bluuebunny/crossref_metadata_2025 huggingface dataset:
Two patients with heparin‐induced thrombocytopenia followed by idiopathic (immune) thrombocytopenic purpura: Case Report
Authors: Waheed Faisal , Naseer Nauman , Ahmed Tauseef , Nelson John C.
Published: July 2003

Heparin‐induced thrombocytopenia (HIT) and idiopathic thrombocytopenic purpura (ITP) are separate and well‐recognized clinical syndromes, 10both having potential for disastrous outcomes. Sequential occurrence of these two diseases has not been reported in the literature. We report herein two patients who were initially diagnosed as having HIT but whose later clinical course was similar to ITP. Although dysfunction of immune system seems to play a role, the precise mechanisms for the development of these diseases are unclear. As both conditions have different natural histories and require different treatment modalities, it is important to recognize that these two diseases may be seen sequentially. Am. J. Hematol. 73:290–293, 2003. © 2003 Wiley‐Liss, Inc.
Delayed introduction of G‐CSF after chemotherapy does not affect peripheral blood stem cell yield and engraftment kinetics in children with high‐risk malignancies: Retrospective study of 45 cases
Authors: Dolgopolov Igor , Andreeva Ludmila , Yankelevich Maxim , Mscheidze Demur , Siegel Stuart , Mentkevich George
Published: July 2003

We retrospectively compared the effects of two time points of G‐CSF (Filgrastim) introduction for PBSC mobilization in 45 children with different malignancies. Seventeen patients received the first G‐CSF dose on day 2 or 3 following chemotherapy (group 1). Twenty‐eight patients received a “flexible” G‐CSF injection schedule when the G‐GSF was started at the time of the first platelet count rise during post‐chemotherapy recovery phase (group 2). Leukapheresis was performed when WBC recovery reached >2.0 × 109/l or if the peripheral blood CD34+ cell level was >0.01 × 109/l. A median of 2 (1–4) leukapheresis procedures was performed in both groups to yield a median of 4.2 and 6.1 × 106 CD34+ cells/kg in groups 1 and 2, respectively, which was generally sufficient for auto‐transplantation. The proportion of patients with a failure of PBSC collection was similar and G‐CSF consumption estimated through the total cycle dose was 2.3 times less in group 2 without increasing infectious risks. The short‐term hematological recovery and the early post‐transplant course were similar in the two groups. Delayed introduction of G‐CSF after chemotherapy allowed PBSC harvest equivalent to that obtained after early G‐CSF introduction. This approach could be an interesting alternative in PBSC mobilization but should be assessed by a prospective controlled study. Am. J. Hematol. 73:225–229, 2003. © 2003 Wiley‐Liss, Inc.
Silent brain infarcts in adult Kuwaiti sickle cell disease patients
Authors: Marouf R. , Gupta R. , Haider M.Z. , Adekile A.D.
Published: July 2003

Although overt stroke is a common complication of sickle cell disease (SCD), its incidence is very low in Kuwaiti patients. On the other hand, the prevalence of silent brain infarcts, which is reported to be about 17–20% in American patients, has not been documented in adult Kuwaiti patients. This is a 1‐year study of consecutive, asymptomatic SCD patients seen in the hematology clinic of Mubarak Al‐Kabeer Hospital. Patients with a past history of seizure or any other neurological abnormality were excluded. The patients' charts were reviewed for frequency of hospitalizations, any documented complications, and steady‐state CBC. MRI was done with a 1.5‐Tesla unit with super‐conducting magnet. T1‐ and T2‐weighted sagittal and axial sections and proton‐density axial images were obtained in 5‐mm‐thick sections. Thirty‐five patients were studied, made up of 25 SS and 10 Sβ0Thal, aged between 17 and 44 years, with a mean age of 26.9 ± 9.3 years. MRI findings consistent with infarcts were found in 7 (20.0%) patients—6 SS and 1 Sβ0thal—with a mean age of 31.8 ± 8.2 years, which was significantly higher (P < 0.05) than the mean age of the unaffected group (25.1 – 9.0 years). There were also no differences in the mean Hb, Hb F, or any other hematological parameter in the two groups. Among the affected 6 SS, 2 had co‐existent α‐thal trait. It is interesting that, while silent infarcts are prevalent in young American patients, it is in the older age group that they occur in Kuwaiti patients. Further studies are needed to investigate the factors modulating this heterogeneity. Am. J. Hematol. 73:240–243, 2003. © 2003 Wiley‐Liss, Inc.
Compound heterozygosity for two novel mutations in a severe factor XI deficiency
Authors: Tsukahara Akiko , Yamada Takayuki , Takagi Akira , Murate Takashi , Matsushita Tadashi , Saito Hidehiko , Kojima Tetsuhito
Published: July 2003

We identified two novel mutations in an asymptomatic 25‐year‐old Japanese patient with severe factor XI deficiency. Direct sequencing analysis of PCR products from his factor XI gene revealed a G to T transversion in exon 12, resulting in the nonsense mutation (Glu447Stop) and a G insertion in five consecutive guanine nucleotides (501Trp(TGG)–502Gly(GGG)) in exon 13 that is expected to lead to the substitution of the last 105 amino acids (503Tyr–607Val) with 32 abnormal amino acid residues (503Val–534Thr) followed by stop codon. We also demonstrated that two mutations are associated with the separate alleles in this patient, indicating compound heterozygosity for these mutations. Both mutations lead to the disruption of the catalytic domain structure of the FXI molecule and thus are responsible for his deficiency of factor XI. Am. J. Hematol. 73:279–284, 2003. © 2003 Wiley‐Liss, Inc.
Prognostic significance of the F‐box protein Skp2 expression in diffuse large B‐cell lymphoma
Authors: Seki Ritsuko , Okamura Takashi , Koga Hironori , Yakushiji Kazuaki , Hashiguchi Michitoshi , Yoshimoto Kohji , Ogata Hideaki , Imamura Rie , Nakashima Yutaka , Kage Masayoshi , Ueno Takato , Sata Michio
Published: July 2003

