Anna Lisa Nucaro

Iron overload and desferrioxamine chelation therapy in β-thalassemia intermedia

This study on serum ferritin levels ind urinary iron excretion after 12h subcutaneous infusion of desferrioxamine in 10 thalassemia intermedia patients shows that even nontransfusion-dependent patients may have positive iron balance resulting in iron overload from 5 years of age. However, the iron overload found in these patients appears to be much lower than in age matched patients with transfusion-dependent thalassemia major. Iron overload increases with advancing age, as shown by increasing serum ferritin levels and desferrioxamine-induced urinary iron elimination. After a six month trial of 12h continuous subcutaneous desferrioxamine administration there was a significant decline in serum ferritin levels.From this study it seems that iron chelation is indicated in thalassemia intermedia patients over 5 years of age in order to prevent iron accumulation. However, the appropriate treatment schedule should be tailored to the individual needs of each patients, established by close monitoring of serum ferritin levels and desferrioxamine-induced urinary iron elimination.

Acute lymphoblastic leukemia in a child with constitutional ring chromosome 21

This report describes a case of acute lymphoblastic leukemia with non-B, non-T, common acute lymphocytic leukemia antigen-positive blasts in a 13-year-old child with constitutional ring chromosome #21. Because ring chromosome #21 is a rare chromosomal disorder, it is likely that the leukemia transformation is related to the chromosomal anomaly.

Ring chromosome 14 mosaicism: an unusual case associated with developmental delay and epilepsy, characterized by genome array-CGH.

Ring Chromosome 14 Mosaicism: An Unusual Case Associated With Developmental Delay and Epilepsy, Characterized by Genome Array-CGH Anna Lisa Nucaro,* Melania Falchi, Tiziana Pisano, Rossano Rossino, Francesca Boscarelli, Giusi Stoico, Angela Milia, Caterina Montaldo, Carlo Cianchetti, and Dario Pruna INN-CNR, Cittadella Universitaria, Monserrato, Cagliari, Italy Clinica di Neuropsichiatria Infantile, Azienda Ospedaliero-Universitaria, Cagliari, Italy Dipartimento di Scienze Pediatriche e Medicina Clinica, Azienda Ospedaliero-Universitaria, Cagliari, Italy Dipartimento di Scienze Chirurgiche e Odontostomatologiche, Universit a di Cagliari, Cagliari, Italy Technogenetics Bouty, Company, Sesto San Giovanni, Italy Dipartimento di Biologia Sperimentale, Universit a di Cagliari, Cagliari, Italy

Trisomy 8 mosaicism in a patient born to a mother with 47,XXX

Trisomy8 isdetected in0.8%of spontaneousabortions [Hassold and Jacobs, 1984]. In liveborn infants trisomy 8 is almost always a mosaic condition. The frequency of mosaic trisomy 8 in newborn children is estimated at 1:30,000 [Nielsen and Wohlert, 1991]. The phenotypic variability of this syndrome is very high, ranging from minimal effects to severe malformations. However, patients with clinical manifestations often present with a recognizable clinical syndrome. Phenotypic characteristics include a long face with myopathic appearance, large ears, high prominent forehead, deep palmar and plantar creases, mental retardation, urogenital anomalies such as cryptorchism or hydronephrosis, bone and joint abnormalities, such as absent patellae, vertebral defects and camptodactyly, cardiovascular, ocular and gastrointestinal anomalies, and agenesis of the corpus callosum. Here,we report anunusual case ofmosaic trisomy8 in a girl born to a mother with karyotype 47,XXX. The patient showed most of the characteristics of this syndrome as: round face, hypertelorism, large ears, micrognathia, clinodactyly, camptodactyly, deep palmar and plantar creases, cryptorchidism, hydronephrosis, cardiovascular anomalies, agenesis of the corpus callosum, and mental retardation. Chromosome analysis using standard cytogenetic protocols and FISH (fluorescent in situ hybridization) was carried out in peripheral blood. Karyotype was: mos,47,XXþ8/46,XX (80% of examined metaphases trisomic for 8 chromosome, 20%withnormalkaryotype). The trisomy 8 mosaicism was confirmed by FISH using a whole chromosome 8 painting biotinilated probe (ONCOR, Inc., Gaithersburg, MD), perfomed according to the manufacturer’s protocol. The phenotype in trisomy 8 mosaicism syndrome can be highly variable [Habecker-Green et al., 1998]. Two hypotheses could explain this phenotypic variability of trisomy 8 mosaicism: first, tissue specific mosaicism may play a role; second, some individuals with trisomy 8 mosaicismmayhavederived it froma trisomic zygote, as reported by Robinson et al. [1995]. In these individuals the normal cell line would be a product of chromosomal loss. Therefore, in some individuals these normal cells could be expected to display uniparental disomy for chromosome 8. Since uniparental disomies have been shown to cause anomalies and mental retardation, it could, therefore, be a factor in phenotypic variability. Concerning the mechanism of formation, it is known that common autosomal trisomy (including mosaic) are due to errors in maternal meiosis in majority of the cases [Nicolaidis et al., 1998]. In trisomy 8 and trisomy 8 mosaicism, the studies carried out by Karadima et al. [1998] demonstrated that nondisjunction was probably due tomitotic (postzigotic) duplication.However, causes of chromosomal nondisjunction remains one of the significant questions in human genetics. The co-occurrence of 47,XXX in the mother and trisomy 8 in child could be only by chance. However, documentation of this patient may help future thinking about nondisjunction in these two disorders.

