile ducts. Intraoperative cholangiogram favored BA, and a Kasai procedure was performed. The liver biopsy demonstrated focal areas of ductular proliferation and periportal ballooning degeneration without bile duct paucity. The patient exhibited worsening cardiac and liver conditions, growth failure, and developmental delay. She died suddenly at home at the age of 34 months. The cholangiographic and histological abnormalities found in our patient were suggestive of BA. At the same time, she displayed four out of five diagnostic criteria for AS. Based on our experience with this case, we suggest expeditious genetic testing should be considered for any case of neonatal cholestasis with diagnostic uncertainty. This may help avoid unwarranted surgical interventions, potentially associated with worse outcomes.

Clinical, Laboratory, Radiological, and Genetic Characteristics of Pediatric Patients with Alagille Syndrome.

Alagille syndrome (ALGS) is an autosomal dominant disease caused by JAG1 or NOTCH2 mutation. It is diagnosed by the presence of three out of five features: characteristic facies, posterior embryotoxon, peripheral pulmonary stenosis, vertebral defects, and interlobular bile duct paucity. This study aimed to review the prevalence, clinical presentations, diagnosis, treatment, and outcome of patients with ALGS. This is a retrospective review of patients with ALGS at the Pediatric Department, Salmaniya Medical Complex, Bahrain, between August 1994 and October 2022. The diagnosis was based on clinical, laboratory, radiological, histopathological, and genetic findings. Five patients were found to have ALGS. The prevalence of ALGS in Bahrain was 1.04 patients per 100,000 (0.001%). Four were Bahraini and three were females. Median birth weight was 2.3 (2.3-2.5) kg. All patients presented at the time of birth with low birth weight, cholestatic jaundice, clay-colored stool, heart murmur, and dysmorphic facial features. All had congenital heart diseases, two had butterfly vertebrae, and one had posterior embryotoxon. All had elevated liver enzymes and normal abdominal ultrasound. Three had positive hepatobiliary iminodiacetic acid scan and one had bile duct paucity in liver biopsy. Three had intraoperative cholangiogram. Four were positive for JAG1 mutation. All received ursodeoxycholic acid and fat-soluble vitamins. Two required liver transplantation. ALGS is a rare disorder in Bahrain. Diagnosis is challenging as the disease can be associated with or misdiagnosed as biliary atresia. Patients with ALGS are at high risk of morbidity either by unnecessary intraoperative cholangiogram or unavoidable liver transplantation.

O-4 | Transcatheter Interventions for Elastinopathy-Associated Peripheral Pulmonary Stenosis

O-4 | Transcatheter Interventions for Elastinopathy-Associated Peripheral Pulmonary Stenosis

Diagnosis of Coarctation of the Aorta From Infancy to Adulthood

Diagnosis of Coarctation of the Aorta From Infancy to Adulthood

A rare nonsense variant of the X-gene in a paediatric patient with severe peripheral pulmonary stenosis

