LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development.

In humans, low peak bone mass is a significant risk factor for osteoporosis. We report that LRP5, encoding the low-density lipoprotein receptor-related protein 5, affects bone mass accrual during growth. Mutations in LRP5 cause the autosomal recessive disorder osteoporosis-pseudoglioma syndrome (OPPG). We find that OPPG carriers have reduced bone mass when compared to age- and gender-matched controls. We demonstrate LRP5 expression by osteoblasts in situ and show that LRP5 can transduce Wnt signaling in vitro via the canonical pathway. We further show that a mutant-secreted form of LRP5 can reduce bone thickness in mouse calvarial explant cultures. These data indicate that Wnt-mediated signaling via LRP5 affects bone accrual during growth and is important for the establishment of peak bone mass.

3-Methylglutaconic aciduria and hypermethioninaemia in a child with clinical and neuroradiological findings of Leigh disease.

We report on a child with a clinical and neuroradiological picture consistent with Leigh disease and an unusual association of isolated hypermethioninaemia and 3-methylglutaconic aciduria. A low-methionine diet normalized both plasma methionine and urine 3-methylglutaconic acid; a methionine-loading test led to significant increase of both metabolites. In the skin fibroblasts the activity of 3-methylglutaconyl-CoA hydratase was essentially normal. No explanation of this uncommon association of hypermethioninaemia and glutaconic aciduria is available. The possibility of a common transporter for 3-methylglutaconic acid and methionine is an attractive hypothesis.

Alterations in the CSB gene in three Italian patients with the severe form of Cockayne syndrome (CS) but without clinical photosensitivity.

Cockayne syndrome (CS) is a rare autosomal recessive disorder characterized by postnatal growth failure, mental retardation and otherwise clinically heterogeneous features which commonly include cutaneous photosensitivity. Cultured cells from sun-sensitive CS patients are hypersensitive to ultraviolet (UV) light and, following UV irradiation, are unable to restore RNA synthesis rates to normal levels. This has been attributed to a specific deficiency in CS cells in the ability to carry out preferential repair of damage in actively transcribed regions of DNA. We report here a cellular and molecular analysis of three Italian CS patients who were of particular interest because none of them was sun-sensitive, despite showing most of the features of the severe form of CS, including the characteristic cellular sensitivity to UV irradiation. They all were altered in the CSB gene. The genetically related patients CS1PV and CS3PV were homozygous for the C1436T transition resulting in the change Arg453opal. Patient CS2PV was a compound heterozygote for two new causative mutations, insertions of an A at position 1051 and of TGTC at 2053, leading to truncated proteins of 367 and 681 amino acids. These mutations result in severely truncated proteins, as do many of those that we previously identified in several sun-sensitive CS-B patients. These observations confirm that the CSB gene is not essential for viability and cell proliferation, an important issue to be considered in any speculation on the recently proposed additional function of the CSB protein in transcription. Our investigations provide data supporting the notion that other factors, besides the site of the mutation, influence the type and severity of the CS clinical features.

Ataxia, ocular telangiectasia, chromosome instability, and Langerhans cell histiocytosis in a patient with an unknown breakage syndrome.

An 8 year old boy who had Langerhans cell histiocytosis when he was 15 months old showed psychomotor regression from the age of 2 years. Microcephaly, severe growth deficiency, and ocular telangiectasia were also evident. Magnetic nuclear resonance imaging showed cerebellar atrophy. Alphafetoprotein was increased. Chromosome instability after x irradiation and rearrangements involving chromosome 7 were found. Molecular study failed to show mutations involving the ataxia-telangiectasia gene. This patient has a clinical picture which is difficult to relate to a known breakage syndrome. Also, the relationship between the clinical phenotype and histiocytosis is unclear.

Genetic mapping to 10q23.3-q24.2, in a large Italian pedigree, of a new syndrome showing bilateral cataracts, gastroesophageal reflux, and spastic paraparesis with amyotrophy.

