Porencephaly in an Italian neonate with foetal alcohol spectrum disorder: A case report

INTRODUCTION: Foetal alcohol spectrum disorder (FASD) is a complex malformative disease caused by the teratogenic effect of alcohol consumed during pregnancy. Mothers are frequently reluctant to admit alcohol consumption during pregnancy. During infancy and particularly during neonatal period, differential diagnosis is difficult. PATIENT CONCERNS: This case is represented by an Italian neonate boy small for gestational age, born by caesarean section at a gestational age of 37 weeks + 6 days by neglect and single-parent pregnancy. On physical examination, he presented particular facial features: microcephaly, epicanthal folds, flat midface, low nasal bridge, indistinct philtrum, and thin upper lip; moreover, examination revealed a macro-penis and recurvation without evidence of glans. DIAGNOSIS: Echocardiogram showed an inter-ventricular defect of medium-muscular type and brain magnetic resonance imaging showed asymmetry of the cerebral hemispheres with hypoplasia of the left cerebral hemisphere, dilatation of the left ventricle, cerebrospinal fluid cavity, and porencephaly. INTERVENTIONS: We investigated the ethylglucuronide (EtG) concentration in the neonate's hair by liquid chromatography-tandem mass spectrometry and we detected EtG in the infant's hair (normal value, 30 pg/mg), demonstrating prenatal alcohol exposure. OUTCOMES: In this neonate, EtG measure in hairs permitted the diagnosis of FASD, so allowing to exclude genetic diseases associated with similar clinical findings. After this result the mother admitted that she drunk alcohol during pregnancy (she declared 3 glasses of wine every day). At the age of 6 months, the child showed a moderate neurodevelopmental delay. CONCLUSION: This case shows that FAD should be considered in neonates with rare neurological diseases as porencephaly. In neonates and infants born to a mother who did not report alcohol use, EtG measure in hairs can significantly improve diagnosis of FASD, so allowing to exclude genetic diseases associated with similar clinical findings

Abnormal hyperventilation in patients with hepatic cirrhosis: Role of enhanced chemosensitivity to carbon dioxide

BACKGROUND: Patients with hepatic cirrhosis frequently show idiopathic hyperventilation at rest, despite no concomitant cardiopulmonary disease. The aim of the study was to determine whether altered chemosensitivity either to hypoxia or hypercapnia could underlie inappropriate hyperventilation in cirrhotic patients. METHODS: We consecutively recruited 30 biopsy proven cirrhotic patients equally distributed in the three Child's classes A, B and C (age 54±8years, mean±SD). All patients underwent evaluation of chemosensitivity to hypoxia and to hypercapnia and blood sampling for brain natriuretic peptide, norepinephrine and progesterone, besides full clinical characterization. We also recruited 10 age- and gender-matched healthy controls (age 55±7years). RESULTS: Overall, 18 patients (60%) showed an increased chemosensitivity to carbon dioxide (CO(2)), while 8 patients (27%) showed enhanced chemosensitivity to hypoxia. Child's class C patients had lower arterial partial pressure of CO(2) (PaCO(2)), higher rest ventilation, increased chemosensitivity to hypercapnia, plasma level of norepinephrine and serum progesterone levels when compared to class A patients and controls (all p<0.05). Rest ventilation was positively related to pH (R=0.41, p=0.023), chemosensitivity to hypercapnia (R=0.54, p=0.002), and progesterone (R=0.53, p=0.016) and negatively to PaCO(2) (R=0.61, p<0.001), but not to hemoglobin level and chemosensitivity to hypoxia. Chemosensitivity to hypercapnia was positively related to PaCO(2) (R=0.74, p<0.001), serum progesterone (R=0.50, p=0.016), and to plasma norepinephrine (R=0.57, p=0.004). CONCLUSIONS: Enhanced chemosensitivity to hypercapnia was found in more decompensated cirrhotic patients and was associated with sympathetic overactivity and elevated serum progesterone, likely representing a key mechanism underlying the "unexplained" hyperventilation observed in such patients

