bluuebunny/crossref_metadata_2025 huggingface dataset:
Case of Epstein‐Barr virus‐associated transformation of mantle cell lymphoma
Authors: Terasawa Teruhiko , Ohashi Haruhiko , Utsumi Makoto , Tsushita Keitaro , Kinoshita Tomohiro , Nakamura Shigeo , Saito Hidehiko
Published: June 2003

We report here a case of mantle cell lymphoma (MCL) in a patient who, following Epstein‐Barr virus (EBV) infection, developed diffuse large B‐cell lymphoma (DLBCL). A 47‐year‐old woman was diagnosed as having MCL with clinical stage IIIA in July 1990. After treatment with a third‐generation chemotherapy without response, she was kept under observation for 8 years. In January 1999, fever and night sweats appeared with laboratory evidence for EBV infection, and acute swelling of lymph nodes and hepatosplenomegaly developed in May 1999. Histopathological examination confirmed the diagnosis of DLBCL. Sequence analysis of the complementarity‐determining region (CDR)‐III of the immunoglobulin heavy chain gene demonstrated clonal identity between the initial MCL and the subsequent DLBCL. Immunohistochemistry revealed that cyclin D1, CD5, and CD20 were expressed in the MCL but lost in the DLBCL cells, and EBER‐ISH confirmed that EBV infection was absent in the former but present in the latter. Southern hybridization with the EBV terminal repeat probe showed a clear monoclonal pattern in the DLBCL specimen. All these results suggest that EBV infection may have been the molecular event that caused transformation of MCL cell(s) to DLBCL in this case. This is, to the best of our knowledge, the first well‐documented case of EBV‐associated transformation of MCL. Am. J. Hematol. 73:194–199, 2003. © 2003 Wiley‐Liss, Inc.
Acute pancreatitis during sickle cell vaso‐occlusive painful crisis
Authors: Ahmed Shahid , Siddiqui Anita K. , Siddiqui Rina K. , Kimpo Miriam , Russo Linda , Mattana Joseph
Published: June 2003

Sickle cell disease is characterized by chronic hemolytic anemia and vaso‐occlusive painful crisis. The vascular occlusion in sickle cell disease is a complex process and accounts for the majority of the clinical manifestations of the disease. Abdominal pain is an important component of vaso‐occlusive painful crisis and may mimic diseases such as acute appendicitis and cholecystitis. Acute pancreatitis is rarely included as a cause of abdominal pain in patients with sickle cell disease. When it occurs it may result form biliary obstruction, but in other instances it might be a consequence of microvessel occlusion causing ischemia. In this series we describe four cases of acute pancreatitis in patients with sickle cell disease apparently due to microvascular occlusion and ischemic injury to the pancreas. All patients responded to conservative management. Acute pancreatitis should be considered in the differential diagnosis of abdominal pain in patients with sickle cell disease. Am. J. Hematol. 73:190–193, 2003. © 2003 Wiley‐Liss, Inc.
Iron chelators for the treatment of iron overload disease: Relationship between structure, redox activity, and toxicity
Authors: Chaston Timothy B. , Richardson Des R.
Published: June 2003

The success of the iron (Fe) chelator desferrioxamine (DFO) in the treatment of β‐thalassemia is limited by its lack of bioavailability. The design and characterization of synthetic alternatives to DFO has attracted much scientific interest and has led to the discovery of orally active chelators that can remove pathological Fe deposits. However, chelators that access intracellular Fe pools can be toxic by either inhibiting Fe‐containing enzymes or promoting Fe‐mediated free radical damage. Interestingly, toxicity does not necessarily correlate with Fe‐binding affinity or with chelation efficacy, suggesting that other factors may promote the cytopathic effects of chelators. In this review, we discuss the interactions of chelators and their Fe complexes with biomolecules that can lead to toxicity and tissue damage. Am. J. Hematol. 73:200–210, 2003. © 2003 Wiley‐Liss, Inc.
Developing human erythroid cells grown in transferrin‐free medium utilize iron originating from extracellular ferritin
Authors: Leimberg J.M. , Konijn A.M. , Fibach E.
Published: June 2003

In addition to transferrin, ferritin can also function as a source of iron for heme synthesis (Gelvin D, et al. Blood 1996;88:3200–3207; Meyron‐Holtz EG, et al. Blood 1999;94:3205–3211). In the present study we investigate the effect of external ferritin on the proliferation and hemoglobinization of human erythroid precursors grown in transferrin‐free cultures. Am. J. Hematol. 73:211–212, 2003. © 2003 Wiley‐Liss, Inc.
Spectrum of β thalassemia mutations and HbF levels in the heterozygous Moroccan population
Authors: Lemsaddek Wafaa , Picanço Isabel , Seuanes Filomena , Mahmal Lahoucine , Benchekroun Saâd , Khattab Mohammed , Nogueira Paulo , Osório‐Almeida Leonor
Published: June 2003

