Effect of beta-blockers and angiotensin receptor blockers in reducing the aortic growth rate in children with bicuspid aortic valve-related aortopathy.

AIMS: The aim of this study is to evaluate the effect of beta-blockers and angiotensin receptor blockers in reducing the aortic growth rate in children with bicuspid aortic valve (BAV)-related aortopathy and ascending phenotype. METHODS: Consecutive paediatric patients (≤16 years) with BAV and ascending aorta (AsAo) dilation (z-score > 3) were enrolled in this observational retrospective cohort study. Patients receiving prophylactic treatment with either atenolol (0.5 to 1.0 mg/kg/daily) or losartan (0.7 to 1.4 mg/kg/daily) were compared with those who did not receive medical prophylaxis (control group). The primary outcome of interest was the annual rate of change in maximal AsAo diameter z-score in the treatment and control groups. RESULTS: From a cohort of 1005 patients, 120 (mean age 11.3 ± 4.5 years, 82% males) fulfilled the inclusion criteria and were included in the study. Patients in the treatment and control group had similar age, sex, family history of BAV, BAV morphology, and baseline AsAo diameter. During a median follow-up of 7.1 years (interquartile range 3.8-10.2), no differences were observed in the annual growth rate of aortic diameter z-score between patients on treatment and controls. The prevalence of aortic diameter progression was similar in the treatment and control groups, and treatment with atenolol or losartan was not associated with a lower rate of aortic disease progression. CONCLUSIONS: The findings revealed no significant difference in the annual aortic growth rate between treated and untreated patients. Larger cohort studies or, ideally, randomized clinical controlled trials are needed to validate these findings.

Unique Features of Cardiovascular Involvement and Progression in Children with Marfan Syndrome Justify Dedicated Multidisciplinary Care.

Marfan syndrome (MIM: # 154700; MFS) is an autosomal dominant disease representing the most common form of heritable connective tissue disorder. The condition presents variable multiorgan expression, typically involving a triad of cardiovascular, eye, and skeletal manifestations. Other multisystemic features are often underdiagnosed. Moreover, the disease is characterized by age related penetrance. Diagnosis and management of MFS in the adult population are well-described in literature. Few studies are focused on MFS in the pediatric population, making the clinical approach (cardiac and multiorgan) to these cases challenging both in terms of diagnosis and serial follow-up. In this review, we provide an overview of MFS manifestations in children, with extensive revision of major organ involvement (cardiovascular ocular and skeletal). We attempt to shed light on minor aspects of MFS that can have a significant progressive impact on the health of affected children. MFS is an example of a syndrome where an early personalized approach to address a dynamic, genetically determined condition can make a difference in outcome. Applying an early multidisciplinary clinical approach to MFS cases can prevent acute and chronic complications, offer tailored management, and improve the quality of life of patients.

Prevalence and Clinical Significance of Intraventricular Conduction Disturbances in Hospitalized Children.

Introduction: Data on the prevalence and clinical significance of interventricular conduction disturbances (IVCDs) in children are scarce. While incomplete right bundle branch blocks (IRBBBs) seem to be the most frequent and benign findings, complete bundle blocks and fascicular blocks are often seen in children with congenital/acquired cardiac conditions. This study aims to delineate the prevalence and the diagnostic accuracy of IVCD in children admitted to a paediatric cardiology unit. Methods: Children admitted to the paediatric cardiology unit between January 2010 and December 2020 who had an ECG were included in the study. IVCDs were diagnosed according to standard criteria adjusted for age. Results: Three thousand nine hundred and ninety-three patients were enrolled. The median age was 3.1 years (IQR: 0.0-9.2 years), and 52.7% were males. IVCDs were present in 22.5% of the population: 17.4% of the population presented with IRBBBs, 4.8% with a complete right bundle branch block (CRBBB), 0.1% with a complete left bundle branch block (CLBBB), 0.2% with a left anterior fascicular block (LAFB) and 0.2% with a combination of CRBBB and LAFB. Also, 26% of children with congenital heart disease had an IVCD, and 18% of children with an IVCD had previous cardiac surgery. The overall sensitivity of IVCD in detecting a cardiac abnormality was 22.2%, with a specificity of 75.5%, a PPV of 83.1% and an NPV of 15.1%, but the values were higher for CLBBB and LAFB. Conclusions: IVCDs were present in one-fifth of children admitted to the cardiology unit. IRBBB was the most frequent disturbance, while CRBBB, CLBBB and fascicular blocks were much rarer, though they had a higher predictive value for cardiac abnormalities.