The F‐box protein Skp2 positively regulates the G1‐S transition by promoting degradation of the cyclin‐dependent kinase inhibitor p27kip1 (p27). Recent evidence has suggested an oncogenic role of Skp2 in not only carcinogenesis but also lymphomagenesis. In this study, we performed immunohistochemical analysis on the cell‐cycle‐associated proteins, Skp2, p27, and Ki‐67, in 27 patients with de novo diffuse large B‐cell lymphoma (DLBCL), evaluating the correlation between the clinical characteristics and expression levels of these proteins. The patients were classified into two groups according to the positivity for Skp2 expression: a high Skp2 expression group (>60% positive for Skp2 in lymphoma cells) and a low Skp2 expression group (⪋%). A high level of Skp2 expression significantly correlated with advanced clinical stage (P = 0.029), although the increase did not correlate with age, gender, LDH levels, presence of extranodal disease, or performance status and resulted in no correlation with the International Prognostic Index‐based risk grading. However, it was noteworthy that the high Skp2 expression group demonstrated a significantly worse prognosis than the low Skp2 expression group (P = 0.0007). The expression level of Skp2 correlated with that of Ki‐67 but not necessarily with that of p27. The p27 expression level did not correlate patients' prognosis. Taken together, it was suggested that Skp2 was a valuable and independent marker predicting the outcome in DLBCL. Am. J. Hematol. 73:230–235, 2003. © 2003 Wiley‐Liss, Inc.
Feasibility and toxicity of high‐dose therapy (HDT) supported by peripheral blood stem cells in elderly patients with multiple myeloma and non‐Hodgkin's lymphoma: Survey from a single institution
Authors: Magagnoli Massimo , Castagna Luca , Balzarotti Monica , Sarina Barbara , Timofeeva Inna , Bertuzzi Alexia , Compasso Silvana , Nozza Andrea , Siracusano Licia , Santoro Armando
Published: July 2003

The aim of this retrospective study was to investigate the feasibility of high‐dose therapy (HDT) followed by peripheral blood stem cell transplantation (PBSCT) in elderly patients with hematological malignancies. From April 1998 to November 2001, 40 elderly patients (defined as ≥60 years) with non‐Hodgkin's lymphoma (12 patients) and multiple myeloma (28 patients) were evaluated. Seven lymphoma and one myeloma patients were in complete remission (CR), 27 in partial remission (PR), two had stable disease (SD), and three progressive disease (PD). The median age was 65 years (range 60–71). Thirty‐nine patients were mobilized with chemotherapy plus granulocyte‐colony stimulating factor (G‐CSF) and one with G‐CSF alone. Patients received HDT including melphalan alone in 32 cases or combined with other drugs in six and BEAM in two. The median number of collected CD34+ cells was 12.4 × 106/kg (range 2.0–68.9). The median number of re‐infused CD34+ cells was 9.9 × 106/kg (range 2.0–68.9). All patients engrafted after PBSC and the median time to neutrophil recovery (N > 500/μl) and platelet recovery (PLT > 20,000/μl) was 8 days (range 5–18) and 6 days (range 5–18), respectively. Nonhematological toxicity was mild and no patient died from transplant‐related toxicity (TRM). Median duration of hospitalization was 18 days (range 12–24). To date, 32 patients are alive and eight died from disease progression at a median follow‐up interval of 24 months. HDT supported by PBSC is a feasible procedure in selected elderly patients, and an age of more than 60 years should not be considered a contraindication for HDT. Am. J. Hematol. 73:267–272, 2003. © 2003 Wiley‐Liss, Inc.
Conjoined twins: Morphogenesis of the heart and a review
Authors: Gilbert‐Barness Enid , Debich‐Spicer Diane , Opitz John M.
Published: July 2003

Five cases of conjoined twins have been studied. These included three thoracopagus twins, one monocephalus diprosopus (prosop = face), and one dicephalus dipus dibrachus. The thoracopagus twins were conjoined only from the upper thorax to the umbilicus with a normal foregut. These three cases shared a single complex multiventricular heart, one with a four chambered heart with one atrium and one ventricle belonging to each twin with complex venous and arterial connection; two had a seven chambered heart with four atria and three ventricles. The mono‐cephalus diprosopus twins had a single heart with tetralogy of Fallot. The dicephalus twins had two separate axial skeletons to the sacrum, two separate hearts were connected between the right atria with a shared inferior vena cava. Thoracopagus twinning is associated with complex cardiac malformations. The cardiac anlagen in cephalopagus or diprosopus are diverted and divided along with the entire rostral end of the embryonic disc and result in two relatively normal shared hearts. However, in thoracopagus twins the single heart is multiventricular and suggests very early union with fusion of the cardiac anlagen before significant differentiation. Cardiac morphogenesis in conjoined twins therefore appears to depend on the site of the conjoined fusion and the temporal and spatial influence that determines morphogenesis as well as abnormally oriented embryonic axes. © 2003 Wiley‐Liss, Inc.
Splenogonadal fusion‐limb defect “syndrome” and associated malformations
Authors: McPherson Fiona , Frias Jaime L. , Spicer Diane , Opitz John M. , Gilbert‐Barness Enid F.
Published: July 2003