A comprehensive hematological and molecular analysis of 57 β thalassemic heterozygotes, 28 homozygotes, 18 double heterozygotes, 3 compound heterozygotes β thal/β S and one compound heterozygote β thal/Hb Newcastle, in 46 Moroccan families with at least one β thalassemia patient is reported. Six major mutations: β039 (C→T), β0FsCD8(−AA), β+IVS1,nt6 (T→C) and β0IVS1,nt1 (G→A), β0FsCD6 (−A) and β+‐29 (A→G) cap site account for 75% of the 86 independent β thal chromosomes studied. For the first time, an extensive mutation/haplotype study has been performed on the Moroccan population, and data are consistent with the geographical location of the country and historical links with both the Mediterranean and the Sub‐Saharan Africa communities. Despite the heterogeneous spectrum of mutations, good genetic counseling can be offered to the carrier population. This study focuses on the analysis of fetal hemoglobin levels in β thalassemic heterozygotes and its correlation with β globin cluster polymorphic markers in this population. Fetal hemoglobin levels in heterozygotes vary from trace quantities to 17.9% (2.38 g/dl) of total hemoglobin in the adult. No statistically significant correlation was found, either between genders and HbF levels, or between the mutation and the HbF level, with the exception of mutation β0FSCD6(−A). We have examined the α globin genotype and the β globin genotype of heterozygotes, namely, the extended haplotype, which includes the XmnI site at −158 bp of the Gγ gene and the microsatellite (AT)xTy at −540 bp of the β globin gene. In this sample, we confirm the existence of linkage disequilibrium between the C→T variation at −158bp of Gγ globin gene (XmnI+) and Orkin's haplotypes III, IV, or IX (the 5′ subhaplotype class A). At 5′ β globin gene, we observe exclusively the allele (AT)7T7. In the β thalassemic heterozygotes studied, no correlation of those genetic markers with HbF levels is observed. Am. J. Hematol. 73:161–168, 2003. © 2003 Wiley‐Liss, Inc.
Newborn with malformations and a combined duplication of 9pter‐q22 and 16q22‐qter resulting from unbalanced segregation of a complex maternal translocation
Authors: Piram Adriana , Ortolan Daniela , Cesar Peres Luis , Monteiro Pina‐Neto João , Riegel Mariluce , Schinzel Albert
Published: June 2003

We report a patient with duplication of 9pter‐q22 combined with duplication of 16q22‐qter. The chromosome anomaly was the result of a 3:1 segregation of a maternal translocation (46,XX,t[9;16;21]). This newborn had intrauterine growth retardation and microcephaly, the characteristic recognizable pattern of trisomy 9p, cerebellar hypoplasia, a porencephalic cyst in the parieto‐occipital region, and rocker‐bottom feet. We compare the clinical features with another previously described case of duplication of an identical 9p segment combined with distal 16q duplication of a similar, but not identical segment, as well as with cases with duplication of either one of the two segments. © 2003 Wiley‐Liss, Inc.
X‐linked Opitz syndrome: Novel mutations in the MID1 gene and redefinition of the clinical spectrum
Authors: De Falco Francesca , Cainarca Silvia , Andolfi Grazia , Ferrentino Rosa , Berti Caterina , Rodríguez Criado German , Rittinger Olaf , Dennis Nick , Odent Sylvie , Rastogi Amit , Liebelt Jan , Chitayat David , Winter Robin , Jawanda Harindar , Ballabio Andrea , Franco Brunella , Meroni Germana
Published: June 2003

Opitz (or G/BBB) syndrome is a pleiotropic genetic disorder characterized by hypertelorism, hypospadias, and additional midline defects. This syndrome is heterogeneous with an X‐linked (XLOS) and an autosomal dominant (ADOS) form. The gene implicated in the XLOS form, MID1, encodes a protein containing a RING‐Bbox‐Coiled‐coil motif belonging to the tripartite motif (TRIM) family. To further clarify the molecular basis of XLOS, we have undertaken mutation analysis of the MID1 gene in patients with Opitz syndrome (OS). We found novel mutations in 11 of 63 male individuals referred to us as sporadic or familial X‐linked OS cases. The mutations are scattered throughout the gene, although more are represented in the 3′ region. By reviewing all the MID1‐mutated OS patients so far described, we confirmed that hypertelorism and hypospadias are the most frequent manifestations, being present in almost every XLOS individual. However, it is clear that laryngo‐tracheo‐esophageal (LTE) defects are also common anomalies, being manifested by all MID1‐mutated male patients. Congenital heart and anal abnormalities are less frequent than reported in literature. In addition, we can include limb defects in the OS clinical synopsis as we found a MID1‐mutated patient showing syndactyly. The low frequency of mutations in MID1 and the high variability of the phenotype suggest the involvement of other genes in the OS phenotype. © 2003 Wiley‐Liss, Inc.
Somatic and germline mosaicism for a R248C missense mutation in FGFR3, resulting in a skeletal dysplasia distinct from thanatophoric dysplasia
Authors: Hyland Valentine J. , Robertson Stephen P. , Flanagan Simon , Savarirayan Ravi , Roscioli Tony , Masel John , Hayes Mark , Glass Ian A.
Published: June 2003

In this communication, we report the identification of a mosaic R248C missense mutation in the IgII–III linker region of the gene encoding the fibroblast growth factor receptor‐3 (FGFR3), in an individual who manifests a skeletal dysplasia and epidermal hyperplasia. By means of Denaturing High Performance Liquid Chromatography (DHPLC), we determined that 25% of her lymphocytes are heterozygous for this particular missense mutation in FGFR3, and that 12.5% of her lymphocyte‐derived genomic DNA encodes a cysteine residue at this position. The proposita has disproportionate short stature, radial head dislocation, coxa vara, and bowing of some of the long bones, associated with an S‐shaped deformity of the humerus, accompanied by widespread acanthosis nigricans in the integument. These features do not match any previously described skeletal dysplasia. Further, the proposita's only pregnancy ended in the delivery of a fetus manifesting a lethal short‐limbed dwarfism with pulmonary hypoplasia, strongly suggestive of an undiagnosed thanatophoric dysplasia. These findings confirm the proposita to be a somatic and germline mosaic for this particular missense mutation in FGFR3. Thus far, all reported FGFR3 R248C mutations have resulted in thanatophoric dysplasia type I (TDI). © 2003 Wiley‐Liss, Inc.
Screening of families with autosomal recessive non‐syndromic hearing impairment (ARNSHI) for mutations in GJB2 gene: Indian scenario
Authors: Maheshwari Manjula , Vijaya R. , Ghosh Manju , Shastri Shivaram , Kabra Madhulika , Menon P.S.N.
Published: June 2003

