Identification of mutations in the MSX2 homeobox gene in families affected with foramina parietalia permagna.

Foramina parietalia permagna (FPP) is an autosomal dominant condition characterized by cranial defects of the parietal bones. It can be present as an isolated feature, but it is also one of the characteristics of a contiguous gene syndrome associated with deletions on chromosome 11p11-p12. One of the proteins known to be involved in skull development is the MSX2 homeobox protein. Previously, MSX2 has been shown to be mutated in patients suffering from Boston type craniosynostosis. We have now analyzed the MSX2 gene in five families affected with FPP. An intragenic microsatellite marker did not reveal any recombination and a cumulated LOD score of +3.2 at theta = 0 was obtained. Sequence analysis further showed that in four out of five families an MSX2 mutation was responsible for the skull defect. Moreover, it appears that FPP is caused by haplo-insufficiency of the MSX2 gene. This implies that Boston type craniosynostosis and FPP are allelic variants of the same gene, with FPP caused by loss of MSX2 function and craniosynostosis Boston type due to gain of MSX2 function.

The ALX4 homeobox gene is mutated in patients with ossification defects of the skull (foramina parietalia permagna, OMIM 168500).

Foramina parietalia permagna (FPP) (OMIM 168500) is caused by ossification defects in the parietal bones. Recently, it was shown that loss of function mutations in the MSX2 homeobox gene on chromosome 5 are responsible for the presence of these lesions in some FPP patients. However, the absence of MSX2 mutations in some of the FPP patients analysed and the presence of FPP associated with chromosome 11p deletions in DEFECT 11 (OMIM 601224) patients or associated with Saethre-Chotzen syndrome suggests genetic heterogeneity for this disorder. Starting from a BAC/P1/cosmid contig of the DEFECT 11 region on chromosome 11, we have now isolated the ALX4 gene, a previously unidentified member of the ALX homeobox gene family in humans. Mutation analysis of the ALX4 gene in three unrelated FPP families without the MSX2 mutation identified mutations in two families, indicating that mutations in ALX4 could be responsible for these skull defects and suggesting further genetic heterogeneity of FPP.

Identification and characterization of a new human gene encoding a small protein with high homology to the proline-rich region of the SH3BGR gene.

As part of an effort to identify genes potentially involved in the Down Syndrome pathogenesis, in this paper we report the identification and characterization of a new human gene (named SH3BGRL), which shows a high homology to the SH3BGR gene, previously mapped to the Down Syndrome region of chromosome 21. The SH3BGRL gene encodes for a small protein of 114 amino acids, sharing 60% identity and 84% conservation on the amino acid level with the middle, proline-rich region of the SH3BGR gene and containing a similar SH3 (Scr homology 3) binding motif. The SH3BGRL and the proline-rich region of SH3BGR proteins appear to be highly conserved, sharing 95 and 98% identity, respectively, with the mouse homologues. A 1.9 kb transcript of the SH3BGRL gene has been found in all the tissues examined, in contrast with the expression pattern of the SH3BGR gene which is transcribed only in heart and skeletal muscle. The SH3BGR gene and its homologue, SH3BGRL, could be members of a new family of genes containing a highly conserved proline-rich functional domain. The SH3BGRL gene has been mapped by fluorescent in situ hybridization to Chromosome Xq13.3.

Identification and characterization of a new human cDNA from chromosome 21q22.3 encoding a basic nuclear protein.

Congenital heart disease (CHD) affects over 40% of Down syndrome (DS) patients. The region proposed to contain the gene(s) for DS CHD has been restricted to 21q22.2-22.3, from D21S55 to MX1. The identification and functional characterization of the genes mapping to this region is a necessary step to understand the pathogenesis of CHD in DS. In an effort to contribute to the construction of a transcriptional map of the DS CHD region we have performed direct cDNA selection using a YAC contig that maps between ETS2 and D21S15 and cDNAs synthesised from fetal heart structures. Here we describe the identification and characterization of a new gene, WRB, that maps to 21q22.3 between ACTL5 and HMG 14 and appears to be widely expressed in adult and fetal tissues. The new gene encodes a basic protein of unknown function containing a tryptophan-rich carboxyl-terminal region and a potential nuclear localization signal. Immunofluorescence analysis shows a predominant localization in the cell nucleus. The understanding of the biological function of the protein product should clarify the potential role of WRB in the pathogenesis of DS CHD.

Cloning a new human gene from chromosome 21q22.3 encoding a glutamic acid-rich protein expressed in heart and skeletal muscle.