Two types of splenogonadal fusion (SGF) have been proposed. In the continuous type the spleen is connected to the gonad, and often it is associated with limb defects and other anomalies such as micrognathia, microglossia, anal atresia, and hypoplastic lungs. Associated abnormalities are lower in the discontinuous type of SGF, where there is fusion between the gonad and accessory splenic tissue, without connection with the normal spleen. The cause of SGF and SGF with limb defects (SGFLD) is unknown. On the basis of associated orofacial limb abnormalities, some authors have suggested that SGFLD may be related to the Hanhart complex. Others have noted the overlap between SGFLD and femoral‐facial syndrome (FFS). We consider SGFLD a developmental field defect that originates during blastogenesis. Although the cause is unknown, the earlier its action, the more severe the involvement resulting in SGFLD; later action may result only in SGF. © 2003 Wiley‐Liss, Inc.
Familial multiple epiphyseal dysplasia due to a matrilin‐3 mutation: Further delineation of the phenotype including 40 years follow‐up
Authors: Mostert A.K. , Dijkstra P.F. , Jansen B.R.H. , van Horn J.R. , de Graaf B. , Heutink P. , Lindhout D.
Published: July 2003

In this study, we followed‐up the family with bilateral hereditary micro‐epiphyseal dysplasia (BHMED) originally described by Elsbach [1959: J Bone Joint Surg [Br] 41‐B:514–523]. Clinical re‐examination of all available family members resulted in further delineation of the clinical and radiological phenotype, which is distinct from common multiple epiphyseal dysplasia (MED). Linkage analysis excluded EDM1, EDM2, and EDM3 as candidate genes. Linkage and mutation analysis of matrilin‐3 (MATN‐3) revealed a new pathogenic mutation confirming that BHMED is indeed a distinct disease entity among MED and MED‐like disorders. © 2003 Wiley‐Liss, Inc.
Severely delayed epiphyseal ossification dysplasia with normal stature
Authors: Baumann Clarisse , Garel Catherine , Vuillemain Lucille , Hassan Max , Verloes Alain
Published: July 2003

We report on a pair of dizygotic twins born to consanguineous parents, showing an extreme delay in skeletal maturation (roughly corresponding to the time of birth at the age of 4 10/12 years), mild metaphyseal irregularities, and normal to large stature (+ 1 to + 2 SD) with normal growth pattern, long fingers, generalized small joint hyperlaxity with flat feet, genua valga, and low normal intellectual development. This disorder was not associated with abnormal endocrine function or abnormal Ca/P metabolism. This epiphyseal disorder is compatible with autosomal recessive inheritance.© 2003 Wiley‐Liss, Inc.
Characterization of terminal chromosome anomalies using multisubtelomere FISH
Authors: Davies Angela F. , Kirby Toby L. , Docherty Zoe , Mackie Ogilvie Caroline
Published: July 2003

Telomeric repeat sequences (TTAGGG) are known to cap the termini of every human chromosome. Proximal to these repeat sequences are chromosome‐specific repeat sequences, which in turn are distal to gene‐rich regions. Submicroscopic, subtle, or cryptic abnormalities in these regions can now be investigated using commercial probe sets for all of the chromosome‐specific subtelomeric regions of the human genome. Using this technology, previously unidentified genomic imbalance has been found in a proportion of patients with idiopathic developmental delay and learning difficulties. We have used these probe sets to investigate cases with apparently terminal anomalies detected on G‐banded chromosome analysis. As a result of such investigations, we have found that 3 (19%) of 16 apparently terminal deletion cases were the result of more complex rearrangements involving other chromosome subtelomeres. The remaining 13 cases contained no chromosome‐specific subtelomere repeats on the deleted arm, but in all 16 cases, the TTAGGG telomere repeat cap was present. A further case was investigated where extra material was found in the terminal region of the chromosome 12 short arm, found to represent a complex inversion/duplication/deletion rearrangement. Investigation of all cases with terminal anomalies, including apparently terminal deletions, is likely to uncover further cases involving complex rearrangements and should lead to a greater understanding of the mechanisms by which these abnormalities arise. © 2003 Wiley‐Liss, Inc.
Antenatal onset of cortical hyperostosis (Caffey disease): Case report and review
Authors: Schweiger Susann , Chaoui Rabih , Tennstedt Cornelia , Lehmann Katarina , Mundlos Stefan , Tinschert Sigrid
Published: July 2003

We report on a fetus of 27 weeks of gestation whose clinical, radiological, and histopathological findings are compatible with the prenatal form of Caffey disease (cortical hyperostosis). Prenatal ultrasound examination showed polyhydramnios and markedly short and angulated long bones, which had led to the incorrect diagnosis of lethal osteogenesis imperfecta. We found 43 published descriptions on the antenatal onset of cortical hyperostosis symptomatic in utero or at birth. Two groups of prenatal cortical hyperostosis (PCH) can be distinguished: (1) severe (25 reports and the fetus presented here), with onset before 35 weeks of gestation and generally associated with polyhydramnios, lung disease, prematurity, and high lethality; (2) mild (18 reports), with onset after 35 weeks of gestation and without complications. Autosomal recessive inheritance has been suggested for the prenatal form of cortical hyperostosis. However, the available evidence suggests that both dominant and recessive inheritance is possible. Moreover, dominant inheritance seems to be more common in the mild prenatal form of cortical hyperostosis. © 2003 Wiley‐Liss, Inc.
Abnormalities of the umbilico‐portal venous system in Down syndrome: A report of two new patients
Authors: Pipitone Salvatore , Garofalo Caterina , Corsello Giovanni , Mongiovì Maurizio , Piccione Maria , Maresi Emiliano , Sperandeo Velio
Published: July 2003

