FBN1 mutation screening of patients with Marfan syndrome and related disorders: detection of 46 novel FBN1 mutations.

Fibrillin-1 gene (FBN1) mutations cause Marfan syndrome (MFS), an inherited connective tissue disorder with autosomal dominant transmission. Major clinical manifestations affect cardiovascular and skeletal apparatuses and ocular and central nervous systems. We analyzed FBN1 gene in 99 patients referred to our Center for Marfan Syndrome and Related Disorders (University of Florence, Florence, Italy): 85 were affected by MFS and 14 by other fibrillinopathies type I. We identified mutations in 80 patients. Among the 77 different mutational events, 46 had not been previously reported. They are represented by 49 missense (61%), 1 silent (1%), 13 nonsense (16%), 6 donor splice site mutations (8%), 8 small deletions (10%), and 3 small duplications (4%). The majority of missense mutations were within the calcium-binding epidermal growth factor-like domains. We found preferential associations between The Cys-missense mutations and ectopia lentis and premature termination codon mutations and skeletal manifestations. In contrast to what reported in literature, the cardiovascular system is severely affected also in patients carrying mutations in exons 1-10 and 59-65. In conclusion, we were able to detect FBN1 mutations in 88% of patients with MFS and in 36% of patients with other fibrillinopathies type I, confirming that FBN1 mutations are good predictors of classic MFS.

Cryptic deletions are a common finding in "balanced" reciprocal and complex chromosome rearrangements: a study of 59 patients.

Using array comparative genome hybridisation (CGH) 41 de novo reciprocal translocations and 18 de novo complex chromosome rearrangements (CCRs) were screened. All cases had been interpreted as "balanced" by conventional cytogenetics. In all, 27 cases of reciprocal translocations were detected in patients with an abnormal phenotype, and after array CGH analysis, 11 were found to be unbalanced. Thus 40% (11 of 27) of patients with a "chromosomal phenotype" and an apparently balanced translocation were in fact unbalanced, and 18% (5 of 27) of the reciprocal translocations were instead complex rearrangements with >3 breakpoints. Fourteen fetuses with de novo, apparently balanced translocations, all but two with normal ultrasound findings, were also analysed and all were found to be normal using array CGH. Thirteen CCRs were detected in patients with abnormal phenotypes, two in women who had experienced repeated spontaneous abortions and three in fetuses. Sixteen patients were found to have unbalanced mutations, with up to 4 deletions. These results suggest that genome-wide array CGH may be advisable in all carriers of "balanced" CCRs. The parental origin of the deletions was investigated in 5 reciprocal translocations and 11 CCRs; all were found to be paternal. Using customized platforms in seven cases of CCRs, the deletion breakpoints were narrowed down to regions of a few hundred base pairs in length. No susceptibility motifs were associated with the imbalances. These results show that the phenotypic abnormalities of apparently balanced de novo CCRs are mainly due to cryptic deletions and that spermatogenesis is more prone to generate multiple chaotic chromosome imbalances and reciprocal translocations than oogenesis.

Central precocious puberty and abnormal chromosomal patterns.

Central precocious puberty (PP) can be caused by chromosomal aberrations. We report three patients presenting with central PP in whom karyotype analysis demonstrated abnormal chromosomal patterns. The first patient was affected by the triple-X syndrome, commonly characterized by premature ovarian failure. The second patient, a girl with inv dup(15)(pter-->q12::q12-->pter), had a chromosomal aberration involving an imprinted region of the human genome, whose deletion is commonly associated with Prader-Willi syndrome (PWS) and hypogonadotrophic hypogonadism. The third patient was a boy carrying a rare chromosome abnormality, the duplication of chromosome 9 (q22-->qter). All patients had mental retardation, which was mild in patient 1, moderate in patient 2, and severe in case 3. They underwent treatment with luteinizing hormone releasing hormone (LHRH) analogs, which were able to stop the progression of the sexual development. We confirm that chromosomal aberrations are an important cause of central PP, and that karyotype analysis in patients with PP and mental retardation, even if mild, is necessary because chromosomal abnormalities can be present.

Carcinomas of sweat glands: report of 60 cases.