Intestinal lymphangiectasia in a 3-month-old girl: A case report of Hennekam syndrome caused by CCBE1 mutation

RATIONAL: Intestinal lymphangiectasia (IL) is a rare disease characterized by dilatation and rupture of intestinal lymphatic channels leading to protein-losing enteropathy. IL is classified as primary and secondary types. PATIENT CONCERNS: A 3-month-old girl born at term from vaginal delivery with an APGAR score of 10/10 and birth weight of 4.310 g (&gt;97° percentile) was admitted to our hospital because of increasing abdominal tenderness and diarrhea. At first examination, she presented an abdominal circumference of 60 cm, edema of the lower extremities and vulva, and facial dysmorphisms (hypertelorism, flat nasal bridge, flat mid-face). DIAGNOSIS: Once admitted, ultrasonography showed a large amount of ascites, while blood laboratory investigations revealed severe hypoproteinemia, hypoalbuminemia and hypogammaglobulinemia. Lymphoscintigraphy with 99m-Tc-nanocolloid demonstrated abnormal leakage of the tracer in the abdomen as evidence of IL. To detect a possible secondary, exams were performed and demonstrated positive antibody titres for CMV-IgM and IgG in blood and CMV-DNA positivity in blood, urine, saliva, maternal milk, and gastric and duodenal biopsies. Genetic investigations identified the genomic variant c.472C&gt;T of the CCBE1 gene, coding for a protein variant (p.Arg158Cys), in homozygosity. INTERVENTIONS: Total parenteral nutrition was started and continued for a total of 18 days, then gradually bridged by enteral nutrition with a special formula. In addition, antiviral therapy for CMV infection was added first with intravenous ganciclovir for 14 days, resulting in the disappearance of blood viral load after 7 days of therapy and then with valganciclovir per os for another 30 days. OUTCOMES: The clinical course of the child gradually improved. A few days after starting treatments, lower extremities and vulvar edema disappeared, and abdominal circumference gradually decreased to a stable value of 38 cm, without any ultrasonographic signs of ascites left. Moreover, serum albumin and IgG rose to normal values after 3 months (4.3 g/dL and 501 mg/dL, respectively). LESSONS: This case suggests that in presence of IL both primary and secondary causes should be evaluated. On the other hand, genetic diagnosis is crucial not only for diagnosis but also for prognosis in HS. Life expectancy and quality could deeply vary among different gene mutations and protein variants of the same gene. Further studies and case reports are needed to better understand the clinical meaning of these genetic results and the role of CMV as trigger of IL

Evaluation of analytical performance and comparison of clinical results of the new generation method AccuTnI+3 for the measurement of cardiac troponin I using both patients and quality control plasma samples

The study aims are to evaluate the analytical performance and the clinical results of the chemiluminescent Access AccuTnI+3 immunoassay for the determination of cardiac troponin I (cTnI)with DxI 800 and Access2 platforms and to compare the clinical results obtained with this method with those of three cTnI immunoassays, recently introduced in the European market. The limits of blank (LoB), detection (LoD), and quantitation (LoQ) at 20% CV and 10% CV were 4.5 ng/L and 10.9 ng/L, 17.1 and 30.4 ng/L, respectively. The results of STAT Architect high Sensitive TnI (Abbott Diagnostics), ADVIA Centaur Troponin I Ultra (Siemens Healthcare Diagnostics), ST AIA-Pack cTnI third generation (Tosoh Bioscience), and Access AccuTnI + 3 (Beckman Coulter Diagnostics) showed very close correlations (R ranging from 0.901 to 0.994) in 122 samples of patients admitted to the emergency department. However, on average there was a difference up to 2.4-fold between the method measuring the highest (ADVIA method) and lowest cTnI values (AccuTnI + 3 method). The consensus mean values between methods ranged from 6.2% to 29.6% in 18 quality control samples distributed in an external quality control study (cTnI concentrations ranging from 29.3 ng/L to 1557.5 ng/L). In conclusion, the results of our analytical evaluation concerning the AccuTnI + 3 method, using the DxI platform, are well in agreement with those suggested by the manufacturer as well as those reported by some recent studies using the Access2 platform. Our results confirm that the AccuTnI + 3 method for the Access2 and DxI 800 platforms is a clinically usable method for cTnI measurement

