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Biomedical subjects

C Danesino

Publications and source records attributed to C Danesino.

At least 37 records · Page 2Linked to original sources
PubMed2001

Familial hemophagocytic lymphohistiocytosis: how late can the onset be?

BACKGROUND AND OBJECTIVES: Most patients with familial hemophagocytic lymphohistiocytosis (HLH) develop the disease within the first two years of age. In a minority of cases a later occurrence has been reported, with an upper age limit of eight years. A significant concordance of the age at onset within each family has also been observed. RESULTS: We report four cases of families with HLH diagnosed at an unusually late age, comprised between between 9 and 17 years; in each of these families another child developed the disease in infancy. The natural killer activity of the patients was depleted; nevertheless, we had indirect evidence that, in at least two families, mutations of the perforin gene were not causing the disease. INTERPRETATION AND CONCLUSIONS: Such a late onset is very unusual and suggests that there is a subgroup of families with HLH in which the disease may present early or late in different members. Thus in some families with HLH the siblings might remain at risk of developing the disease for several years. Their actual risk cannot be defined until the genetic mutation is identified in each family and assessed in each member.

Adolescent↗
PubMed2000

Deletion of a 5-cM region at chromosome 8p23 is associated with a spectrum of congenital heart defects.

BACKGROUND: Cytogenetic evidence suggests that the haploinsufficiency of > or =1 gene located in 8p23 behaves as a dominant mutation, impairing heart differentiation and leading to a wide spectrum of congenital heart defects (CHDs), including conotruncal lesions, atrial septal defects, atrioventricular canal defects, and pulmonary valve stenosis. An 8p heart-defect-critical region was delineated, and the zinc finger transcription factor GATA4 was considered a likely candidate for these defects. We narrowed this region and excluded a major role of GATA4 in these CHDs. METHODS AND RESULTS: We studied 12 patients (7 had CHD and 5 did not) with distal 8p deletions from 9 families by defining their chromosome rearrangements at the molecular level by fluorescent in situ hybridization and short-tandem repeat analysis. Subjects with 8p deletions distal to D8S1706, at approximately 10 cM from the 8p telomere, did not have CHD, whereas subjects with a deletion that included the more proximal region suffered from the spectrum of heart defects reported in patients with 8p distal deletions. The 5-cM critical region is flanked distally by D8S1706 and WI-8327, both at approximately 10 cM, and proximally by D8S1825, at 15 cM. Neither GATA4 nor angiopoietin-2 (ANGPT2; a gene in 8p23 involved in blood vessel formation) were found to be deleted in some of the critical patients. We also found that CHDs are not related to the parental origin of deletion. CONCLUSIONS: Haploinsufficiency for a gene between WI-8327 and D8S1825 is critical for heart development. A causal relationship does not seem to exist between GATA4 and ANGPT2 haploinsufficiency and CHDs.

Adolescent↗
PubMed2000

Isochromosome (7)(q10) in Shwachman syndrome without MDS/AML and role of chromosome 7 anomalies in myeloproliferative disorders.

Shwachman syndrome (SS) is an autosomal recessive disorder in which bone marrow dysfunction is observed, with development of myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML) in up to one third of the cases. Inconclusive data are available as to increased chromosome breakage in SS, while chromosome 7 anomalies, and often an isochromosome (7)(q10), are frequent in cases with MDS/AML. We report on the consistent presence of an i(7)(q10) in the bone marrow and blood lymphocytes in one of two sisters affected with SS without any clinical or cytological signs of MDS/AML. Thus, this patient was either a case of constitutional mosaicism for the i(7)(q10), or this had to be acquired in a nondysplastic and non-neoplastic marrow clone. DNA polymorphism analysis demonstrated the paternal origin of the i(7q). We postulate that the SS mutation acts as a mutator gene, and causes karyotype instability; abnormal clones would thus arise in the marrow, and chromosome 7 anomalies, i(7q) in particular, will in turn lead to MDS/AML. If this interpretation is correct, it would be also an indication to consider chromosome 7 anomalies in general, out of SS, as primary changes in MDS/AML pathogenesis.

Bone Marrow Diseases↗
PubMed2000

Cytogenetic abnormalities in PHA-stimulated lymphocytes from patients with Langerhans cell histocytosis. AIEOP-Istiocitosi Group.

