Biventricular Hypertrophic Cardiomyopathy in a Child with LEOPARD Syndrome: a Case Report (original) (raw)
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Severe, early onset hypertrophic cardiomyopathy in a family with LEOPARD syndrome
Journal of prenatal medicine, 2008
Leopard syndrome is an acronym (multiple Lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) describing an autosomal dominant disease due to mutations in the raS-MapK pathway. Here, we describe a family (mother and daughter) with clinical and molecular diagnosis of Leopard syndrome 1 and HCM, and we report the prenatal diagnosis of HCM in a fetus at risk for Leopard syndrome. An echocardiography was conducted showing a significant hypertrophy of both ventricles (left and right ventricular wall thickness 9mm and 3 mm). After a multidisciplinary counseling the couple opted for the termination of pregnancy Further genotype-phenotype studies are warranted to fully elucidate the impact of the genotype on the natural history of patients with LS and LVH.
Acta Clinica Belgica, 2018
Introduction: LEOPARD syndrome is a rare genetic disorder characterised by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth and sensorineural deafness. Clinical manifestations are often mild, which may result in difficult and late diagnosis. Cardiac involvement may have a significant impact on the prognosis, however, appearance of severe abnormalities such as hypertrophic cardiomyopathy usually precedes the occurrence of multiple lentigines and may be asymptomatic. Case presentation: We report two cases of LEOPARD syndrome with hypertrophic cardiomyopathy in a 10-year-old girl and an 18-year-old boy. In both cases, multiple lentigines, ocular hypertelorism and growth retardation were present. The first patient was followed up at the paediatric cardiology clinic due to the risk of progression of septal hypertrophy and pressure gradient across the left ventricular outflow tract, the second patient underwent surgery for a moderate obstruction of the left ventricular outflow tract with uncomplicated post-operative follow-up. Conclusion: In both presented patients, hypertrophic cardiomyopathy was clinically silent and the murmur over the precordium was the sole cardiac abnormality revealed during routine visit. A detailed cardiologic examination should be considered in the patients with suspicion of LEOPARD syndrome since the ventricular hypertrophy is thought to precede the occurrence of lentigines and progress over time.
Circulation: Heart Failure, 2018
EOPARD syndrome (LS) is a form of RASopathy caused by mutations in the PTPN11 gene an upstream regulator of RAS/MAPK signaling. Although hypertrophic cardiomyopathy (HCM) is a shared cardiac phenotype among RASopathies, HCM complicating patients with LS is characteristic for its unique early-onset and progressive features. We herein report a neonate with LS who presented with an extremely severe form of HCM. Autopsy revealed remarkable evidence of active cardiomyocyte proliferation contributing to the overt cardiomegaly. The case suggests an intriguing association between the observed dramatic increase in cardiomyocyte mitotic activity and the fatal clinical course of LS-associated HCM. CASE PRESENTATION The patient was the second daughter born to nonconsanguineous parents with no significant family history. Marked biventricular hypertrophy was noted on fetal echocardiography at the 28th week of gestation. After an uneventful delivery, the patient was immediately admitted to the neonatal intensive care unit. Physical examination at birth revealed multiple dysmorphic features, including a wide forehead, low