Congenital hypothyroidism in Young-Simpson syndrome.

We describe a patient with the clinical spectrum of Young-Simpson syndrome. This rare genetic disorder is characterized by congenital hypothyroidism, mental retardation and blepharophimosis. Young-Simpson syndrome is, at present, poorly known to endocrinologists and pediatricians, and should be included in the differential diagnosis of congenital hypothyroidism. It is important to underline that the association of congenital hypothyroidism, blepharophimosis and ptosis allows an exact clinical diagnosis, since the majority of other clinical aspects are common to other disorders.

Congenital microgastria and primary ciliary dyskinesia in a newborn with DiGeorge syndrome and 22q11.2 deletion.

BACKGROUND: Congenital microgastria is an uncommon result of impairment of normal foregut development and rotation during early embryology. Only about 50 cases have been reported in the literature, mostly associated with other multiple congenital anomalies. CASE REPORT: The case of a female newborn with multiple abnormalities, including cardiovascular malformation (type I truncus arteriosus communis) with deletion of chromosome 22q11.2, severe immunodeficiency (DiGeorge syndrome), microgastria, and impaired mucociliary function (primary ciliary dyskinesia) is reported. CONCLUSIONS: An association between the deletion of chromosome 22q11.2, microgastria, and impaired mucociliary function has never been observed before. A casual association seems highly unlikely and we can not exclude the possibility of genetic mechanisms that may link those syndromes.

DHPLC analysis of the MECP2 gene in Italian Rett patients.

Rett Syndrome (RTT) is an X-linked dominant neurodevelopmental disorder, which almost exclusively affects girls, with an estimated prevalence of one in 10,000-15,000 female births. Mutations in the methyl CpG binding protein 2 gene (MECP2) have been identified in roughly 75% of classical Rett girls. The vast majority of Rett cases (99%) are sporadic in origin, and are due to de novo mutations. We collected DNA samples from 50 Italian classical Rett girls, and screened the MECP2 coding region for mutations by denaturing high-performance liquid chromatography (DHPLC) and subsequent direct sequencing. DHPLC is a recently developed method for mutation screening which identifies heteroduplexes formed in DNA samples containing mismatches between wild type and mutant DNA strands, combining high sensitivity, reduced cost per run, and high throughput. In our series, 19 different de novo MECP2 mutations, eight of which were previously unreported, were found in 35 out of 50 Rett girls (70%). Seven recurrent mutations were characterized in a total of 22 unrelated cases. Initial DHPLC screening allowed the identification of 17 out of 19 different mutations (90%); after optimal conditions were established, this figure increased to 100%, with all recurrent MECP2 mutations generating a characteristic chromatographic profile. Detailed clinical data were available for 27 out of 35 mutation carrying Rett girls. Milder disease was detectable in patients carrying nonsense mutation as compared to patients carrying missense mutations, although this difference was not statistically significant (P = 0.077).

Fragile X founder chromosomes in Italy: a few initial events and possible explanation for their heterogeneity.

A total of 137 fragile X and 235 control chromosomes from various regions of Italy were haplotyped by analyzing two neighbouring marker microsatellites, FRAXAC1 and DXS548. The number of CGG repeats at the 5' end of the FMR1 gene was also assessed in 141 control chromosomes and correlated with their haplotypes. Significant linkage disequilibrium between some "major" haplotypes and fragile X was observed, while other "minor" haplotypes may have originated by subsequent mutation at the marker microsatellite loci and/or recombination between them. Recent evidence suggests that the initial mechanism leading to CGG instability might consist of rare (10 (-6/-7)) CGG repeat slippage events and/or loss of a stabilizing AGG via A-to-C transversion. Also, the apparently high variety of fragile X chromosomes may be partly due to the relatively high mutation rate (10 (-4/-5)) of the microsatellite markers used in haplotyping. Our fragile X sample also showed a higher than expected heterozygosity when compared to the control sample and we suggest that this might be explained by the chance occurrence of the few founding events on different chromosomes, irrespective of their actual frequency in the population. Alternatively, a local mechanism could enhance the microsatellite mutation rate only on fragile X chromosomes, or fragile X mutations might occur more frequently on certain background haplotypes.

