Endocrine system involvement in patients with RASopathies: A case series.

Background and Objectives: Endocrine complications have been described in patients affected by RASopathies but no systematic assessment has been reported. In this study, we investigate the prevalence of endocrine disorders in a consecutive unselected cohort of patients with RASopathies. Study Design: 72 patients with a genetically confirmed RASopathy (Noonan syndrome [NS], N=53; 29 LEOPARD syndrome [LS], N=2; cardiofaciocutaneous syndrome [CFCS], N=14; subjects showing co-occurring pathogenic variants in PTPN11 and NF1, N=3) and an age- and sex-matched healthy controls were included in the study. Endocrine system involvement was investigated by assessing the thyroid function, pubertal development, auxological parameters, adrenal function and bone metabolism. Results: Short stature was detected in 40% and 64% of the NS and CFCS subcohorts, respectively. Patients showed lower Z-scores at DXA than controls (p<0.05) when considering the entire case load and both NS and CFCS groups. Vitamin D and Calcitonin levels were significantly lower (p< 0.01), Parathormone levels significantly higher (p<0.05) in patients compared to the control group (p<0.05). Patients with lower BMD showed reduced physical activity and joint pain. Finally, anti-TPO antibody levels were significantly higher in patients than in controls when considering the entire case load and both NS and CFCS groups. Conclusions: The collected data demonstrate a high prevalence of thyroid autoimmunity, confirming an increased risk to develop autoimmune disorders both in NS and CFCS. Reduced BMD, probably associated to reduced physical activity and inflammatory cytokines, also occurs. These findings are expected to have implications for the follow-up and prevention of osteopenia/osteoporosis in both NS and CFCS.

Risk of autoimmune diseases in patients with RASopathies: systematic study of humoral and cellular immunity.

BACKGROUND: Abnormalities of the immune system are rarely reported in patients affected by RASopathies. Aim of the current study was to investigate the prevalence of immune system dysfunction in a cohort of patients affected by RASopathies. STUDY DESIGN: A group of 69 patients was enrolled: 60 at the Federico II University, Naples, 7 at University Magna Graecia of Catanzaro, 2 at "Scuola Medica Salernitana", Salerno. An age- and sex-matched control group was also enrolled. Autoimmune disorders were investigated according to international consensus criteria. Immune framework was also evaluated by immunoglobulin levels, CD3, CD4, CD8, CD19, CD56 lymphocyte subpopulations, autoantibodies levels and panel of inflammatory molecules, in both patients and controls. RESULTS: Frequent upper respiratory tract infections were recorded in 2 patients; pneumonia, psoriasis and alopecia in single patients. Low IgA levels were detected in 8/44 patients (18.18%), low CD8 T cells in 13/35 patients (37.14%). Anti-tg and anti-TPO antibodies were detected in 3/24 patients (12.5%), anti r-TSH in 2 cases (8.33%), all in euthyroidism. Serum IgA and CD8 levels were significantly lower in patients than in controls (p 0.00685; p 0.000656 respectively). All tested patients showed increased inflammatory molecules compared to controls. These findings may anticipate the detection of overt autoimmune disease. CONCLUSIONS: Patients affected by RASopathies are at risk to develop autoimmune disorders. Routine screening for autoimmunity is recommended in patients with RASopathy.

Relationship between Macrovascular and Microvascular Hemodynamics Assessed by Spectrophotometry in Periodontal Diseases.

OBJECTIVE: The aim of this study is to identify a possible link between macrovascular hemodynamic status and microvascular hemodynamic indices in patients with periodontal disease. METHODS AND MATERIALS: Seventeen adult patients are recruited on a voluntary basis at the Dentistry Department of the "Mater Domini" University of Catanzaro, with sampling that determines the lipid profile, blood glucose, inflammatory mediators, blood plasma viscosity: anamnesis, blood pressure measurement, and detection of anthropometric parameters: eco-Doppler of the carotid arteries and brachial arteries with noninvasive measurements of hemodynamics and evaluation of inflammation and periodontal circulation with a noninvasive spectroscopic technique. The subjects underwent a dental inspection with periodontal proves. The different indices of periodontal disease were evaluated. RESULTS: The sites with high probing depth differ from the healthy ones, showing low oxygen saturation and a notable increase in tissue edema, but no correlation between macro- and microvascular values was found. CONCLUSION: Periodontal probing and spectroscopic examination showed the correlation between low oxygen saturation levels and tissue edema values with probing depth; however, no correlation between macrovascular hemodynamic status and microvascular hemodynamics indices was found probably given the heterogeneity of the population under consideration, the low number of data gathered, and the small sample size.