Several studies have reported that mutations in the GJB2 gene (coding for connexin26) are a common cause of recessive non‐syndromic hearing impairment. A GJB2 mutant allele, 35delG, has been found to have a high prevalence in most ethnic groups. Though mutations in the GJB2 gene have been shown to cause autosomal recessive deafness in Indian families, the frequencies of the various mutations are still unknown. In the present study, we analyzed 45 Indian families belonging to three different states, namely, Karnataka, Tamil Nadu, and Delhi with non‐syndromic hearing impairment and an apparently autosomal recessive mode of inheritance. All the families were initially screened for three mutations (W24X, W77X, and Q124X) by using allele‐specific PCR primers; mutations were confirmed by DNA sequencing. Families that were heterozygous or negative for tested mutations of the GJB2 gene were sequenced directly to identify the complementary mutation and other mutations in GJB2. Four families were homozygous for W24X, constituting around 8.8%. In two families, the affected individuals were compound heterozygotes for W24X; one family (DKB16) carried 35delG with W24X while the other family (DKB7) carried R143W with W24X. We suggest that W24X is a common allele among the mutations screened, causing autosomal recessive non‐syndromic hearing impairment (ARNSHI) in the Indian population. © 2003 Wiley‐Liss, Inc.
Paternal origin of der(X)t(X;6) in a girl with trisomy 6p and unbalanced t(6;10) mosaicism in her mother
Authors: Petković Iskra , Barišić Ingeborg , Bastić Mislav , Hećimović Silva , Bago Ružica
Published: June 2003

We present a case of trisomy for the whole short arm of chromosome 6 in a 3‐year‐old girl with moderate mental retardation, mild facial dysmorphism, short stature, failure to thrive, and no abnormalities of the visceral organs. Cytogenetic and fluorescence in situ hybridization (FISH) analysis revealed a 46, X, der(X)t(X;6)(q22; p11.1) karyotype. The derived X was late replicating with variable spreading of X chromosome inactivation onto the translocated 6p. A normal karyotype was observed in the father, while the mother presented 46,XX/46,XX, der(10)t(6;10)(p11;p11). The mother is a mosaic with unbalanced t(6;10) in 4.7% of cells. To the best of our knowledge, this unusual mosaicism has not yet been reported. In this family the short arm of chromosome 6 was involved in an unbalanced rearrangement with chromosome X in the proband and with chromosome 10 in the mother. In order to study the mechanism of the formation of t(X;6) in the girl we performed DNA polymorphism analysis. These investigations revealed that chromosomes X and 6 involved in the rearrangement are of paternal origin. Our patient exhibits only discrete facial features characteristic of partial trisomy 6p. We suggest that mild phenotypic expression be probably due to X chromosome inactivation spreading onto the translocated 6p. This report show that combined cytogenetic, FISH, and molecular analysis of chromosomal aberrations are necessary for the understanding of the mechanism of formation, parental origin, and genetic counseling. © 2003 Wiley‐Liss, Inc.
De novo 1q32q44 duplication and distal 1q trisomy syndrome
Authors: Nowaczyk Małgorzata J.M. , Bayani Jane , Freeman Viola , Watts John , Squire Jeremy , Xu Jie
Published: June 2003

We report on an infant with minor anomalies and a de novo 1q duplication. The chromosomal abnormality was diagnosed prenatally after sonographic detection of cerebral ventriculomegaly and bilateral choroid plexus cysts in the fetus. The amniocentesis showed an abnormal male karyotype, 46,XY,dup(1)(q32q44), subsequently confirmed by fluorescence in situ hybridization using whole chromosome paint 1 and comparative genomic hybridization. The baby, born at 37 weeks of gestation, had wide cranial sutures and large fontanelles, sloping forehead, hypertelorism, short and downward‐slanting palpebral fissures, a high‐arched and narrow palate, malformed ears, and long feet with overriding second and third toes. This is the sixth case of known duplication involving the 1q32q44 segment; the physical findings in the case reported herein are similar to those of other patients reported previously, providing further evidence of the existence of the “distal 1q trisomy” phenotype. © 2003 Wiley‐Liss, Inc.
Parental attitudes regarding newborn screening of PKU and DMD
Authors: Campbell Elizabeth , Ross Lainie Friedman
Published: June 2003

The ability to perform predictive genetic testing of children raises ethical concerns. Current guidelines support the screening of newborns for conditions in which early treatment reduces morbidity and mortality, and oppose most other predictive genetic screening and testing in childhood. Little is known, however, about parental attitudes. We conducted focus groups to gain information on the attitudes, beliefs, and concerns of parents about newborn screening and testing for both treatable and untreatable conditions that present in childhood. Respondents across racial groups support mandatory newborn screening for treatable conditions like phenylketonuria (PKU), citing lack of parental knowledge, and concerns about immature parental decision‐makers. Parents do, however, want more information. Citing a variety of psychosocial concerns, respondents believe that parents should have access to predictive genetic testing for childhood onset conditions, even when there are no proven treatments. Respondents want this information to make reproductive and non‐reproductive plans and decisions. Although respondents varied in their personal interest in testing, overwhelmingly they believed that the decisions belong to the parents. Professional guidelines that proscribe predictive testing for untreatable childhood onset conditions should be re‐examined in light of consumer attitudes. © 2003 Wiley‐Liss, Inc.
Reticular erythrokeratoderma: A new disorder of cornification
Authors: Itin Peter H. , Moschopulos Michael , Richard Gabriela
Published: June 2003

