Avraham Zeharia

Skin Indurations in Response to Tuberculin Testing in Patients with Nontuberculous Mycobacterial Lymphadenitis

Mantoux results were examined for 29 children with culture-proven nontuberculous mycobacterial lymphadenitis, and 4 species were isolated: Mycobacterium avium-intracellulare complex (from 14 patients [48%]), Mycobacterium haemophilum (from 12 [41%]), Mycobacterium simiae (from 2 [7%]), and Mycobacterium scrofulaceum (from 1 [3%]); the median indurations for each species were 15.5 mm, 14.5 mm, 20 mm, and 23 mm, respectively, and in 17 cases (59%), they were > or =15 mm. In regions with a low incidence of tuberculosis, lymphadenitis thought to be due to nontuberculous mycobacteria should be managed as such, regardless of Mantoux results, thereby avoiding antituberculosis treatment.

An Israeli Arab patient with a de novo TNFRSF1A mutation causing tumor necrosis factor receptor-associated periodic syndrome.

OBJECTIVE To investigate genetic susceptibility to recurrent fevers, generalized severe myalgia, and migratory erythema in an Israeli Arab child with no family history of similar disease. METHODS DNA sequencing of exons 1-6 of the TNFRSF1A gene (formerly TNFR1) was performed in the patient and his parents to determine the presence of the autosomal-dominant tumor necrosis factor receptor-associated periodic syndrome (TRAPS); informative markers spanning the TNFRSF1A locus were used to genotype all available members of the patients family. The TNFRSF1A gene was subsequently screened in 69 healthy Arab controls and 96 Caucasian controls. Formal forensic paternity testing was performed on the child. RESULTS We found a de novo missense mutation in exon 3 of the TNFRSF1A gene, involving a novel C-->T transition encoding a Cys70Arg (C70R) variant, in the Israeli Arab patient. Eight of the common familial Mediterranean fever (FMF) gene MEFV mutations were excluded. This mutation was not present in the parents or siblings, or among the 69 healthy Arab controls. However, another TNFRSF1A variant, Pro46Lys (P46L), was present in 1 of the Arab controls. CONCLUSION We have identified a TNFRSF1A mutation associated with periodic fever in an Arab patient, and a TNFRSF1A variant, which is variably pathogenic in Caucasians, in an Arab control. This is the first report of a de novo mutation in periodic fevers in general, and also of TRAPS in the Arab population. These findings demonstrate the need to include TRAPS in the differential diagnosis of recurrent fevers in this population.

Transient Infantile Hypertriglyceridemia, Fatty Liver, and Hepatic Fibrosis Caused by Mutated GPD1, Encoding Glycerol-3-Phosphate Dehydrogenase 1

The molecular basis for primary hereditary hypertriglyceridemia has been identified in fewer than 5% of cases. Investigation of monogenic dyslipidemias has the potential to expose key metabolic pathways. We describe a hitherto unreported disease in ten individuals manifesting as moderate to severe transient childhood hypertriglyceridemia and fatty liver followed by hepatic fibrosis and the identification of the mutated gene responsible for this condition. We performed SNP array-based homozygosity mapping and found a single large continuous segment of homozygosity on chromosomal region 12q13.12. The candidate region contained 35 genes that are listed in Online Mendelian Inheritance in Man (OMIM) and 27 other genes. We performed candidate gene sequencing and screened both clinically affected individuals (children and adults with hypertriglyceridemia) and also a healthy cohort for mutations in GPD1, which encodes glycerol-3-phosphate dehydrogenase 1. Mutation analysis revealed a homozygous splicing mutation, c.361-1G>C, which resulted in an aberrantly spliced mRNA in the ten affected individuals. This mutation is predicted to result in a truncated protein lacking essential conserved residues, including a functional site responsible for initial substrate recognition. Functional consequences of the mutation were evaluated by measuring intracellular concentrations of cholesterol and triglyceride as well as triglyceride secretion in HepG2 (hepatocellular carcinoma) human cells lines overexpressing normal and mutant GPD1 cDNA. Overexpression of mutant GPD1 in HepG2 cells, in comparison to overexpression of wild-type GPD1, resulted in increased secretion of triglycerides (p = 0.01). This finding supports the pathogenicity of the identified mutation.