Left Ventricular Non-Compaction in Children: Aetiology and Diagnostic Criteria.

Left ventricular non-compaction (LVNC) is a heterogeneous myocardial disorder characterized by prominent trabeculae protruding into the left ventricular lumen and deep intertrabecular recesses. LVNC can manifest in isolation or alongside other heart muscle diseases. Its occurrence among children is rising due to advancements in imaging techniques. The origins of LVNC are diverse, involving both genetic and acquired forms. The clinical manifestation varies greatly, with some cases presenting no symptoms, while others typically manifesting with heart failure, systemic embolism, and arrhythmias. Diagnosis mainly relies on assessing heart structure using imaging tools like echocardiography and cardiac magnetic resonance. However, the absence of a universally agreed-upon standard and limitations in diagnostic criteria have led to ongoing debates in the scientific community regarding the most reliable methods. Further research is crucial to enhance the diagnosis of LVNC, particularly in early life stages.

[Clinical and genetic manifestations of left ventricular non-compaction in children]. / Caratteristiche cliniche e genetiche del ventricolo sinistro non compatto in età pediatrica.

Left ventricular non-compaction (LVNC) is a myocardial disease characterized by a two-layered structure typically seen at the apical and lateral left portions of the ventricular myocardium, distal to the papillary muscles. While considered a rare disease, its prevalence in children is increasing due to the increased awareness of this condition and improved resolution of imaging techniques. The etiology is heterogeneous, ranging from inherited conditions to acquired diseases. Although many patients are asymptomatic, some patients may experience adverse events, including heart failure, arrhythmias, or thromboembolic events. Several echocardiographic or cardiac magnetic resonance imaging diagnostic criteria have been proposed for diagnosing LVNC. However, their application in children is significantly limited. This review aims to describe the clinical and genetic characteristics of children with LVNC and discuss the role of the proposed diagnostic criteria.

Prediction of incident atrial fibrillation in hypertrophic cardiomyopathy.

BACKGROUND AND AIM: Atrial fibrillation (AF) is the most common sustained arrhythmia in hypertrophic cardiomyopathy (HCM) with significant effects on outcome. We aim to compare the left atrial (LA) diameter measurement with HCM-AF Score in predicting atrial fibrillation (AF) development in HCM. METHODS: From the regional cohort of the Campania Region, Italy, 519 HCM patients (38% women, age45 ± 17 years) without history of AF, were enrolled in the study. The primary clinical endpoint was the development of AF, defined as at least 1 episode documented by ECG. RESULTS: During the follow-up (mean 8 ± 6, IQ range 2.5-11.2 years), 99 patients (19%) developed AF. Patients who developed AF were more symptomatic, had higher prevalence of ICD implantation, had larger LA diameter, greater left ventricular (LV) maximal wall thickness and LV outflow tract obstruction (p < 0.01). Both LA diameter and HCM-AF score were higher in patients who developed AF versus those who did not (LA diameter 49 ± 7 versus 43 ± 6 mm; HCM-AF score 22 ± 4 versus 19 ± 4; p < 0.0001); however, ROC curve analysis demonstrated that LA diameter had a significant greater area under the curve than HCM-AF Score (p < 0.0001). At 5 years follow-up, a LA diameter > 46 mm, showed a similar accuracy in predicting AF development of HCM-AF score ≥ 22, which identifies patients at high risk to develop AF. CONCLUSION: Our analysis shows that LA diameter, a worldwide and simple echocardiographic measure, is capable alone to predict AF development in HCM patients.

Cardiovascular Involvement in Fabry's Disease: New Advances in Diagnostic Strategies, Outcome Prediction and Management.

Cardiovascular involvement is common in Fabry's disease and is the leading cause of morbidity and mortality. The research is focused on identifying diagnostic clues suggestive of cardiovascular involvement in the preclinical stage of the disease through clinical and imaging markers. Different pathophysiologically driven therapies are currently or will soon be available for the treatment of Fabry's disease, with the most significant benefit observed in the early stages of the disease. Thus, early diagnosis and risk stratification for adverse outcomes are crucial to determine when to start an aetiological treatment. This review describes the cardiovascular involvement in Fabry's disease, focusing on the advances in diagnostic strategies, outcome prediction and disease management.