Abstract Background Most cases of peripheral pulmonary stenosis (PPS) associated with William's syndrome are usually very mild or resolve spontaneously. However, we encountered a paediatric case of William's syndrome (WS) with severe PPS. In this case, we investigate whether the patient's genetic background was responsible for the severity of the PPS. Case presentation Shortly after birth, the male patient was suspected as WS because of his peculiar facial appearance and PPS. Fluorescence in situ hybridization identified microdeletion in the 7q11.23 region, and he had a confirmed diagnosis of WS. PPS became worsened subsequently, and a cardiac catheterization was performed at the age of 7 years. Due to severe multiple PPS, the right ventricular pressure exceeded the left ventricular pressure. At the age of 12, he had haemoptysis, which required ventilatory management. A pseudoaneurysm of the right pulmonary artery was identified and a right middle lobectomy was performed. Methods and results First, we performed multiplex ligation-dependent probe amplification and whole exome sequencing, considering the possibility of homozygous mutations in the region responsible for WS (7q11.23) or a larger deletion of this region in the patient. The deletion was confirmed to be a heterozygous deletion with a typical range for WS. Therefore, we hypothesized that the causative gene of severe PPS may exist separately from the region responsible for WS. After reviewing the result of the whole exome sequencing, we identified a rare nonsense variant of the “X”-gene as the disease-causing gene. The X-gene is involved in the suppression of vascular smooth muscle cell proliferation and the generation of pulmonary arteriolar dilator “Y”. The X-gene has been reported as a disease-causing gene in patients with pulmonary arterial hypertension. Based on these previous reports, we assumed that the X gene variant could be a cause of PPS; therefore, we performed functional analysis. We first introduced a mutant X-gene construct into human pulmonary arterial endothelial cells (hPAECs) and human pulmonary arterial smooth muscle cells and found that the mutant significantly reduced the production of Y compared to the wild-type X-gene. When transfected into hPAECs, the mutant X gene significantly increased cell proliferation compared to the wild-type X-gene. The hPAECs also showed reduced caspase 3/7 activity and reduced apoptosis compared to wild-type X-gene transfected cells. In the patient's own lung pathology specimens, irregular fibrous thickening of the intima of the intrapulmonary arteries was observed, which supported the results of the functional analysis. Conclusion Our study showed that an X-gene variant could lead to reduced Y production in the pulmonary arteries, abnormal proliferation of hPAECs, and the development of severe PPS. As Y-replenishing drugs are already in clinical use, the results may lead to the development of medical treatments for severe PPS. Funding Acknowledgement Type of funding sources: None.

See Spots? Look Deeper!

See Spots? Look Deeper!

Oblique coronary transfer technique in arterial switch operation for transposition of the great arteries.

Mortality rates after the arterial switch operation (ASO) for transposition of the great arteries (TGA) are still suboptimal mainly due to postoperative myocardial ischemia. The present study aimed to investigate the clinical impact of our modification of coronary transfer technique, wherein the coronary cuffs are transferred oblique to the pulmonary trunk to avoid torsion of the coronary arteries. From September 2010 to August 2020, all 37 consecutive patients who underwent ASO for TGA with our modification, that is, the oblique coronary transfer technique, were retrospectively reviewed. Cardiac dimensions and patency of the coronary arteries were examined by cineangiography, and hemodynamic parameters were measured by cardiac catheterization and transthoracic echocardiography. During a median 5.3 years of postoperative follow-up, there were no deaths and no patient required mechanical circulatory support. Median left ventricular ejection fraction was 68.8% (interquartile range 66.8-71.0, minimum 54.6). All patients maintained normal sinus rhythm without arrhythmia, except in the early postoperative period. Five patients underwent unplanned re-intervention for peripheral pulmonary stenosis, but none for coronary insufficiency. The 8-year freedom from re-intervention rate was 85.6%. Among a total of 110 transplanted coronary arteries, 108 (98.2%) remained patent, and two circumflex arteries were occluded much later after surgery, although with preserved ventricular function due to compensatory growth of other coronary branches. The oblique coronary transfer technique, which aims to avoid torsion of the coronary arteries, provides good patency of the coronary arteries and subsequent improvement of postoperative mortality rates following ASO.

Kabızlık ve Üfürümle Tespit Edilen Williams-Beuren Sendromu

Williams-Beuren Syndrome Detected with Constipation and Murmur Williams-Beuren syndrome (WBS) is a rare disease that occurs as a result of microdeletion of 11.23 of the long arm of chromosome 7, with a frequency of 1/20.000-30.000. Typical facial appearance, mental retardation, various congenital cardiovascular anomalies and endocrinological disorders may accompany this syndrome. In cases suspected as a result of clinical and laboratory findings, the diagnosis is made by showing the deletion of the mentioned region using the fluorescent in situ hybridization (FISH) method. We detected WBS in a 17-month-old male patient who presented with chronic constipation and had peripheral pulmonary stenosis in echocardiography performed with accompanying clinical findings, and aimed to emphasize the importance of multidimensional evaluation and early diagnosis. Keywords: Congenital heart disease, pulmonary stenosis, microdeletion syndromes, constipation, Williams-Beuren syndrome

Supravalvar aortic stenosis: Imaging characteristics and associations on multidetector computed tomography angiography.

