Silvana Briuglia

Cadmium concentration in maternal and cord blood and infant birth weight: a study on healthy non-smoking women.

Abstract The aim of our study was to measure, at delivery, maternal and cord blood cadmium levels (by means of atomic absorption spectrometry) in 45 healthy non-smoking pregnant women exposed to a low cadmium challenge, and to evaluate the relationship between these cadmium levels and the birth weight of the infants. Our results showed fairly low cadmium levels in maternal blood, in accordance with the fact that all women enrolled in this study lived in areas with low toxic metal contamination and that they did not smoke during their pregnancy. Furthermore, a highly significant direct correlation was found between maternal and cord blood cadmium concentrations. Since cadmium concentration appeared of the same order of magnitudine both in cord and maternal serum, one could speculate that cadmium is transferred easily from the mother to the fetus through the placenta. Finally, we found that birth weight is inversely correlated with maternal and cord blood cadmium concentrations; thus birth weight might be negatively influenced by cadmium levels as a result of the toxic effects of the metal on the placenta. Although preliminary, our data show that (also not-predictable) prenatal exposure to even low cadmium levels might be a risk factor for developmental impairment in infants.

Spectrum of MEK1 and MEK2 gene mutations in cardio-facio-cutaneous syndrome and genotype–phenotype correlations

Cardio-facio-cutaneous syndrome (CFCS) is a rare disease characterized by mental retardation, facial dysmorphisms, ectodermal abnormalities, heart defects and developmental delay. CFCS is genetically heterogeneous and mutations in the KRAS, BRAF, MAP2K1 (MEK1) and MAP2K2 (MEK2) genes, encoding for components of the RAS–mitogen activated protein kinase (MAPK) signaling pathway, have been identified in up to 90% of cases. Here we screened a cohort of 33 individuals with CFCS for MEK1 and MEK2 gene mutations to further explore their molecular spectrum in this disorder, and to analyze genotype–phenotype correlations. Three MEK1 and two MEK2 mutations were detected in six patients. Two missense MEK1 (L42F and Y130H) changes and one in-frame MEK2 (K63_E66del) deletion had not been reported earlier. All mutations were localized within exon 2 or 3. Together with the available records, the present data document that MEK1 mutations are relatively more frequent than those in MEK2, with exons 2 and 3 being mutational hot spots in both genes. Mutational analysis of the affected MEK1 and MEK2 exons did not reveal occurrence of mutations among 75 patients with Noonan syndrome, confirming the low prevalence of MEK gene defects in this disorder. Clinical review of known individuals with MEK1/MEK2 mutations suggests that these patients show dysmorphic features, ectodermal abnormalities and cognitive deficit similar to what was observed in BRAF-mutated patients and in the general CFCS population. Conversely, congenital heart defects, particularly mitral valve and septal defects, and ocular anomalies seem to be less frequent among MEK1/MEK2 mutation-positive patients.

Angiotensin-Converting Enzyme and Angiotensin Type 2 Receptor Gene Genotype Distributions in Italian Children with Congenital Uropathies

Angiotensin I–converting enzyme (ACE) and angiotensin type 2 receptor (AT2R) gene polymorphisms have been associated with an increased incidence of congenital anomalies of the kidney and urinary tract (CAKUT). We investigated the genotype distribution of these polymorphisms in Italian children with CAKUT. We also evaluated the association between the ACE insertion/deletion and the AT2R gene polymorphisms with the progression of renal damage in subgroups of CAKUT patients. We recruited 102 Italian children with CAKUT; 27 with vesicoureteral reflux; 12 with hypoplastic kidneys; 20 with multicystic dysplastic kidneys; 13 with ureteropelvic junctions stenosis/atresia; 18 with nonobstructed, nonrefluxing primary megaureters; and 12 with posterior urethral valves and compared them with 92 healthy control subjects. ACE and AT2R gene polymorphisms were analyzed by PCR. The identification of AT2R gene polymorphisms in intron 1 and in exon 3 was revealed by enzymatic digestion. ACE genotype distribution in children with CAKUT was no different from that of the control subjects, but the subgroup of patients with radiographic renal parenchymal abnormalities showed an increased occurrence of the D/D genotype. The frequency of the G allele of AT2R gene in children with CAKUT was increased in respect to that of the control subjects. By contrast, no significant difference in the frequency of the C and A alleles of the AT2R gene was found. Our findings indicate that the ACE gene can be a risk factor in the progression of renal parenchymal damage in CAKUT patients. Moreover, a major role of the AT2R gene in the development of CAKUT has been found, at least in Italian children.

Gene-environment interaction in childhood asthma.