Heritable disorders of cornification form a large, clinically and genetically heterogeneous group. Recent advances in molecular genetics provide for the first time the opportunity to reliably classify some of these disorders based on their underlying etiology. Many rare phenotypes, however, still remain unclassified and do not fit into established classification schemes. We report here a 12‐year‐old girl who developed an ichthyosis vulgaris‐like skin disorder 6 months after birth. Several years later, the clinical features had changed considerably. The patient had developed streaks of hyperkeratotic, slightly scaling skin with underlying erythema distributed in a reticulate, occasionally annular pattern on the trunk and extremities. The lesions were stable and had not changed significantly in size or distribution over the ensuing years. Histopathologic and ultrastructural findings were nonspecific and there was no evidence for metabolic disorders. The partial clinical overlap with erythrokeratodermia variabilis prompted us to screen several connexin genes but no pathogenic mutations were identified. We believe that this disorder belongs to the group of erythrokeratodermas and represents a novel, previously unrecognized entity. © 2003 Wiley‐Liss, Inc.
Seven new cases of familial isolated bladder exstrophy and epispadias complex (BEEC) and review of the literature
Authors: Reutter Heiko , Shapiro Ellen , Gruen Jeffrey R.
Published: June 2003

Clustering of the bladder exstrophy and epispadias complex (BEEC) has been described in 29 families. To explore the genetic contribution we located new families through the German and Austrian Bladder Exstrophy Support Group and the Association for the Bladder Exstrophy Community (predominantly US and Canada). We report six new families with two occurrences of BEEC, one family where the proband is the product of a consanguineous union, and four discordant twin pairs. In conjunction with the published clinical and epidemiological reports this collection suggests that there is a significant genetic predisposition for susceptibility to the BEEC. It also highlights the importance of self‐referral groups for recruiting families for multicenter collaborative research efforts to identify susceptibility loci. © 2003 Wiley‐Liss, Inc.
A new dominant branchiogenic‐deafness syndrome with internal auditory canal hypoplasia and abnormal extremities
Authors: Mégarbané André , Rassi Simon , Chouery Eliane , Delague Valérie , Leal Gustavo Perez de Nanclares , Tabet Murielle , Castaño Luis , Loiselet Jacques
Published: June 2003

Two sibs from one Lebanese family presented with congenital hearing loss, meatal atresia, preauricular tags and pits, branchial cysts or fistulae, strabismus, difficulty in opening the mouth wide enough, abnormal fifth fingers, somewhat short stature, and learning disability and patchy skin depigmentation in one. Temporal bone abnormalities identified on computed tomography included atresia of the external auditory canal with reduction in size of the middle ear, malformed ossicles, and unilateral internal auditory canal hypoplasia. Hand radiographs showed pointed phalanges of the 5th fingers with osseous erosions. Their father, his sister, and his half‐brother had unilateral auricular pits and/or branchial cysts. Results of all laboratory investigations including sequencing of the EYA1 gene were normal. Differential diagnosis is discussed and the possibility of the report of a new autosomal dominant type of branchiogenic‐deafness syndrome with variable expressivity is raised. © 2003 Wiley‐Liss, Inc.
Athabascan brainstem dysgenesis syndrome
Authors: Holve Steve , Friedman Barbara , Hoyme H. Eugene , Tarby Theodore J. , Johnstone Sharon J. , Erickson Robert P. , Clericuzio Carol L. , Cunniff Christopher
Published: June 2003

We report a new disorder with diverse neurological problems resulting from abnormal brainstem function. Consistent features of this disorder, which we propose should be called the Atabascan brainstem dysgenesis syndrome, include horizontal gaze palsy, sensorineural deafness, central hypoventilation, and developmental delay. Other features seen in some patients include swallowing dysfunction, vocal cord paralysis, facial paresis, seizures, and cardiac outflow tract anomalies. All affected children described are of Athabascan Indian heritage, with eight children from the Navajo tribe and two patients who are of Apache background. The disorder can be distinguished from the Moebius syndrome by the pattern of central nervous system findings, especially the sensorineural deafness, horizontal gaze palsy, and central hypoventilation. Recognition of children with some features of Athabascan brainstem dysgenesis syndrome should prompt investigation for other related abnormalities. Published 2003 Wiley‐Liss, Inc.
Relation between apolipoprotein E genotype, hepatitis b virus status, and thyroid status in a sample of older persons with down syndrome
Authors: Percy Maire E. , Potyomkina Zoya , Dalton Arthur J. , Fedor Bettye , Mehta Pankaj , Andrews David F. , Mazzulli Tony , Murk Lillian , Warren Andrew C. , Wallace Robyn A. , Chau Hien , Jeng Winnie , Moalem Sharon , O'Brien Lisa , Schellenberger Sonia , Tran Helen , Wu Linda
Published: June 2003