To evaluate the imaging features and associations in patients with supravalvar aortic stenosis on multidetector computed tomography (CT) angiography. We retrospectively reviewed all CT angiography studies performed for evaluation of congenital heart diseases at our institution through the period from January 2014 to June 2020. Cases with supravalvar aortic stenosis were identified and classified as syndromic and nonsyndromic based on history, physical examination, and relevant investigations. The type and extent of vascular involvement and associated cardiovascular abnormalities were characterized. Supravalvar aortic stenosis was identified in 26/3926 (0.66%) patients (22 males and 4 females; Age range: 2 months to 20 years). Discrete stenosis was seen in 14/26 (53.8%) patients, while diffuse involvement of the ascending aorta to varying degrees was seen in the remaining 12 (46.2%) patients. About 15/26 (57.7%) patients had pulmonary involvement at some level, namely,infundibular, valvar, supravalvar, or peripheral pulmonic stenosiswhile 15/26 (57.7%) patients had coronary arterial involvement either in the form of stenosis, occlusion, or ectasia. Aortic valvular abnormality including thickening, partial fusion, and adhesion of leaflet edges to the sinutubular junction causing reduced coronary inflow was seen in 15/26 (57.7%) patients. Associated ventricular septal defect, patent ductus arteriosus, and mitral valvular prolapse were seen in four (15.4%), five (19.2%), and two (7.7%) patients respectively. Supravalvar aortic stenosis is a rare abnormality showing associated pulmonary arterial involvement, coronary arterial involvement, aortic valvular abnormalities, and associated congenital cardiac defects in the majority of cases, which may influence surgical outcomes.

SUN-096 Incidentally Found Severe Hypercalcemia in a Pediatric Patient, Diagnostic Challenge

Introduction: Idiopathic infantile hypercalcemia is an intriguing feature of Williams syndrome (WS), occurring in ~15% of diagnoses and is typically not clinically severe. Symptomatic hypercalcemia usually resolves during childhood, but lifelong abnormalities of calcium(Ca) and vitamin D metabolism may persist. The cause of the abnormality in Ca metabolism is still unknown. Hypercalciuria generally accompanies hypercalcemia, but isolated hypercalciuria, especially after infancy, can also occur. Nephrocalcinosis is relatively rare, found in less than 10% of patients undergoing renal ultrasonography. We report a 13-month-old female infant with a history of peripheral pulmonary stenosis and constipation, who presented with severe hypercalcemia that led to a new diagnosis of WS. Case presentation: A 13-month-old girl with a history of peripheral pulmonary stenosis, global developmental delay, and constipation presented to the neurology clinic for evaluation of gross motor delay. She was found to have upper body part hypotonia, decreased reflexes, and on laboratory evaluation, severe hypercalcemia with Ca level of 15.0 mg/dL (8.7 - 10.7). The patient was admitted for management of severe hypercalcemia. Physical exam was also remarkable for subtle features of WS: a happy baby, very social, with prominent eyes, full cheeks, flat nasal bridge, round nasal tip, full lips, and a wide smile. Repeated Ca level on admission was 15.9 mg/dL, with normal albumin level of 4.6 g/dL (2.9-5.5), elevated ionized calcium (iCal) of 1.99 mmol/L (0.95 - 1.32), and intact parathyroid hormone (PTH) of <4.0 pg/mL (8.0 - 85.0). Further evaluation revealed a normal 25 hydroxy-vitamin D:41 ng/mL (30-80) and low 1,25-dihydroxy vitamin D:10pg/mL (31-87). Further evaluation revealed elevated urine calcium to creatinine ratio of 0.7 (normal for age <0.56) and renal ultrasound remarkable for medullary nephrocalcinosis. The patient had a complete blood count within normal limits and a PTH related protein of 26 pg/mL (14-27), ruling out malignancy. Hypercalcemia responded well to intravenous fluids and diuretics, the patient being discharged home after two days on furosemide and potassium supplements with close electrolytes monitoring. The patient required calcium reducing therapy for four months to maintain Ca levels within 9-12 range. The medication was decreased gradually based on calcium and ical levels. The patient is currently doing well, with a normal calcium level, and has being off medication for the past three months. Conclusion: This is a rare case of severe hypercalcemia, which led to the diagnosis of WS. Although idiopathic infantile hypercalcemia occurs in 15% of patients with WS, usually the presentation is mild, and the patients do not require medical interventions. Our patient presented with severe hypercalcemia and subtle physical features of WS that led to genetic testing and final diagnosis.