Prevalence and clinical significance of right ventricular pulmonary arterial uncoupling in cardiac amyloidosis.

BACKGROUND: This study aims to evaluate the prevalence and the clinical significance of the right ventricular pulmonary arterial (RV-PA) uncoupling in patients with cardiac amyloidosis (CA). METHODS: The study population consisted in 92 consecutive patients with CA (age 71.1 ± 12.2 years, 71% males; 47% with immunoglobulin light chain (AL), 53% with transthyretin [ATTR]). A pre-specified tricuspid anulus plane systolic excursion on pulmonary arterial systolic pressure (TAPSE/PASP) value <0.31 mm/mmHg was used to define RV-PA uncoupling and to dichotomize the study population. RESULTS: Thirty-two patients (35%) showed RV-PA uncoupling at baseline evaluation (15/44 [34%] AL and 17/48 [35%] ATTR). Patients with RV-PA uncoupling, in both AL and ATTR, showed worse NYHA functional class, lower systemic blood pressure, and more pronounced left ventricular and RV systolic dysfunction than those with RV-PA coupling. During a median follow-up of 8 months (IQR 4-13), 26 patients (28%) experienced cardiovascular death. Patients with RV-PA uncoupling showed lower survival at 12 months follow-up than those with RV-PA coupling (42.7% [95%CI 21.7-63.7%] vs. 87.3% [95%CI 78.3-96.3%], p-value<0.001). Multivariate analysis identified high-sensitivity troponin I values (HR 1.01 [95%CI 1.00-1.02] per 1 pg/mL increase; p-value 0.013) and TAPSE/PASP (HR 1.07 [95%CI 1.03-1.11] per 0.01 mm/mmHg decrease; p-value 0.002) as independent predictors of cardiovascular death. CONCLUSIONS: RV-PA uncoupling is common among patient with CA, and it is a marker of advanced disease and worse outcome. This study suggest that TAPSE/PASP ratio has the potential to improve risk stratification and guide management strategies in patients with CA of different etiology and advanced disease.

The Role of Genetic Testing in Patients with Heritable Thoracic Aortic Diseases.

Heritable thoracic aortic disease (HTAD) is a term used to define a large group of disorders characterized by the occurrence of aortic events, mainly represented by aneurysm or dissection. These events generally involve the ascending aorta, although the involvement of other districts of the aorta or peripheral vessels may occur. HTAD can be classified as non-syndromic if the disorder is limited to the aorta, and syndromic when associated with extra-aortic features. About 20-25% of patients with non-syndromic HTAD exhibit a family history of aortic disease. Thus, a careful clinical evaluation of the proband and the first-degree family members is required to differentiate familial and sporadic cases. Genetic testing is essential since it allows confirmation of the etiological diagnosis of HTAD (particularly in patients with a significant family history) and may guide family screening. In addition, genetic diagnosis significantly impacts patients' management since the different conditions significantly differ with respect to natural history and treatment strategies. The prognosis in all HTADs is determined by the progressive dilation of the aorta, potentially leading to acute aortic events, such as dissection or rupture. Moreover, the prognosis varies according to the underlying genetic mutations. This review aims to describe the clinical characteristics and natural history of the most common HTADs, with particular emphasis on the role of genetic testing in risk stratification and management.

Multimodality Imaging in Arrhythmogenic Left Ventricular Cardiomyopathy.

The term arrhythmogenic cardiomyopathy (ACM) describes a large spectrum of myocardial diseases characterized by progressive fibrotic or fibrofatty replacement, which gives the substrate for the occurrence of ventricular tachyarrhythmias and the development of ventricular dysfunction. This condition may exclusively affect the left ventricle, leading to the introduction of the term arrhythmogenic left ventricular cardiomyopathy (ALVC). The clinical features of ALVC are progressive fibrotic replacement with the absence or mild dilation of the LV and the occurrence of ventricular arrhythmias within the left ventricle. In 2019, the diagnostic criteria for the diagnosis of ALVC, based on family history and clinical, electrocardiographic, and imaging features, have been proposed. However, since the significant clinical and imaging overlap with other cardiac diseases, genetic testing with the demonstration of a pathogenic variant in an ACM-related gene is required for diagnostic confirmation. In ALVC, the multimodality imaging approach comprises different imaging techniques, such as echocardiography, cardiac magnetic resonance, and cardiac nuclear imaging. It provides essential information for the diagnosis, differential diagnosis, sudden cardiac death risk stratification, and management purposes. This review aims to elucidate the current role of the different multimodality imaging techniques in patients with ALVC.