The aetiopathogenesis of Langerhans cell histiocytosis (LCH) is still undefined. Constitutional abnormalities in LCH have rarely been reported. One study showed chromosomal instability in lesional cells from three patients. No chromosomal studies are available on peripheral blood lymphocytes. Peripheral blood lymphocytes were analysed for the presence of chromatid and/or chromosomal breaks and structural rearrangements. A fluorescence in situ hybridization (FISH) painting technique was also applied in two cases. Sixteen patients with multisystem (MS, n = 11) or single system (SS, n = 5) LCH were studied. either at the diagnosis (n = 8), during treatment (n = 2) or during follow-up, when asymptomatic (n = 6). Thirteen patients had chromosomal abnormalities. Eleven patients (69%) had chromatid and chromosomal breaks in 7-45% of cells. Overall, chromosome and chromatid breaks were significantly more frequent in the 11 patients with MS disease than in the five patients with SS disease: the mean percentage of cells showing chromosome and chromatid breaks was 13.4% in MS patients vs. 6.2% in SS patients (P = 0.003). Chromosomal abnormalities may be found in phytohaemagglutinin (PHA)-stimulated peripheral blood lymphocytes of LCH patients at diagnosis, during the disease course and even during long-term follow-up, more frequently in MS disease. Chromosome instability may be considered as either a basic genetic instability or as a landmark of reaction to an environmental agent (viral?) that, through genome alteration, may play a role in histiocyte proliferation and, in some cases, also in the increased risk of malignancy.

Adult↗
PubMed1999

Hemophagocytic lymphohistiocytosis in a patient with deletion of 22q11.2.

We report on a new patient with deletion of 22q11 associated with hemophagocytic lymphohistiocytosis and a fatal outcome. She had minor facial anomalies and cardiac malformation corresponding to those described in del (22q11) syndrome, normal T and B cell function and NK activity; bone marrow aspiration showed active erythrophagocytosis. Our case in addition to two other children reported previously suggest that such a rare association between lymphocyte-macrophage activation and deletion of 22q11 may be more frequent than previously recognized.

Abnormalities, Multiple↗
PubMed1999

Early onset of gastric carcinoma and constitutional deletion of 18p.

We report on the association of a gastric carcinoma and a constitutional deletion of the short arm of chromosome 18 in a 14-year-old patient. The phenotype of the patient, including microcephaly, ptosis, micrognathia, tetralogy of Fallot, and mental retardation, fits well with previously reported cases of del(18p); she also showed a positive serology against Helicobacter pylori. The comparison of the alleles of polymorphic loci located on the short arm of chromosome 18 between the patient and her parents showed a maternal origin of the abnormal chromosome. Loss of heterozygosity (LOH) for loci located in the long arm of chromosome 18 is a frequent event in gastric carcinomas; it was observed in the tumoral mass of our patient and again, the alleles lost were of maternal origin. We postulate that the constitutional chromosomal abnormality may have favored the loss of the abnormal chromosome in some cells and that the loss of the deleted chromosome 18 (demonstrated by LOH for this chromosome in the tumoral mass) has been an early step in the pathogenesis of the gastric carcinoma of our patient with Helicobacter pylori infection acting as a cofactor.

Abnormalities, Multiple↗
PubMed1999

Mutation analysis of the RPGR gene reveals novel mutations in south European patients with X-linked retinitis pigmentosa.

The RPGR (retinitis pigmentosa GTPase regulator) gene has been shown to be mutated in 10-20% of patients with X-linked retinitis pigmentosa (XLRP), a severe form of inherited progressive retinal degeneration. A total of 29 different RPGR mutations have been identified in northern European and United States patients. We have performed mutation analysis of the RPGR gene in a cohort of 49 southern European males affected with XLRP. By multiplex SSCA and automatic direct sequencing of all 19 RPGR exons, seven different and novel mutations were identified in eight of the 49 families; these include three splice site mutations, two microdeletions, and two missense mutations. RNA analysis showed that the three splice site defects resulted in the generation of aberrant RPGR transcripts. Six of these mutations were detected in the conserved amino-terminal region of RPGR protein, containing tandem repeats homologous to the RCC1 protein, a guanine nucleotide-exchange factor for Ran-GTPase. Several exonic and intronic sequence variations were also detected. None of the RPGR mutations reported in other populations were identified in our series. Our results are consistent with the notions of heterogeneity and minority causation of XLRP by mutations in RPGR in Caucasian populations.

Base Sequence↗
PubMed1999

The breakpoints of a constitutional inversion of chromosome 9 associated with haemophagocytic lymphohistiocytosis are not linked to the disease gene.

Haemophagocytic lymphohistiocytosis (HLH) is a severe disorder of early infancy consistent with an autosomal recessive inheritance. Neither the genetic locus nor the biochemical defect is known for the disease. A constitutional pericentric inversion of chromosome 9, with breakpoints in bands 9p23 and 9q31, has been reported in a case of HLH, suggesting a possible relationship between this chromosome abnormality and the disease. We investigated such an association, performing a genetic linkage analysis in a set of five consanguineous HLH families. 27 polymorphic markers on chromosome 9 were studied, excluding most of chromosome 9 as a putative site for the HLH gene.