Meiotic origin of two ring chromosomes 18 in a girl with developmental delay.

We report on the cytogenetic, fluorescence in situ hybridization (FISH), and molecular results obtained for a patient with a mild and nonspecific pattern of minor anomalies and developmental delay. In the proband's karyotype one chromosome 18 was replaced by a ring chromosome 18 in all metaphases, with deletion of the terminal regions. Furthermore, 56% of the metaphases contained a supernumerary small ring chromosome. Microdissection followed by FISH analysis demonstrated that the small ring chromosome consisted of material from the pericentromeric region of chromosome 18. The karyotype was defined as 46,XX,r(18)(p11.3q23)[88]/47,XX,r(18)(p11.3q23)+r(18)(p11.22q12.2)[112]. Thus, the patient has a deletion at 18pter and at 18qter, and a mosaic partial trisomy of the pericentromeric region of chromosome 18. We undertook molecular analysis using DNA samples of the patient and her parents in order to clarify the origin and possible mode of formation of the chromosome abnormalities. Our results show a paternal origin of the structurally normal chromosome 18 and a maternal origin for both ring chromosomes 18. Interestingly, the smaller ring chromosome did not arise postzygotically from the larger ring, since the two ring chromosomes contain genetic material derived from the two different maternal chromosomes 18. The abnormalities appear to have arisen during a meiotic division, and it could be speculated that both ring chromosomes 18 arose simultaneously due to complex pairing and recombination events. After fertilization, the small ring chromosome was lost in a subset of cells, thus leading to mosaicism.

Y-chromosomal STR haplotype in Toscany (central Italy).

Here we show the Y-haplotype database consisting in the loci DYS19, DYS388, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS385, YCAII and DXYS156Y of 107 males living in Toscany (central Italy).

[A case of 9p partial monosomy caused by paternal translocation. Clinical and cytogenetic aspects]. / Un caso di monosomia parziale 9p- da traslocazione paterna. Aspetti clinici e citogenetici.

The authors describe a case of partial monosomy 9p in a newborn infant, with breakpoint in the region p221, due to a father's balanced translocation with karyotype 46 XY t(9;16)(p221;q224). The phenotypical features of our patient reproduce those reported in other 35 cases described up to now in the literature: trigonocephaly, upward slanting palpebral fistures, little and horizontal mouth, disproportionally long fingers and toes. Some peculiar clinical and cytogenetical features of the case are discussed, particularly the early closure of the sternal body ossification centers (already detected during the prenatal life), the partial agenesia of the splenium corporis callosi and the partial anomalous pulmonary venous return. The Authors point out the importance of an early diagnosis, based on the awareness to the clinical abnormalities and dysmorphisms, in order to provide for an adequate and opportune genetic counseling.

[A new case of fronto-nasal dysplasia associated with craniosynostosis]. / Una nuova osservazione di displasia fronto-nasale associata a craniosinostosi.

The Authors report a case of frontonasal dysplasia, a rare congenital syndrome, accompanied by multiple cranial synostosis. According to Cohen, frontonasal dysplasia associated with craniosynostosis may be considered as a separate syndrome and Cohen himself has described its occurrence in members of two families as "Craniofrontonasal Dysplasia". The Authors describe a sporadical case presenting various minor abnormality reported by Cohen, in addition to the hypoplasia of the corpus callosum, demonstrated by the Cranial Ultrasonography and by the NMR study of the brain.

[Two new cases of triploidy in premature liveborn infants (author's transl)]. / Su due nuovi casi di sindrome da triploidia in prematuri plurimalformati.