Congenital anomalies of the umbilical and portal venous system are rare vascular malformations which are often associated with anomalies of the heart and gastrointestinal tract. Association with chromosomal disorders has been sporadically reported. We now report on two patients with trisomy 21 and congenital anomalies of the umbilico‐portal system. A male fetus showed absence of the intrahepatic portal vein (PV) and ductus venosus with a direct communication between portal sinus and inferior vena cava exhibiting an umbilicosystemic total shunt during the fetal life and a portosystemic total shunt after birth. A female infant showed absence of the intrahepatic PV and a total portocaval shunt. Both patients also had heart defects. As previously documented in other reports, our cases demonstrated that this association may be causally‐related to the chromosomal aberration. In addition, the umbilico‐portal venous system abnormalities seems to be the most frequent congenital vascular malformation in Down syndrome. A presumptive pathogenetic mechanism could be a trisomy 21‐related altered angiogenesis of the vitelloumbilical plexus. © 2003 Wiley‐Liss, Inc.
Autistic disorder and chromosomal mosaicism 46,XY[123]/46,XY,del(20)(pter → p12.2)[10]
Authors: Sauter S. , von Beust G. , Burfeind P. , Weise A. , Starke H. , Liehr T. , Zoll B.
Published: July 2003

We report on a 3‐year‐old boy with a moderate to severe mental retardation, autistic behavior patterns, and myoclonic epilepsy of early childhood. The cytogenetic analysis of blood lymphocytes revealed a deletion of chromosome 20pter → p12.2 occurring as mosaicism in 8% of the analyzed metaphases: 46,XY[123]/46,XY,del(20)(pter → p12.2)[10]. The deletion was confirmed by the recently developed multicolor banding approach and additionally by region specific fluorescence in situ hybridization (FISH) probes. To the best of our knowledge, this is the first report on a patient with autistic behavior with terminal 20p deletion mosaicism reported up to present. © 2003 Wiley‐Liss, Inc.
Developmental anomalies of the scapula—the “omo”st forgotten bone
Authors: Williams Marc S.
Published: July 2003

Congenital malformations of the scapula, ranging from complete absence, to abnormal shape and position (Sprengel anomaly) are encountered, not infrequently, in genetic practice. Despite this, little is known of the embryologic origin of the scapula and the relationship of the embryology to the observed birth defects. Standard embryology texts, when discussing the subject at all, generally consider the scapula as part of the upper limb. The pattern of associated birth defects suggests that this is at least an oversimplification and may be inaccurate. Sprengel anomaly is the most frequently encountered malformation of the scapula. It can be seen in isolation, but is often seen in association with other defects that include; scoliosis, hemivertebrae, segmentation abnormalities of vertebrae and ribs (including Klippel‐Feil sequence), spina bifida, clavicular abnormalities, renal abnormalities and hypoplasia of the muscles of the neck and shoulder. The ipsilateral limb is usually normal. An unappreciated association between Sprengel anomaly and diastematomyelia of the lumbar spine also raises questions about the embryologic origin of the scapula. 25–50% of Sprengel anomaly patients have an associated omovertebral band or bone that arises from the posterior process of a vertebral body and attaches to the superior angle/medial portion of the scapula. This is felt to be of scapular origin, but the report of at least one patient with an omovertebral bone, not associated with a Sprengel anomaly questions this assumption. Scapuloiliac dysostosis (Kosenow syndrome), a rare skeletal dysplasia, is associated with marked hypoplasia of the scapulae, clavicles and pelvis. Associated anomalies include eye anomalies, rib anomalies and spina bifida. The limbs are normal. Knockout of the Emx2 gene in mice yields a similar skeletal phenotype. Mutations in EMX2 in humans are associated with schizencephaly, not skeletal anomalies. Data on gene expression in the scapula will be reviewed. Based on this information, the author proposes that the scapula arises from 2 or more distinct embryologic anlage under different genetic control than the upper limb. © 2003 Wiley‐Liss, Inc.
Preempting genetic discrimination and assaults on privacy: Report of a symposium
Authors: Shinaman Aileen , Bain Lisa J. , Shoulson Ira
Published: July 2003

At a symposium in June, 2002, biomedical researchers, clinicians, legal experts, policymakers, and representatives of the insurance industry and the advocacy community gathered to address issues of genetic privacy and discrimination; and to identify research, legal, and policy gaps needing to be filled. They concluded that over the next decade, as more genetic information becomes available and the public becomes more aware of individual risks, concerns about privacy and discrimination will become increasingly important. Documented cases of genetic discrimination are rare and largely anecdotal, yet individuals with genetic conditions harbor significant fears about discrimination. Current laws enacted to protect individuals from workplace and insurance discrimination offer some measure of protection, but leave many unfilled gaps. Moreover, the use of genetic information in potentially discriminatory ways is not limited to employment and insurability. Existing laws do little to protect people seeking life, disability, or long‐term care insurance. And the courts have used genetic information in a wide variety of cases including paternity, criminal, and tort (personal injury) cases. Genetic information that might jeopardize an individual's right to privacy may also be obtained in the course of research studies, including through the collection of DNA and tissue samples. The insurance industry, State and Federal agencies, and the advocacy community are all making efforts to address some of these gaps through legislation and education of clinicians, the public, and policy makers. © 2003 Wiley‐Liss, Inc.
Craniosynostosis and congenital heart anomalies associated with a maternal deletion of 15q15‐22.1
Authors: Shur Natasha , Cowan Janet , Wheeler Patricia G.
Published: July 2003

