Irene Bruno

Mass screening for coeliac disease using antihuman transglutaminase antibody assay

Aims: To determine coeliac disease prevalence by an anti-transglutaminase antibody assay in a large paediatric population; to evaluate acceptance of the screening programme, dietary compliance, and long term health effects. Methods: Cross-sectional survey of 3188 schoolchildren (aged 6–12) and prospective follow up of diagnosed cases. Main outcome measures were: prevalence of coeliac disease defined by intestinal biopsy or positivity to both human tissue transglutaminase and anti-endomysium antibodies in HLA DQ2-8 positive subjects; percentage of children whose families accepted screening; dietary compliance as defined by negativity for anti-transglutaminase antibodies; and presence of clinical or laboratory abnormalities at 24 month follow up. Results: The families of 3188/3665 children gave their consent (87%). Thirty biopsy proven coeliacs were identified (prevalence 1:106). Three other children testing positive for both coeliac related autoantibodies and HLA DQ2-8 but refusing biopsy were considered as having coeliac disease (prevalence 1:96). Of 33 cases, 12 had coeliac related symptoms. The 30 biopsy proven coeliacs followed a gluten-free diet. Of 28 subjects completing 18–24 months follow up, 20 (71.4%) were negative for anti-transglutaminase antibodies, while eight were slightly positive; symptoms resolved in all 12 symptomatic children. Conclusions: Prevalence of coeliac disease is high in Italian schoolchildren. Two thirds of cases were asymptomatic. Acceptance of the programme was good, as was dietary compliance. Given the high prevalence and possible complications of untreated coeliac disease, the availability of a valid screening method, and evidence of willingness to comply with dietary treatment population mass screening deserves careful consideration.

Attitudes of children with leukemia toward repeated deep sedations with propofol

Procedural sedation is generally recommended for children requiring repeated painful diagnostic or therapeutic procedures. A child with leukemia undergoes an average of 20 procedures such as lumbar puncture and bone marrow aspiration through the course of illness. No data are currently available about the psychological impact of repeated sedations on children. The objective of this study was to evaluate the attitudes of patients with leukemia toward repeated deep sedations using propofol. A questionnaire addressing sedation-related distress was given to 30 children with leukemia. Procedure-related distress was evaluated using the Amended Observational Scale of Behavioural Distress. Another questionnaire concerning the same issues was given to an historical group of 39 children who had undergone painful procedures without sedation in previous years. Fear and distress were significantly reduced in the sedation group compared with the historical one. Fear of sedation was reported by 17% of children of this group. Distressed behavior was observed in 27%. In conclusion, sedation-related distress was observed in a subgroup of patients; in these cases, specific strategies could be considered to reduce sedation-related distress.

Co-inheritance of two ABCC8 mutations causing an unresponsive congenital hyperinsulinism: Clinical and functional characterization of two novel ABCC8 mutations

Congenital hyperinsulinism (CHI) occurs as a consequence of unregulated insulin secretion from the pancreatic beta-cells. Severe recessive mutations and milder dominant mutations have been described in the ABCC8 and KCNJ11 genes encoding SUR1 and Kir6.2 subunits of the beta-cell ATP-sensitive K(+) channel. Here we report two patients with CHI unresponsive to medical therapy with diazoxide. Sequencing analysis identified a compound heterozygous mutation in ABCC8 in both patients. The first one is a carrier for the known mild dominant mutation p.Glu1506Lys jointly with the novel mutation p.Glu1323Lys. The second carries the p.Glu1323Lys mutation and a second novel mutation, p.Met1394Arg. Functional studies of both novel alleles showed reduced or null cell surface expression, typical of recessive mutations. Compound heterozygous mutations in congenital hyperinsulinism result in complex interactions. Studying these mechanisms can improve the knowledge of this disease and modify its therapy.

Autosomal recessive stickler syndrome due to a loss of function mutation in the COL9A3 gene

Stickler syndrome (STL) is a clinically variable and genetically heterogeneous syndrome characterized by ophthalmic, articular, orofacial, and auditory manifestations. STL has been described with both autosomal dominant and recessive inheritance. The dominant form is caused by mutations of COL2A1 (STL 1, OMIM 108300), COL11A1 (STL 2, OMIM 604841), and COL11A2 (STL 3, OMIM 184840) genes, while recessive forms have been associated with mutations of COL9A1 (OMIM 120210) and COL9A2 (OMIM 120260) genes. Type IX collagen is a heterotrimeric molecule formed by three genetically distinct chains: α1, α2, and α3 encoded by the COL9A1, COL9A2, and COL9A3 genes. Up to this time, only heterozygous mutations of COL9A3 gene have been reported in human and related to: (1) multiple epiphyseal dysplasia type 3, (2) susceptibility to an intervertebral disc disease, and (3) hearing loss. Here, we describe the first autosomal recessive Stickler family due to loss of function mutations (c.1176_1198del, p.Gln393Cysfs*25) of COL9A3 gene. These findings extend further the role of collagen genes family in the disease pathogenesis.

A Novel CRYBB2 Missense Mutation Causing Congenital Autosomal Dominant Cataract in an Italian Family

Congenital cataract is a leading cause of visual impairment in children and brings approximately 10% of childhood blindness worldwide. Molecular analysis revealed ~60 loci to be associated with several phenotypes of childhood cataracts. Until now, more than 30 loci and 18 genes on different chromosomes have been associated with autosomal dominant congenital cataract (ADCC). Here, we present a three-generation Italian family with a non syndromic ADCC. A linkage analysis carried out using HumanCytoSNP-12 DNA Analysis BeadChip led us to identify ten genomic regions virtually involved in the disease. All the genes located in these regions were scored for possible relationship with ADCC and, according to a strict clinical and genetic selection, 4 genes have been analyzed. A novel sequence variant was found in the CRYBB2 gene (p.Ser143Phe). This variant affects a conserved aminoacid in the third Greek key motif of the protein, cosegregates with the disease phenotype in all affected individuals and is not present both in the unaffected family members and 100 healthy control subjects. Finally, we identified the first CRYBB2 mutation in an Italian family causing a clinical picture of ADCC.