We have recently observed a large pedigree with a new rare autosomal dominant spastic paraparesis. In three subsequent generations, 13 affected individuals presented with bilateral cataracts, gastroesophageal reflux with persistent vomiting, and spastic paraparesis with amyotrophy. Bilateral cataracts occurred in all affected individuals, with the exception of one patient who presented with a chorioretinal dystrophy, whereas clinical signs of spastic paraparesis showed a variable expressivity. Using a genomewide mapping approach, we mapped the disorder to the long arm of chromosome 10 on band q23.3-q24.2, in a 12-cM chromosomal region where additional neurologic disorders have been localized. The spectrum of phenotypic manifestations in this family is reminiscent of a smaller pedigree, reported recently, confirming the possibility of a new syndrome. Finally, the anticipation of symptoms suggests that an unstable trinucleotide repeat may be responsible for the condition.

Differences in tumor necrosis factor-alpha soluble receptor serum concentrations between patients with Henoch-Schönlein purpura and pediatric systemic lupus erythematosus: pathogenetic implications.

OBJECTIVE: Animal models of immune complex mediated tissue injury have shown different patterns of proinflammatory cytokine production according to the subtype of immunoglobulin involved. The IgA immune complex model differs from the IgG model by the lack of involvement of tumor necrosis factor (TNF) in the pathogenesis of tissue damage. We investigated in age matched patients the possible difference in TNF involvement in a predominantly IgA mediated disease, Henoch-Schönlein purpura (HSP), in comparison with systemic lupus erythematosus (SLE), in which vascular injury is mostly associated with local deposition of IgG immune complexes. METHODS: Serum concentrations of TNF-alpha and its soluble receptors (sTNF-R) p55 and p75 were studied in 20 patients with pediatric SLE at various degrees of disease activity, in 16 patients with highly active HSP, and in 15 healthy controls by enzyme amplified sensitivity immunoassay. SLE disease activity was evaluated using 2 scores, the European Consensus Group Study for SLE Disease Activity Criteria and the SLE Disease Activity Index. RESULTS: Serum concentrations of TNF-alpha fell within the normal range in patients with both SLE and HSP irrespective of disease activity. Conversely, patients with SLE displayed increased serum levels of sTNF-R that correlated positively with the degree of disease activity (r = 0.60, p < 0.001; r = 0.71, p < 0.001, for p55 and p75, respectively). In contrast, no difference in the serum levels of sTNF-R was found between patients with highly active HSP and controls. CONCLUSION: Our study provides the first circumstantial evidence that pediatric SLE and HSP are characterized by differential involvement of TNF in the pathogenesis of tissue damage.

Erythema multiforme-like manifestations and arthritis in a 3-year-old child with leukocytoclastic vasculitis.

A 3-year-old boy with erythema multiforme-like manifestations and severe articular involvement is reported. Because of the unusual onset of the cutaneous lesion a skin biopsy was performed, revealing the typical features of a leukocytoclastic vasculitis. A direct immunofluorescent study revealed C3 and IgM deposition within the wall and around the small vessels. The clinical and immunopathological findings in this patient were similar to those reported for the acute hemorrhagic edema of infancy (AHE) described in children younger than 2 years of age. The present case supports the hypothesis that AHE is a distinctive leukocytoclastic vasculitis of childhood, irrespective of the age at onset.

Retinitis pigmentosa, hypopituitarism, nephronophthisis, and mild skeletal dysplasia (RHYNS): a new syndrome?

We report on a 17 6/12-year-old boy with nephronophthisis, retinitis pigmentosa, left upper eyelid ptosis, enopthalmos, transmissive deafness, GH and TSH deficiency, and mild skeletal dysplasia. A similar case was reported by Bianchi et al. [1988: Helv Paediatr Acta 43:449-455] in another Italian patient. Here we confirm the previous observations and argue that both patients might be affected by a new syndrome.

Molecular basis of hereditary fructose intolerance in Italy: identification of two novel mutations in the aldolase B gene.

We screened the aldolase B gene in 14 unrelated Italian patients with hereditary fructose intolerance (HFI), and found two novel disease related mutations: a single nucleotide deletion in exon 2 (delta A20) that leads to an early stop codon, and a C-->T transition in exon 8 that substitutes an Arg with a Trp residue at codon 303 (R303W).

Apparent preferential loss of heterozygosity at TSC2 over TSC1 chromosomal region in tuberous sclerosis hamartomas.

