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

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 (>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>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

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 > A (in intron 3) and c.757A > 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

Complications of mechanical thrombectomy for acute ischemic stroke: Incidence, risk factors, and clinical relevance in the Italian Registry of Endovascular Treatment in acute stroke

BACKGROUND: There are limited data concerning procedure-related complications of endovascular thrombectomy for large vessel occlusion strokes. AIMS: We evaluated the cumulative incidence, the clinical relevance in terms of increased disability and mortality, and risk factors for complications. METHODS: From January 2011 to December 2017, 4799 patients were enrolled by 36 centers in the Italian Registry of Endovascular Stroke Treatment. Data on demographic and procedural characteristics, complications, and clinical outcome at three months were prospectively collected. RESULTS: The complications cumulative incidence was 201 per 1000 patients undergoing endovascular thrombectomy. Ongoing antiplatelet therapy (p < 0.01; OR 1.82, 95% CI: 1.21-2.73) and large vessel occlusion site (carotid-T, p < 0.03; OR 3.05, 95% CI: 1.13-8.19; M2-segment-MCA, p < 0.01; OR 4.54, 95% CI: 1.66-12.44) were associated with a higher risk of subarachnoid hemorrhage/arterial perforation. Thrombectomy alone (p < 0.01; OR 0.50, 95% CI: 0.31-0.83) and younger age (p < 0.04; OR 0.98, 95% CI: 0.97-0.99) revealed a lower risk of developing dissection. M2-segment-MCA occlusion (p < 0.01; OR 0.35, 95% CI: 0.19-0.64) and hypertension (p < 0.04; OR 0.77, 95% CI: 0.6-0.98) were less related to clot embolization. Higher NIHSS at onset (p < 0.01; OR 1.04, 95% CI: 1.02-1.06), longer groin-to-reperfusion time (p < 0.01; OR 1.05, 95% CI: 1.02-1.07), diabetes (p < 0.01; OR 1.67, 95% CI: 1.25-2.23), and LVO site (carotid-T, p < 0.01; OR 1.96, 95% CI: 1.26-3.05; M2-segment-MCA, p < 0.02; OR 1.62, 95% CI: 1.08-2.42) were associated with a higher risk of developing symptomatic intracerebral hemorrhage compared to no/asymptomatic intracerebral hemorrhage. The subgroup of patients treated with thrombectomy alone presented a lower risk of symptomatic intracerebral hemorrhage (p < 0.01; OR 0.70; 95% CI: 0.55-0.90). Subarachnoid hemorrhage/arterial perforation and symptomatic intracerebral hemorrhage after endovascular thrombectomy worsen both functional independence and mortality at three-month follow-up (p < 0.01). Distal embolization is associated with neurological deterioration (p < 0.01), while arterial dissection did not affect clinical outcome at follow-up. CONCLUSIONS: Complications globally considered are not uncommon and may result in poor clinical outcome. Early recognition of risk factors might help to prevent complications and manage them appropriately in order to maximize endovascular thrombectomy benefits

Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders

Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we describe 19 novel episignature disorders and compare the findings alongside 38 previously established episignatures for a total of 57 episignatures associated with 65 genetic syndromes. We demonstrate increasing resolution and specificity ranging from protein complex, gene, sub-gene, protein domain, and even single nucleotide-level Mendelian episignatures. We show the power of multiclass modeling to develop highly accurate and disease-specific diagnostic classifiers. This study significantly expands the number and spectrum of disorders with detectable DNA methylation episignatures, improves the clinical diagnostic capabilities through the resolution of unsolved cases and the reclassification of variants of unknown clinical significance, and provides further insight into the molecular etiology of Mendelian conditions