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.

Distribution and age of onset of psychopathological risk in a cohort of children with Down syndrome in developmental age.

BACKGROUND: Aim of the study is to intercept specific characteristics and psychiatric comorbidity in Down Syndrome (DS). The study describes the distribution and the age of specific aspects of behavioral phenotype in a sample of subjects with DS. METHODS: Psychopathological risk has been evaluated in a 97 DS patient cohort, aged 1 to 18 years, during regular follow-up neuropsychiatric visit and through administration of Child Behavior Checklist (CBCL); Childhood Autism Rating Scale (CARS-T) was assessed to verify the presence of autistic behaviors. RESULTS: The results show the presence of specific psychopathological risk factors in 90% of the sample. 7% of sample presents autistic features. The risk of psychopathology is independent of the degree of intellectual disability. CONCLUSION: The high frequency of psychopathological risk factors indicates the need for accurate monitoring to intercept specific characteristics, such as in the case of comorbidity for autism. The search for specific psychopathological factors is a little explored aspect to date, as evidenced by the literature. Despite the studies available to date highlight the presence of psychopathological vulnerability in DS, so far there are only few reports that explore this issue systematically.

Steroid therapy in an alpha-dystroglycanopathy due to GMPPB gene mutations: A case report.

Alpha-dystroglycanopathies are a group of progressive and untreatable neuromuscular disorders, due to aberrant alpha-dystroglycan glycosylation. We describe the effects of a short-term cycle of corticosteroid therapy in a 9-year-old boy, affected by an alpha-dystroglycanopathy due to GMPPB gene mutations. The patient was affected by a congenital progressive muscular dystrophy since the first month of life, associated with psychomotor delay, seizures, and congenital bilateral cataracts. Despite physical therapy he had a progressive motor impairment. At the age of 9 years, he was treated with 0.75 mg/kg/day of prednisone for 3 months and showed improvements in muscle strength and function scores and creatine kinase reduction. When steroid therapy was discontinued he showed again clinical and biochemical deterioration. These data suggest that corticosteroid may be considered as a treatment for patients with alpha-dystroglycanopathies due to GMPPB mutations.

Long-term treatment of phenylketonuria with a new medical food containing large neutral amino acids.

This corrects the article DOI: 10.1038/ejcn.2016.166.

Long-term treatment of phenylketonuria with a new medical food containing large neutral amino acids.

BACKGROUND/OBJECTIVES: Phenylketonuria (PKU) is an autosomal recessive disease caused by deficient activity of phenylalanine hydroxylase. A low phenylalanine (Phe) diet is used to treat PKU. The diet is very restrictive, and dietary adherence tends to decrease as patients get older. Methods to improve dietary adherence and blood Phe control are continuously under investigation. SUBJECTS/METHODS: A new formula Phe-neutral amino acid (PheLNAA) has been tested in this study with the purpose of improving the compliance and lowering blood phenylalanine. The formula has been tested for nitrogen balance, and it is nutritionally complete. It is fortified with more nutritional additives that can be deficient in the PKU diet, such as B12, Biotin, DHA, Lutein and increased levels of large neutral amino acids to help lower blood Phe. The new formula has been tested on 12 patients with a loading test of 4 weeks. RESULTS: Fifty-eight percent of patients had a significant decline in blood Phe concentration from baseline throughout the study. The PheLNAA was well tolerated with excellent compliance and without illnesses during the study. CONCLUSIONS: In conclusion, the new formula is suitable for life-long treatment of PKU, and it offers the PKU clinic a new choice for treatment.

Hypertension and obesity in Italian school children: The role of diet, lifestyle and family history.

BACKGROUND AND AIMS: In Italy, the prevalence of hypertension, obesity and overweight in paediatric patients has increased in the past years. The purpose of this study was to analyse the relationship between obesity and hypertension and related factors in Italian students. METHODS AND RESULTS: We studied 2007 healthy individuals between the ages of 6 and 17 years of age (998 males and 1009 females) attending schools in the cities of Varese (northern Italy), Rome (central Italy) and Catanzaro (southern Italy). The blood pressure, weight and height of the students were measured. We also assessed their daily intake of foods and the amount of physical activity they performed. A questionnaire was administered to the parents of the subjects to obtain information on the child's medical history and family lifestyle. Of the students, 27.2% were overweight, and 6.6% were obese, with the highest percentages in southern Italy. A total of 6.2% of students had hypertension, and the region with the highest percentage was found to be northern Italy. Obese students had a risk of developing hypertension that was four times greater than those subjects who were of normal weight. CONCLUSION: Overweight and obese children/adolescents were more frequently found in southern Italy as opposed to northern and central Italy, and hypertensive children were more prevalent in the north. An unhealthy diet might explain the more widely spread obesity among children living in the south; an excess use of salt could explain the greater rate of hypertension found among children/adolescents living in the north.

Intrafamilial phenotypic variability in four families with Anderson-Fabry disease.