SURGICAL REPAIR OF PERIPHERAL PULMONARY ARTERY STENOSIS

Peripheral pulmonary artery stenosis (PPAS) is a rare form of congenital heart disease and is typically associated with Williams or Alagille syndrome. However, there are patients without either syndrome who present with PPAS. The purpose of this study was to review our surgical experience in those patients. This is a retrospective review of 30 patients without either Williams or Alagille syndrome who underwent surgical repair of PPAS at a single institution. Median age at surgery was 3.6 years (range 0.3-18.8 years). Seventeen of the 30 patients (57%) had undergone previous cardiac operations and 16 patients (53%) previously underwent peripheral pulmonary artery balloon angioplasty or stent implantation. Concomitant anatomical diagnoses were found in 20 patients (67%) and included: supravalvar aortic stenosis (n=8), tetralogy of Fallot (n=4), d-transposition of the great arteries(n=2), truncus arteriosus (n=2), hypoplastic left heart syndrome (n=2), ventricular septal defect (n=1) and patent ductus arteriosus (n=1). Additional medical diagnoses were found in 15 patients (50%) and included: elastin arteriopathy (n=9), pulmonary artery calcinosis (n=1), arterial tortuosity syndrome (n=1), DiGeorge syndrome (n=1), Noonan syndrome (n=1) and others (n=2). The mean number of peripheral pulmonary stenoses surgically addressed was 19±8. Median duration of cardiopulmonary bypass was 369 minutes (IQR 292 to 515 minutes). With surgical repair, mean right ventricle-to-aortic systolic pressure ratio decreased from 0.95±0.2 pre-operatively to 0.28±0.08 post-operatively (p < 0.0001). Similarly, mean right ventricle systolic pressure decreased from 81±22mmHg to 26±8mmHg (p < 0.0001). Survival to hospital discharge was 100% and there was no mortality at a mean follow-up of 2.3 years. Post-operatively, 4 patients underwent balloon dilation of peripheral pulmonary arteries and no patient required cardiac reoperation. Freedom from pulmonary artery catheter-based reintervention was 95% and 80% at 12 and 36 months, respectively. This cohort of patients with PPAS underwent successful surgical repair with a significant reduction in right ventricle to aortic pressure ratios, achieving absolute right ventricular systolic pressures within the normal range. Various medical and anatomic diagnoses may be associated with PPAS. These results suggest a surgical approach should be considered the first-line treatment for PPAS.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

P6009Poor outcomes in pulmonary arterial hypertension as a member of RNF213-associated vascular diseases

Abstract Background A variant of c.14429G&gt;A (p.Arg4810Lys, rs112735431) in the ring finger protein 213 gene (RNF213; NM_001256071.2) has been recently identified as a risk allele for pulmonary arterial hypertension (PAH), suggesting that PAH can be added as a new member of RNF213-associated vascular diseases including Moyamoya disease and peripheral pulmonary stenosis. Purpose Our aim was to identify the clinical features and outcomes of PAH patients with RNF213 p.Arg4810Lys variant. Methods Whole-exome sequencing was performed in 139 idiopathic (or possibly heritable) PAH patients. Hemodynamics and prognosis were evaluated in the patients with RNF213 p.Arg4810Lys variant and the patients with bone morphogenic protein receptor type 2 (BMPR2) mutations. Results The RNF213 p.Arg4810Lys variant was identified in a heterozygous state in 11 patients (7.9%). Time-course changes in hemodynamics after combination therapy in the patients with the RNF213 p.Arg4810Lys variant were significantly poorer compared with those in BMPR2 mutation carriers (n=36) (comparison of changes in mean pulmonary arterial pressure, P=0.007). The event-free rate of death or lung transplantation was significantly poorer in RNF213 p.Arg4810Lys variant carriers than in BMPR2 mutation carriers (5-year event-free rate since the introduction of prostaglandin I2 infusion, 0% vs. 93%, P&lt;0.001) (Figure). Time to death or lung transplantation Conclusions PAH patients with the RNF213 p.Arg4810Lys variant were associated with a poor reactivity to vasodilator drugs and poor clinical outcomes even in the recent era. Earlier consideration of lung transplantation might be required for RNF213 p.Arg4810Lys variant carriers developing PAH. Documentation of the RNF213 p.Arg4810Lys variant, as well as already known pathogenic genes, can provide clinically relevant information for therapeutic strategies, leading to a personalized approach for the treatment of PAH.