Copper deficiency in infants fed cow milk

NUTRITIONAL COPPER DEFICIENCY in infancy has been observed by Tanaka et al. ~ in a premature baby fed milk formula low in copper. Copper deficiency has also been reported in infants given total parenteral nutrition w i thou t copper supplementation in cases of severe diarrhea, malabsorption, protein loss, or the use of chelating agents. 2-5 Copper deficiency may cause anemia and other subtle symptoms that may go undiagnosed but resolve with diet enrichment. We describe two infants with copper deficiency, and draw attention to the similarities between our patients and those of Tanaka.

Mutations in GMPPA Cause a Glycosylation Disorder Characterized by Intellectual Disability and Autonomic Dysfunction

In guanosine diphosphate (GDP)-mannose pyrophosphorylase A (GMPPA), we identified a homozygous nonsense mutation that segregated with achalasia and alacrima, delayed developmental milestones, and gait abnormalities in a consanguineous Pakistani pedigree. Mutations in GMPPA were subsequently found in ten additional individuals from eight independent families affected by the combination of achalasia, alacrima, and neurological deficits. This autosomal-recessive disorder shows many similarities with triple A syndrome, which is characterized by achalasia, alacrima, and variable neurological deficits in combination with adrenal insufficiency. GMPPA is a largely uncharacterized homolog of GMPPB. GMPPB catalyzes the formation of GDP-mannose, which is an essential precursor of glycan moieties of glycoproteins and glycolipids and is associated with congenital and limb-girdle muscular dystrophies with hypoglycosylation of α-dystroglycan. Surprisingly, GDP-mannose pyrophosphorylase activity was unchanged and GDP-mannose levels were strongly increased in lymphoblasts of individuals with GMPPA mutations. This suggests that GMPPA might serve as a GMPPB regulatory subunit mediating feedback inhibition of GMPPB instead of displaying catalytic enzyme activity itself. Thus, a triple-A-like syndrome can be added to the growing list of congenital disorders of glycosylation, in which dysregulation rather than mere enzyme deficiency is the basal pathophysiological mechanism.

Conversion reaction: management by the paediatrician

Abstract We describe the diagnosis and management of 47 children with conversion reaction seen during the past 9 years in our outpatient department. Some illustrative cases are reported in detail. The study shows that conversion reactions in children can often be accurately diagnosed by detailed history and physical examination. When the diagnosis was made early and presented with certainty, both parental acceptance and the childs recovery were easier, and the need for expensive and unnecessary diagnostic procedures was eliminated. Immediate intervention by the paediatrician prevented perpetuation of the problem, secondary gains and continuing family stress. Most of the patients recovered after a few days without recurrence. The major role of the paediatrician is emphasized. Co-operation between the patients, parents and the paediatrician is important, as is close follow up. Conclusion Paediatricians cope successfully with children with conversion reaction with early diagnosis and immediate intervention.

A novel PEX12 mutation identified as the cause of a peroxisomal biogenesis disorder with mild clinical phenotype, mild biochemical abnormalities in fibroblasts and a mosaic catalase immunofluorescence pattern, even at 40 °C

AbstractMutations in 12 different PEX genes can cause a generalized peroxisomal biogenesis disorder with clinical phenotypes ranging from Zellweger syndrome to infantile Refsum disease. To identify the specific PEX gene to be sequenced, complementation analysis is first performed in fibroblasts using catalase immunofluorescence. A patient with a relatively mild phenotype of infantile cholestasis, hypotonia and motor delay had elevated plasma very long-chain fatty acids and bile acid precursors, but fibroblast studies revealed normal or only mildly abnormal peroxisomal parameters and mosaic catalase immunofluorescence. This mosaicism persisted even when the incubation temperature was increased from 37 °C to 40 °C, a maneuver previously shown to abolish mosaicism by exacerbating peroxisomal dysfunction. As mosaicism precludes complementation analysis, a candidate gene approach was employed. After PEX1 sequencing was unrewarding, PEX12 sequencing revealed homozygosity for a novel c.102A>T (p.R34S) missense mutation affecting a partially conserved residue in the N-terminal region important for localization to peroxisomes. Transfection of patient fibroblasts with wild-type PEX12 cDNA confirmed that a PEX12 defect was the basis for the PBD. Homozygosity for c.102A>T was identified in a second patient of similar ethnic origin also presenting with a mild phenotype. PEX12 is a highly probable candidate gene for direct sequencing in the context of a mild clinical phenotype with mosaicism and minimally abnormal peroxisomal parameters in fibroblasts.