Dementia of the Alzheimer type (DAT) is common in older persons with Down syndrome (DS). There are three common alleles of the apolipoprotein E (ApoE) gene (Σ2, Σ3, and Σ4) resulting in three different isoforms (E2, E3, and E4) and six different genotypes (2,2; 2,3; 2,4; 3,3; 3,4; and 4,4). Σ4 is a risk factor for DAT whereas Σ2 appears prophylactic. As hepatitis B virus (HBV) infection and hypothyroidism also are common in DS, we evaluated associations between ApoE type, HBV status, and thyroid status in a sample of older persons with DS (n = 55; mean age, 44.3 ± 10.8 years) using chi‐squared analysis. Participants were classified as E2 (2,2 or 2,3), E3 (3,3), or E4 (3,4 or 4,4); positive for markers of HBV infection in the present or past (i.e., total HBcAb+ and/or HBsAg+ with or without infectivity, defined as HBV+) or negative for markers of HBV infection (defined as HBV−) and, currently receiving thyroid hormone supplement (defined as “hypothyroidism”) or having normal thyroid function. The majority of the HBV+ were currently HBcAb+ and HBsAb+, but not HBsAg+. In females, there was an ApoE allele effect on thyroid status (P ≤ 0.01), E2 being negatively (P ≤ 0.01) and E4 being positively (P ≤ 0.05) associated with “hypothyroidism”. There was no evidence for an ApoE allele effect on thyroid status in males. There was no evidence for an ApoE allele effect on HBV status, or for an HBV status effect on thyroid status. As thyroid status can affect cognitive function, ApoE allele effects in DAT may, in part, be thyroid effects. © 2003 Wiley‐Liss, Inc.
Multiple macrodontic multituberculism
Authors: Benjamin Martinez R. , Rodrigo Fariña S. , Gorlin Robert J.
Published: June 2003

Ekman‐Westborg and Julin [1974: Oral Surg 38:217–222], described multiple macrodontia and multituberculism affecting the teeth without other anomalies (E‐WJ). We describe a Chilean case in a 12‐year‐old with the typical dental alterations and with histopathologic findings that include absence of predentin layer and prominent reduced enamel epithelium. E‐WJ is not a syndrome and we propose “multiple macrodontic multituberculism” as a better name for this anomaly of uncertain etiology affecting only the crowns of the teeth. © 2003 Wiley‐Liss, Inc.
Two brothers with findings resembling congenital intrauterine infection‐like syndrome (pseudo‐TORCH syndrome)
Authors: Knoblauch Hans , Tennstedt Cornelia , Brueck Wolfgang , Hammer Hannes , Vulliamy Tom , Dokal Inderjeet , Lehmann Rüdiger , Hanefeld Folker , Tinschert Sigrid
Published: June 2003

Clinical, pathological, and X‐ray findings of two brothers with features resembling congenital intrauterine infection‐like syndrome are presented. Extensive screening for intrauterine infection was performed. Nevertheless all confirmatory tests were normal. Both brothers showed extensive intra‐ and extra‐cranial calcifications, thrombocytopenia, a septum pellucidum cyst, one‐sided paresis of the diaphragm, and metaphyseal changes on X‐ray scans resembling intrauterine infection. Within the first days of life, they developed seizures and died from severe cerebral hemorrhage. The MRI scan of the brain showed cerebellar hypoplasia in one of the boys, while the cerebellum had normal size in the other. No indication of a metabolic disorder, especially in calcium metabolism, was identified. Due to the clinical overlap with Hoyeraal‐Hreidarsson syndrome, mutations in the DKC1 gene (Xq28) and the hTR gene (RNA component of telomerase on chromosome 3q) have been excluded. The parents are non‐consanguineous and further family history was unremarkable. The findings in these boys overlap with features described in congenital intrauterine infection‐like syndrome (pseudo‐TORCH syndrome). © 2003 Wiley‐Liss, Inc.
Intrafamilial variability in the phenotypic expression of adenylosuccinate lyase deficiency: A report on three patients
Authors: Edery Patrick , Chabrier Stéphane , Ceballos‐Picot Irène , Marie Sandrine , Vincent Marie‐Françoise , Tardieu Marc
Published: June 2003

We report on the striking variable expression of adenylosuccinate lyase (ADSL) deficiency in three patients belonging to a family which originates from Portugal. ADSL deficiency is a rare autosomal recessive disorder of the de novo purine synthesis which results in accumulation of succinylpurines in body fluids. As a result, patients may have variable combinations of psychomotor retardation and/or regression, seizures, autistic features and cerebellar vermis hypoplasia. However, intrafamilial variable expression of the phenotype has not been documented to date in this disease and is not commonly observed in metabolic disorders. Here, while the proband had marked psychomotor regression and progressive cerebellar vermis atrophy, the other two affected patients presented mainly autistic features. Mutation analysis of the ADSL gene revealed the presence of a homozygous R426H mutation in this family. Finally, although ADSL deficiency is a rare disorder, this diagnosis should be considered and assessed using a simple urinary screening method for the presence of succinylpurines in any patient with mental retardation of unexplained origin. © 2003 Wiley‐Liss, Inc.
657del5 mutation in the gene for Nijmegen breakage syndrome (NBS1) in a cohort of Russian children with lymphoid tissue malignancies and controls
Authors: Resnick Igor B. , Kondratenko Irina , Pashanov Eugeni , Maschan Alexey A. , Karachunsky Alexander , Togoev Oleg , Timakov Andrey , Polyakov Alexander , Tverskaya Svetlana , Evgrafov Oleg , Roumiantsev Alexander G.
Published: June 2003

Nijmegen breakage syndrome (NBS, OMIM 251260) is a rare hereditary disease, characterized by immune deficiency, microcephaly, and an extremely high incidence of lymphoid tissue malignancies. The gene mutated in NBS, NBS1, was recently cloned from its location on chromosome 8q21. The encoded protein, nibrin (p95), together with hMre11 and hRad50, is involved in the double‐strand DNA break repair system. We screened two Russian cohorts for the 657del5 NBS1 mutation and found no carriers in 548 controls and two carriers in 68 patients with lymphoid malignancies: one with acute lymphoblastic leukemia (ALL) and one with non‐Hodgkin lymphoma (NHL). Several relatives of the second patient, who were carriers of the same mutation, had cancer (ALL, breast cancer, GI cancers). These preliminary data suggest that NBS1 mutation carriers can be predisposed to malignant disorders. © 2003 Wiley‐Liss, Inc.
Aberrant Pax1 and Pax9 expression in Jarcho‐Levin syndrome: Report of two Caucasian siblings and literature review
Authors: Bannykh Sergei I. , Emery Shawn Clark , Gerber Josef‐Karl , Jones Kenneth L. , Benirschke Kurt , Masliah Eliezer
Published: June 2003