CONTEXT: Several aspects of sweat gland carcinomas (incidence, classification, diagnosis, and behavior) have not been definitively clarified and need to be studied further. OBJECTIVE: The clinicopathologic findings of a large series of sweat gland carcinomas, collected during a period of 15 years, are presented. METHODS: Sixty sweat gland carcinomas (41 porocarcinomas, 3 syringomatous carcinomas, 8 ductal carcinomas, 5 adenoid cystic carcinomas, and 3 mucinous carcinomas) were analyzed histologically and immunohistochemically. RESULTS: Porocarcinomas were composed of eosinophilic and clear atypical cells arranged in solid-cystic lobular masses. These tumors were divided into 2 subgroups: horizontal porocarcinomas, showing a prominent intraepidermal component, and nodular porocarcinomas, which demonstrated predominant nodular growth. Syringomatous carcinomas presented keratinizing and nonkeratinizing cysts, dilated tubules (sometimes with a "tadpole" appearance), small neoplastic ducts, solid islands, and cellular cords. Ductal carcinomas were characterized by a prominent formation of tubules, solid islands, and cellular cords. Adenoid cystic carcinomas presented a characteristic pattern, showing basaloid monomorphous cells with moderately atypical nuclei, arranged in cribriform or solid islands and in tubular structures. Mucinous carcinomas were composed of moderately atypical cells with eosinophilic vacuolated cytoplasm, forming solid and cystic islands floating in large mucin pools. Immunohistochemically, cytokeratin was found in neoplastic cells in all cases, carcinoembryonic antigen was detected in 73% of cases, and actin-positive (myoepithelial) cells were not found. CONCLUSIONS: Although numerous studies have been published in recent years, the histologic features, histogenesis, and classification of sweat gland carcinomas still remain controversial and need to be clarified by further studies.

Intravenous leiomyoma with cardiac involvement.

We report a case of intravenous leiomyomatosis (IVL) in a 44-year-old woman, presenting with cardiothoracic clinical manifestations. Such a rare neoplastic condition most often arises from the uterine veins. At times it may reach the right cavities of the heart and it must be considered in the differential diagnosis with a cardiac myxoma or a thrombus.

[Cerebrotendinous xanthomatosis. A case report]. / Xantomatosi cerebrotendinea. Presentatazione di un caso.

We describe a patient with cerebrotendinous xanthomatosis (CTX) who saw a Rheumatologist because of joint and muscle pain in the lower limbs. Clinical examination did not reveal any classic joint disease; however, tendon lesions and clumsy gait were noted. The patient presented with a swollen Achilles tendon bilaterally and a parapareto-spastic gait; Babinski sign was positive on the right side, and hyperreflexia of both lower limbs could be demonstrated. As bilateral cataracts were present, we have interpreted the aforementioned signs as CTX with spinal involvement; mean plasma cholesterol was increased, thus confirming the diagnosis. The primary biochemical abnormality of this disease is a defect in the synthesis of bile acids; therefore, chenodeoxycholic acid (CDCA) has been tried, and beneficial effects following CDCA treatment, especially in the early stages of CTX, have been reported in the literature. We report this case because of the severity and the rarity of this disease, and also because of its hereditary transmission. Our aim is to underline the need of a precocious diagnosis, in order to prevent a further progression of the disease; this therapeutic goal can now be achieved, thanks to the therapeutic regimens recently developed.

[Wolf-Hirschhorn syndrome]. / La sindrome di Wolf-Hirschhorn.

We refer about two children with Wolf-Hirschhorn's syndrome or syndrome with partial deletion of short arm of chromosome number 4. The diagnosis was possible with an accurate estimation of phenotype. Cytogenetics examination showed the chromosomal aberration typical for this syndrome.

[Multiple pterygium syndrome]. / La sindrome degli pterigi multipli.

The authors relate about a non sporadic case of "Multiple pterygium syndrome" in a child born to consanguineous parents. Clinical features of the syndrome are: short stature, articular contractures, pterygia of the neck, axillae, elbows, facial anomalies, vertebral malformation, mental retardation. The syndrome, delineated as a distinct entity by Escobar, is a rare autosomal recessive disorder with a clinical heterogeneity, which is included within the "Arthrogryposis syndromes".

Antioxidant effects of potassium ascorbate with ribose therapy in a case with Prader Willi Syndrome.