set ears, hypertelorism, and wide set nipples. No skin lesions, such as café-au-lait spots or lentigines, were noticed, whereas mild hearing loss was detected by newborn screening. The findings were suggestive of LS. Imaging studies were remarkable for cardiomegaly (Figure [A]), and echocardiogram showed severe ventricular wall thickening (Z score of >5). Elevation of plasma brain natriuretic peptide levels accompanied clinical deterioration, rising from 1993 pg/mL at day 1 up to 7314 pg/mL at day 13. Outflow tract obstructions were severe and progressive, the estimated pressure gradients exceeding 50 mm Hg at day 16. Despite medical therapy with β-blockers and diuretics, she developed progressive cardiac failure and deceased at day 29. Sequencing of the patient's genomic DNA identified a Gly464Ala mutation in exon 12 of the PTPN11 gene, a previously well-described loss-of-function mutation, 1 establishing the molecular diagnosis of LS. Parental sequencing confirmed the de novo origin of the mutation. Autopsy examinations revealed multiple hallmark features of HCM, such as concentric hypertrophy, myocardial thickening, myofibrillar disarray, and enlarged hyperchromatic nuclei (Figure [B]). The extent of fibrosis was only modest, indicating that the hypertrophy had mainly resulted from the increased myocardial mass. Strikingly, immunohistochemical staining for Ki-67 (MIB-1), a widely accepted marker of cell proliferation, showed a marked increase in Ki-67 positive nuclei throughout all regions of the myocardium (Figure [C]). This unexpected finding clearly contrasted with the MIB-1 staining results from age-matched control specimens or cardiomyopathy samples of different etiologies, which showed no
LEOPARD syndrome in an infant with severe hypertrophic cardiomyopathy and PTPN11 mutation
Annals of Pediatric Cardiology, 2011
In LEOPARD syndrome, mutations affecting exon 13 of the PTPN11 gene have been correlated with a rapidly progressive severe biventricular obstructive hypertrophic cardiomyopathy (HCM). This is a report of early onset severe HCM in an infant with LEOPARD syndrome and an unusual mutation in exon 13, showing genotypephenotype correlation.
American Journal of Cardiology, 2007
The aim of this study was to characterize cardiovascular involvement in a large number of patients with LEOPARD syndrome. Twenty-six patients (age range 0 to 63 years, median age at the time of the study evaluation 17 years) underwent clinical and genetic investigations. Familial disease was ascertained in 9 patients. Nineteen patients (73%) showed electrocardiographic abnormalities. Left ventricular (LV) hypertrophy was present in 19 patients (73%), including 9 with LV outflow tract obstructions; right ventricular hypertrophy was present in 8 patients (30%). Valve (57%) and coronary artery (15%) anomalies were also observed. Single patients showed LV apical aneurysm, LV noncompaction, isolated LV dilation, and atrioventricular canal defect. During follow-up (9.1 ؎ 4.5 years), 2 patients died suddenly, and 2 patients had cardiac arrest. These patients had LV hypertrophy. Despite the limited number of subjects studied, genotype-phenotype correlations were observed in familial cases. In conclusion, most patients with LEOPARD syndrome showed LV hypertrophy, often in association with other valvular or congenital defects. A spectrum of underrecognized cardiac anomalies were also observed. Long-term prognosis was benign, but the occurrence of 4 fatal events in patients with LV hypertrophy indicates that such patients require careful risk assessment and, in some cases, consideration for prophylaxis against sudden death.