Juvenile moyamoya and craniosynostosis in a child with deletion 1p32p31: Expanding the clinical spectrum of 1p32p31 deletion syndrome and a review of the literature

Moyamoya angiopathy (MA) is a rare cerebrovascular disorder characterised by the progressive occlusion of the internal carotid artery. Its aetiology is uncertain, but a genetic background seems likely, given the high MA familial rate. To investigate the aetiology of craniosynostosis and juvenile moyamoya in a 14-year-old male patient, we performed an array-comparative genomic hybridisation revealing a de novo interstitial deletion of 8.5 Mb in chromosome region 1p32p31. The deletion involved 34 protein coding genes, including NF1A, whose haploinsufficiency is indicated as being mainly responsible for the 1p32-p31 chromosome deletion syndrome phenotype (OMIM 613735). Our patient also has a deleted FOXD3 of the FOX gene family of transcription factors, which plays an important role in neural crest cell growth and differentiation. As the murine FOXD3-/- model shows craniofacial anomalies and abnormal common carotid artery morphology, it can be hypothesised that FOXD3 is involved in the pathogenesis of the craniofacial and vascular defects observed in our patient. In support of our assumption, we found in the literature another patient with a syndromic form of MA who had a deletion involving another FOX gene (FOXC1). In addition to describing the clinical history of our patient, we have reviewed all of the available literature concerning other patients with a 1p32p31 deletion, including cases from the Decipher database, and we have also reviewed the genetic disorders associated with MA, which is a useful guide for the diagnosis of syndromic form of MA

2P15-p16.1 microdeletions encompassing and proximal to BCL11A are associated with elevated HbF in addition to neurologic impairment

Elevated fetal hemoglobin (HbF) ameliorates the clinical severity of hemoglobinopathies such as β-thalassemia and sickle cell anemia. Currently, the only curative approach for individuals under chronic transfusion/chelation support therapy is allogeneic stem cell transplantation. However, recent analyses of heritable variations in HbF levels have provided a new therapeutic target for HbF reactivation: the transcriptional repressor BCL11A. Erythroid-specific BCL11A abrogation is now actively being sought as a therapeutic avenue, but the specific impact of such disruption in humans remains to be determined. Although single nucleotide polymorphisms in BCL11A erythroid regulatory elements have been reported, coding mutations are scarcer. It is thus of great interest that patients have recently been described with microdeletions encompassing BCL11A. These patients display neurodevelopmental abnormalities, but whether they show increased HbF has not been reported. We have examined the hematological phenotype, HbF levels, and erythroid BCL11A expression in 3 such patients. Haploinsufficiency of BCL11A induces only partial developmental g-globin silencing. Of greater interest is that a patient with a downstream deletion exhibits reduced BCL11A expression and increased HbF. Novel erythroid-specific regulatory elements in this region may be required for normal erythroid BCL11A expression, whereas loss of separate elements in the developing brain may explain the neurological phenotype

Novel mutations in the WFS1 gene are associated with Wolfram syndrome and systemic inflammation