Isolated sphenoidal sinusitis in children

Abstract Acute isolated infectious sphenoiditis is an uncommon, potentially dangerous condition which is often misdiagnosed because of its nonspecific symptoms and paucity of clinical signs. We present eight children with isolated sphenoiditis who were managed in our medical centre during the last 2 years and review the literature. All the patients were adolescents or pre-adolescents and all experienced moderate to severe refractory oppressive headache. Four had a history of sinusitis or allergic rhinitis. None had fever or any other directing clinical sign. Diagnosis was made by cranial computer tomography. All were treated with antibiotics and recovered completely without infectious or neurological complications. Conclusion Acute isolated infectious sphenoiditis should be considered in adolescents and pre-adolescents who present with constant moderate to severe oppressive headache. Awareness of this entity will enable early diagnosis and initiation of antibiotic treatment which is essential to avoid complications and surgical intervention.

Mutations in HAO1 encoding glycolate oxidase cause isolated glycolic aciduria

Background The primary hyperoxalurias are a group of recessive kidney diseases, characterised by extensive accumulation of calcium oxalate that progressively coalesces into kidney stones. Oxalate overproduction is facilitated by perturbations in the metabolism of glyoxylate, the product of glycolate oxidation, and the immediate precursor of oxalate. Glycolic aciduria associated with hyperoxaluria is regarded as the hallmark of type 1 primary hyperoxaluria. The genetic basis of isolated glycolic aciduria is reported here. Methods and results Two brothers, born to consanguineous healthy parents of Arab descent, were evaluated for psychomotor delay associated with triple-A-like syndrome (anisocoria, alacrima and achalasia). The proband showed markedly increased urinary glycolic acid excretion with normal excretion of oxalate, citrate and glycerate. Abdominal ultrasound showed normal-sized kidneys with normal echotexture. The genetic nature of triple-A-like syndrome in this kindred was found to be unrelated to this metabolic abnormality. Direct DNA sequencing of glycolate oxidase gene (HAO1) revealed a homozygous c.814-1G>C mutation in the invariant -1 position of intron 5 splice acceptor site. Since HAO1 is a liver-specific enzyme, the effect of this novel mutation on splicing was validated by an in vitro hybrid-minigene approach. We confirmed the appearance of an abnormal splice variant in cells transfected with mutant minigene vector. Conclusions Our results pinpoint the expression of defective splice variant of glycolate oxidase as the cause of isolated asymptomatic glycolic aciduria. This observation contributes to the development of novel approaches, namely, substrate reduction, for the treatment of primary hyperoxaluria type I.

Symptoms of Migraine in The Paediatric Population by Age Group

The revised criteria of the International Headache Society (IHS) for paediatric headache do not differentiate among age groups. This study aims to determine if different symptoms of migraine are specific or typical of different age groups of children. The files of 160 children (79 boys, 81 girls, mean age 10.39 ± 3.71 years) with migraine treated at the paediatric headache clinic of a tertiary centre were reviewed. The diagnosis was based on the criteria of the IHS (ICHD-II). The patients were divided by age into three groups according to educational status, ≤6 years (preschool, group 1), >6 to ≤12 years (elementary school, group 2) and >12 to ≤18 years (secondary school, group 3), and compared by symptoms and signs. Symptoms of migraine with and without aura were also compared. There was no significant difference among the groups in rates of unilateral headache, phonophobia, photophobia, awakening pain, nausea or worsening of pain during physical activity. The parameters found to be statistically significant were dizziness and duration of migraine, and aura which increased with time. Frequency of attacks increased with age. The single statistically significant parameter found to be more frequent in younger age was vomiting. The statistically significant parameters of nausea and duration of migraine were more frequent in migraine with aura compared with migraine without aura. In conclusion, most of the migraine symptoms included in the 2004 recommendations of the IHS are not typical for specific paediatric age groups, probably because brain maturity is a continuous process. A familial history of migraine is a frequent finding among all age groups and should be considered in the paediatric criteria, especially in younger children in whom diagnosis is more difficult. Vomiting may help the diagnosis of migraine in young children with a familial history of migraine.