We report two consecutive Caucasian male siblings of nonconsanguineous parents autopsied at 22 and 13 weeks gestational age both with prenatal diagnosis of Jarcho‐Levin syndrome (JLS). Segmentation anomalies of the vertebrae and ribs encompass a spectrum of syndromes with or without associated anomalies of other developmental fields, and include spondylothoracic dysostosis (STD), JLS, Casamassima‐Morton‐Nance (CMN) syndrome, and spondylocostal dysostosis (SCD), among others. In both these new JLS cases the autopsies confirmed that there were severe developmental alterations in the thoracic and vertebral skeleton (including “crab‐like” thorax), accompanied in the older fetus by renal defects. Because vertebral development is controlled by a limited number of master genes including Pax1 and Pax9, we analyzed protein expression from these genes in these two cases compared to age‐matched controls. Immunochemical analysis showed a significant reduction in levels of Pax1 and Pax9 protein expression in chondrocytes of the vertebral column. Implications for the etiology and pathogenesis of JLS and related disorders are discussed. © 2003 Wiley‐Liss, Inc.
Variations in the dopamine β‐hydroxylase gene are not associated with the autonomic disorders, pure autonomic failure, or multiple system atrophy
Authors: Cho Sonhae , Kim Chun‐Hyung , Cubells Joseph F. , Zabetian Cyrus P. , Hwang Dong‐Youn , Kim Jang‐Woo , Cohen Bruce M. , Biaggioni Italo , Robertson David , Kim Kwang‐Soo
Published: June 2003

Norepinephrine (NE) is the major neurotransmitter of the sympathetic division of the autonomic nervous system (ANS). Recent findings of an association between human NE deficiency and variants at the dopamine β‐hydroxylase (DBH) gene [Kim et al., 2002] prompted us to investigate these markers in patients with autonomic disorders; 38 with orthostatic intolerance (OI), 26 with pure autonomic failure (PAF), and 39 with multiple system atrophy (MSA). Eighty‐eight normal controls were included in this study. In contrast to NE deficiency, allele frequency and genotype distribution of the genetic variants showed no differences between autonomic disease patients and controls. In addition, no DBH mutation was found that distinguished autonomic disease patients from controls, suggesting that genetic variants of the DBH gene are not associated with the autonomic diseases OI, PAF, and MSA. © 2003 Wiley‐Liss, Inc.
Brachyolmia and spinal stenosis
Authors: Mukamel Masza , Karmazyn Boaz , de Vries Liat , Horev Gadi , Shohat Mordechai
Published: June 2003

Brachyolmia is a rare short‐trunk short stature skeletal dysplasia characterized by generalized platyspondyly without significant epiphyseal or metaphyseal changes in the long bones. This group of skeletal dysplasia is heterogeneous and four types have been differentiated on the basis of radiological and genetic findings. We report on two siblings with Hobaek‐type brachyolmia complicated by spinal stenosis. This combination has never been reported in the literature and suggests further genetic heterogeneity within brachyolmia. © 2003 Wiley‐Liss, Inc.
Is it a new syndrome or a clinical variability in cerebro‐oculo‐nasal syndrome?
Authors: Semerci C. Nur , Zorlu Pelin , Topal Yasar , Izbudak Izlem , Karacan Candemir , Balci Sevim
Published: June 2003

We present a male infant 2.5‐months old with asymmetric skull, anophthalmia, apparent hypertelorism, abnormal nares, unilateral cleft lip and palate, and structural abnormalities of the central nervous system. These findings are similar to cerebro‐oculo‐nasal syndrome except for the appearance of nose. This case is either a clinical variability in cerebro‐oculo‐nasal syndrome or a new entity. © 2003 Wiley‐Liss, Inc.
Typical facial clefting and constriction band anomalies: an unusual association in three unrelated patients
Authors: Taub Peter J. , Bradley James P. , Setoguchi Yoshio , Schimmenti Lisa , Kawamoto Henry K.
Published: June 2003

The amniotic band sequence is a rare congenital condition in which it is hypothesized that fibrous band of amniotic tissue result in variable soft tissue derangements. Other terms that have been used to describe this condition are amniotic band syndrome and amnion rupture sequence. Patients may present with craniofacial, thoracic, abdominal, and/or limb involvement. Previous reports have described the association between the amniotic band sequence and unusual patterns of facial clefting, as described by Tessier, that do not follow normal embryonic lines of fusion [Keller et al., 1978; Bagatin et al., 1997]. We describe three successive cases of the amniotic band sequence, which presented with rather typical facial clefts (cleft lip and palate) in unrelated patients. © 2003 Wiley‐Liss, Inc.
Population screening for cystic fibrosis: Knowledge and emotional consequences 18 months later
Authors: Gordon Claire , Walpole Ian , Zubrick Stephen R. , Bower Carol
Published: June 2003

