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Phenylketonuria (PKU) was the first inherited metabolic disease in which dietary treatment was found to prevent the disease’s clinical features. Treatment of phenylketonuria remains difficult due to progressive decrease in adherence to diet and the presence of neurocognitive defects despite therapy. This review aims to summarize the current literature on new treatment strategies. Additions to treatment include new, more palatable foods based on glycomacropeptide that contains very limited amount of aromatic amino acids, the administration of large neutral amino acids to prevent phenylalanine entry into the brain or tetrahydropterina cofactor capable of increasing residual activity of phenylalanine hydroxylase. Moreover, human trials have recently been performed with subcutaneous administration of phenylalanine ammonia-lyase, and further efforts are underway to develop an oral therapy containing phenylanine ammonia-lyase. Gene therapy also seems to be a promising approach in the near future.

Myoglobinuria is a frequent complication of metabolic myopathies and may also occur in Duchenne and Becker dystrophies but is not a typical sign of limb–girdle muscular dystrophy. We describe an unusual presentation of alpha-sarcoglycanopathy with myoglobinuria at the onset of the disease. The boy presented an episode of dark urine, identified as presence of blood by a urine dipstick, occurred 10 days after an episode of fever and sore throat treated with antibiotics. He was admitted to the hospital and investigated for post-infectious nephritis, but further analysis revealed the presence of myoglobinuria. Immunohistochemistry on muscle tissue revealed absent expression of α-sarcoglycan confirmed by detection of a homozygous mutation in the alpha-sarcoglycan gene. Myoglobinuria has been previously reported four times in sarcoglycanopathies but only once in alpha-sarcoglycanopathy. Conclusion The present observation reinforces the idea that the myoglobinuria should be considered a manifestation of a primary sarcoglycanopathy even as the only recognizable sign at the debut of the disease.

We report on a new case of a syndrome first described by Cantú et al. [1982: Hum Genet 60:36-41] comprising congenital hypertrichosis, "coarse" facial appearance, and mild osteochondrodysplasia. Our case has some unusual radiological findings, namely proximal and distal megaepiphyses of long bones and advanced bone age.

Background: Little information is available about the relationships between Helicobacter pylori cytotoxin-associated protein (CagA) and clinicopathologic features in children. The purpose of this study was to test whether determining serum IgG antibodies to CagA is a useful tool for detecting more severe disease. Methods: One hundred twenty-seven consecutive children (age, range, 0.75-17.8 years; median, 9.4 years) referred for gastroscopy were included in the study. Antral and corpus biopsies were taken for gastric histology and H. pylori detection. Major symptoms and endoscopic findings were recorded. A serum sample was drawn from each child and assayed for IgG antibodies CagA by a commercial enzyme-linked immunosorbent assay. Results: Sixty-three (50%) children had no evidence of H. pylori infection, 28 (22%) were H. pylori positive/CagA positive, and 36 (28%) were H. pylori positive/CagA negative. There were no differences in clinical diagnosis and occurrence of any predominant symptom according to H. pylori and CagA status. Findings of antral nodularity were more frequent (p = 0.003) in H. pylori-positive/CagA-positive children than in H. pylori-positive/CagA-negative children. The gastritis score was significantly higher in H. pylori-positive/CagA-positive children than in H. pylori-positive/CagA-negative children (5.7 ± 1.9 vs. 3.8 ± 1.6, respectively; p = 0.0003), either in the antral (p = 0.0002) or in the corpus (p = 0.001) mucosa. Inflammation (p = 0.0001) and activity (p = 0.0001) scores were both higher in H. pylori-positive/CagA-positive children than in H. pylori-positive/CagA-negative children, but the H. pylori density score was not significantly different (p = NS). In no case was normal gastric mucosa found in H. pylori-positive/CagA-positive children. Lymphocytic gastritis (p = 0.0008) and lymphoid follicles (p = 0.000003) were a more frequent finding in H. pylori-positive children than in H. pylori negative children, irrespective of CagA status. Conclusion: Testing for serum IgG to CagA detects higher grades of gastric inflammation among children with H. pylori infection. It may be useful in targeting H. pylori-positive/CagA-positive children for antimicrobial therapy while reducing the need for endoscopy and gastric biopsy.

Roberts syndrome is a rare autosomal recessive condition characterized by growth retardation, cranio-facial abnormalities and symmetrical limb reduction of variable severity. Most patients with Roberts syndrome show a typical cytogenetic finding known as "Roberts syndrome effect". We describe a 4-month-old patient with a mild form of this syndrome, who presented with an asymmetrical reduction of the right upper limb.