We analysed the clinical history of 16 hemizygous males affected by Anderson-Fabry Disease, from four families, to verify their intrafamilial phenotypic variability. Seven male patients, ranging from 26 to 61 years of age, died, whereas nine (age range 23-55) are alive. Eleven patients have undergone enzyme replacement therapy (ERT) for a period of 5-10 years. We have found a wide range of intrafamilial phenotypic variability in these families, both in terms of target-organs and severity of the disease. Overall, our findings confirm previous data from the literature showing a high degree of intrafamilial phenotypic variability in patients carrying the same mutation. Furthermore, our results underscore the difficulty in giving accurate prognostic information to patients during genetic counselling, both in terms of rate of disease progression and involvement of different organs, when such prognosis is solely based on the patient's family history.

A de novo 8q22.2-24.3 duplication in a patient with mild phenotype.

We report a new case of 8q interstitial duplication in a patient with dysmorphic features, umbilical hernia, cryptorchidism, short stature, congenital heart defect and mild mental retardation (MR). Chromosome analysis with high resolution QFQ bands showed 46,XY, 8q+, which was interpreted as a partial duplication of the distal long arm of chromosome 8 (q22 â†’ qter). This chromosomal aberration was further characterized using fluorescence in situ hybridization (FISH) analyses with multiple DNA probes and array-CGH (Comparative Genomic Hybridization) experiment which demonstrated a de novo direct duplication (8)(q22.2-q24.3). We have compared this case with other partially trisomic 8q patients reported in literature and highlighted the common clinical features in 8q22-8q24 duplication syndrome.

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.

[High percentage of obesity during childhood and adolescence and subsequent increases in childhood arterial hypertension]. / Alta percentuale di obesi in età evolutiva e conseguente aumento dell'ipertensione arteriosa infantile.

AIM: The main objective of the study was to assess the prevalence of obesity, overweight and blood hypertension amongst children and adolescents. METHODS: The study enrolled 2045 students between 6 and 17 years of age in three Italian cities, Varese (in the North), Rome (in the Center) and Catanzaro (in the South). RESULTS: The findings demonstrate that the obesity rate is 3.5% in the North, 6.1% in the Center and 8.8% in the South; these figures represent an increase both in the North and in the South. At the same time, the incidence of arterial hypertension has increased in respect to past years with 5.5% of the total study population diagnosed with hypertension over the 95 degrees percentile and 7.1% with borderline hypertension. Parental obesity has been demonstrated to be a key factor in determining the presence or level of obesity in their children. CONCLUSION: Obesity and arterial hypertension represent a worrisome departure point for a dangerous metabolic syndrome and hence require the full dedication of pediatricians in order to prevent the disease, with an urgent need for school interventions, support for a healthy diet and insistence on the necessity of adequate daily exercise.

Phenotypic variability, neurological outcome and genetics background of 6-pyruvoyl-tetrahydropterin synthase deficiency.

This study aimed to investigate the clinical variability and factors implied in the outcome of 6-pyruvoyl-tetrahydropterin synthase deficiency (PTPSd). Biochemical and clinical phenotype, treatment variables, and 6-pyruvoyl-tetrahydropterin synthase (PTS) genotype, were explored retrospectively in 19 Italian patients (12 males and 7 females, aged 4 months to 33 years). According to the level of biogenic amines in cerebrospinal fluid (CSF) at the diagnosis, the patients were classified as mild (6) (normal level) or severe (13) (abnormal low level) form (MF and SF, respectively). Blood Phe ranged from 151 to 1053 micromol/l in MF (mean +/- SD: 698 +/- 403) and 342-2120 micromol/l in SF (mean +/- SD: 1175 +/- 517) (p = 0.063). Patients with MF showed a normal neurological development (a transient dystonia was detected in one), while all SF patients except one presented with severe neurological impairment and only four had a normal neurological development. The outcome of the SF was influenced by the precocity of the treatment. Serial CSF examinations revealed a decline of 5-hydroxyindolacetic acid in MFs and an incomplete restoration of neurotransmitters in SFs: neither obviously affected the prognosis. PTS gene analysis detected 17 different mutations (seven so far unreported) (only one affected allele was identified in three subjects). A good correlation was found between genotype and clinical and biochemical phenotype. The occurrence of brain neurotransmitter deficiency and its early correction (by the therapy) are the main prognostic factors in PTPSd.

Enzyme replacement therapy with agalsidase alfa in a cohort of Italian patients with Anderson-Fabry disease: testing the effects with the Mainz Severity Score Index.

Anderson-Fabry disease (AFD) is a rare X-linked disorder caused by lysosomal storage of several glycosphingolipids, affecting virtually all organs and systems. Enzyme replacement therapy (ERT) for AFD has been available since 2001. Due to the highly variable nature of clinical manifestations in patients with AFD, it is very difficult to assess disease progression and the effects of therapy. We used the Mainz Severity Score Index (MSSI) as a measure of disease severity to study the effects of ERT in a population of 30 patients treated with agalsidase alfa for a median of 2.9 years (range, 1.0-6.2 years). Our data show that the MSSI captures the correlation between disease severity and both gender and age (1 - males performing worse than females at baseline and 2 - severity of diseases progresses with age in both sex). Furthermore, after at least 1 year of ERT, total MSSI scores were significantly lower than those at baseline (p < 0.001), suggesting a marked clinical improvement under ERT. In conclusion, the MSSI is a sensitive and useful tool for monitoring disease progression and assessing the effects of ERT in a population of patients from different treatment centres.