Oxidative stress (OS) is involved in several human diseases, including obesity, diabetes, atherosclerosis, carcinogenesis, as well as genetic diseases. We previously found that OS occurs in Down Syndrome as well as in Beckwith-Wiedemann Syndrome (BWS). Here we describe the clinical case of a female patient with Prader Willi Syndrome (PWS), a genomic imprinting disorder, characterized by obesity, atherosclerosis and diabetes mellitus type 2, pathologies in which a continuous and important production of free radicals takes place. We verified the presence of OS by measuring a redox biomarkers profile including total hydroperoxides (TH), non protein-bound iron (NPBI), thiols (SH), advanced oxidation protein products (AOPP) and isoprostanes (IPs). Thus we introduced in therapy an antioxidant agent, namely potassium ascorbate with ribose (PAR), in addition to GH therapy and we monitored the redox biomarkers profile for four years. A progressive decrease in OS biomarkers occurred until their normalization. In the meantime a weight loss was observed together with a steady growth in standards for age and sex.

Sperm ultrastructure and meiotic segregation in an infertile 47, XYY man.

The majority of 47, XYY males are fertile and contribute to produce chromosomally normal children. In 47, XYY carriers, most meiotic studies indicated that the extra Y chromosomes were lost in the pre-meiotic stages, but in some cases the presence of one X and the two Y chromosomes has been detected during prophase I as an X univalent plus a YY bivalent. The aim of this study was to describe sperm parameters and meiotic segregation in a case of an infertile man with a 47, XYY karyotype. Sperm morphology was evaluated for the first time by transmission electron microscopy highlighting apoptosis and necrosis as the most frequent pathologies. Meiotic segregation was explored by fluorescence in situ hybridisation technique, which makes us capable of detecting aneuploidies of sex chromosomes. The fact that the frequency of 1818XY diploidy was very high reveals an error occurring during first meiotic division. Polymerase chain reaction analysis did not show any Y microdeletion. The combination of these two techniques led us to clarify the status of the spermatogenic process, showing an altered meiotic segregation concomitant with the presence of sperm apoptosis and necrosis in a patient 47, XYY.

TEM, FISH and molecular studies in infertile men with pericentric inversion of chromosome 9.

Pericentric inversions involving the secondary constriction (qh) region of chromosome 9 are considered to be normal variants of human karyotype. A number of investigators have suggested that chromosomal anomalies can contribute to human infertility causing spermatogenetic derangement. The present study was aimed at verifying the influence of chromosome 9 inversion on human spermatogenesis. Semen samples of 18 male carriers of chromosome 9 inversion, analysed by light microscopy, revealed that five patients were azoospermic. PCR analysis demonstrated that two of them also had Y microdeletions. The other 13 showed generally normal sperm concentrations and reduced motility. The morphological characteristics of sperm were studied by TEM and the data were elaborated by a mathematical formula. Sperm pathologies resulted more frequently in the studied group compared to controls, particularly apoptosis. Partial sequences of the A-kinase anchoring protein (Akap) 4 and 3 genes were performed in all patients, as a previous study by our group highlighted Dysplasia of Fibrous Sheath (DFS) defect in two men with inv 9 investigations. The possible effect of chromosome 9 inversion on meiotic chromosome segregation was investigated by FISH, which showed an increased incidence of diploidy. We hypothesized that this inversion could have variable effects on spermatogenesis, from azoospermia to severely altered sperm morphology, motility and meiotic segregation.

[Approach to the study of vasculitides: general aspects and classification]. / Approccio allo studio delle vasculiti: generalità e inquadramento.

Since etiology and pathogenesis of most systemic and/or isolated vasculitides are unknown, any attempt to make a rational classification of these entities is far from being perfect. Vasculitis may be a primary disease or it may be associated with connective tissue diseases, infectious diseases, neoplasms, drug assumption, allograft rejection and so on. As secondary vasculitides constitute the majority of cases, diagnosis of primary vasculitis is made by exclusion. At the present time, the 1993 Chapel Hill Consensus Conference on Nomenclature of Primary Vasculitides provides a useful guide to clinician and pathologist for evaluating a patient with an idiopathic form of vasculitis. This classification is based on the predominant size of vessels affected and describes the main clinico-pathologic features of the various clearly defined types of systemic vasculitis. Though it suffers from omissions and contradictions, in routine practice it is of great help to distinguish diseases in this intriguing chapter of pathology.

Chromosome 18 aberrations and epilepsy: a review.