The aim of the study was to investigate the frequency of breastfeeding among children with Down syndrome.The mothers of 560 children with Down syndrome attending four university hospitals in Italy were interviewed and the neonatal clinical records retrieved. Information was collected on the type of infant feeding and on why some mothers had not breastfed their children. Two groups of healthy children whose feeding habits had been previously investigated were recruited as control subjects (1601 and 714, respectively). A paediatrician in each hospital was interviewed about the neonatal admission policy of children with Down syndrome.Among the 560 Down children, 246 (44%) were admitted to the neonatal unit. Compared with the two control groups, children with Down syndrome were significantly more frequently bottle-fed (57% vs 15% and 24%, respectively, odds ratio 7.5, 95% CI 6.0-9.4 and 4.2, 95% CI 3.3-5.4. respectively). Only 30% of infants admitted to the neonatal unit were breastfed. The main reasons reported by the mothers for not having breastfed were infants' illness in infants who had been admitted to the neonatal unit and frustration or depression, perceived milk insufficiency and difficulty with suckling for those babies who had not been admitted to the unit. The paediatricians reported that the admission of a baby with Down syndrome to the neonatal unit could sometimes take place not for medical reasons, but for diagnostic work-up or for a more appropriate diagnosis and to maintain communication with the family.Down syndrome babies are less frequently breastfed compared with healthy children. Support in breastfeeding should become a relevant point of health supervision for children with Down syndrome.

AIM: To evaluate gastric emptying in girls with Turner's syndrome to detect if gastrointestinal motor dysfunction was present. SUBJECTS: Thirteen girls (mean age 8.1 years) with Turner's syndrome, seven girls with familial short stature (6.1 years), and eight control girls (7.6 years). METHODS: Gastric emptying studies were performed by using 500 microCi of technetium 99m-sulphur colloid bound to a scrambled egg, and scintigraphic measurements were made for 60 to 90 minutes. RESULTS: Mean (SD) percentage retention of gastric isotope was significantly greater in girls with Turner's syndrome than in children with short stature and in controls. Furthermore, in contrast with control subjects, in whom there was an inverse linear relationship between gastric emptying rate and body mass index, in children with Turner's syndrome the delay in gastric emptying was independent of the body mass. CONCLUSIONS: The results of the study suggest that delayed gastric emptying is detectable in girls with Turner's syndrome independent of age, body mass index, karyotype, and growth promoting treatment.

Pulmonary disease of unknown etiology is a potentially fatal complication in patients with lysinuric protein intolerance (LPI), an autosomal recessive disorder caused by the defective transport of cationic amino acids. Lung involvement was investigated in nine Italian LPI patients through pulmonary function tests and lung imaging studies consisting of conventional chest radiography, high-resolution computed tomography (HRCT), and perfusion and ventilation scintigraphy. One 10-yr-old patient died of severe respiratory insufficiency from alveolar proteinosis. All of the remaining patients were asymptomatic at the time of the study, although HRCT scans revealed signs of lung involvement defined by the presence of acinar nodules, inter- and/or intralobular thickening of the interstitial septa, and subpleural cysts in five of the patients. Radioisotope studies showed an uneven distribution of perfusion and ventilation, and confirmed the presence of segmental and/or diffuse pulmonary functional defects. No abnormalities of pulmonary function were evident, and answers to a questionnaire excluded primary coexisting lung disease. In patients with LPI, including those without clinical and functional impairment, HRCT and radioisotopic studies appear to be the most sensitive methods for the early diagnosis of lung disease and correct assessment of its progression.

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 → 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.

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.

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.

Background/Aims To describe in detail the specific clinical and biological characteristics of three patients with MPV17 gene mutations, a rare hepatocerebral mitochondrial DNA depletion syndrome (MDS) and the positive effects of a novel dietetic treatment based on avoidance of fasting. Methods We describe the case histories of three members of the same family with MPV17 mutations. Results Two patients had a very severe and progressive liver disease: 1 died in the first year of life and the other underwent liver transplantation. The third patient, now 13 years of age, had a milder form of liver disease and developed progressive ataxia. Psychomotor involvement at onset of disease was mild or absent. No patient had severe hyperlactataemia. In vivo functional studies on two patients showed no hyperlactataemia even after intravenous and oral glucose loading, regular fasting hypoglycemia 3–4h after meals and no response to glucagon. Liver function tests improved when patients received continuous iv glucose infusion or were regularly fed every 3h. Conclusions These clinical and biochemical features allow us to differentiate patients with MPV17 mutations from other liver MDS and suggest that regular glucose intake at short intervals may be beneficial in slowing the progression of the disease.