Mutations in the WFS1 gene, encoding wolframin (WFS1), cause endoplasmic reticulum (ER) stress and are associated with a rare autosomal-recessive disorder known as Wolfram syndrome (WS). WS is clinically characterized by childhood-onset diabetes mellitus, optic atrophy, deafness, diabetes insipidus and neurological signs. We identified two novel WFS1 mutations in a patient with WS, namely, c.316-1G &gt; A (in intron 3) and c.757A &gt; T (in exon 7). Both mutations, located in the N-terminal region of the protein, were predicted to generate a truncated and inactive form of WFS1. We found that although the WFS1 protein was not expressed in peripheral blood mononuclear cells (PBMCs) of the proband, no constitutive ER stress activation could be detected in those cells. In contrast, WS proband's PBMCs produced very high levels of proinflammatory cytokines (i.e. TNF-α, IL-1β, and IL-6) in the absence of any stimulus. WFS1 silencing in PBMCs from control subjects by means of small RNA interference also induced a pronounced proinflammatory cytokine profile. The same cytokines were also significantly higher in sera from the WS patient as compared to matched healthy controls. Moreover, the chronic inflammatory state was associated with a dominance of proinflammatory T helper 17 (Th17)-type cells over regulatory T (Treg) lymphocytes in the WS PBMCs. The identification of a state of systemic chronic inflammation associated with WFS1 deficiency may pave the way to innovative and personalized therapeutic interventions in WS

The calculation of the cardiac troponin T 99th percentile of the reference population is affected by age, gender, and population selection: A multicenter study in Italy.

Background: The aim of this study is to determine the 99th upper-reference limit (URL) for cardiac troponin T (cTnT) in Italian apparently healthy subjects. Methods: The reference population was selected from 5 cities: Bolzano (n = 290), Milano (CAMELIA-Study, n = 287), Montignoso (MEHLP-Study, n = 306), Pisa (n = 182), and Reggio Calabria (MAREA-Study, n = 535). Subjects having cardiac/systemic acute/chronic diseases were excluded. Participants to MEHLP project underwent cardiac imaging investigation. High-sensitive cTnT was measured with Cobas-e411 (Roche Diagnostics). Results: We enrolled 1600 healthy subjects [54.6%males; age range 10–90 years; mean (SD): 36.4 (21.2) years], including 34.6% aged b20 years, 54.5% between 20 and 64 years, and 10.9% over 65 years. In the youngest the 99th URL was 10.9 ng/L in males and 6.8 ng/L in females; in adults 23.2 ng/L and 10.2 ng/L; and in elderly 36.8 ng/L and 28.6 ng/L. After the exclusion of outliers the 99th URL values were significantly decreased (P b 0.05) in particular those of the oldest (13.8 ng/L and 14 ng/L). MEHLP participants were divided in healthy and asymptomatic, according to known cardiovascular risk factors (HDL, LDL, glucose, C-reactive protein): the 99th URL of cTnT values of these subgroups was significantly different (19.5 vs. 22.7, P b 0.05). Conclusions: 99th URL of cTnT valueswas strongly affected by age, gender, selection of subjects and the statistical evaluation of outliers

Mutation spectrum of MLL2 in a cohort of kabuki syndrome patients

ABSTRACT: BACKGROUND: Kabuki syndrome (Niikawa-Kuroki syndrome) is a rare, multiple congenital anomalies/mental retardation syndrome characterized by a peculiar face, short stature, skeletal, visceral and dermatoglyphic abnormalities, cardiac anomalies, and immunological defects. Recently mutations in the histone methyl transferase MLL2 gene have been identified as its underlying cause. METHODS: Genomic DNAs were extracted from 62 index patients clinically diagnosed as affected by Kabuki syndrome. Sanger sequencing was performed to analyze the whole coding region of the MLL2 gene including intron-exon junctions. The putative causal and possible functional effect of each nucleotide variant identified was estimated by in silico prediction tools. RESULTS: We identified 45 patients with MLL2 nucleotide variants. 38 out of the 42 variants were never described before. Consistently with previous reports, the majority are nonsense or frameshift mutations predicted to generate a truncated polypeptide. We also identified 3 indel, 7 missense and 3 splice site. CONCLUSIONS: This study emphasizes the relevance of mutational screening of the MLL2 gene among patients diagnosed with Kabuki syndrome. The identification of a large spectrum of MLL2 mutations possibly offers the opportunity to improve the actual knowledge on the clinical basis of this multiple congenital anomalies/mental retardation syndrome, design functional studies to understand the molecular mechanisms underlying this disease, establish genotype-phenotype correlations and improve clinical management