We assessed cystic fibrosis (CF) knowledge and emotional consequences of CF population testing 18 months after screening was offered. Questionnaires were sent to 593 individuals and 353 responded (59.5%). All respondents had sound knowledge of CF disease, although carriers were more likely to correctly state the pattern of CF inheritance and CF carrier rate in Australia. Eleven of 47 carriers falsely believed they were only very likely to be carriers, while nearly a third of test‐negative individuals falsely believed they were definitely not carriers. Imprecise recall of the meaning of results may be due to memory loss over time, simplification of result meaning and minimization of risk. The Health Orientation Scale (HOS) was used to assess emotional consequences of CF carrier testing 18 months after testing. Both carriers and test‐negative individuals thought most carriers would experience more negative feelings than most non‐carriers. Carriers experienced less positive feelings about their test result compared to non‐carriers. Interestingly, the carriers' own feelings about their result were more positive compared to how they thought most carriers would feel. These results suggest that carriers experience minimal adverse psychological effects, although a negative social stigma may be attached to carrying the CF gene mutation. © 2003 Wiley‐Liss, Inc.
Homocysteine interference in neurulation: A chick embryo model
Authors: Afman L.A. , Blom H.J. , Van Der Put N.M.J. , Van Straaten H.W.M.
Published: June 2003

BACKGROUND

Periconceptional folic acid supplementation reduces the occurrence and recurrence risk of neural tube defects (NTD). Mothers of children with NTD have elevated plasma homocysteine levels. Administering homocysteine to chick embryos is reported to cause 27% NTD. Therefore, elevated plasma homocysteine levels per se or a disturbed homocysteine metabolism may be teratogenic to the embryo and may interfere with neural tube closure. Our aim was to obtain a chick embryo model to explore the interference of homocysteine in neural tube closure.

METHODS

Homocysteine or saline was administered to chick embryos in ovo at 3 hr, 30 hr, and 60 hr of incubation and harvested at 74 hr. Homocysteine was then applied to chick embryos in vitro at a defined time window of four to six somites and followed for 6 hr.

RESULTS

Homocysteine administration to chick embryos in ovo resulted in several malformations but not in an increased number of NTDs. Homocysteine administration to chick embryos in vitro resulted in a transient, dose‐dependent widening of the anterior neuropore and closure delay of the rhombencephalic neuropore. After 16 hr of incubation the neural tube was closed.

CONCLUSIONS

The in vitro chick embryo model appears a good model to explore the interference of a disturbed homocysteine metabolism in neurulation. Birth Defects Research (Part A) 67:421–428, 2003. © 2003 Wiley‐Liss, Inc.
Reduced SOD activity and increased neural tube defects in embryos of the sensitive but not of the resistant Cohen diabetic rats cultured under diabetic conditions
Authors: Weksler‐Zangen Sarah , Yaffe Pirhiya , Ornoy Asher
Published: June 2003

BACKGROUND

The role of reactive oxygen species in the etiology of diabetes‐induced anomalies was studied in a genetic model of nutritionally induced Type 2 diabetes mellitus: the Cohen diabetic sensitive (CDs) and resistant (CDr) rats. We have previously shown in this model that embryopathy may be induced by a combination of genetic and environmental factors. In our study we investigated the role of the antioxidant defense mechanism, genetic predisposition or environmental factors in embryos cultured under diabetic conditions.

METHODS

CDs, CDr and Sabra rat 11.5‐day old embryos were studied after 28 hr of culture in control (low glucose), high glucose, diabetic sub‐teratogenic, and diabetic teratogenic media. Embryos were monitored for growth retardation and congenital anomalies. Activity of superoxide dismutase (SOD) and catalase‐like (CAT) enzymes was measured in embryonic homogenates.

RESULTS

In control medium, CDs embryos were significantly underdeveloped but exhibited no anomalies and SOD activity was not significantly different from that of CDr embryos. In high glucose medium, CDs embryos were smaller than CDr and Sabra embryos and smaller than CDs embryos cultured in control medium. Neural tube defects (NTD) were found predominantly in the CDs embryos starting from 14% in the high glucose medium and increasing to 29% in the sub‐teratogenic medium. In the teratogenic medium, <50% of the CDs and Sabra embryos were alive whereas all (100%) of the CDr embryos were alive. SOD activity significantly increased in CDs embryos when cultured in the high glucose medium but was significantly reduced in the sub‐teratogenic medium. SOD activity was increased significantly in the Sabra embryos cultured in the sub‐teratogenic medium but did not change in CDr embryos cultured in either one of the different culture media. CAT activity did not show any significant trend in either one of the rat strains or in any of the different culture conditions.

CONCLUSIONS

Our results suggest that genetic susceptibility plays an important role in inducing underdevelopment and NTD in cultured CDs embryos in sub‐teratogenic medium and in protecting the CDr embryos under the same conditions. The combination of a sub‐teratogenic environment with genetic susceptibility is sufficient to reduce the activity of SOD, hence decreasing the ability of the CDs embryos to cope with diabetic sub‐teratogenic environment and prevent NTD. Birth Defects Research (Part A) 67:429–437, 2003. © 2003 Wiley‐Liss, Inc.
Genetic dissection of hyperthermia‐induced neural tube defects in mice
Authors: Lundberg Yunxia Wang , Wing Michael J. , Xiong Wanfen , Zhao Jian , Finnell Richard H.
Published: June 2003

BACKGROUND

Maternal hyperthermia has been shown to induce neural tube defects (NTD) in humans and in experimental animal systems. We report the first genetic dissection of maternal hyperthermia‐induced NTD in mice.

METHODS

After maternal exposure on E8.5 to 43°C water bath for 10 min, we observed exencephaly frequencies among E15.5–17.5 fetuses from the following crosses and backcrosses, SWV/Fnn(SWV)xSWV, C57BL/6J(C57)xC57, SWVxC57 (F1), F1xSWV and SWVxF1.

RESULTS

The fetuses with maternal hyperthermia exposure developed exencephaly in a strain‐dependent manner and the exencephaly frequencies among the above crosses were 46.2, 14.3, 13.6, 11.3, and 27.0%, respectively, expressed over total live fetuses. The fetal death rates were 47.3, 24.6, 37.1, 4.3, and 35.5%, respectively, expressed over total implants.