We report an infant with multiple congenital anomalies, including craniosynostosis, tetralogy of Fallot variant, and limb anomalies associated with a maternal deletion of 15q15‐22.1. Only two other patients have been reported with a similar deletion, but the deletion was paternal in both cases. We review our patient's findings and compare them to previously reported individuals with similar 15q abnormalities. Our patient allows an expansion of phenotype associated with mid‐15q deletions to include severe craniosynostosis, congenital heart disease, and limb anomalies. This will assist in prenatal counseling and predicting postnatal outcome for other affected individuals. The specific breakpoints in our patient and the other patients with similar deletions may also assist in determining a critical region for suture formation. © 2003 Wiley‐Liss, Inc.
Toriello–Carey syndrome associated with respiratory failure and non‐mechanical ileus
Authors: Kataoka Tatsuki R. , Ito Akihiko , Nakabori Tasuku , Koma Yu‐ichiro , Nakai Hiroshi , Kamata Shinkichi , Kitamura Yukihiko
Published: July 2003

Toriello–Carey syndrome comprises agenesis of the corpus callosum, telecanthus, small palpebral fissures, Pierre Robin sequence, abnormal ears, and cardiac defects. We report a boy who has some additional findings, including a severe respiratory failure and intestinal dysmotility. The boy died of these two disorders at age 13 months. Histological examination revealed pulmonary immaturity and a defect of smooth muscle cells in the longitudinal muscle coat of the intestinal musculature, both of which might explain some aspects of the pathophysiology of the patient. © 2003 Wiley‐Liss, Inc.
Spondyloepiphyseal dysplasia Maroteaux type: Report of three patients from two families and exclusion of type II collagen defects
Authors: Nishimura Gen , Kizu Rika , Kijima Yoshimaro , Sakai Kiyoshi , Kawaguchi Yoshiharu , Kimura Tomoatsu , Matsushita Isao , Shirahama Shuya , Ikeda Toshiyuki , Ikegawa Shiro , Hasegawa Tomonobu
Published: July 2003

Spondyloepiphyseal dysplasia (SED) Maroteaux type is an autosomal dominant skeletal dysplasia, characterized by spondylar dysplasia, mild epiphyseal dysplasia of the large joints, and type E‐like brachydactyly. These manifestations overlap with those of spondyloperipheral dysplasia (SPD), in which a sporadic case with a mutation of COL2A1 has been reported. We report on three patients (an affected woman and her son and a sporadic case of an affected man) with SED Maroteaux type. The affected adults were severely short along with stubby hands and feet, and one developed myelopathy as a result of thoracolumbar gibbus. The affected child was mildly short at birth, and developed brachydactyly in early childhood. The radiological hallmarks of these patients included severe platyspondyly with square‐shaped vertebral bodies, iliac hypoplasia, epiphyseal hypoplasia of the large joints, and strikingly short metacarpals and phalanges. These radiological findings appeared already apparent in early childhood. SED Maroteaux type was radiologically discriminative from SPD. Brachydactyly was much severe in the former than in the latter, and spondylar dysplasia manifestation was different between both disorders. Mutation screen by polymerase chain reaction‐direct sequencing for all exons and their flanking regions of COL2A1 did not reveal any mutations in the three patients. © 2003 Wiley‐Liss, Inc.
Functional disomy for Xq22‐q23 in a girl with complex rearrangements of chromosomes 3 and X
Authors: Ida Tomoko , Miharu Norio , Hayashitani Michiko , Shimokawa Osamu , Harada Naoki , Samura Osamu , Kubota Takeo , Niikawa Norio , Matsumoto Naomichi
Published: July 2003

A 5‐year‐old girl with developmental and growth retardation is reported with complex chromosome rearrangements consisting of a partial Xq deletion and an abnormal chromosome 3 with multiple breakpoints. GTG‐banding, and multiplex and conventional FISH studies showed that a 6.6‐Mb Xq22‐q23 segment was inserted into 3q, in addition to three intrachromosomal insertions in chromosome 3. Her karyotype was thus interpreted as 46,X,der(X)(Xpter→Xq22::Xq23→Xqter),der(3)(3pter→3p26::3p12→3q25.3::3p12→3p26::Xq22→Xq23::3q25.3→3qter). Replication R‐banding study showed that the der(X) was inactivated in all blood lymphocytes analyzed. Methylation‐specific PCR at the androgen receptor gene (HUMARA) locus at Xq11‐q12 showed a skewed inactivation pattern with the active/inactive X chromosome ratio of 92/8. These data indicated the presence, in the majority of cells, of a functioning Xq22‐q23 segment in both the normal X and the der(3) chromosomes. Her growth retardation, developmental delay, and other minor anomalies were most likely caused by dosage effects of the genes in the functionally disomic Xq22‐q23 region. Despite the presence of two active copies of the proteolipid protein 1 gene (PLP1), she did not show the symptoms of Pelizaeus‐Merzbacher disease, a subset of which has been known to be caused by the duplication of PLP1. © 2003 Wiley‐Liss, Inc.
D‐2‐hydroxyglutaric aciduria: A case with an intermediate phenotype and prenatal diagnosis of two affected fetuses
Authors: Clarke Nigel F. , Andrews Ian , Carpenter Kevin , Jakobs Cornelis , van der Knaap Marjo S. , Kirk Edwin P.
Published: July 2003