Pathophysiology, Functional Assessment and Prognostic Implications of Nutritional Disorders in Systemic Amyloidosis.

Gastrointestinal involvement is a common clinical feature of patients with systemic amyloidosis. This condition is responsible for invalidating gastrointestinal symptoms, a significant macro and micronutrient deficit, and is a marker of disease severity. Gastrointestinal involvement should be actively sought in patients with systemic amyloidosis, while its diagnosis is challenging in patients with isolated gastrointestinal symptoms. The nutritional status in systemic amyloidosis plays an essential role in the clinical course and is considered a significant prognostic factor. However, the definition of nutritional status is still challenging due to the lack of internationally accepted thresholds for anthropometric and biochemical variables, especially in specific populations such as those with systemic amyloidosis. This review aims to elucidate the fundamental steps for nutritional assessment by using clinical and instrumental tools for better prognostic stratification and patient management regarding quality of life and outcomes.

Severe Lymphatic Disorder and Multifocal Atrial Tachycardia Treated with Trametinib in a Patient with Noonan Syndrome and SOS1 Mutation.

Noonan syndrome (NS) is a multisystemic disorder caused by germline mutations in the Ras/MAPK cascade, causing a broad spectrum of phenotypical abnormalities, including abnormal facies, developmental delay, bleeding diathesis, congenital heart disease (mainly pulmonary stenosis and hypertrophic cardiomyopathy), lymphatic disorders, and uro-genital abnormalities. Multifocal atrial tachycardia has been associated with NS, where it may occur independently of hypertrophic cardiomyopathy. Trametinib, a highly selective MEK1/2 inhibitor currently approved for the treatment of cancer, has been shown to reverse left ventricular hypertrophy in two RIT1-mutated newborns with NS and severe hypertrophic cardiomyopathy. Severe lymphatic abnormalities may contribute to decreased pulmonary compliance in NS, and pulmonary lymphangiectasias should be included in the differential diagnosis of a newborn requiring prolonged oxygen administration. Herein we report the case of a pre-term newborn who was admitted to our unit for the occurrence of severe respiratory distress and subentrant MAT treated with trametinib.

Thoracic Aortic Dilation: Implications for Physical Activity and Sport Participation.

Thoracic aortic dilatation is a progressive condition that results from aging and many pathological conditions (i.e., connective tissue, inflammatory, shear stress disorders, severe valvular heart disease) that induce degenerative changes in the elastic properties, leading to the loss of elasticity and compliance of the aortic wall. Mild aortic root enlargement may be also observed in athletes and is considered as a normal adaptation to regular exercise training. On the other hand, high-intensity physical activity in individuals with a particular genetic substrate, such as those carrying gene variants associated with Marfan syndrome or other inherited aortopathies, can favor an excessive aortic enlargement and trigger an acute aortic dissection. The evaluation of the aortic valve and aortic root diameters, as well as the detection of a disease-causing mutation for inherited aortic disease, should be followed by a tailored decision about sport eligibility. In addition, the risk of aortic complications associated with sport in patients with genetic aortic disease is poorly characterized and is often difficult to stratify for each individual athlete. This review aims to describe the relationship between regular physical activity and aortic dilation, focusing on patients with bicuspid aortic valve and inherited aortic disease, and discuss the implications in terms of aortic disease progression and sport participation.

Bisoprolol for treatment of symptomatic patients with obstructive hypertrophic cardiomyopathy. The BASIC (bisoprolol AS therapy in hypertrophic cardiomyopathy) study.