Poor outcomes in carriers of the RNF213 variant (p.Arg4810Lys) with pulmonary arterial hypertension

A variant of c.14429G>A (p.Arg4810Lys, rs112735431) in the ring finger protein 213 gene (RNF213; NM_001256071.2) has been recently identified as a risk allele for pulmonary arterial hypertension (PAH). PAH can be added as a new member of RNF213-associated vascular diseases, which include Moyamoya disease and peripheral pulmonary stenosis. Our aim was to identify the clinical features and outcomes of PAH patients with this variant. Whole-exome sequencing was performed in 139 idiopathic (or possibly heritable) PAH patients. The RNF213 p.Arg4810Lys variant was identified in a heterozygous state in 11 patients (7.9%). Time-course changes in hemodynamics after combination therapy in the patients with the RNF213 p.Arg4810Lys variant were significantly poorer compared with those carrying the bone morphogenic protein receptor type 2 (BMPR2) mutation (n = 36) (comparison of changes in mean pulmonary arterial pressure, p = 0.007). The event-free rate of death or lung transplantation was significantly poorer in RNF213 p.Arg4810Lys variant carriers than in BMPR2 mutation carriers (5-year event-free rate since the introduction of prostaglandin I2 infusion, 0% vs 93%, respectively; p < 0.001). Idiopathic PAH patients with the RNF213 p.Arg4810Lys variant are associated with poor clinical outcomes even in recent times. Earlier consideration of lung transplantation might be required for RNF213 p.Arg4810Lys variant carriers who are developing PAH. Documentation of the RNF213 p.Arg4810Lys variant, as well as already known pathogenic genes, such as BMPR2, can provide clinically relevant information for therapeutic strategies, leading to a personalized approach for the treatment of PAH.

FISH Analysis in Taiwanese Children with Suspected Diagnosis of Williams Syndrome

Williams syndrome (WS) is a contiguous gene syndrome caused by deletion of chromosome 7q11.23 involving the elastin gene. This study aimed to use the fluorescent in situ hybridization (FISH) to detect the elastin gene deletion in Taiwanese children with suspected diagnosis of WS. Thirty four children (22 boys, 12 girls; median age 1.9 years, age range: 2 day to 16.8 years) with suspected diagnosis of WS including a typical dysmorphic face, mental retardation, supravalvular aortic stenosis (SVAS) or peripheral pulmonary stenosis (PPS) were studied. Metaphase chromosome slides were prepared from peripheral blood. FISH was performed using the chromosome 7q11.23 probe for elastin gene and control probe for chromosome 7q31. FISH was positive in 82% (28/34) patients with suspected WS, 100% (27/27) patients with typical dysmorphic face and mental retardation and 14% (1/7) patients with SVAS or PPS. Microdeletion of elastin gene was positive in all typical WS patients but only in 14% patients with SVAS or PPS.

CONGENITAL MYOPATHIES: NEMALINE AND TITINOPATHIES: P.239Congenital titinopathy: severe and atypical presentations

Congenital titinopathy is a prenatal/infant-onset genetic muscle disorder caused by recessive TTN mutations. The true prevalence of of this disorder remains unknown, however the number of confirmed cases is climbing exponentially. We have identified four informative congenital titinopathy cases with convincingly pathogenic TTN mutations in trans. These cases extend our understanding of the spectrum of weakness and additional clinical features that can be associated with this emerging titinopathy. The first three cases are severely affected infants. All had a history of reduced fetal movements and were born at term with profound hypotonia and no respiratory effort. All required immediate resuscitation and intubation. One had congenital fractures, two had congenital quadrimelic joint contractures, two had atrial or ventricular septal cardiac defects, and two had intracerebral abnormalities likely secondary to birth trauma. Two died shortly after withdrawal of care on day one of life & three months of age respectively. The third remains reliant on full time ventilatory support (age 9 months). The fourth case is a 21-year-old female who was born with several congenital-titinopathy-like features including congenital contractures (camptodactyly, unilateral talipes), a cardiac abnormality (peripheral pulmonary stenosis), ptosis (congenital), and a high arched palate. However, this patient was not clinically weak at birth and has remained strong over time. She also has a range of striking additional features including Noonan-like facies, a low posterior hairline, neck webbing, short stature and bilateral axillary pterygia. She has no pathogenic-looking variants within established Noonan syndrome/syndrome-like genes. In view of the features present in these patients, we recommend that congenital titinopathy be considered in all weak infants with features suggestive of a primary muscle disorder and in patients with Noonan-like or multiple-pterygia-contracture phenotypes.