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 1year 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.

We describe the clinical findings over the first 18 years of a patient with a novel phenotype for galactosialidosis, the storage disease produced by the combined deficiency of beta-galactosidase and neuraminidase. Clinical findings in the first few months included somewhat unusual appearance and hepatosplenomegaly. Dysostosis multiplex was evident by age 2 1/2 years. Mitral and aortic valvular disease appeared over the next few years and cardiac disease has become the most important clinical problem. Foam cells were present in the bone marrow, and vacuolated lymphocytes were present in the peripheral blood smear. The patient had no neurological symptoms, cherry red spots, or intellectual deterioration during the first 18 years. Evidence presented elsewhere indicates that the basic defect in this late infantile form of galactosialidosis (as is thought to be true for the other forms of galactosialidosis) is a reduced amount of the 32 kDa phosphoglycoprotein which associates with beta-galactosidase and alpha-neuraminidase in lysosomes.

Fourteen patients (six males, eight females; mean age, 20 years) with homocystinuria due to homozygous cystathionine-beta-synthase (CBS) deficiency, underwent a vascular examination. Fourteen heterozygotes (seven males, seven females; mean age, 46 years), including 12 parents and one daughter of homozygotes (obligate heterozygotes), and one sister of a homozygote (with low enzyme activity as evaluated in vitro), were also examined. Homozygotes and heterozygotes were compared with two separate control groups of different age (mean age, 20 and 43 years, respectively). Ankle/arm systolic pressure index (by continuous-wave Doppler) was, on average, lower in homozygotes (P less than .01) and heterozygotes (P less than .05) as compared with the controls. An ankle/arm index less than 0.97 and suggesting flow-reducing arterial lesions was found in six (21%) lower limbs of homozygotes versus zero in controls (P less than .05). Echo Doppler (Duplex Scanner) abnormalities, indicating early, non-flow-reducing lesions of iliac arteries were more frequent in homozygotes (seven wall abnormalities or stenoses less than 15%) than in young controls (P less than .05). The corresponding figures for heterozygotes were seven wall abnormalities or stenoses (1% to 15% and one stenosis 16% to 50%) (P less than .01 v middle-aged controls). Early lesions (three wall abnormalities or stenoses less than 15%, three stenoses 16% to 50%) were detected in six (23%) internal carotids of heterozygotes versus three (3%) of corresponding controls (P less than .05). Technical limitations precluded the accurate detection of early lesions in the internal carotid arteries of young homozygotes and controls.(ABSTRACT TRUNCATED AT 250 WORDS)

To date the association between mucopolysaccharidosis (MPS) IIIA and precocious puberty has been found in only three polish patients. We observed two children affected by MPS IIIA with central precocious puberty (CPP) both treated with GnRH agonists. The occurrence of CPP in both patients with MPS IIIA suggests that it is necessary to look for an association between the two conditions. The follow-up of our two patients leads us to believe also that GnRH agonist treatment can have a beneficial effect on final height and probably on the improvement of behavioural problems.

We report a female patient with a 46,XX,der(8)t(1;8)(q42.1;p23.3) karyotype who had a mild phenotype characterised by a few subtle dysmorphic features and mild developmental retardation, probably resulting from trisomy 1q42-->qter. The deletion on the short arm of the chromosome 8 appeared to be confined to the distal chromosomal segment.

Aims To verify the importance of podiatric evaluation in patients with Down syndrome for the early diagnosis and treatment of minor orthopaedic problems. Methods Case-control study of 50 children affected by Down syndrome (aged 4-10 y) without major orthopaedic malformations compared to 100 healthy children. A complete podiatric examination was performed on all patients and controls. Results Children with Down syndrome showed several orthopaedic anomalies including bony deformity of the forefoot (90%), flat foot (60%), isolated calcaneal valgus (24%), knee valgus (22%) and pronated flat foot (16%). These abnormalities were responsible for postural alterations as confirmed by baropodometric examination. Conclusion The data demonstrated a greater incidence of minor orthopaedic alterations and suggest the necessity of regular podiatric examinations in the follow-up of this syndrome.