To investigate the molecular mechanisms of tuberous sclerosis (TSC) histopathologic lesions, we have tested for loss of heterozygosity the two TSC loci (TSC1 and TSC2) and seven tumor suppressor gene-containing regions (TP53, NF1, NF2, BRCA1, APC, VHL, and MLM) in 20 hamartomas from 18 TSC patients. Overall, eight angiomyolipomas, eight giant cell astrocytomas, one cortical tuber, and three rhabdomyomas were analyzed. Loss of heterozygosity at either TSC locus was found in a large fraction of the informative patients, both sporadic (7/14) and familial (1/4). Interestingly, a statistically significant preponderance of loss of heterozygosity at TSC2 was observed in the sporadic group (P < 0.01). Among the possible explanations considered, the bias in the selection for TSC patients with the most severe organ impairment seems particularly appealing. According to this view, a TSC2 defect might confer a greater risk for early kidney failure or, possibly, a more rapid growth of a giant cell astrocytoma. None of the seven antioncogenes tested showed loss of heterozygosity, indicating that the loss of either TSC gene product may be sufficient to promote hamartomatous cell growth. Finally, the observation of loss of heterozygosity at different markers in an astrocytoma and in an angiomyolipoma from the same patient might suggest the multifocal origin of the second-hit mutation.

Maternal uniparental disomy for chromosome 14.

A girl carrying a de novo balanced 13-14 robertsonian translocation showed a clinical phenotype with severe hypotonia, hyperextensible joints, frontal bossing, asymmetric face, no mental retardation, severe scoliosis and motor delay. In situ hybridization analysis on chromosome spreads revealed the presence of the two centromeres in the rearranged chromosomes. Molecular analysis on genomic DNA showed the presence in the proposita of two chromosomes 14 of maternal origin and no chromosome 14 from the father indicating a maternal monocentric uniparental disomy for chromosome 14 (mUPD14). Our patient shows several similarities with other reported cases of mUPD14, suggesting imprinting of a region(s) of chromosome 14 and defining a possible mUPD14 Syndrome.

6-methylprednisolone 'mini-pulses': a new modality of glucocorticoid treatment in systemic onset juvenile chronic arthritis.

From 1989 to 1994 we have been following in our Department 22 patients (12 males, 10 females, age range 1-13.5 years) affected by sJCA who underwent glucocorticoid (GC) treatment. These patients were randomised to receive for 6 months two different GC schedules: group A (12) received 6 methylprednisolone (6MP) i.v. for 3 days with 5 mg/kg/d and for an additional 3 days at 2.5 mg/kg/d followed by po prednisone (1 mg/kg/d); group B (10) received po prednisone (1 mg/kg/d). A remarkable decrease of disease activity and fever score and a prompt improvement of joint involvement were observed. A CPR serum concentration decrease associated to a consistent increase of Hb over baseline values were disclosed in group A. GC cumulative daily requirement was significantly lower in group A. Four patients from group B but only one from group A developed a cushingoid appearance: no differences of BMI were found in the two groups. Our study shows that in sJCA patients i.v. GC mini pulses are effective on early clinical and biological parameters of inflammation and requires a lower cumulative daily dosage than conventional oral GC treatment.

Primary hypothyroidism as a consequence of 131-I-metaiodobenzylguanidine treatment for children with neuroblastoma.

BACKGROUND: 131-I-metaiodobenzylguanidine is a radioiodinated compound selectively concentrated by cells of neuroectodermal origin, including neuroblastoma cells, for this reason it may represent a promising treatment modality for neuroblastoma in childhood. Although a potential side effect of 131-I-MIBG administration is thyroid dysfunction, relatively few data are reported about this issue. METHODS: A series of 14 long term surviving patients with neuroblastoma who had been treated with 131-I-MIBG courses ranging from 2.5 to 5.5 gigabecquerels after surgical and conventional pharmacologic therapy is reported. RESULTS: Twelve patients developed primary hypothyroidism that was clinically overt in 8 patients and compensated in 4 patients within 6-12 months of completion of 131-I-MIBG administration. Only in two patients was thyroid function spared. Significant correlations between the cumulative dose of 131-I-MIBG and the degree of thyroid failure were not found. CONCLUSIONS: Primary hypothyroidism appears to be a common side effect in children with neuroblastoma treated with 131-I-MIBG. This finding suggests that methods to preserve thyroid function other than oral administration of iodide should be sought.