Iron chelation in transfusion-dependent thalassemia with chronic hepatitis.

In this study maximum urinary iron elimination with continuous desferrioxamine subcutaneous infusion was obtained in thalassemia major patients with chronic persistent or active hepatitis with lower doses (60 mg/kg) than those necessary in patients without hepatitis (80 mg/kg). Since dose-response curves were highly variable the treatment schedule should be tailored to the individual needs of each patient. Both groups may achieve iron balance but chronic hepatitis patients have more frequently a net urinary iron excretion. In patients with chronic hepatitis no correlation was found between serum ferritin levels or serum ferritin/aspartate aminotransferase ratios and transfusional iron overload while serum ferritin/aspartate aminotransferase ratios were seen to be correlated with liver iron stores.

Turner syndrome mosaicism: an unusual case with a de novo large dicentric marker chromosome: mos 45,X/46,X, ter rea(X;X)(p22.3;p22.3)

X/X translocations are quite rare in humans. The effect of this anomaly on the phenotype is variable and depends on the amount of deleted material and whether the chromosomes are joined by their long or short arms. We report an unusual case of Turner syndrome mosaicism in a 16-year-old girl, who was referred to our Institute for primary amenorrhoea associated with short stature. Endocrine evaluation revealed hypergonadotropic hypogonadism, which required a study of the karyotype. Cytogenetic analysis, performed on peripheral blood leucocytes, showed a mos 45,X/46,X,ter rea (X;X)(p22.3;p22.3) de novo karyotype. The prevalent cell line was 45,X (90% cells). A second cell line (10% cells) showed a very large marker chromosome, similar to a large metacentric chromosome. FISH (fluorescent in situ hybridisation) and molecular analysis revealed that the marker chromosome was dicentric and totally derived from the paternal X chromosome.

Ring 20 syndrome mosaicism and epilepsy: a case with duplication of two BAC clones in 20q11.21-q11.22 defined by genome array-CGH

Herein, we report an unusual case of ring 20 mosaicism in a 15-year-old non-dysmorphic girl with epilepsy refractory to drug therapy. Ring 20 syndrome is a rare condition still not well characterised both at the genetic and clinical levels. It was described for the first time by Borgaonkar and Bolling1 as a genetic syndrome. To date, about 60 mostly sporadic cases of patients have been reported with de novo ring formation. This syndrome is characterised by a large degree of phenotypic variability, in association with a characteristic form of epilepsy, refractory to any pharmacological therapy with non-convulsive status epilepticus and cognitive problems. The first seizures occur in the first years of life and represent the first clinical signs. Further clinical signs are mental retardation of varying degrees, and behavioural disorders. The case reported showed an unusual ring chromosome 20 mosaicism associated with epilepsy and generalised tonic clonic seizures refractory to drug therapy and behaviour disorders. Cytogenetic analysis, performed on cultured peripheral blood, revealed the presence of ring 20 mosaicism in 40% of the metaphases examined (20 out of 50). The patient, the firstborn of non-consanguineous healthy parents, was born after a normal pregnancy. The neonatal period followed a normal course, with increases in weight–height and psychomotor development. The parents reported …