Chromosome Breakage↗
PubMed1999

Familial clustering of Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is considered a non-hereditary disorder. Evaluation of the few familial cases might provide insight into its aetiology and pathogenesis. We conducted a survey to identify familial LCH cases. Data on family history, zygosity assessment in twins, clinical and laboratory features, treatment outcome, and present status were collected. According to variable confidence for twins monozygosity assessment, we termed these pairs 'presumed monozygotic' (pMZ). Nine families had more than one affected relative: five with LCH-concordant twin pairs, four with LCH in siblings or cousins. Three twin pairs not concordant for LCH were also studied. Overall, four of five pMZ twin pairs and one of three dizygotic (DZ) pairs were concordant for LCH. The pMZ twins had simultaneous and early disease onset (mean age 5.4 months); onset was at 21 months in the DZ pair. Clinical features were similar in the pMZ pairs. One pair of DZ twins had disseminated LCH. The three healthy twins (one pMZ, two DZ) remain asymptomatic 0.3, 5.9 and 4.7 years, respectively, after disease onset in their co-twins. Of the two families with affected non-twin siblings, one had known parental consanguinity and the other possible consanguinity. Potential consanguinity was also present in one of the two families with affected first cousins. Our data support high LCH concordance rates in pMZ twins and add the finding of LCH concordance in one of three dizygotic pairs studied. Taken together with our identification of LCH in siblings and first cousins from known or possibly consanguineous families, and with prior reports of three affected parent-child pairs, the data support a role for genetic factor(s) in LCH. The work-up of newly diagnosed patients should include a careful, extensive family history and chromosome studies. When possible, constitutional and/or lesional DNA should be obtained for future study.

Child, Preschool↗
PubMed1998

Coexistence of mitochondrial DNA and beta myosin heavy chain mutations in hypertrophic cardiomyopathy with late congestive heart failure.

OBJECTIVE: To investigate the possible coexistence of mitochondrial DNA (mtDNA) mutations in patients with beta myosin heavy chain (beta MHC) linked hypertrophic cardiomyopathy (HCM) who develop congestive heart failure. DESIGN: Molecular analysis of beta MHC and mtDNA gene defects in patients with HCM. SETTING: Cardiovascular molecular diagnostic and heart transplantation reference centre in north Italy. PATIENTS: Four patients with HCM who underwent heart transplantation for end stage heart failure, and after pedigree analysis of 60 relatives, eight additional affected patients and 27 unaffected relatives. A total of 111 unrelated healthy adult volunteers served as controls. Disease controls included an additional 27 patients with HCM and 102 with dilated cardiomyopathy. INTERVENTION: Molecular analysis of DNA from myocardial and skeletal muscle tissue and from peripheral blood specimens. MAIN OUTCOME MEASURES: Screening for mutations in beta MHC (exons 3-23) and mtDNA tRNA (n = 22) genes with denaturing gradient gel electrophoresis or single strand conformational polymorphism followed by automated DNA sequencing. RESULTS: One proband (kindred A) (plus seven affected relatives) had arginine 249 glutamine (Arg249Gln) beta MHC and heteroplasmic mtDNA tRNAIle A4300G mutations. Another unrelated patient (kindred B) with sporadic HCM had identical mutations. The remaining two patients (kindred C), a mother and son, had a novel beta MHC mutation (lysine 450 glutamic acid) (Lys450Glu) and a heteroplasmic missense (T9957C, phenylalanine (Phe)-->leucine (Leu)) mtDNA mutation in subunit III of the cytochrome C oxidase gene. The amount of mutant mtDNA was higher in the myocardium than in skeletal muscle or peripheral blood and in affected patients than in asymptomatic relatives. Mutations were absent in the controls. Pathological and biochemical characteristics of patients with mutations Arg249Gln plus A4300G (kindreds A and B) were identical, but different from those of the two patients with Lys450Glu plus T9957C(Phe-->Leu) mutations (kindred C). Cytochrome C oxidase activity and histoenzymatic staining were severely decreased in the two patients in kindreds A and B, but were unaffected in the two in kindred C. CONCLUSIONS: beta MHC gene and mtDNA mutations may coexist in patients with HCM and end stage congestive heart failure. Although beta MHC gene mutations seem to be the true determinants of HCM, both mtDNA mutations in these patients have known prerequisites for pathogenicity. Coexistence of other genetic abnormalities in beta MHC linked HCM, such as mtDNA mutations, may contribute to variable phenotypic expression and explain the heterogeneous behaviour of HCM.

Adult↗