CONCLUSION

The data demonstrate that a single fetal genetic locus, plus a maternal effect, have likely caused the strain differences in the susceptibility to hyperthermia‐induced exencephaly. A maternal effect alone may have caused the higher prenatal mortality rates in the SWVxF1 cross versus the reciprocal cross. Analysis of gender ratios among those affected from these crosses excludes an X‐ or Y‐linked effect in causing the higher numbers of affected females. Birth Defects Research (Part A) 67:409–413, 2003. © 2003 Wiley‐Liss, Inc.
Zinc influences the in vitro development of peri‐implantation mouse embryos
Authors: Hanna Lynn A. , Clegg Michael S. , Momma Tony Y. , Daston George P. , Rogers John M. , Keen Carl L.
Published: June 2003

BACKGROUND

For humans, it is estimated that over 70% of concepti are lost during early development. In culture, mouse peri‐implantation embryos can mimic development from the blastocyst to the egg cylinder stage of development, a period during which implantation occurs in vivo. We describe a novel application of this model to investigate nutritional factors that may influence this stage of development. We investigated the influence of zinc (Zn) deficiency on embryonic development at the time of embryo implantation.

METHODS

Mouse blastocysts were cultured for 144 hr in low Zn, Zn‐replete or control medium.

RESULTS

Embryos developed normally when they were cultured in the control and Zn‐replete media. Embryos cultured in the low Zn medium were significantly impaired in forming egg cylinder morphology. This was associated with a reduction in extraembryonic endoderm as determined by immunohistochemistry for markers of visceral and parietal endoderm and correlated with an increase in TUNEL positive cells in the low Zn group. There was no change in the frequency of cells positive for phosphorylated Histone H3, a marker for S‐phase, indicating that an increase in apoptosis was primarily responsible for the smaller size and reduction in extraembryonic endoderm. The increased cell death was not associated with an increase in reactive oxygen species (ROS) detected by dichlorodihydrofluorescein staining.

CONCLUSIONS

These data support an important role for Zn in promoting differentiation and cell survival in the early embryo and suggest that sub‐optimal nutrition is an important factor that contributes to defects in primary germ layers and early embryonic loss. Birth Defects Research (Part A) 67: 414–420, 2003. © 2003 Wiley‐Liss, Inc.
Cleft‐palate lateral synechia syndrome: Insight into the phenotypic spectrum of Fryns syndrome?
Authors: Jaeger April , Kapur Raj , Whelan Michael , Leung Eric , Cunningham Michael
Published: June 2003

BACKGROUND

In 1972, Fuhrmann et al. (Humangenetik 1972;14:196–203) described a novel syndrome consisting of cleft palate (CP) and lateral synechiae (LS) between the palate and the floor of the mouth. This constellation of malformations, since denoted as cleft‐palate lateral synechiae syndrome (CPLS), is a rare syndrome; only five cases have been reported since the original description. Because of the paucity of recognized cases, little is known regarding the phenotypic spectrum of this presumably autosomal dominant condition.

CASES

We report two unrelated patients who presented with remarkably similar phenotypic features, including multiple intraoral synechiae (filiforme intraalveolar bands), cleft palate, micrognathia, and redundant lower lip tissue. Their phenotypic findings indicate a diagnosis of CPLS; however, case 3 (the monozygotic twin of case 2) had classic phenotypic features of Fryns syndrome.

CONCLUSIONS

This report presents two new cases of CPLS, and suggests that the CPLS phenotype may represent the mild end of the Fryns syndrome phenotypic spectrum. Supplementary material for this article can be found on the Birth Defects Research (Part A) website (http://www.interscience.wiley.com/jpages/1542‐0752/suppmat/67/fig5.xls) Birth Defects Research (Part A) 67:460–466, 2003. © 2003 Wiley‐Liss, Inc.
Cell‐cycle alterations underlie cyclophosphamide‐induced teratogenesis in the chick embryo
Authors: Heringová L. , Jelínek R. , Dostál M.
Published: June 2003

BACKGROUND

Cyclophosphamide (CP) embryotoxicity was documented in several studies on different experimental models. We investigate quantitatively the relationship between the embryotoxic effect of CP and the disturbance of the cell‐cycle using flow cytometry.

METHODS

Chick embryos on Days 2–4 were treated with 0.5, 1, 2, 4, 8, and 16 μg doses of pure substance of CP by intraamniotic or subgerminal administration routes. Cell‐cycle analysis was carried out in the brain, limb buds, hearts, and facial outgrowths dissected from the embryos 6 hr after administration. Samples of nuclear suspensions were obtained by enzymatic and mechanical disintegration of solid tissues in collagenase‐dispase, followed by detergent and RNA‐ase mediated cytolysis. Nuclei were stained by ethidium bromide.

RESULTS

A dose‐dependent increase of S‐phase cells followed by decrement of G2M cell compartment was observed. The significant block of S‐phase cells, however, was not always associated with malformations. The degree of cell‐cycle disturbance was expressed more readily by the ratio G2M/S that demonstrated consistently the threshold character of both teratogenic and lethal effects.

CONCLUSION

CP‐induced cytotoxicity manifested by dose‐dependent disturbance of cell‐cycle resulted in an overall depression of proliferation activity clearly associated with the occurrence of malformations and embryonic death. Although a non‐significant depression of mitotic activity appeared sufficient to produce malformations on Day 2, remarkably deeper disturbance was needed to interfere with the development of the embryos in more advanced stages. Changes in proliferation rate appear to be a primary and most important event in teratogenesis induced by general toxic agents. Birth Defects Research (Part A) 67438–443, 2003. © 2003 Wiley‐Liss, Inc.