The mitochondrial (mt) DNA depletion syndromes (MDDS) are genetic disorders characterized by a severe, tissue-specific decrease of mtDNA copy number, leading to organ failure. There are two main clinical presentations: myopathic (OMIM 609560) and hepatocerebral1 (OMIM 251880). Known mutant genes, including TK2 (ref. 2), SUCLA2 (ref. 3), DGUOK (ref. 4) and POLG5,6, account for only a fraction of MDDS cases7. We found a new locus for hepatocerebral MDDS on chromosome 2p21-23 and prioritized the genes on this locus using a new integrative genomics strategy. One of the top-scoring candidates was the human ortholog of the mouse kidney disease gene Mpv17 (ref. 8). We found disease-segregating mutations in three families with hepatocerebral MDDS and demonstrated that, contrary to the alleged peroxisomal localization of the MPV17 gene product9, MPV17 is a mitochondrial inner membrane protein, and its absence or malfunction causes oxidative phosphorylation (OXPHOS) failure and mtDNA depletion, not only in affected individuals but also in Mpv17 –/– mice.

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.

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.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.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 (p0.000 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 (p0.0001) was found between the IgA-AAA serum titre and the degree of IVA (rs 0.56).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.

Ornithine transcarbamylase deficiency (OTCD) is an X-linked urea cycle disorder due to a defect of the mithocondrial enzyme ornithine transcarbamylase (OTC). Genetic analysis in nine unrelated Italian patients affected by OTCD (one male patient and eight female manifesting carriers) led to the detection of three novel mutations and six previously reported mutations in the OTC gene. The analysis was performed by direct sequencing of OTC cDNA, OTC exons, and intron-exon boundaries and enzymatic restriction analysis on the patients' genomic DNA and total RNA isolated from peripheral blood lymphocytes. In the male patient the new mutation S132P due to the nucleotide change c.394T>C was identified. In a manifesting carrier the nucleotide change c.292G>A that leads to the novel amino acid substitution E98K was identified; this mutation is close to the OTC protein's carbamyl phospate binding site. In another manifesting carrier the OTC cDNA analysis revealed the normally spliced transcript and an aberrant transcript with an insertion of two nucleotides (c.77-78insAG). In the patient's genomic DNA we identified a new transvertion IVS1-3C>G at the heterozygous state; this nucleotide change generates a new splice acceptor site in intron 1 that induces an RNA splicing defect. This insertion causes a frame shift in OTC cDNA ORF and leads to a premature stop codon. The previously described mutations N161S, R141Q, T178M, R92X, A208T, M268T were identified in the other six manifesting carriers.

We describe a family in whom a pericentric inversion of chromosome 5 segregates with benign familial neonatal convulsions (BFNC). BFNC is an autosomal dominant form of epilepsy characterised by spontaneous partial or generalised clonic convulsions beginning within the first months of life. Seizures usually disappear by the age of 6 months; intercritical electroencephalogram and subsequent psychomotor development are normal. BFNC loci have been mapped to human chromosomes 20q13.3 ( BFNC1 ) and 8q24 ( BFNC2 ), based on linkage analysis.1, 2 Recently, two potassium channel genes ( KCNQ2 and KCNQ3 ), located in these two regions, were shown to be mutated in BFNC1 and BFNC2, respectively.3, 4 We report a family with BFNC and a pericentric inversion of chromosome 5 cosegregating with BFNC. Fluorescence in situ hybridisation (FISH) experiments were performed to define the breakpoints at YAC level. The linkage of BFNC to KCNQ2 and mutations in the KCNQ3 gene were excluded. This report raises the possibility of a new locus for BFNC on chromosome 5. The proband, a male, was the second child of unrelated parents, born at 40 weeks of gestation after an uneventful pregnancy. Apgar score was 10 at one and five minutes. The parents were both 32 years old at his birth. Birth weight was 3400 g (50-75th centile), length was 51 cm (50-75th centile), head circumference was 35 cm (50-75th centile), and the clinical examination was normal except for the presence of hypotelorism. …