Two liveborn triploid infants are described. The phenotype agrees, in the first case, with that reported in the other observations of the literature. In the second case, hydranencephaly was associated with ambiguous genitalia. Cytogenetic studies, made on cultivated leucocytes, showed triploid number of morphologically normal chromosomes; and constitution 69, XXY in the first case. Mosaicism were found in the second child, with constitution 46XY/69XXY. It is remarked the usefulness of an early diagnosis in order to the genetic counseling.

[Velo-cardio-facial syndrome (Shprintzen syndrome)]. / Sindrome velo-cardio-faciale (Sindrome di Shprintzen).

A patient with the velo-cardio-facial syndrome is described. The most frequent features include cleft palate, cardiac anomalies, typical facies, and learning disabilities. Less frequent findings include microcephaly, mental retardation, small stature, slender hands and digits, minor auricolar anomalies, and inguinal hernia. There were four instances of familial transmission in the 39 patients of the literature.

The anterior segment anomalies in the Warburg syndrome. A study of new cases.

The Warburg syndrome is a primary lethal neurodysplasia recently defined with autosomal recessive inheritance. The clinical diagnosis is based on the association of brain alterations with ocular defects, among which the anterior segment anomalies and the retinal dysplasia appear to be the most significant. The authors report a clinical and histopathological study on personal observations.

Ocular aspects in biotinidase deficiency. Clinical and genetic original studies.

There are two distinct forms of multiple carboxylase deficiency. A neonatal onset form is due to deficiency of holocarboxylase-synthetase. A later onset form in which neurological abnormalities are seen as well as those of the skin and hair is due to biotinidase deficiency. It is the purpose of this report to describe a patient with biotinidase deficiency who presents bilateral optic atrophy. The dosage of biotinidase enzyme in the patient's serum and in other members of his family confirms the autosomal recessive transmission of this condition.

Increased mutagen-induced chromosome damage in patients with transformed laryngeal pre-cancerosis.

Factors that contribute to malignant transformation of laryngeal pre-neoplastic lesions remain largely unknown. Potential etiological factors may be related to a genetically controlled sensitivity to environmental carcinogens. In this study, we investigated bleomycin-induced chromosome damage in 15 patients who experienced a malignant transformation of preneoplastic laryngeal lesions during follow-up, as compared with chromosome fragility in 30 historical controls with no progression of keratoses during a 10-year follow-up, in a match-paired analysis. Chromosomal analysis demonstrated higher sensitivity to clastogens in patients with malignant progression of laryngeal pre-neoplastic lesions than that of control patients with no evolution of their original laryngeal keratoses (p = 0.003). Furthermore, among the study patients, chromosome sensitivity was most apparent in non-tobacco users with malignant transformation of laryngeal disease. Our data suggest that subjects with pre-neoplastic laryngeal lesion showing increased susceptibility to carcinogens could be at higher risk for development of laryngeal carcinoma.

Deletions in HOXD13 segregate with an identical, novel foot malformation in two unrelated families.

Synpolydactyly (SPD) is a dominantly inherited congenital limb malformation consisting of 3/4 syndactyly in the hands and 4/5 syndactyly in the feet, with digit duplication in the syndactylous web. The condition recently has been found to result from different-sized expansions of an amino-terminal polyalanine tract in HOXD13. We report a novel type of mutation in HOXD13, associated in some cases with features of classic SPD and in all cases with a novel foot phenotype. In two unrelated families, each with a different intragenic deletion in HOXD13, all mutation carriers have a rudimentary extra digit between the first and second metatarsals and often between the fourth and fifth metatarsals as well. This phenotype has not been reported in any mice with genetic modifications of the HoxD gene cluster. The two different deletions affect the first exon and the homeobox, respectively, in each case producing frameshifts followed by a long stretch of novel sequence and a premature stop codon. Although the affected genes may encode proteins that exert a dominant negative or novel effect, they are most likely to act as null alleles. Either possibility has interesting implications for the role of HOXD13 in human autopod development.