Epilepsy is commonly observed in patients with chromosomal aberrations. We evaluated epilepsy and electroencephalographic (EEG) features in a group of patients carrying aberrations of chromosome 18. Fourteen patients were recruited: five with an 18p deletion syndrome (18pDS); six with an 18q deletion syndrome (18qDS); two with trisomy 18p syndrome; and one with a 45,XY,t(17-18) (cen-q11.2) karyotype. Patients with 18pDS had neither epilepsy nor EEG anomalies; four patients with 18qDS had epilepsy with partial seizures occurring during infancy or early childhood. Partial seizures were also present in both patients with trisomy 18p. By contrast, mixed seizures were observed in the patient carrying a translocation between chromosomes 17 and 18. Our data and a re-evaluation of the literature suggest that epilepsy is infrequent in patients with 18pDS. Conversely, partial seizures and focal EEG anomalies may be observed in those with patients with 18qDS. Our observations suggest that the haplo-insufficiency of genes located on the long arm of chromosome 18 is more likely to be associated with epilepsy, than is haplo-insufficiency of genes located on the short arm. While further EEG/clinical investigations are needed to validate these observations, this study indicates a possible relationship between chromosome 18 genes and epilepsy.

[A variety of mediastinal bronchogenic cyst: the broncho-alveolar cyst]. / Varietà di cisti broncogena del mediastino: cisti bronco-alveolare.

Congenital bronchogenic cysts are usually located in the mediastinum or develop as intrapulmonary cysts. Gross examination of excised bronchogenic cysts shows them to be unilocular; histologically, these lesions are characterized by the presence of respiratory-type pseudostratified epithelium as well as small islands of cartilage and seromucinous glands. We report a case of a mediastinal bronchogenic cyst having pulmonary parenchyma within the cyst wall. The rarity of our case, the pathological and clinical features and the embryological development of bronchogenic cysts are briefly discussed.

Alternate centromere inactivation in a pseudodicentric (15;20)(pter;pter) associated with a progressive neurological disorder.

A 13 year old male with a severe progressive neurological disorder was found to have a pseudodicentric chromosome resulting from a telomeric fusion 15p;20p. In lymphocytes, the centromeric constriction of the abnormal chromosome was always that of the chromosome 20, while in fibroblasts both centromeres were alternately constricted. Cd staining was positive only at the active centromere, but a weak anticentromere immunofluorescence was present at the inactive one. We suggest that centromere inactivation results from a modified conformation of the functional DNA sequences preventing normal binding to centromere specific proteins. We also postulate that the patient's disorder, reminiscent of a spongy glioneuronal dystrophy as seen in Alper's and Creutzfeldt-Jakob diseases, may be secondary to the presence of the pathogenic isoform of the prion protein encoded by a gene mapped to 20p12----pter.

A dominantly inherited syndrome (microcephaly, short stature, peculiar facies, mental retardation) associated with two balanced rearrangements involving chromosomes 2;7 and 5;20.

A complex balanced three-break-point rearrangement between chromosome 2 and chromosome 7 and a balanced reciprocal translocation between chromosome 5 and chromosome 20, were found associated in a girl and in her mother and grandmother. All three of them have microcephaly, low stature, peculiar asymmetric facies and slight mental retardation. We postulate that one (or more) of the five chromosome break-points disrupted one (or more) gene, leading to the expression of the syndrome and to its segregation with the chromosome rearrangement in three generation. Our finding confirms the efficiency of balanced translocations for gene mapping, althought it has led only to the exclusion mapping of all chromosomes except 2, 5, 7 and 20.

[Correlations between karyotype and phenotype in structural and numerical abnormalities of chromosome 18]. / Correlazioni tra cariotipo e fenotipo nelle anomalie strutturali e numeriche del cromosoma 18.

Five cases with different abnormalities of chromosome 18 are described: one case with trisomy 18, two cases with ring 18, one case with partial trisomy 18q and one case with a mosaic 18p-/iso 18q. The karyotypes of the parents were normal. Cytogenetic analysis was performed on PHA stimulated blood lymphocytes. GTG, QFQ, MTX banding techniques were used. Karyotype-phenotype correlations are made. All patients present mental retardation, hypotonia and facial dismorphisms. The different degree of mental retardation and the clinical signs are in relation to the different size of deletions or trisomies of the short or long arm of chromosome 18. In the case with mosaicism 18p-/iso18q the phenotype is determined from the chromosomal abnormality more frequent in the cells (18p-).