Serum prolactin as a tool for the follow-up of treated DHPR-deficient patients.

Deficiency of dihydropteridine reductase causes a variant form of phenylketonuria associated with a devastating neurological disease characterized by mental retardation, hypokinesis and other features relating to basal ganglia disorder. Hyperphenylalaninaemias with tetrahydrobiopterin deficiency make up about 1-3% of all hyperphenylalaninaemias. We describe three patients from Calabria, a southern region of Italy, who have a dihydropteridine reductase deficiency, caused by the same mutation (p.L14P) also found in the nearby region of Sicily. We report the evolution of clinical and biochemical data during the treatment of these patients where we used prolactin serum determination to adapt the specific therapy. This report suggests that serum prolactin levels can be a good biomarker for optimal dosage of hydroxylated precursors in long-term treatment monitoring.

Vitamin D status in patients affected by Smith-Lemli-Opitz syndrome.

Smith-Lemli-Opitz syndrome (SLOS) is an inborn error of cholesterol biosynthesis characterized by developmental delay and multiple malformations. Some of the patients have skin photosensitivity and therefore tend to avoid direct exposure to sunlight.SLOS patients typically have low concentrations of cholesterol and abnormally high concentrations of its precursor 7-dehydrocholesterol (7-DHC) in biological fluids and tissues. 7-DHC is also a precursor in the cutaneous synthesis of vitamin D. Sunlight exposure plays a major role in this pathway and reactions transforming 7-DHC into vitamin D and then into 25-hydroxyvitamin D are known not to be specifically regulated. The aim of this study was to evaluate vitamin D status in SLOS patients. We measured 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D serum concentrations and markers of calcium metabolism in five SLOS patients. Despite abnormally high concentrations of 7-DHC, circulating concentrations of vitamin D metabolites were not significantly different from appropriate controls matched for sex, age and season of blood collection. The analysis of historical serum samples stored in our laboratory from the same cases plus 10 other SLOS patients further supported these findings. Our data suggest that SLOS patients have a peculiar vitamin D metabolism that protects them from vitamin D intoxication. This appears to be due in most cases to decreased transformation of 7-DHC into 25-hydroxyvitamin D, perhaps depending on reduced sunlight exposure as a consequence of photosensitivity. Possible alternative mechanisms are discussed.

Enterocyte actin autoantibody detection: a new diagnostic tool in celiac disease diagnosis: results of a multicenter study.

OBJECTIVES: This study describes a new method to detect autoantibodies against actin filaments (AAA) as a serological marker of intestinal villous atrophy (IVA) in celiac disease (CD), and reports the results of an Italian double-blind multicenter study. METHODS: IgA-AAA were analyzed by immunofluorescence using a newly developed method based on intestinal epithelial cells cultured in presence of colchicine. IgA-AAA were blindly evaluated prospectively in 223 antiendomysial antibody (AEA) and/or antitransglutaminase antibody (TGA) positive subjects and in 78 AEA and TGA negative subjects. IgA-AAA positive patients underwent an intestinal biopsy to confirm the diagnosis. Moreover, IgA-AAA were retrospectively investigated in 84 biopsy-proven CD patients and in 2,000 new consecutively collected serum samples from AEA and TGA negative nonbiopsied subjects. RESULTS: IgA-AAA were positive in 98.2% of the CD patients with flat mucosa, in 89% with subtotal villous atrophy, and in 30% with partial villous atrophy. IgA-AAA were present in none of the AEA and TGA negative nonbiopsied controls. In AEA and/or TGA positive CD patients IgA-AAA positivity significantly correlated with IVA (p < 0.000 in the prospective study, p = 0.005 in the retrospective study). In the prospective study, the values of sensitivity, specificity, the positive predictive value, the negative predictive value, and the efficiency of the IgA-AAA test to identify patients with IVA were, respectively, 83.9%, 95.1%, 97.8%, 69.2%, and 87.0%. Furthermore, a significant correlation (p < 0.0001) was found between the IgA-AAA serum titre and the degree of IVA (rs 0.56). CONCLUSIONS: The results of this multicenter study show that the new method for IgA-AAA detection could represent a practical diagnostic tool in AEA and/or TGA positive subjects, which would be especially useful when IVA shows a patchy distribution, when the histological picture is difficult to interpret, or when a biopsy could represent a life-threatening risk.

High seroprevalence of Helicobacter pylori infection in non-institutionalised children with mental retardation.

Eighty-four children with mental retardation (34 boys, 50 girls; age range 2-18 years, median 6 years) and 84 age- and gender-matched outpatient controls were studied. All children were living at home, had never stayed in an institution, and came from the same urban area. Seropositivity for Helicobacter pylori was found in 42 (50%) of 84 mentally retarded children and 16 (19%) of 84 controls (p < 0.01). Socio-economic factors did not differ between the two groups. The findings indicated that a higher prevalence of H. pylori infection occurs in children with mental retardation, regardless of whether they are institutionalised.