Prenatal diagnosis of a double trisomy 48, XXY, +13: Klinefelter and Patau syndromes

As a reply to research letter: ‘‘Double trisomy’’, by Shibo et al. [2004], we report on the prenatal diagnosis of a double aneuploidy involving chromosome X and chromosome 13, in a women who was referred for CVS. To our knowledge, this is the first report describing a prenatal diagnosis of Klinefelter and Patau syndromes. Prenatal diagnosis of simultaneous occurrence of double trisomy is extremely rare. Cytogenetic data on products of conception from spontaneous abortions studied over a 10-year period have been reviewed for double trisomy by Reddy [1997]. A total of 3,034 spontaneous abortions were karyotyped between 1986 and 1997. Twenty-two cases with double trisomy were found. Here, we describe the first prenatally detected case of a double trisomy involving chromosome 13 and the sex chromosomes (48, XXY,þ13) (Klinefelter/Patau syndrome) in a 39year-old female who was referred for CVS at 11 weeks of gestation. Ultrasonorographic examination showed nuchal translucency. Chromosome analysis of both direct (cytotrophoblast) and long-term (extra embryonic) cultures, showed an abnormal 48, XXY, þ13 in all examined metaphases (10 metaphases from direct and 10 from long-term culture). Both parents had a normal karyotype. The patient elected to terminate the pregnancy at 14 weeks of gestation. Posttermination tissue sample investigations and skin biopsy of the aborted fetus confirmed the karyotype. Unfortunately, the parents were not seen after the abortion, so, it was not possible to determine the possible origin of the two abnormalities by molecular comparison of the fetal and parental genotypes. Although non-disjunction is the most common cause of chromosome abnormalities, the presence of two numerical abnormalities in a single conceptus is rarely observed. From a careful review of the literature, only a few cases of double trisomy have been reported so far. Recently, a prenatal diagnosis of double trisomy 48, XXX, þ18 has been described by Chen et al. [2000] in one case of Klinefelter/Edwards syndrome. Another patient of 48, XXY,þ18 has been presented as a poster during the Third European Cytogenetics Conference by Tunca et al. [2001]. A prenatally detected case of 48, XXX, þ21 has been reported by Park et al. [1995]. Shibo et al. [2004] indicated that no report of 48, XXX, þ13 and 48,XXY, þ13 is known. Here, we report on the first prenatally detected case of Klinefelter and Patau syndromes (48, XXY, þ13). The mechanisms by which double aneuploidies arise have not been well studied. Robinson et al. [2001] report cytogenetic and molecular findings from 122 spontaneous abortions and demonstrate that the only double trisomy found was the consequence of both a maternal and a paternal meiotic error. We think that various mechanisms may be considered by which they might arise. All require a minimum of two errors in cell division. Random non-disjunction in both gametes could lead to the formation of a doubly aneuploid zygote. Alternatively, a single global defect might cause multiple nondisjunctions in the formation of a single gamete. Study of additional examples of multiple aneuploidy are needed to determine the nature of the errors in such cases.

Familial translocation t(3;10) (p26.3;p12.31) leading to trisomy 10p12.31 pter and monosomy 3p26.3 pter in seven members†‡

Anna Lisa Nucaro, Marta Meloni, Tiziana Pisano, Paola Melis, Elena Rossi, Rossano Rossino, Simona Corona, Mario Loi, Francesco Achena, Orsetta Zuffardi, and Carlo Cianchetti* Institute of Neurogenetic and Neuropharmacology of CNR, Monserrato, Cagliari, Italy Clinic of Child Neurology and Psychiatry, Azienda Ospedaliero-Universitaria of Cagliari, Cagliari, Italy Department of Pediatric Sciences, Azienda Ospedaliero-Universitaria of Cagliari, Cagliari, Italy Medical Genetics, University of Pavia, Pavia, Italy Division of Otorinolaringology, Presidio Ospedaliero CTO Iglesias, Cagliari, Italy IRCCS Fondazione Policlinico San Matteo, Pavia, Italy