Background. The aim of this study was to assess whether the endoscopic finding of antral nodularity and serum IgG antibodies to CagA are associated with higher grades of gastric inflammation. Materials and methods. The comprehensive data of two previously published trials were reanalysed. One hundred and fifty-three children (median age 9.5 years) who underwent gastroscopy were included. Biopsy specimens from the antrum and corpus were taken to assess Helicobacter pylori status, gastritis score and lymphoid follicles. During endoscopy, antral nodularity was noted. Serum samples were assayed for IgG antibodies to CagA. Results. The presence of antral nodularity (nod+) and positive CagA serology (CagA+) were each found in 32 of the 77 (41.5%) children who had evidence of H. pylori infection. Crosstabulation showed that 20 children (26%) were nod+/CagA+, 12 (15.5%) nod+/CagA−, 12 (15.5%) nod-/CagA+ and 33 (43%) nod−/CagA−. Gastritis score was significantly lower in nod−/CagA−children than in nod+/CagA− (p = .004), nod−/CagA+ (p = .002) and nod+/CagA+ (p

Background: The endoscopic pattern of antral nodularity is a peculiar finding in children with Helicobacter pylori infection. The aim of this study was to determine whether this finding is related to more severe gastritis. Methods: One hundred seventy-four consecutive children (median age 8.7 years) referred for gastroscopy were studied. Biopsy specimens from the antrum and body of the stomach were taken to assess H pylori status, gastritis score, and lymphoid follicles. Clinical diagnosis, major symptoms and endoscopic findings were recorded. Results: Eighty-four (48%) children (median age 10.5 years) had evidence of H pylori infection. The endoscopic pattern of antral nodularity was found only in children infected with H pylori (34/84, 40.5% vs. 0/90, 0%, p < 0.0001; 100% specificity, 40.5% sensitivity). Among all children infected with H pylori, the gastritis score was higher (p < 0.0001) in those with antral nodularity (n = 34) than in those without (n = 50). Completely normal gastric mucosal histology was never found in children infected with H pylori with antral nodularity. The presence and number of lymphoid follicles was strongly related to the finding of antral nodularity (p < 0.01). Conclusions: The endoscopic pattern of antral nodularity identifies children with H pylori infection, severe gastritis, and increased lymphoid follicles. (Gastrointest Endosc 2001;53:60-4.) Helicobacter pylori infection is common and invariably causes chronic gastritis. Although clinical and epidemiologic evidence indicates that H pylori is generally acquired during childhood1 or early infancy,2 high grades of gastric inflammation are uncommon in children.3-6 Endoscopic features of H pylori-associated gastritis include erythema, prominent areae gastrica, erosions, and nodularity. Antral nodularity has been reported to be a specific but insensitive endoscopic marker for gastric H pylori infection, mostly occurring in children.7-15 Furthermore, it has been shown to be a reproducible endoscopic feature.12 This study investigated whether the appearance of antral nodularity was related to more severe gastritis in a large series of children who underwent upper GI endoscopy with biopsies. MATERIALS AND METHODS Patients and sampling Included in this retrospective study were 174 children (74 boys, 100 girls; age range: 0.75 to 17.2 years, median 8.7 years) consecutively referred for gastroscopy. The following diagnoses were made: recurrent abdominal pain (n = 80, 46%), celiac disease (n = 54, 31%), esophagitis (n = 27, 16%), erosive gastritis (n = 2, 1%), duodenitis (n = 5, 2.8%), erosive duodenitis (n = 2, 1%), and duodenal ulcer (n = 4, 2.2%). Endoscopy was performed by the same investigator (F.L.). In each child at least 3 gastric biopsy specimens were taken, 1 from the antrum for a urease quick test (Yamanouchi Pharma, Milan, Italy) and 2 from the antral lesser curve (near the incisura) and mid-body greater curve for histologic examination. To obtain adequate tissue, biopsy forceps with fenestrated cups, grasper teeth, and needle were used. Occasional poor biopsy specimens were compensated for with a further specimen taken during the same endoscopy. No child had previously undergone anti-H pylori treatment. Informed parental consent was obtained for all endoscopies and biopsies performed. The study was approved by the ethical committee of our university. Clinical and endoscopic assessment

We report two patients with clinical and radiological findings of achondroplasia, who had the most common FGFR3 mutation occurring in thanatophoric dysplasia type I and hypochondroplasia, respectively. Thanatophoric dysplasia is usually a lethal condition, but the patient carrying this mutation is alive and presents a medical history similar to that of patients with achondroplasia. The events leading to such a discrepancy between genotype and phenotype are unclear. These rare cases may influence an appropriate medical and genetic counseling.