D‐2‐hydroxyglutaric aciduria (D2HGA) is a rare autosomal recessive disorder with variable clinical expression. The biochemical defect is unknown at present. Previously reported cases have either followed a severe clinical course characterized by neonatal epileptic encephalopathy, cortical blindness, and profound developmental delay, or a mild course characterized by mild developmental delay, manageable epilepsy, and mild hypotonia. To date there has been a clear distinction between these two groups. We report the second case of a child with D2HGA who has followed an intermediate course. She presented in infancy with hypotonia, manageable epilepsy and developed moderate to severe developmental delay, and cortical visual impairment. The proposita had a coarse facial appearance, flat face, broad nasal bridge, up‐turned nose, and simple, anteverted ears. These facial anomalies have been noted in other children with D2HGA and this case strengthens the proposed association between this facial phenotype and D2HGA. We also report the third and fourth instances of prenatal diagnosis for D2HGA. At each prenatal diagnosis, an affected fetus was diagnosed on the basis of markedly increased levels of D‐2‐hydroxyglutaric acid in amniotic fluid. © 2003 Wiley‐Liss, Inc.
Maternal inheritance in cyclic vomiting syndrome with neuromuscular disease
Authors: Boles Richard G. , Adams Kathleen , Ito Masamichi , Li B.U.K.
Published: July 2003

Cyclic vomiting syndrome (CVS), characterized by severe discrete episodes of nausea, vomiting, and lethargy, is a predominately childhood condition associated with migraine and dysautonomic features. Disease‐associated mitochondrial DNA (mtDNA) sequence variants are suggested by a strong maternal bias in the inheritance of migraine, and the recent findings of mtDNA variants in a few children with CVS and additional neuromuscular disease manifestations (“CVS+”). A clinical interview using a questionnaire was administered (generally) to one parent of 62 children with CVS+. Non‐senile disease manifestations, including migraine, myopathy, seizures, and dysautonomia‐like symptoms, were far more common in matrilineal versus non‐matrilineal relatives, including being present in 75% of the mothers versus in only 11% of the fathers (P < 0.001). Overall, maternal inheritance is suggested in 86% of the families (in 65% strongly so). Disease manifestations in subjects and their affected matrilineal relatives are predominately intermittent and consistent with dysautonomia, including increased vital sign fluctuations. Body fluid metabolites and muscle biopsy findings are consistent with mitochondrial dysfunction in most cases tested. We conclude that mtDNA sequence variants are at least risk factors in the development of disease in most children at this “severe” end of the CVS spectrum, likely involving a maternally inherited propensity towards dysautonomia. © 2003 Wiley‐Liss, Inc.
Living with achondroplasia in an average‐sized world: An assessment of quality of life
Authors: Gollust Sarah E. , Thompson Richard E. , Gooding Holly C. , Biesecker Barbara B.
Published: July 2003

Mutations in the gene encoding fibroblast growth factor receptor 3 cause achondroplasia, the most common form of inherited skeletal dysplasia. Although there are more than 10,000 individuals with achondroplasia living in the United States, there has been little study of their quality of life (QOL). For this study, surveys were collected from 189 individuals affected with achondroplasia (ACH) and 136 unaffected first‐degree relatives (FDRs) of affected individuals. Individuals affected with achondroplasia had lower annual income, less education, and were less likely to be married than FDRs. They also differed significantly in their perceptions of achondroplasia, with FDRs believing that achondroplasia is a more serious condition. Total QOL indices and indices in each of four QOL subdomains were significantly lower in affected individuals than in relatives. When controlling for demographic characteristics and affected status, having lower self‐esteem scores and perceiving achondroplasia as more serious were the independent factors most highly associated with lower QOL. A qualitative analysis of open responses to questions about the advantages and disadvantages of achondroplasia revealed that individuals were as likely to cite disadvantages relating to social barriers as they were to cite those relating to health and functioning. We interpret the low QOL scores to reflect the social challenges that individuals with achondroplasia regularly experience in the average‐sized world. Genetics professionals should consider sources of lower QOL for affected individuals in their counseling sessions to acknowledge the relative importance of non‐medical contributions. Published 2003 Wiley‐Liss, Inc.
Case‐control study of cleft lip or palate after maternal use of topical corticosteroids during pregnancy
Authors: Edwards Matthew J. , Agho Kingsley , Attia John , Diaz Pedro , Hayes Teresa , Illingworth Alice , Roddick Laurence G.
Published: July 2003