PPHN and oxidative stress: a review of literature.

Persistent pulmonary hypertension of the neonate is a multifactorial condition characterized by maladaptive pulmonary vascular remodeling and abnormal contractile reactivity. This review evaluates the role of oxidative stress and antioxidant treatment on the persistent pulmonary hypertension of the neonate.

Cardiac malformations in children with congenital hypothyroidism.

Congenital hypothyroidism (CH) is the most common endocrine disease in children, according to literature, infants with CH have an increased risk of associated congenital malformations (CM), especially cardiac defects (CD), compared to the general population. We retrospectively analyzed medical records of 255 patients with a positive screening result for CH in the period 1991-2016 followed at our Center. At the time of enrollment, the clinical examination included looking for the presence of heart murmurs and dysmorphic features. In all patients an echocardiography with cardiological evaluation were performed. Of all patients, 191 were included in the final analysis. Of these, 51.3% (98/191) presented an eutopic normally sized thyroid gland while 48.7% (93/191) showed a thyroid dysgenesis. Among the studied infants, 13.6% (26/191) presented CD. The most frequent cardiac anomaly was atrial septal defect (ASD) which was found in 65.4% (17/26) of patients with CD. Other defects were ventricular septal defect (VSD), patent ductus arteriosus (PDA), pulmonary valve stenosis (PvS), transposition of the great vessels (TGV), aortic valve stenosis (AvS). Six patients had multiple defects. In the analysed group, there was no significant relation with sex, type of CH, median blood-TSH (b-TSH) and serum-TSH (s-TSH) values and frequency of CD. There is a high prevalence of CD in CH, indicating the need of routine echocardiography in these patients to achieve an early diagnosis and management of CD.

Dilated cardiomyopathy in mucolipidosis type 2.

Mucolipidosis II and III are lysosomal storage diseases caused by pathogenetic mutations in GNPTAB and GNPTG genes which cause an impaired activity of the lysosomal hydrolase N-acetylglucosamine- 1-phosphotransferase, a key enzyme in the synthesis of the mannose-6-phosphate targeting signals on lysosomal enzymes. Patients with MLII alpha/beta present coarse facial features, cessation of statural growth, important skeletal manifestations, impaired neuromotor development and cardiorespiratory involvement. All children appear to have cardiac involvement, but severe dilated cardiomyopathy is uncommon. In this report we describe the case of an 11-month-old girl who is affected by a MLII. Analysis of the GNPTAB gene identified at a heterozygous level the previously described gene variants c. 2693delA p(Lys898Serfs*13) and c. 2956C>T p(Arg986Cys). Her main clinical features were coarse face with gingival hypertrophy, dysostosis multiplex, recurrent respiratory infection and an early onset of dilated cardiomyopathy, an uncommon feature for MLII. To our knowledge, dilated cardiomyopathy has been previously described in literature in only two cases of MLII and in one patient affected by MLIII.

Cardiac involvement in Lysosomal Storage Diseases.

Lysosomal storage diseases (LSDs) include a heterogeneous group of rare, inborn, metabolic diseases characterized by deficiency of lysosomal enzymes or of other proteins involved in lysosomal function, leading to multi organ system substrates accumulation, with consequent multi systemic clinical presentation. Cardiac disease is particularly important in some group of LSDs as glycogen storage diseases (Pompe), mucopolysaccharidoses and in glycosphingolipidoses (Anderson-Fabry disease and less frequently Gaucher disease). Various cardiac manifestations may be observed including hypertrophic and dilated cardiomyopathy, coronary artery disease and valvular disease. The availability of enzyme replacement therapy (ERT) has changed the natural history of some LSDs such as Pompe disease, thanks to the significant effects on cardiological involvement. In other LSDs such as MPSs or Fabry disease, ERT has been shown to stabilize or slow the progression of heart damage. This imposes the need for a timely diagnosis that allows a rapid onset of ERT.

Prevalence of elevated pulmonary artery systolic pressure in Down Syndrome young patients with and without congenital heart disease.