The importance of early life environmental influences on the etiology of asthma is implied by the observed geographic and temporal variation in the prevalence of the disease among children. There is evidence pointing to the role of exposure to allergen, various aspects of diet and hygiene-related factors in the etiology of asthma. There is also evidence that heritable factors influence the impact of hygiene-related exposures on the risk of having asthma. A number of important gene-environment interactions have been identified. These interactions point to the biology of environmental exposures as the involved genetic variation is suggestive of certain underlying mechanisms. Polymorphisms within genes coding for the toll-like receptor-lipopolysaccharide (TLR-LPS) signaling pathway may underlie variations in effects of hygiene-related exposures, including specifically endotoxin, on the risk of developing allergic sensitization and allergic disease. This review presents recent findings illustrating the role of gene-environment interactions in childhood asthma susceptibility.

Increased protein carbonyl groups in the serum of patients affected by thalassemia major

High oxidative stress status is known to be one of the most important factors determining cell injury in thalassemic patients and causing other serious medical complications, including a continuous proinflammatory status. The quantification of protein carbonyl groups in peripheral blood is widely used to measure the extent of oxidative modification. Thus, we measured serum concentrations of protein carbonyl groups in 30 patients affected by thalassemia major and in 15 healthy subjects. Strongly higher levels of protein carbonyl groups were measured in the blood from thalassemic patients than in that from healthy controls. Our findings evidence that thalassemic patients suffer from protein oxidative stress; the possibility of a role for carbonyl stress in the progression and severity of the disease needs further investigation.

Disomy of distal Xq in males: case report and overview.

A 46,XYq 8‐year‐old male was referred for microcephaly, growth, and mental retardation, hypotonia, genital hypoplasia, and dysmorphisms. FISH analysis showed that the rearranged Y chromosome originated from an unbalanced translocation of Xq27.3‐qter onto the deleted Yq11.22. Analysis of reported patients with disomy of region distal to Xq26 suggests that this rare anomaly, associated with failure to dosage compensate X‐linked genes that are normally inactivated, when present in two copies, is causing a quite distinct phenotype. This imbalance is the aberrant by product of the recombinogenic pairing of the distal pseudoautosomal Xq–Yq region at male meiosis.

Familial chronic nail candidiasis with ICAM-1 deficiency: a new form of chronic mucocutaneous candidiasis

Chronic mucocutaneous candidiasis (CMC) includes a group of rare disorders with altered immune responses, selective against Candida, characterised by persistent and/or recurrent infections of the skin, nails, and mucous membranes, caused by organisms of the genus Candida, mainly Candida albicans . Familial occurrence of CMC was originally reported by Wells et al ,1 who described both males and females affected and consanguinity in a number of their pedigrees. The classification of CMCs is based on clinical features and pattern of inheritance, which can be either autosomal dominant or recessive (table 1). Most CMC types have an early age of onset, affect skin, nails, and mucous membranes, and are associated with altered phagocytosis and chemotaxis. The classical form of CMC does not include endocrinological diseases, which represent a major component of the immune polyendocrinopathy syndrome (APECED, MIM *240300), caused by mutations of the autoimmune regulator gene ( AIRE ) on chromosome 21q22.3.2,3 View this table: Table 1 Classification of CMCs We describe a distinct form of familial chronic candidiasis (FCNC), characterised by early onset infections caused by different species of Candida, restricted to the nails of the hands and feet, associated with low serum concentration of intercellular adhesion molecule I (ICAM-1). The family originates from a rural village in Sicily and includes 11 affected subjects in five generations (fig 1). Based on clinical and anamnestic records, III.8 was the first affected member of this family. She developed nail dystrophy, presenting with hyperkeratosis and dark and thick nails, similar to those found in other family members. IV.5, a 71 year old female, was unaffected. V.4, a 48 year old female, was a blood relative of her husband. From the age of 6 months, she was affected by onycomycosis caused by Candida involving all the nails of her hands and feet (figs 2 and 3). Caustication was …