Computational simulation of postoperative pulmonary flow distribution in Alagille patients with peripheral pulmonary artery stenosis.

Up to 90% of individuals with Alagille syndrome have congenital heart diseases. Peripheral pulmonary artery stenosis (PPS), resulting in right ventricular hypertension and pulmonary flow disparity, is one of the most common abnormalities, yet the hemodynamic effects are ill-defined, and optimal patient management and treatment strategies are not well established. The purpose of this pilot study is to use recently refined computational simulation in the setting of multiple surgical strategies, to examine the influence of pulmonary artery reconstruction on hemodynamics in this population. Based on computed tomography angiography and cardiac catheterization data, preoperative pulmonary artery models were constructed for 4 patients with Alagille syndrome with PPS (all male, age range: 0.6-2.9 years), and flow simulations with deformable walls were performed. Surgeon directed virtual surgery, mimicking the surgical procedure, was then performed to derive postoperative models. Postoperative simulation-derived hemodynamics and blood flow distribution were then compared with the clinical results. Simulations confirmed substantial resistance, resulting from preoperative severe ostial stenoses, and the use of newly developed adaptive outflow boundary conditions led to excellent agreement with in vivo measurements. Relief of PPS decreased pulmonary artery pressures and improved pulmonary flow distribution both in vivo and in silico with good correlation. Using adaptive outflow boundary conditions, computational simulations can estimate postoperative overall pulmonary flow distribution in patients with Alagille syndrome after pulmonary artery reconstruction. Obstruction relief along with pulmonary artery vasodilation determines postoperative pulmonary flow distribution and newer methods can incorporate these physiologic changes. Evolving blood flow simulations may be useful in surgical or transcatheter planning and in understanding the complex interplay among various obstructions in patients with peripheral pulmonary stenosis.

Alagille-Watson syndrome

Alagille syndrome (AS) is also known as arteriohepatic dysplasia, Watson Miller syndrome, and syndromic bile duct paucity. It is rare autosomal dominant genetic syndrome with incidence of 1 in 100,000 live births. The major manifestations include paucity of interlobular bile ducts, characteristic facies, posterior embryotoxon, vertebral defects, and peripheral pulmonary stenosis. A developmentally normal 14-month-old male toddler born of a non-consanguineous marriage presented with progressive jaundice since 4 months of age and was associated with generalized pruritus, high-colored urine, and pale-colored stools. On examination, broad forehead, pointed chin, low-set eyes, xanthomas over the cheek, and posterior embryotoxon were noticed. Ultrasonography showed hepatomegaly and ectopic kidney, and blood investigations revealed anemia, conjugated hyperbilirubinemia, raised serum glutamic pyruvic transaminase, and serum glutamic oxaloacetic transaminase, with altered triglyceride and cholesterol levels. Liver biopsy revealed paucity of intrahepatic bile ducts and diagnosis of AS. The above case report stresses the need to look for any dysmorphic features in a case of neonatal cholestasis as AS, though rare, is a cause of neonatal cholestasis.

Alagille syndrome with moyamoya disease

&lt;p&gt;We report a 5 year old male child who presented with a history of progressive jaundice since infancy and generalized pruritus. He was also found to have typical triangular facies, posterior embryotoxon on both eyes, peripheral pulmonary stenosis and paucity of bile ducts in liver biopsy. Magnetic resonance angiography of brain showed typical features of moyamoya disease. The child was diagnosed as a case of Alagille syndrome. This particular syndrome with feature of moyamoya disease has been rarely reported.&lt;/p&gt;