Detection of a homozygous four base pair deletion in the protein X gene in a case of pyruvate dehydrogenase complex deficiency.

While the presence of a lipoyl-containing protein (protein X) separate from lipoyl transacetylase in the pyruvate dehydrogenase complex (PDC) has been known for some time, until recently only the cDNA for the yeast enzyme has been cloned. We have cloned, sequenced and characterized the cDNA encoding the human protein X and localized the protein X gene to chromosome 11p13. We also report here a new case of protein X deficiency identified immunologically, with decreased activity of PDC and without mutations in the E1alpha subunit or E1beta subunit. We report that the cDNA and gene of this patient for protein X has a homozygous 4 bp deletion, specifically in the putative mitochondrial targeting signal sequence which results in a premature stop codon. This is the first documented case of a molecular defect in pyruvate dehydrogenase protein X.

Modified primers for D12S391 and a modified silver staining technique.

In this paper we describe a new primer pair for the short tandem repeat (STR) D12S391 which makes it possible to obtain considerably shorter amplification fragments (125-173 bp), compared to the previously published primers (205-253 bp). The primers were tested on 70 samples with known genotypes, and no differing results were found. In sensitivity studies, forensic casework samples and DNA quality studies, we proved that the new primers can improve the efficiency of the amplification. Moreover, the resolution of this locus on denaturing PAGE followed by silver staining was dramatically improved. This improvement was found to be most valuable for typing the rare.3 variants known for this locus. We also present and propose a new method for silver staining denaturing acrylamide gels.

Synpolydactyly phenotypes correlate with size of expansions in HOXD13 polyalanine tract.

Synpolydactyly (SPD) is a dominantly inherited congenital limb malformation. Typical cases have 3/4 finger and 4/5 toe syndactyly, with a duplicated digit in the syndactylous web, but incomplete penetrance and variable expressivity are common. The condition has recently been shown to be caused by expansions of an imperfect trinucleotide repeat sequence encoding a 15-residue polyalanine tract in HOXD13. We have studied 16 new and 4 previously published SPD families, with between 7 and 14 extra residues in the tract, to analyze the molecular basis for the observed variation in phenotype. Although there is no evidence of change in expansion size within families, even over six generations, there is a highly significant increase in the penetrance and severity of phenotype with increasing expansion size, affecting both hands (P = 0.012) and feet (P < 0. 00005). Affected individuals from a family with a 14-alanine expansion, the largest so far reported, all have a strikingly similar and unusually severe limb phenotype, involving the first digits and distal carpals. Affected males from this family also have hypospadias, not previously described in SPD, but consistent with HOXD13 expression in the developing genital tubercle. The remarkable correlation between phenotype and expansion size suggests that expansion of the tract leads to a specific gain of function in the mutant HOXD13 protein, and has interesting implications for the role of polyalanine tracts in the control of transcription.

Contribution of computerized tomography to the study of severe congenital ocular dysplasias. Study of a case of clinical anophthalmos.

The present report summarizes the results of a study by computerized tomography (CT) in a child suffering from congenital bilateral anophthalmos and slight mental deficiency. The CT images suggest that this case can be classified as primary anophthalmos. We report a case of suspected congenital bilateral anophthalmos whom we investigated by computerized tomography (CT). A thorough examination of the brain and intraorbital contents was carried out.

Study on the STR TPOX in an Italian and an Austrian population using two different primer pairs and three different electrophoretic methods.

The short tandem repeat TPOX was studied using two different pairs of primers and three different electrophoretic methods with the aim of optimizing and standardizing the typing conditions for this locus. A genetic population study was subsequently conducted on two population samples from Central Italy (151 individuals) and from Austria (153 individuals) and compared using an R x C contingency table. With the aim of using this system for forensic samples, differences in sensitivity between the methods utilized were studied and several parameters of forensic interest for the two populations (PD, MEC, MEP, pM, PIC) were calculated. A new multiplex system for the loci CSF1PO, TPOX and CD4 is also presented.