A mitochondrial DNA mutation (A3243G mtDNA) in a family with cyclic vomiting

We report the incidence of mitochondrial DNA (mtDNA) mutations and/or deletions in a family from Southern Italy in which four members were affected by a cyclic vomiting syndrome (CVS). The A3243G mtDNA mutation was detected in a boy, his mother, maternal grandmother, and aunt but not in other relatives of the family. Patients with a CVS experience a minimum of three distinct episodes of vomiting and nausea, usually involving more than four emeses in one hour at the peak. They feel quite well between episodes. There is no apparent underlying cause for the vomiting [4]. In the differential diagnosis of CVS, mtDNA mutations should be considered when there is a maternal history of CVS and migraine, clinical findings of seizures, neuromuscular and gastrointestinal symptoms and laboratory evidence of lactate increase [5]. A family was recruited with four members suffering from CVS: a 5-year-old boy, his mother, the maternal grandmother and aunt. The three adults were affected by CVS during childhood, whilst they suffered from migraine at an adult age (Fig. 1). Metabolic investigations revealed permanent hyperlactataemia (5–8 mM) with elevated lactate/pyruvate ratios (L/P) (25–30) in the boy’s mother. In the maternal grandmother and aunt, lactate levels (2.6 and 3.0 mM respectively) were slightly elevated and L/P molar ratios remained in the normal range. The young patient suffered from vomiting fits which lasted for many hours until spontaneous resolution and recurrence with the same characteristics after an interval of 15–20 days. Metabolic acidosis (pH 7.3, bicarbonate 16 mM) with hyperlactataemia (2.5–5.35 mM) and elevated L/P (19–32; normal <16) and ketone body molar ratios were found (2–4.6, normal <2). Hyperalaninaemia, lactic aciduria, and an abnormal excretion of suberic, adipic, and 3-hydroxybutyric acids was observed. Laboratory, clinical and instrumental findings of all four patients excluded organic diseases. To check for point mutations and for a previously described 8.1 kb deletion [3], the region between nucleotides 6687 and 15123 was amplified by the polymerase chain reaction (PCR) in ten overlapping segments and completely sequenced. Screening for the 3243 np mutation in mtDNA was carried out by PCR-RFLP. The relevant region of mtDNA was amplified using the following primers according to the Cambridge sequence [1]: 5’CCCACAGGTCCTAAACTACC-3’ (np 2770–2789) and 5’AGCGAAGGGTTGTAGTAGCC-3’ (np 3456– 3437). The PCR products (10 ll) were then purified and digested with 15 U of the restriction endonuclease ApaI for 1 h at 32 C. The A-to-G mutation at 3243 np created an ApaI restriction site (GAGCCC to GGGCCC) and was easily detected by ethidium bromide staining in a 2.5% agarose gel. In order to detect small amounts of mutated mtDNA in the presence of an excess of wildFig. 1 Pedigree of the family with CVS; the arrow indicates the index case. The percentage of mutated mtDNA in blood and muscle of the patients is I:2=25% and 30%; II:2=35% and 38%; II:3=30% and 32%; III:1=70% and 75% respectively. Affected individuals are indicated by solid symbols Eur J Pediatr (2003) 162: 727–728 DOI 10.1007/s00431-003-1280-1

Molecular analysis of sequence variants in the Fce receptor I b gene and IL-4 gene promoter in Italian atopic families

Background:  The genetic variants in the Fcɛ receptor I β gene (Glu237Gly) and the T allele of the (C590T) polymorphism of interleukin (IL)‐4 gene promoter were reported to be associated with atopy. But the data of the studies in different populations are contrasting with one another.

Hallerman-Streiff syndrome: patient with decreased GH and insulin-like growth factor-1.

We observed a 10-year-old boy with Hallerman– Streiff syndrome (HSS). The proband was the second child of healthy non-consanguineous parents. Family history was unremarkable. Pregnancy was uncomplicated and delivery at term with normal birth weight and length. There was mild psychomotor retardation. On physical examination, the child showed short stature (123 cm, 2.4 SD) with a distinctive triangular bird face. The head was brachycephalic with frontal bossing sparse curly and thin scalp hair. The eyebrows were hypoplastic. The palpebral fissures were short and downslanted with telecanthus and sparse eyelashes. The nasal bridge was narrow, the nose small with a rather beaked appearance and hypoplastic alae nasi. The philtrum was long and mouth small with thin lips. Palate was high arched. There was a distinct maxillary and mandibular hypoplasia. Malocclusion, prominent upper incisors, and dental crowding were quite remarkable. The ears were slightly low set with prominent ear lobes. Hands and feet were small with clinodactylous of 5th fingers. Distal interphalangeal joints of fingers and toes were enlarged. Laboratory tests, including extensive metabolic studies and karyotype yielded normal results. X-ray of left hand and wrist documented retarded bone age (8.5 years vs. 9.6 of chronologic age). Repeated insulin-like growth factor-1 (IGF-1) blood determinations disclosed constantly decreased levels in the range of 39–66.8 ng/ml (normal levels 128–458 ng/ml). The GH response to pharmacological stimuli yielded abnormal results with maximal levels of 5.8 ng/ ml after insulin stimulus and 8.5 ng/ml after clonidine stimulus (the maximal response must exceed 10 ng/ml). An ophthalmologic examination documented myopia and disclosed normal fundus oculi (Figs. 1–3). Short stature is a common feature in this syndrome, but to our knowledge, a deficiency of GH and IGF-1 has