A case‐control survey of 48 children with nonsyndromic cleft lip or palate showed a significant increase in prevalence of maternal use of topical corticosteroid preparations in the first trimester of pregnancy, compared to 58 controls born in the same hospital; the odds ratio was 13.154, 95% confidence interval 1.67–586, P = 0.0049 on Fisher's exact two‐tail test. The results were statistically significant although the wide confidence interval reflected the small sample size. Although older epidemiological studies have not detected any association between systemic corticosteroid treatment and the combined incidence of all congenital malformations, experimental studies over several decades have shown that maternal corticosteroid exposure in several species of animals is specifically associated with oral clefts. This association has been confirmed by more specific case‐control surveys where the cases were children with cleft lip or palate and the exposure was maternal systemic corticosteroid treatment in the first trimester. Only one previous survey also analyzed topical corticosteroids, and it demonstrated an increased odds ratio for cleft lip or palate. A national survey of children with cleft palate will be necessary to evaluate the results of this pilot study. © 2003 Wiley‐Liss, Inc.
X‐linked mild non‐syndromic mental retardation with neuropsychiatric problems and the missense mutation A365E in PAK3
Authors: Gedeon Agi K. , Nelson John , Gécz Jozef , Mulley John C.
Published: July 2003

We describe a family of 19 males in five generations with mild to borderline non‐syndromic X‐linked mental retardation (MRX). There were no clinical manifestations in the affected males other than mental impairment and relatively long ears, with neuropsychiatric problems in some cases. Linkage analysis carried out on part of the pedigree using 34 markers spanning the X chromosome localized the gene between DXS454 and DXS1001 in Xq23. The maximum two‐point lod score was 3.21 at DXS1059. PAK3 is a known MRX gene mapping to the same region. The affected males and obligate carrier females were found to have a missense mutation c.1094C > A in exon 10 causing an A365E substitution in a highly conserved region of the protein. The C to A base change abolishes a PvuII restriction enzyme site providing the basis for a simple test, if required, for carrier detection and prenatal diagnosis in the extended family. © 2003 Wiley‐Liss, Inc.
Prenatal detection of mosaic trisomy 1q due to an unbalanced translocation in one fetus of a twin pregnancy following in vitro fertilization: A postzygotic error
Authors: Zeng Shemin , Patil Shivanand R. , Yankowitz Jerome
Published: July 2003

Complete or mosaic trisomy for all of chromosome 1q has been seen rarely in a recognized pregnancy. A patient presented with twins following in vitro fertilization (IVF). Ultrasound showed twin A to have a diaphragmatic hernia, thick nuchal fold, and subtle intracranial abnormalities. Twin B appeared normal and a thick dividing membrane was seen. Amniocentesis of twin A showed a male karyotype with mosaic trisomy 1q in 57% of cells resulting from a translocation between chromosomes Yq12 and 1q12. Parental karyotypes were normal. The twins were delivered at 33 weeks. Twin A died at 1 hr of life. Autopsy confirmed the left diaphragmatic hernia and hypoplastic lungs. Autopsy also revealed a partial cleft palate, syndactyly of the second and third toes bilaterally, external deviation of the left 5th toe, and contractures of the index fingers bilaterally. A recent report documented formation of a chimera resulting from embryo amalgamation after IVF. Given the rarity of the cytogenetic findings in our case, we sought to determine if the mosaicism was a result of chimera formation related to the IVF. Thirteen polymorphic loci throughout the genome, in addition to four on 1q and four on 1p, were amplified by PCR. Only two alleles were observed at each of these loci in twin A, one paternal and the other maternal. We present further clinical findings of this case with a rare cytogenetic abnormality that appears to have originated from a postzygotic mitotic error and not embryo amalgamation. © 2003 Wiley‐Liss, Inc.
Sirenomelia sequence according to the distance between the first sacral vertebra and the ilia
Authors: Kjaer Klaus W. , Keeling Jean W. , Opitz John M. , Gilbert‐Barness Enid , Hartling Ulla , Hansen Birgit Fischer , Kjær Inger
Published: July 2003

The development of the iliac bones and lower limbs are parallel processes depending on the normal ontogeny of the caudal blastema [O'Rahilly and Müller, 1989; Opitz, 1993; Opitz et al., 2000]. We hypothesized that the pathogenetic mechanisms leading to fused lower limbs would in parallel displace the ilia caudally and medially and that the degree of this displacement might correlate with the severity of the iliac and lower limb defects. Thus the purpose of the study was to test this hypothesis in a sample of 12 sirenomelic fetuses. The fetuses GA 16–39 weeks, spontaneously or therapeutically aborted, were radiographed in the frontal projection as part of a requested autopsy. From each radiograph, a line was drawn connecting the most cranial part or the two ilia. After that the distance was measured vertically between this line and the most cranial part of the first sacral vertebral body (iliac‐sacral distance (ISD)). A second distance was measured horizontally between the most lateral part of the two iliae (bi‐iliac distance (BD)). As a result, ISD correlates with the iliac/femur phenotype. Separate ilia and femora occur only in cases with normal ISD. Fused ilia or femora or both are seen only in fetuses with mildly increased ISD, whereas a single iliac bone and femur occur only in cases with greatly increased ISD. The increase of the ISD does not correlate with the severity of more distal limb involvement. There was a correlation between the ISD and the BD values; the higher the ISD, the shorter the BD. Based on these findings, we propose an extended classification of Sirenomelia to be tested by other researchers. © 2003 Wiley‐Liss, Inc.
Screening of patients with craniosynostosis: Molecular strategy
Authors: Chun Kathy , Teebi Ahmad S. , Azimi Cyrus , Steele Leslie , Ray Peter N.
Published: July 2003