Phylloid Pattern of Hypomelanosis Closely Related to Chromosomal Abnormalities in the 13q Detected by SNP Array Analysis

Phylloid hypomelanosis is a distinct type of pigmentary mosaicism characterized by congenital hypochromic macules resembling a floral ornament with various elements such as round or oval patches, asymmetrical macules similar to begonia leaves, or oblong lesions. It has been found to be predominantly associated with abnormalities in chromosome 13 and sometimes as-sociated with different extracutaneous abnormalities. Here, we report 2 new cases of phylloid hypomelanosis due to mosaicism involving chromosome 13. The first one is a mosaicism for a supernumerary marker belonging to chromosome 13 and the second one is the first report of phylloid hypomelanosis associated with a mosaic deletion of 13q. Because of the extremely low level of mosaicism in these 2 cases, SNP array analysis on skin fibroblasts was carried out, showing a 13q21.33-q34 duplication (71,024,411-115,103,529) and a 13q13.3-q34 (38,368,012-115,103,529) deletion. Both cases underline on the one hand the strict connection between phylloid hypomelanosis and anomalies of chromosome 13, and on the other hand the relevance of the SNP array analysis on skin fibroblasts in the detection of low-level mosaicism.

Antigranulocyte monoclonal antibody immunoscintigraphy in inflammatory bowel disease in children and young adolescents.

Aim: Diagnostic delay for inflammatory bowel disease (IBD) is frequent, especially in paediatric patients. Scintigraphy with labelled leucocytes has been proposed as a very sensitive diagnostic tool for detecting bowel inflammation. The aim of this study was to evaluate the sensitivity and specificity of immunoscintigraphy in the diagnosis and follow‐up of children with IBD and to compare this technique with other diagnostic techniques. Methods: Sixty‐six children with histologically confirmed IBD were enrolled in the study. Twenty‐one children in whom IBD was suspected but subsequently not confirmed were used as controls. A total of 138 immunoscintigraphies were performed using 99mTechnetium‐labelled monoclonal anti‐granulocyte antibodies. Immunoscintigraphy was also compared with other diagnostic techniques. Results: Overall sensitivity of monoclonal antibody immunoscintigraphy (MoAb‐IS) in patients with clinically active disease was 94% for Crohns disease (CD) and 85% for ulcerative colitis (UC). Ultrasonography, endoscopy and radiology were carried out at the same time in 29 patients with CD and in 6 patients with UC: sensitivity of IS was 90% compared with 76% of colonoscopy, 75% for enemas, and 55% for sonography. IS was negative (specificity) in 24% of patients with CD and in 67% of patients with UC during remission, and in 64% of controls with other causes of intestinal inflammation. Diagnostic delay was significantly shorter when compared with a historical cohort of patients.

Efficacy of clonidine in hyperammonemia induced hyperexcitability syndrome

and patient was discharged home a week later. Because of the large head, a pressure gradient exists between the heart and the veins of the head in infants predisposing them to VAE (1). We hypothesize that the sudden decrease in raised ICP upon CSF drainage led to rupture of a bridging vein or emissary veins, resulting in venous air embolism (VAE). The reappearance of signs of air embolism after the reintroduction of nitrous oxide was probably because of the expansion of the air which was still present in the circulation (2). Change in position from supine to prone might have played a role in the recurrence of VAE symptoms as well. The change in position could have caused the air bubbles present in the upper part of the right atrium to have floated into the right ventricular out flow tract and subsequently to the pulmonary arteries and pulmonary arterioles producing the symptoms of the second VAE. As compared with hypoxia, tachycardia and hypotension are the most common initial signs of VAE (3). An episode of VAE severe enough to cause hypoxia is likely to be preceded by hemodynamic instability, which was conspicuously absent during the first episode. We suspect pulmonary hypertension following air entrainment resulted in shunt reversal causing hypoxia. Absence of tachycardia and hypotension during the first episode was most likely because of the preservation of sufficient blood flow from right to left atrium preserving adequate cardiac output (4). During the second episode of VAE, the occurrence of hypoxia preceding fall in EtCO2 was most likely because of the persisting pulmonary hypertension. Readministration of the nitrous oxide at this stage aggravated the preexisting pulmonary hypertension resulting in the reappearance of the right to left shunt before the increase in dead space. In presence of right to left shunt, fall in EtCO2 normally seen with VAE, may be absent due to the relatively well preserved left heart filling (4). PFO is very common in newborns and infants (5). Our case emphasizes that because of the high prevalence of PFO in newborn and infants, the signs of VAE in this group may be unusual and a high index of suspicion is needed for timely diagnosis. The increased chance of shunt reversal following hypoxia, hypercarbia, and acidosis predisposes them to the development of paradoxical air embolism with grave consequences. In light of this experience, we also caution the readers against the reintroduction of N2O when a VAE has been suspected earlier, even when all symptoms have abated.

ACE-inhibitors-induced metabolic acidosis in a child with nephrotic syndrome

In recent years there has been an increase in the use of ACE inhibitors in the paediatric population. We describe a case of hyperchloraemic metabolic acidosis with hypoaldosteronism in a 4-year-old boy with nephrotic syndrome who was receiving ACE inhibitors.

A red baby should not be taken too lightly.

Aim:  To identify clinical and laboratory features that can drive the differential diagnosis of a primary immunodeficiency diseases in patients with ectodermal defects.