The identification and functional characterization of genes on chromosome 21 is a necessary step to understand the pathogenesis of the various phenotypic anomalies that affect Down syndrome patients. Using direct cDNA selection we have identified a new gene, SH3BGR, that maps to 21q22.3, proximal to HMG14, and is differentially expressed in heart and skeletal muscle. SH3BGR encodes a novel protein that is characterized by the presence of a proline-rich region containing the consensus sequence for a SH3-binding domain and by an acidic carboxyl-terminal region containing a glutamic acid-rich domain predicted to assume a coiled coil. The presence of two functional domains involved in protein-protein interactions suggests that SH3BGR could be part of a multimeric complex. Its overexpression might alter specific functions of muscular tissue and therefore take part in the pathophysiology of muscular hypotonia in Down syndrome.

Down syndrome and coeliac disease: usefulness of antigliadin and antiendomysium antibodies.

The usefulness of antigliadin (AGA) and antiendomysium antibodies (EMA) as a screening test for coeliac disease (CD) in 113 Down syndrome (DS) patients (61 children) was evaluated. AGA IgA were present in 22.1%, AGA IgG in 48.6%, EMA in 6.2%. Four symptomatic patients, AGA- and EMA-positive, were affected by CD (3.5%). In three AGA-positive and EMA-positive subjects, permission for intestinal biopsy was refused, while in two AGA-positive and EMA-negative children, the intestinal mucosa was normal. Our study confirms the association of CD and DS, and suggests the usefulness of EMA determination as a test for selecting DS patients for intestinal biopsy.

Assessment of growth hormone insulin like growth factor-I axis in Down's syndrome.

As GH therapy has been reported to increase growth velocity in children with Down's syndrome (DS), we studied the GH-IGF-I axis in some DS patients affected by growth retardation without serious congenital malformation, malnutrition or pathological thyroid or adrenal function. IGF-I and IGF-II were evaluated in 39 patients in basal conditions. The patients were subsequently divided into two groups with respect to the IGF-I basal value: Group 1 (GR 1) consisting of patients with abnormally low basal IGF-I concentration as compared to age matched control subjects, group 2 (GR 2) consisting of patients with IGF-I in the normal range. In 6 GR 1 patients and 12 GR 2 patients we evaluated GH and IGF-I concentrations after stimulation with arginine (0.5 g/kg bw), and recombinant GH (4 IU im). In the same patients, GH radioreceptor assay and serum GH-binding protein were evaluated. In all patients IGF-II proved normal (534 +/- 23 ng/ml; mean +/- SE), while IGF-I was pathological in 36% of subjects. The cause of the defective IGF-I secretion in these patients does not seem to depend on an impaired GH axis, as no significant difference in arginine-stimulated GH peak values was seen between GR 1 (29.6 +/- 5.3 ng/ml) and GR 2 (15.1 +/- 2.24 ng/ml). IGF-I concentration evaluated 12, 24, and 48 h after arginine stimulation was significantly increased only in GR 2 patients (peak value: 0.95 +/- 0.1, p = 0.0003 vs baseline; GR 1: 0.34 +/- 0.05 U/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

[Pharmacokinetics of cytochrome P-450]. / La farmacogenetica dei citocromi P-450.

Pharmacogenetics of cytochromes P-450. Cytochromes P-450 are a large family of enzymes found in all living species whose function is the activation of molecular oxygen which, in turn, will oxidize an organic substrate. They are divided in two groups: one including the constitutive enzymes that intervene in vital processes such as cholesterol synthesis, cholesterol transfer into steroid and sex hormones, prostaglandin synthesis, etc.; the other group including the inducible enzymes, responsible of the metabolism of exogenous substances. Their concentration increases in the presence of specific substrates, like herbicides, cigarette smoke, hydrocarbons, insecticides, etc.. Of the latter group, the genetic polymorphism of two families is described. Family I is involved in the metabolism of polycyclic aromatic hydrocarbons: an allele codifying for a low activity cytoplasmic receptor (autosomic recessive inheritance) and a high affinity one (recessive inheritance) are present. The transformations carried out by the cytochromes P-450 give origin to intermediate reactive products, epoxides, that bonding to nucleoproteins or nucleic acids, can have either toxic or carcinogenic action. Therefore, the subjects with high affinity genes have an increased risk of cancer. This phenomenon, relating to pulmonary cancer, has been demonstrated in cigarette smokers. Family II is the group of greatest pharmacogenetic and clinical interest, since it is responsible of the polymorphism of the response to different drugs, such as halothane, (malignant hyperthermia), ethanol (alcohol intolerance), nitrosamine, (cancer), debrisoquine (hypotension), spartein (excessive uterine contractions). An increased or reduced ability to metabolize specific substances is the consequence: the pharmacological effects can therefore vary very much in the two classes of carriers of different alleles. Possible future applications of these polymorphisms in clinical practice are discussed.