This study examined the prevalence and distribution of elevated systolic pulmonary arterial pressure, measured by echocardiography, in young patients with down syndrome associated or not with congenital heart disease and surgical correction during childhood. Pulmonary artery systolic pressure, computed by regurgitant tricuspid flow velocity evaluation, is the most frequently used parameter for the screening of pulmonary hypertension. Down syndrome and congenital heart disease often coexist and the probability to detect elevated systolic pulmonary arterial pressure in this setting is high. However, little is known about the evaluation of pulmonary arterial pressure during growth of patients with down syndrome with or without congenital heart disease. We enrolled 47 young patients (55% of male sex; mean age: 18.4 ± 6.0 years), 40 with congenital heart disease and 7 without a cardiac defect. Systolic pulmonary arterial pressure was assessed by echocardiography. No difference was found in the population dichotomized by presence or absence of CHD. Only male sex (p=0.000), highly sensitive troponin-T (P=0.027), tricuspid annular plane systolic excursion (TAPSE, p=0.045) and sPAP (p=0.004) were elevated in surgical group. The ASD was found as, the most common structural abnormality in our patients (50%), followed by VSD (27.5%) and complex CHD (such as complete atrioventricular canal defect, CAVC = 25% and Fallot disease = 15%). Furthermore, about 45% of patients had the combined defect. Only 37.5% of patients underwent to corrective surgery during the first months of life. We observed a significantly increase of sPAP values in patients with complex CHD, such as CAVC (p=0.019) and Fallot disease (p=0.001) but, in the following multivariate analysis performed in the patients with CHD, only Fallot disease remains as independent predictors of elevated values of sPAP (p=0.022). An elevated systolic pulmonary arterial pressure may represent the key screening tool in the diagnostic assessment of suspect pulmonary arterial hypertension in high risk population with down syndrome regardless the presence of congenital heart disease.

Covid-19 and cardiac involvement in childhood: state of the art.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first described in a cluster of patients in Wuhan, China, in December of 2019. Over the past few months, COVID-19 has rapidly spread worldwide becoming the first pandemic of the 21st century. COVID-19 results in mild symptoms in most infected children but can cause acute cardiac injury and death. In comparison to younger children, teenagers and infants are at higher risk for morbidity and mortality, with particular risk factors including pre-existing conditions like cardiovascular disease. Since this is an emerging infectious disease, there are limited data about the effects of this infection on patients especially in the pediatric population. We summarize here with the data on cardiovascular involvement in children and adolescents.

Oxidative stress biomarkers in Fabry disease: is there a room for them?

BACKGROUND: Fabry disease (FD) is an X-linked lysosomal storage disorder, caused by deficient activity of the alpha-galactosidase A enzyme leading to progressive and multisystemic accumulation of globotriaosylceramide. Recent data point toward oxidative stress signalling which could play an important role in both pathophysiology and disease progression. METHODS: We have examined oxidative stress biomarkers [Advanced Oxidation Protein Products (AOPP), Ferric Reducing Antioxidant Power (FRAP), thiolic groups] in blood samples from 60 patients and 77 healthy controls. RESULTS: AOPP levels were higher in patients than in controls (p < 0.00001) and patients presented decreased levels of antioxidant defences (FRAP and thiols) with respect to controls (p < 0.00001). In a small group of eight treatment-naïve subjects with FD-related mutations, we found altered levels of oxidative stress parameters and incipient signs of organ damage despite normal lyso-Gb3 levels. CONCLUSIONS: Oxidative stress occurs in FD in both treated and naïve patients, highlighting the need of further research in oxidative stress-targeted therapies. Furthermore, we found that oxidative stress biomarkers may represent early markers of disease in treatment-naïve patients with a potential role in helping interpretation of FD-related mutations and time to treatment decision.

Alport's syndrome.

Alport's syndrome (AS, OMIM 301050) is a hereditary disorder characterized by progressive renal failure, hearing impairment and ocular changes. It is clinically and genetically heterogeneous and in its natural history, renal disease progresses from microscopic haematuria to proteinuria, and finally to progressive renal insufficiency. AS is caused by an inherited defect in a type IV collagen, a structural material, expressed in many tissues that is essential for the normal function of different parts of the body. In most of cases, about the 85%, Alport's syndrome is X-linked and is originated by mutations in the COL4A5 gene. In the remaining cases, it may be inherited in either an autosomal recessive, or rarely in an autosomal dominant manner. Mostly, the condition is caused by mutations in the COL4A3 or COL4A4 genes. Coexisting mutations in COL4A3, COL4A4, COL4A5 or COL4A6 were found to cause an Alport's syndrome phenotype with digenic inheritance. Diagnosis of the condition is based on family history, clinical signs, and specific procedures such as a kidney biopsy. The diagnosis can be confirmed by genetic testing. Treatment may include use of a hearing aid, hemodialysis, and peritoneal dialysis to treat those with end-stage renal failure, and, as the last step, kidney transplantation. Firstly described by Arthur C. Alport's, in 1927, over the years it has become a pathology of high scientific interest. At the moment, thanks to advances in diagnostic techniques, it is possible to make an early diagnosis avoiding irreversible damages and life -threatening complications.