Summary Lysinuric protein intolerance (LPI) is a rare autosomal recessive defect of cationic amino acid transport caused by mutations in the SLC7A7 gene. We report the genomic structure of the gene and the results of the mutational analysis in Italian, Tunisian, and Japanese patients. The SLC7A7 gene consists of 10 exons; sequences of all of the exon-intron boundaries are reported here. All of the mutant alleles were characterized and eight novel mutations were detected, including two missense mutations, 242A→C (M1L) and 1399C→A (S386R); a nonsense mutation 967G→A (W242X); two splice mutations IVS3 +1G→A and IVS6 +1G→T; a single-base insertion, 786insT; and two 4-bp deletions, 455delCTCT and 1425delTTCT. In addition, a previously reported mutation, 1625insATCA, was found in one patient. It is noteworthy that 242A→C causes the change of Met 1 to Leu, a rare mutational event previously found in a few inherited conditions. We failed to establish a genotype/phenotype correlation. In fact, both intrafamilial and interfamilial phenotypic variability were observed in homozygotes for the same mutation. The DNA-based tests are now easily accessible for molecular diagnosis, genetic counseling, and prenatal diagnosis of LPI.

Helicobacter pylori infection is mainly acquired in childhood and may predispose to peptic ulcer or gastric cancer later in life.1 Non-invasive diagnostic tools are particularly useful in children as screening tests and for epidemiological studies, but their accuracy has to be tested against that of invasive tests in symptomatic patients before they are used in any particular population. Of the non-invasive tests now available, serological testing is not accurate in young patients and the 13C urea breath test is expensive. In 1998 an enzyme linked immunoassay (ELISA) (Premier-Platinum-HpSA, Meridian Diagnostics, Cincinnati, OH, USA) was approved by the Food and Drug Administration for both diagnosis in adult symptomatic patients, and monitoring the response to treatment. It is now commercially available, but its correlation with gastric infection has not been assessed in children. We evaluated its diagnostic accuracy against invasive tests in children undergoing endoscopy for clinical evaluation, and we determined the cut off values for the paediatric population. View this table: Test performance calculated according to different reading techniques (at 450 …

A centric fission of chromosome 9 was found in a boy with trisomy 9p resulting from a de novo del (9p) and a 9p isochromosome. The patient presented with clinical findings similar to those described in previously reported cases of trisomy 9p. The cytogenetic evaluation and the molecular analysis using fluorescence in situ hybridization (FISH) with specific alphoid probe for chromosome 9 showed a karyotype of 47,XY,+del(9)(q10),+i(9p). We suggest that the mechanism leading to this situation is unusual.

Phenylketonuria (PKU) is an autosomal recessive disease caused by the deficiency of a liver-specific enzyme, phenylalanine hydroxylase (PAH). The pattern of PAH mutations in Mediterranean populations appears to be different from that observed in northern Europe and Asia. Our aim was to study the molecular basis of PKU in Campania and Calabria, two regions of southern Italy. We studied 99 unrelated alleles, detecting 75.8% of the mutations. Our results show that 57% of all the PKU alleles are caused by three different mutations: IVS10nt-546, R261Q and L48S, which display significant differences in their relative distribution across Italy. A novel mutation, a G-to-T transversion at the codon 257 (G257C), was also identified. This mutation results in a Gly-to-Cys change in the catalytic domain of the protein.

Smith-Lemli-Opitz syndrome (SLOS) is a multiple congenital anomalies/mental retardation disorder possibly due to a defect of delta 7-sterol reductase, leading to low plasma cholesterol levels and to the accumulation of 7-dehydrocholesterol (7-DHC) and other cholesterol precursors. This study aimed to identify clinical features that could potentially be specific indicators for the clinical diagnosis of SLOS, and to test the reliability of ultraviolet spectrophotometry (UVS) as a biochemical screening procedure for the syndrome. Twenty patients with clinical suspicion of SLOS, referred to 11 Italian paediatric and clinical genetic centres, were collected during 1994. In 10 patients the diagnosis was confirmed biochemically by gas chromatography/mass spectrometry (GC/MS) analysis of serum sterols, whereas in the other 10 patients the serum sterol profiles were normal. A comparison between confirmed SLOS patients and biochemically negative subjects did not show clinical signs specific for the syndrome. UVS measurement of 7-DHC correlated well with GC/MS profiles, showing 100% sensitivity and specificity. Four out of five patients had serum bile acid concentrations below the normal range of controls.