[Syndromes from birth to adulthood]. / Le sindromi dall'età evolutiva all'età adulta.

A follow-up program of Down's syndrome is reported. Divided into age groups, it outlines the importance of a periodic clinical checks involving many disciplines and covering the entire lifespan of the patient. To do that we need a specific knowledge of the natural history of the syndromes.

[The multidisciplinary treatment of rhabdomyosarcoma in childhood. A 10-year multicenter experience (1978-1988) in Liguria]. / Trattamento multidisciplinare del rabdomiosarcoma in età pediatrica. Esperienza pluricentrica decennale (1978-1988) in Liguria.

The authors retrospectively analyzed the therapy results in a large group of children affected by rhabdomyosarcoma and treated from 1978 to 1988 with chemotherapy, radiotherapy and surgery. 39/58 patients (67%) achieved a complete response and 25/39 maintained the NED status. An individualized treatment was given to 13 patients who relapsed, but only 3 of them obtained a second response. Those with primary tumor in the orbit or in the genito-urinary tract had lower recurrence rate than patients with head and neck, extremities, pelvis and trunk diseases. Patients in clinical group I and II (according with I.R.S. stadiation) had a significantly better survival than those with more advanced disease (clinical groups III and IV). Relatively to the primary site of the disease, the late effects of combined treatment are mentioned.

Dyskeratosis congenita: unusual presenting features within a kindred.

We report on a family in which one member is affected by dyskeratosis congenita (DC), who had two cousins who died at 44 months and 36 months, respectively, with aplastic anemia and neurological abnormalities. The patient affected by DC presented with bone marrow hypoplasia at age 4; DC was diagnosed at age 6. In DC the marrow abnormalities rarely appear before the skin manifestations. The observation of this kindred poses the question whether an extremely early onset with a rapidly fatal course before the appearance of skin abnormalities is possible. We believe this report to be important for the differential diagnosis of DC and other forms of congenital aplastic anemia.

[Spondylo-epiphyseal dysplasia tarda with progressive arthropathy: description of a patient whose mother showed minimal features of the disease]. / Displasia spondilo-epifisaria tarda con artropatia progressiva: descrizione di un paziente la cui madre presentava segni minimi della malattia.

An 8-year-old male patient with Spondylo-Epiphyseal Tarda with Progressive Arthropathy (SEDT-PA) or Progressive Pseudo-rheumatoid Arthropathy of Childhood is reported. Abnormal gait, fatigability, and joint symptoms began at 3 years. Radiological changes were: generalized osteoporosis, platyspondyly, and enlarged epiphyses. The patient's mother showed reduced muscular massa, joint swelling, moderate osteoporosis, and normal vertebrae. SEDT-PA has an autosomal recessive mode of inheritance. In this case, as the propositus' mother showed minimal signs of the disease, either an X-linked trait or an autosomal dominant mutation with variable expressivity could also be assumed.

Expression of the human ETS-2 oncogene in normal fetal tissues and in the brain of a fetus with trisomy 21.

The expression of the ETS-2 proto-oncogene, located on chromosome 21, in normal fetal tissues and in neural tissue of a fetus affected by Down syndrome has been investigated. The results show that the ETS-2 proto-oncogene is expressed in almost all the tissues examined and that it is transcribed at constant levels in neural tissue between the 13th and 24th weeks. ETS-2 expression appeared to be slightly increased in Down syndrome brain compared with that of normal controls of the same gestational age.

[Yersinia enterocolitica sepsis in splenectomized thalassemic subjects. Description of 2 cases]. / La sepsi da Yersinia enterocolitica nei soggetti talassemici splenectomizzati. Descrizione di due casi.

Two cases of Yersinia enterocolitica septicemia in two splenectomized children with thalassemia major are reported. Human Yersinia enterocolitica septicemia is an uncommon condition, but its frequency may increase in patients having debilitating diseases or blood disorders, as well as a consequence of the splenectomy. Some brief considerations on the pathogenetic factors yielding, to severe infections in splenectomized thalassemic children are discussed. The high number of thalassemic people in Italy makes necessary an early diagnosis in case of septicemia. Particularly important is the blood culture, because of the slowness of the microbic development in stools.