AIMS: To evaluate the role of bisoprolol to control symptoms and left ventricular outflow tract obstruction (LVOTO) in a consecutive cohort of adults with hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: In this retrospective study, patients with HCM with an LVOT gradient ≥50 mmHg after Valsalva manoeuvre and New York Heart Association (NYHA) class II-III symptoms were assigned to receive bisoprolol (starting at 1.25 mg daily). The initial dose was increased every two weeks to achieve the target in LVOT gradient <30 mmHg or the maximum tolerated dose. The primary endpoint was the achievement of a LVOT gradient <30 mmHg and ≥ 1 NYHA class improvement. The secondary endpoints were proportion of patients with LVOT gradient <30 mmHg or < 50 mmHg, proportion of patients with ≥1 NYHA class improvement, and change from baseline in LVOT gradient. Between December 2001 and December 2020, 92 patients were enrolled into the study. Sixteen (17%) patients on bisoprolol met the primary endpoint. Bisoprolol reduced the LVOT gradient to less than 30 mmHg in 33 (36%) patients, to less than 50 mmHg in 57 (62%), and improved NYHA class in 30 (33%). The mean reduction of LVOT gradient on bisoprolol was 28 (±14) mmHg and the percentage reduction was 42 (±21) %. In 35 (38%) patients, bisoprolol did not reduce the gradient to less than 50 mmHg requiring disopyramide and/or myectomy to achieve this goal. CONCLUSION: Treatment with bisoprolol was well-tolerated and effective in relieving obstruction and improving symptoms in a significant proportion of patients with symptomatic obstructive HCM.

Multimodality Imaging in Cardiomyopathies with Hypertrophic Phenotypes.

Multimodality imaging is a comprehensive strategy to investigate left ventricular hypertrophy (LVH), providing morphologic, functional, and often clinical information to clinicians. Hypertrophic cardiomyopathy (HCM) is defined by an increased LV wall thickness not only explainable by abnormal loading conditions. In the context of HCM, multimodality imaging, by different imaging techniques, such as echocardiography, cardiac magnetic resonance, cardiac computer tomography, and cardiac nuclear imaging, provides essential information for diagnosis, sudden cardiac death stratification, and management. Furthermore, it is essential to uncover the specific cause of HCM, such as Fabry disease and cardiac amyloidosis, which can benefit of specific treatments. This review aims to elucidate the current role of multimodality imaging in adult patients with HCM.

Diagnostic issues faced by a rare disease healthcare network during Covid-19 outbreak: data from the Campania Rare Disease Registry.

BACKGROUND: The aims of this study were: to investigate the capacity of the rare disease healthcare network in Campania to diagnose patients with rare diseases during the outbreak of Covid-19; and to shed light on problematic diagnoses during this period. METHODS: To describe the impact of the Covid-19 pandemic on the diagnosis of patients with rare diseases, a retrospective analysis of the Campania Region Rare Disease Registry was performed. A tailored questionnaire was sent to rare disease experts to investigate major issues during the emergency period. RESULTS: Prevalence of new diagnoses of rare disease in March and April 2020 was significantly lower than in 2019 (117 versus 317, P < 0.001 and 37 versus 349, P < 0.001, respectively) and 2018 (117 versus 389, P < 0.001 and 37 versus 282, P < 0.001, respectively). Eighty-two among 98 rare disease experts completed the questionnaire. Diagnostic success (95%), access to diagnosis (80%) and follow-up (72%), lack of Personal Protective Equipment (60%), lack of Covid-19 guidelines (50%) and the need for home therapy (78%) were the most important issues raised during Covid-19 outbreak. CONCLUSIONS: This study describes the effects of the Covid-19 outbreak on the diagnosis of rare disease in a single Italian region and investigates potential issues of diagnosis and management during this period.

Aberrant right subclavian artery: the association with chromosomal defects and the related post-natal outcomes in a third level referral centre.