Mutations in the gene encoding lysosomal protective protein/cathepsin A (PPCA) are the cause of the lysosomal disorder galactosialidosis (GS). Depending on age of onset and severity of the symptoms, patients present with either an early infantile (EI), a late infantile (LI), or a juvenile/adult (J/A) form of the disease. To study genotype-phenotype correlation in this disorder, we have analyzed the mutations in the PPCA gene of eight clinically different patients. In two EI and one J/A patient, we have identified four novel point mutations (Val104Met, Leu208Pro, Gly411Ser and Ser23Tyr), that prevent phosphorylation and, hence, lysosomal localization and maturation of the mutant precursors. Two amino acid substitutions (Phe412Val and Tyr221Asn) are shared by five LI patients. These mutations appear to be pathognomonic for this phenotype, and determine the clinical outcome depending on whether they are present together or in combination with other mutations. The latter include a single base deletion and a novel amino acid change (Met378Thr), which generates an additional glycosylation site. Within the LI group, patients carrying the Phe412Val mutation are clinically more severe than those with the Tyr221Asn substitution. This is in agreement with the biochemical behavior of the Asn221-mutant protein, that is, like the Phe412Val protein, phosphorylated, routed to lysosomes and proteolytically processed, but its intralysosomal stability is intermediate between that of wild-type PPCA and Val412-PPCA. Overall, these results may explain the clinical heterogeneity observed in GS patients and may help to correlate mutant allelic combinations with specific clinical phenotypes.

Study objective : To evaluate phenotypic variability of lysinuric protein intolerance in a cohort of nine Italian patients. Design : Retrospective analysis of patient records. Subjects : Nine Italian patients (seven independent families), all originating from southern Italy, observed during the last 14 years. Results : Some of the patients had unique clinical features, including bone marrow abnormalities featuring erythroblastophagocytosis (five patients) and acute pancreatitis (two patients). Severe complications, known to affect the clinical course and the outcome of the disease, have also been observed: respiratory involvement was present in five cases, with a lethal picture of "alveolar proteinosis" in one. Severe kidney involvement, with both glomerular and tubular damage and rapidly progressing to chronic renal failure, has been observed in one case. Conclusion : Lysinuric protein intolerance may cause severe multisystem involvement, which requires early and careful monitoring. Some peculiar clinical findings observed in Italian patients point to a genetic heterogeneity of lysinuric protein intolerance. (J PEDIATR 1995;126:246-51)

Friedreich Ataxia (FA) is a neurodegenerative disorder characterised by progressive gait disturbance, dysarthria, dysmetria and other coordination disorders. The genetic defect is represented by an expansion of GAA repeats in the frataxin gene (FRDA or X25). Hypertrophic cardiomyopathy is a common finding in FA, and it is widely recognised as specific for the diagnosis of disease status. In this study, we report the co-existence, in a 5-year old boy with FA, of a double mutation in two distinct genes [X25 (A allele: 850 triplets; B allele: 1000 triplets), and cardiac troponin T (TNNT2) (287G>A)]. TNNT2 gene mutations have been previously identified in individuals with a familial form of hypertrophic cardiomyopathy (FHC), an autosomal dominant inherited disease characterised by unexplained cardiac hypertrophy and high incidence of sudden death. Although we cannot rule out the impact of each gene defect on cardiac morphology, it is of interest that these two mechanisms may be acting in a synergistic fashion to produce the extreme degree of cardiac hypertrophy detected in the child. This is, to our knowledge, the first description of a double gene defect in individuals with FA and FHC.

The Marshall-Smith syndrome is characterised by overgrowth, accelerated skeletal maturation, and dysmorphic facial features, often associated with mental retardation of variable degree. Most of the reported patients died in the first three years of life mainly because of respiratory problems. We describe a 5 year old patient with this rare syndrome, who has optic atrophy and agenesis of the corpus callosum, but has no respiratory problems so far. This observation underlines the clinical variability of the Marshall-Smith syndrome and indicates that life expectancy may be prolonged.