Renal involvement in paediatric Fabry disease.

Anderson-Fabry Disease (AFD) is a rare, X-linked inborn error of glycosphingolipid catabolism caused by a deficient or absent activity of the lysosomal enzyme, α-galactosidase A, resulting in the progressive multisystem lysosomal accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3). Among the wide spectrum of clinical signs and symptoms and the life-threatening complications of Fabry disease, renal failure causes significant morbidity and mortality. Various evidence shows that the accumulation of Gb3 in different renal cells is present since the first years of life, many years and usually decades before manifest symptoms and signs of renal involvement. Early renal damage can be demonstrated by clinical signs as microalbuminuria and proteinuria, developing as early as in the second decade of life. A decline in GFR is uncommon at paediatric ages but may be seen as early as adolescence. Renal biopsy is rarely used in paediatric patients with Fabry disease although evidence shows that it may be considered a valid tool for the diagnosis of early and potentially reversible nephropathy, as well as for the evaluation of the effectiveness of enzyme replacement therapy (ERT). Although there is consensus in considering the early initiation of ERT as the only tool able to prevent the progression of nephropathy, the issue on the correct timing for the onset of ERT in pediatric age remains open in the management of this chronic and progressive disease.

Genetics and Gene Therapy in Hunter Disease.

Mucopolysaccharidosis type II or Hunter syndrome is an X-linked lysosomal storage disease caused by a mutation in the gene encoding the lysosomal enzyme iduronate-2-sulfatase. The consequent enzyme deficiency causes a progressive, multisystem accumulation of glycosaminoglycans, which is the cause of the clinical manifestations involving also Central Nervous System for patients with the severe form of disease. The limits of the currently available therapies for Hunter syndrome, hematopoietic stem cell transplantation and recombinant enzyme replacement therapy, mainly regarding brain achievement, have encouraged several studies which recognized gene therapy as a potential therapeutic option for this condition. In vitro studies firstly aimed at the demonstration that viral vector- mediated IDS gene expression could lead to high levels of enzyme activity in transduced cells. The encouraging results obtained allowed the realization of many preclinical studies investigating the utilization of gene therapy vectors in animal models of Mucopolysaccharidosis II, together with a phase I clinical trial approved for Hunter patients affected by the mild form of the disease. Together to in vivo studies in which recombinant vectors are directly administered, systematically or by direct injection into Central Nervous System, also ex vivo gene therapy, consisting in transplantation of autologous hematopoietic stem cells, modified in vitro, into the animal or patient, has been tested. A wider clinical application of the results obtained so far is essential to ensure that gene therapy can be definitively validated as a therapeutic option available and usable for this rare but life-threatening disorder.

Mitochondrial DNA haplogroups may influence Fabry disease phenotype.

While the genetic origin of Fabry disease (FD) is well known, it is still unclear why the disease presents a wide heterogeneity of clinical presentation and progression, even within the same family. Emerging observations reveal that mitochondrial impairment and oxidative stress may be implicated in the pathogenesis of FD. To investigate if specific genetic polymorphisms within the mitochondrial genome (mtDNA) could act as susceptibility factors and contribute to the clinical expression of FD, we have genotyped European mtDNA haplogroups in 77 Italian FD patients and 151 healthy controls. Haplogroups H and I, and haplogroup cluster HV were significantly more frequent in patients than controls. However, no correlation with gender, age of onset, organ involvement was observed. Our study seems to provide some evidence of a contribution of mitochondrial variation in FD pathogenesis, at least in Italy.

Clericuzio-type poikiloderma with neutropenia syndrome in three sibs with mutations in the C16orf57 gene: delineation of the phenotype.

We report on three sibs who have autosomal recessive Clericuzio-type poikiloderma neutropenia (PN) syndrome. Recently, this consanguineous family was reported and shown to be informative in identifying the C16orf57 gene as the causative gene for this syndrome. Here we present the clinical data in detail. PN is a distinct and recognizable entity belonging to the group of poikiloderma syndromes among which Rothmund-Thomson is perhaps the best described and understood. PN is characterized by cutaneous poikiloderma, hyperkeratotic nails, generalized hyperkeratosis on palms and soles, neutropenia, short stature, and recurrent pulmonary infections. In order to delineate the phenotype of this rare genodermatosis, the clinical presentation together with the molecular investigations in our patients are reported and compared to those from the literature.