Aberrant right subclavian artery (ARSA) is the most common embryologic abnormality of the aortic arch. The presence of ARSA has been previously associated with an increased risk of Down syndrome. ARSA at birth may be associated with dysphagia, respiratory distress and stridor and there is no clear evidence-based management. The aim of this study was to describe the associations with chromosomal abnormalities and the postnatal outcome of fetuses diagnosed with ARSA. We analysed fetuses diagnosed antenatally with ARSA between January 2013 and September 2019 in the fetal echocardiography unit of the Hospital Monaldi, University 'Vanvitelli' of Naples, Italy. The results showed fifty fetuses diagnosed with ARSA, all confirmed after birth. The ARSA was an isolated finding in 46 fetuses (92%), while in 4 fetuses the ARSA was associated with other cardiac and/or extra-cardiac anomalies. Only one fetus was diagnosed with trisomy 21 (2%). In this fetus the ARSA was the only ultrasound anomaly identified. There were no cases necessitating referral due to the presence of compression symptoms at birth. The presence of ARSA was associated with trisomy 21 in the 2% of cases in our series and there were no neonatal complications due to airway compression at birth.IMPACT STATEMENTWhat is already known on this subject? Aberrant right subclavian artery (ARSA) is the most common embryologic abnormality of the aortich arch. ARSA at birth could be associated with dysphagia, respiratory distress and stridor and no evidence-based management of these fetuses has been described yet. The presence of ARSA has been previously associated with an increased risk of Down syndrome.What do the results of this study add? This study confirms known data on association with chromosomal defects and provides some original data on the absence of symptomatology due to tracheal compression with a postnatal follow-up up to three years of age.What are the implications of these findings for clinical practice and/or further research? Our findings suggest that in cases with adequate prenatal assessment performed by experienced clinicians, delivery can safely take place at local hospitals, with no need of referral soon after birth. The use of transthoracic echocardiography to confirm the diagnoses of ARSA after birth and to plan the next follow-up appointments can be supported.

Natural history of left ventricular hypertrophy in infants of diabetic mothers.

BACKGROUND: This study sought to describe the characteristics and the natural course of left ventricular hypertrophy (LVH) in a well-characterized consecutive cohort of infants of diabetic mothers (IDMs). METHODS: Sixty consecutive IDMs with LVH have been retrospectively identified and enrolled in the study. All IDMs were evaluated at baseline and every 6 months until LV wall thickness regression, defined as the decrease of wall thickness measurement into the normal reference range for cardiac parameters (z-score > -2 and < 2). A comprehensive assessment was performed in those patients with diagnostic markers suggestive of a different cause and/or without significant reduction of the LVH during follow-up. RESULTS: At 1-year follow-up, all IDMs showed a significant reduction of maximal wall thickness MWT (6.00 mm [IQR 5.00-712] vs. 5.50 mm [IQR 5.00-6.00], p-value <0.001; MWT-z-score: 4.86 [IQR 3.93-7.61] vs. 1.72 [IQR 1.08-2.85], p-value <0.001) compared to baseline, and all patients showed LV wall thickness regression or residual mild or moderate LVH (57%, 28%, and 12%, respectively), except 2 patients with persistent severe LVH, that after a comprehensive clinical-genetic assessment were diagnosed as Noonan syndrome with multiple lentigines. At multivariate analysis, MWT was negatively associated with LV wall thickness regression at 1-year follow-up (MWT-mm: OR 0.48[0.29-0.79], p-value = 0.004; MWT-z-score: OR 0.71[0.56-0.90], p-value = 0.004). CONCLUSIONS: LVH in IDMs represents a benign condition with complete regression during the first years of life. In those patients without LV wall thickness regression, combined with clinical markers suggesting a specific disease, a complete work-up is required for a definite diagnosis.

The Risk of Sudden Unexpected Cardiac Death in Children: Epidemiology, Clinical Causes, and Prevention.

"Sudden unexplained death (SUD) is a tragic event for both the family and community, particularly when it occurs in young individuals. Sudden cardiac death (SCD) represents the leading form of SUD and is defined as an unexpected event without an obvious extracardiac cause, occurring within 1 hour after the onset of symptoms. In children, the main causes of SCD are inherited cardiac disorders, whereas coronary artery diseases (congenital or acquired), congenital heart diseases, and myocarditis are rare. The present review examines the current state of knowledge regarding SCD in children, discussing the epidemiology, clinical causes, and prevention strategies."

Clinical Manifestations of 22q11.2 Deletion Syndrome.

DiGeorge syndrome (DGS), also known as "22q11.2 deletion syndrome" (22q11DS) (MIM # 192430 # 188400), is a genetic disorder caused by hemizygous microdeletion of the long arm of chromosome 22. In the last decades, the introduction of fluorescence in situ hybridization assays, and in selected cases the use of multiplex ligation-dependent probe amplification, has allowed the detection of chromosomal microdeletions that could not be previously identified using standard karyotype analysis. The aim of this review is to address cardiovascular and systemic involvement in children with DGS, provide genotype-phenotype correlations, and discuss their medical management and therapeutic options.