Homocystinuria due to homozygous cystathionine beta-synthase deficiency is an inborn error of metabolism characterized by a high incidence of thrombosis and premature atherosclerosis. We evaluated TXA2 biosynthesis in vivo and several in vitro tests of platelet function in 11 homocystinuric patients and 12 healthy controls. In vitro, patients' platelet aggregation was within control values as were TXB2 formation, fibrinogen binding, and ATP secretion in response to thrombin. In contrast, the urinary excretion of 11-dehydro-TXB2, a major enzymatic derivative of TXA2, was > 2 SD of controls in all patients (1,724 +/- 828 pg/mg creatinine, mean +/- SD, in patients vs. 345 +/- 136 in controls, P < 0.001). The administration to four patients of low-dose aspirin (50 mg/d for 1 wk) reduced metabolite excretion by > 80%. The recovery of 11-dehydro-TXB2 excretion over the 10 d that followed aspirin cessation occurred with a pattern consistent with the entry into the circulation of platelets with intact cyclooxygenase activity. Prolonged partial reduction in the abnormally high excretion of both 11-dehydro-TXB2 and 2,3-dinor-TXB2, was also observed in seven patients who ingested 500 mg daily for 3 wk of the antioxidant drug probucol. These results provide evidence for enhanced thromboxane biosynthesis in homocystinuria and for its partial dependence on probucol-sensitive mechanisms. Furthermore, the elevated TXA2 formation in homocystinuria is likely to reflect, at least in part, in vivo platelet activation.

We observed a boy with short stature, chondrodysplasia punctata, ichthyosis, and a terminal deletion of Xp. Steroid sulfatase deficiency was demonstrated in the patient's fibroblasts. Molecular analysis showed a deletion of the entire steroid sulfatase gene. This case represents another example of a contiguous gene syndrome in which the co-deletion of adjacent genes on a chromosome is responsible for a complex phenotype.

Hereditary fructose intolerance (HFI) is an inborn error of metabolism caused by aldolase B deficiency. The aldolase B gene has been cloned and the following mutations causing HFI have been identified: A149P (a G----C transversion in exon 5), A174D (a C----A transversion in exon 5), L288 delta C (a base pair deletion in exon 8), and N334K (a G----C transversion in exon 9). We have investigated the occurrence of these mutations in 11 Italian patients affected by HFI using PCR and hybridisation to specific oligomers. We found that four patients were homozygous for the A149P mutation, two patients were homozygous for the A174D mutation, three patients were compound heterozygotes for both the A149P and A174D mutations, one patient was homozygous for the N334K mutation, and one patient did not show any of the reported mutations (HFI diagnosis carried out by aldolase B assay). The L288 delta C mutation has not been found in this survey.

The clinical and biochemical findings in an Italian sibship affected by carbonic anhydrase II deficiency are described. Evidence of clinical heterogeneity and an increased frequency of the disease in the Mediterranean area and the Middle East are discussed.

2 cases of posterior lenticonus associated with hyperglycinuria without iminoaciduria, found in the same family, were examined. After a review of the literature, the rarity of this association is stressed.

We report a girl with Niemann-Pick disease type B in whom short stature was recorded over a long period. Association of short stature with the presence of a polyglandular involvement in this patient is discussed.

A 15-year-old female was found to have the typical features of Wildervanck's syndrome, including Klippel-Feil anomaly, abducens paralysis, retraction of the bulbi, and deafness. In addition, she had bilateral lens subluxation and facial paralysis, neither of which have been reported in patients with Wildervanck's syndrome.

Martsolf's syndrome has been described in Jewish people. We describe a patient of non-Jewish ancestry who has minor differences from other patients. The possible pattern of inheritance is discussed.

Summary: Neuraminidase activity in fibroblasts obtained from a patient with combined β-galactosidase-neuraminidase deficiency (β-gal−/neur−) was partially restored by fusion with two ML I cell lines and an ML II cell line. As observed with neuraminidase activity, β-galactosidase also showed complementation with an increase in activity when β-gal−/neur− fibroblasts were fused with an ML II or a GHi gangliosidosis cell line. Both GM, gangliosidosis and sialidosis fibroblasts secreted a “corrective factor” which, when added to medium above β-gal−/neur− fibroblasts, was pinocytosed and partially corrected its deficiencies for these two enzymes.This partial correction of β-galactosidase and neuraminidase activities persisted for at least 72 h after removal of the “corrective factor” from the medium. A “corrective factor” with similar properties was obtained from glycoproteins isolated by chromatography of human spleen homogenates on concanavalin A-Sepharose. Treatment of-β-gal−/neur− fibroblasts with leupeptin or EP475, two inhibitors of lysosomal thiolproteases, partially restored β-galactosidase activity but caused no significant improvement in neuraminidase levels. The partial corrective effect of leupeptin on partial corrective effect of leupeptin on β-galactosidase activity persisted for at least 2 d after removal of the drug, even in the presence of cycloheximide.-galactosidase activity persisted for at least 2 d after removal of the drug, even in the presence of cycloheximide.