Craniosynostosis is the premature fusion of calvarial bones leading to an abnormal head shape. The craniosynostosis syndromes are clinically heterogeneous with overlapping features, which make an accurate diagnosis difficult at times. Although the clarification of a genetic lesion does not have a direct impact on patient management in many cases, there is a significant benefit in providing accurate prenatal diagnosis. Genetic counsellors are also able to offer better risk estimates of recurrences to non‐manifesting carriers and their extended family members and for affected patients of reproductive age. Advances in gene discovery have shown that craniosynostosis syndromes delineated on clinical bases, with the possible exception of Apert syndrome, are genetically heterogeneous, and mutations have been found in fibroblast growth factor receptors (FGFR) 1, 2, 3 and TWIST. We surveyed 99 craniosynostosis patients at the molecular level and found mutations in 50 of them. Six novel point mutations were identified: three in FGFR2 and three in TWIST. Two Saethre–Chotzen patients with TWIST microdeletions at 7p21 were also found. The other mutations identified have been previously reported. In studying these 99 patients, we developed a diagnostic strategy for craniosynostosis testing, where sequential analysis of recurrent mutations was followed by selective sequencing. This algorithm makes testing of craniosynostosis disorders more efficient and cost‐effective. © 2003 Wiley‐Liss, Inc.
Brief communication: Multiplex X/Y‐PCR improves sex identification in aDNA analysis
Authors: Schmidt Diane , Hummel Susanne , Herrmann Bernd
Published: July 2003

This study introduces a polymerase chain reaction (PCR)‐based multiplex approach to improve the certainty of molecular sex identification on archaeological skeletal material. We coamplified amelogenin, two X‐chromosomal short tandem repeats (STRs) (DXS6789 and DXS9898), and two Y‐specific STRs (DYS391 and DYS392). The amplification results of this multiplex approach back each other up, and enable a reliable sex identification. This coamplification of X‐ and Y‐specific markers in a multiplex assay combines the added advantage of positive identification of both female and male individuals with raising the validity of the diagnosis by obtaining multiple data simultaneously. This multiplex system was successfully applied to 3,000‐year‐old bone material. Am J Phys Anthropol 121:000–000, 2003. © 2003 Wiley‐Liss, Inc.
Asymmetric regional cerebral blood flow in sedated baboons measured by positron emission tomography (PET)
Authors: Kaufman Jason A. , Phillips‐Conroy Jane E. , Black Kevin J. , Perlmutter Joel S.
Published: July 2003

The analysis of structural brain asymmetry has been a focal point in anthropological theories of human brain evolution and the development of lateralized behaviors. While physiological brain asymmetries have been documented for humans and animals presenting with pathological conditions or under certain activation tasks, published studies on baseline asymmetries in healthy individuals have produced conflicting results. We tested for the presence of cerebral blood flow asymmetries in 7 healthy, sedated baboons using positron emission tomography, a method of in vivo autoradiography. Five of the 7 baboons exhibited hemispheric asymmetries in which left‐sided flow was significantly greater than right‐sided flow. Furthermore, the degree of asymmetry in 8 of 24 brain regions was found to be significantly correlated with age; older individuals exhibited a higher degree of asymmetry than younger individuals. Cerebral blood flow itself was uncorrelated with age, and differences between males and females were not significant. Am J Phys Anthropol, 2003. © 2003 Wiley‐Liss, Inc.
Mitochondrial DNA sequence from an enigmatic gorilla population (Gorilla gorilla uellensis)
Authors: Hofreiter Michael , Siedel Heike , Van Neer Wim , Vigilant Linda
Published: July 2003

Although today gorillas are found in only two widely separate, discontinuous western and eastern African populations, rumors of the existence of an additional gorilla population in central Africa have inspired recent unsuccessful field expeditions in search of the “mystery ape” termed Gorilla gorilla uellensis. Such a gorilla population would have considerable conservation and scientific interest, and would presumably have descended from a population of gorillas that was thought to exist until the end of the 19th century on the Uele River in the current‐day Democratic Republic of Congo. However, the sole evidence for the existence of these gorillas is three skulls and one mandible brought to the Royal Museum for Central Africa (Tervuren, Belgium) in 1898. We determined a mitochondrial DNA sequence from one of these specimens and compared it to sequences from other gorillas. Contrary to expectations, the sequence obtained did not exhibit the phylogenetic distinctiveness typical of a representative of a peripheral isolated population. Rather, the results suggest a scenario in which the museum specimens did not originally derive from the northern Congo, but were brought from the area of current distribution of western gorillas to that location; the subsequent discovery and collection of the specimens there gave rise to the false inference of a local gorilla population. Am J Phys Anthropol 121:000–000, 2003. © 2003 Wiley‐Liss, Inc.
Osteon remodeling dynamics in the Cayo Santiago Macaca mulatta: The effect of matriline
Authors: Havill Lorena M.
Published: July 2003

At the microstructural level, bones remodel throughout life. This process is recorded in bone cortex as osteons. A more comprehensive understanding of the interaction between genetic regulation and environmental factors in osteon remodeling will increase the value of this skeletal record and enable more accurate reconstruction of individual life histories. The purpose of this study was to examine the contribution of maternal lineage to normal age and sex variation in osteon remodeling dynamics in Macaca mulatta. Femoral cross sections from 57 Cayo Santiago‐derived rhesus macaques representing five matrilines were examined to evaluate the effect of genetic relatedness on osteon remodeling dynamics. Analysis of variance revealed an effect of maternal lineage on osteon area and Haversian canal area. The other variables did not differ significantly among matrilines. Analysis of covariance revealed no significant interactions among age, sex, and matriline for any of the microstructural variables. Am J Phys Anthropol 121:000–000, 2003. © 2003 Wiley‐Liss, Inc.