Genotype–phenotype analysis and natural history of left ventricular hypertrophy in LEOPARD syndrome
American Journal of Medical Genetics Part A, 2008
Because it is unclear whether the genotype may influence the clinical course in patients with LEOPARD syndrome (LS), we analyzed clinical and molecular predictors of adverse cardiac events in patients with left ventricular hypertrophy (LVH). A comprehensive cardiovascular evaluation, including baseline electrocardiogram, echocardiography, exercise test and 24 hr Holter monitoring at the time of clinical diagnosis and during follow-up was conducted on 24 patients referred to our departments. Phenotypical examination and diagnosis were performed by expert clinical geneticists. The entire PTPN11 and RAF1 coding regions were screened for mutations by DHPLC analysis, followed by sequencing. Patients without PTPN11 mutations (34%) showed a higher frequency of family history of sudden death (P ¼ 0.007), increased left atrial dimensions (P ¼ 0.05), bradyarrhythmias (P ¼ 0.04), episodes of supraventricular tachycardias (P ¼ 0.06), atrial fibrillation (P ¼ 0.009), and nonsustained ventricular tachycardias (P ¼ 0.05) during Holter monitoring. Six patients (25%) had adverse cardiac events during follow-up (including sudden deaths, resuscitated cardiac arrest, septal myectomy, and heart failure). LVH, New York Heart Association Class, left ventricular outflow tract obstruction, and nonsustained ventricular tachycardias were associated to adverse cardiac events. Of note, three patients with mutations in exon 13 showed a severe obstructive cardiomyopathy, with serious cardiac complications during follow-up (heart failure, septal myectomy, and sudden death). In conclusion, patients with LVH associated with LS seem to carry a relatively high risk of adverse (arrhythmic and nonarrhythmic) events. Further genotype-phenotype studies are warranted to fully elucidate the impact of the genotype on the natural history of patients with LS and LVH. ß
LEOPARD syndrome: Clinical diagnosis in the first year of life
American Journal of Medical Genetics Part A, 2006
LEOPARD syndrome (LS) is an autosomal dominant syndrome characterized by multiple lentigines and café-au-lait spots, electrocardiographic-conduction abnormalities, ocular hypertelorism/obstructive cardiomyopathy, pulmonary stenosis, abnormalities of the genitalia in males, retardation of growth, and deafness. LS shares many features with Noonan syndrome (NS), in which lentigines and deafness are usually not present. Molecular studies have shown that LS and NS are allelic disorders, caused by different missense mutations in PTPN11, a gene encoding the protein tyrosine phosphatase SHP-2 located at chromosome 12q22-qter. The clinical diagnosis of LS is generally difficult in the first months of life because the distinctive lentigines are generally not present at birth and develop during childhood. From January 2002 to December 2004, we suspected LS clinically in 10 patients admitted to our genetic counseling services in the first 12 months of life. A PTPN11 gene mutation was detected in 8/10 (80%) patients. In one patient without a PTPN11 mutation a subsequent clinical diagnosis of neurofibromatosis type 1 (NF1) was made, following the evaluation of the mother, who had previously undiagnosed classic NF1. The age of LS patients with PTPN11 mutation ranged between 1 and 11 months (mean age AE SD 7.5 AE 3.96 months). Review of the clinical characteristics of patients with LS confirmed by molecular study during the first year of life demonstrates that the diagnosis of LS in the first months of age can be clinically suspected in patients presenting with three main features, that is, characteristic facial features (100%), hypertrophic cardiomyopathy (HCM) (87%), and cafe-au-lait spots (75%). Characteristic facial features can be mild or severe, and consist of hypertelorism, downslanting palpebral fissures, ptosis, and dysmorphic ears. The clinical suspicion of LS may be confirmed by molecular screening for PTPN11 mutations. An early diagnosis of the disease is useful for the prospective care of associated medical problems and for precise genetic counseling.
FELINE HYPERTROPHIC CARDIOMYOPATHY: CASE REPORT (Atena Editora)
FELINE HYPERTROPHIC CARDIOMYOPATHY: CASE REPORT (Atena Editora), 2023
In domestic felines, cardiomyopathies are identified as structural and functional diseases of the heart muscle, among them, hypertrophic cardiomyopathy is the most prevalent, characterized by thickening of the left ventricle, which can vary from mild to severe, with diastolic dysfunction. Cats as young as three months old, with no sex or breed predilection, may be affected. Mutations in contractile protein genes, generating dysfunctional sarcomeres, have already been described in some pure breeds, therefore it can be considered a primary hereditary disease. Clinical signs are usually associated with dyspnea as a result of pulmonary edema and/or pleural effusion, in addition to the possibility of paresis or quadriplegia of the limbs as a result of arterial thrombi. The diagnosis has the echocardiographic examination as the gold standard. This work aims to describe the clinical signs, diagnosis and therapeutic approach of a young feline, mixed breed, 2 years old, with Hypertrophic Cardiomyopathy, attended at the Animal Health Unit Hospital Victória in the city of Porto Alegre, RS.