bluuebunny/crossref_metadata_2025 huggingface dataset:
Asymptomatic and late‐onset ornithine transcarbamylase (OTC) deficiency in males of a five‐generation family, caused by an A208T mutation
Authors: van Diggelen O.P. , Zaremba J. , He Wang , Keulemans J. L. M. , Boer A. M. , Reuser A. J. J. , Ausems M. G. E. M. , Smeitink J. A. M. , Kowalczyk J. , Pronicka E. , Rokicki D. , Tarnowska‐Dziduszko E. , Kneppers A. L. J. , Bakker E.
Published: July 2010

In a large five‐generation Polish family, late‐onset ornithine transcarbamylase (OTC) deficiency in males segregated with the missense mutation Ala208Thr (A208T), and all heterozygous females were asymptomatic. No other mutations were found in the coding sequences and intron‐exon boundaries of the OTC gene. Surprisingly, the mutation originated from the great‐grandfather of the index patient who died at age 59 of liver carcinoma. He never had dietary restrictions or hyperammonemic spells throughout life and appears to be the oldest male reported with OTC deficiency. The index patient had a severe OTC deficiency (3% of normal). Eight males died suddenly at ages 4 months to 23 years (average 14 years) after a foudroyant episode triggered by a common infection. The patients remained undiagnosed for 28 years because a metabolic defect was not considered to be the cause of the acute episodes. Recognition of the familial pattern of inheritance was initially unnoticed since the patients were admitted to eight different hospitals. DNA analysis predicted that two ‘healthy’ boys also had OTC deficiency, which was confirmed by abnormal results of allopurinol challenge tests. Initial suspicion of OTC deficiency in such families is complicated, since symptoms can develop at any age, or even remain absent. This obscures the typical pattern of X‐linked inheritance in small families.
Dermatological manifestations of 71 Down syndrome children admitted to a clinical genetics unit
Authors: Erics M. , Balci Sevim , Atakan Nilgün
Published: July 2010

Seventy‐one children with Down syndrome who were admitted consecutively to Hacettepe University Children's Hospital Genetics Department were examined for skin disorders. None of the patients suffered directly from skin disorders. All were living with their families and had approximately similar living conditions. There were 29 children with palmoplantar hyperkeratosis (40.8%), seven with xerosis (9.8%), 22 with seborrheic dermatitis (30.9%), 14 with fissured tongue (20%), eight with geographic tongue (11.2%), and nine with cutis marmorata (12.6%). Nine had normal skin findings. Since palmoplantar hyperkeratosis may be a result of vitamin A deficiency, the serum vitamin A levels of these patients were evaluated. There was no statistical difference between vitamin A levels of the children with Down syndrome and the control group.
Routine clinical application of the FRAXA Pfu PCR assay: limits and utility
Authors: Condorelli D. F. , Milana G. , Dell'Albani P. , Roccazzello A. M. , Insirello E. , Pavone L. , Mollica F.
Published: July 2010

Fragile X genotype is characterized by the excessive amplification of an unstable region of DNA: a trinucleotide repeat CGG of variable copy number present in the FRAXA locus. Methods based on polymerase chain reaction (PCR) amplification of the CGG repeat region could facilitate the development of a rapid screening assay. Unfortunately, amplification across CGG repeats can be inefficient and unreliable due to their 100% G+C base composition. The utility of the exonuclease‐deficient Pfu polymerase for amplification and detection of the CGG repeats at the FRAXA locus has been reported. In the present study we analysed the utility of a Pfu PCR assay as a rapid initial screening method to rule out a diagnosis of fragile X syndrome in males with mental retardation. Affected males did not show any amplification products or a smear of amplification products between 350 and 550 bp. Only 10% of affected male samples did not show any amplification products, while the vast majority showed the amplification smear. The amplification smears represent a serious drawback of the method, since they cannot be distinguished from the amplification products of normal samples after separation in 1 % agarose gel. Several modifications of the PCR conditions were attempted to eliminate this problem, but none was appropriate for clinical applications. However, the problem was easily solved by using a higher resolution electro‐phoretic system that allows a clear distinction of normal bands from pathological smears. We tested the specificity of the Pfu PCR assay, followed by an improved MetaPhor gel electrophoretic separation of PCR products, on 50 samples from normal males and 24 samples from affected males. The results showed that this method is a rapid, sensitive and specific assay for the exclusion of fragile X syndrome diagnosis in mentally retarded males.
Is intensive follow‐up for early detection of tumors effective in children with Beckwith‐Wiedemann syndrome?
Authors: Cataldo Andrea Di , Haupt Riccardo , Fabietti Paola , Schilirò Gino
Published: July 2010

Two cases of Beckwith‐Wiedemann syndrome who developed malignant tumor and eventually died are reported. The patients followed two different screening programs for early detection of cancer, and the most appropriate schedule of follow‐up in carriers of this syndrome is discussed.
Phenotypic characterization of a patient homozygous for the D558N LDL receptor gene mutation
Authors: Jensen H. K. , Jensen L. G. , Heath F. , Melsen F. , Hansen P. S. , Meinertz H. , Bolund L. , Gregersen N. , Færgeman O.
Published: July 2010

We describe the clinical, biochemical, and genetic features of a patient with true homozygous familial hypercholesterolemia due to the D558N low‐density lipoprotein receptor gene mutation, previously designated FH Cincinnati‐4. Functional flow‐cytometric analysis of the LDL receptorR protein on upregulated EB V‐transformed lymphocytes indicated reduction of the number of receptors on the cell surface by 87% and reduction of receptor activity by 89% compared to control cells. With drugs and a portacaval shunt operation, performed when the patient was 15 years old, serum cholesterol was reduced from about 28 to about 15 mmol/l. He died at the age of 32 of a myocardial infarction. The autopsy showed generalized atherosclerosis, especially in the coronary arteries, which were severely stenosed proximally. A rare finding was a large intracranial xanthoma that apparently had been asymptomatic.
A case of pycnodysostosis with growth hormone deficiency
Authors: Darcan Siikran , Akisü Mete , Taneli Baha , Kendir Gaye
Published: July 2010

Pycnodysostosis is a skeletal dysplasia characterized by short stature. Treatment of pycnodysostosis with growth hormone (GH) has not been reported so far. We describe a case of pycnodysostosis with growth hormone deficiency in addition to low mean insulin‐lüce growth factor 1 (IGF‐1) concentration. Complete GH deficiency was determined by two pharmacological provocative tests (insulin and L‐dopa). A good height‐velocity response was obtained after GH replacement treatment. Pycnodysostosis with GH deficiency and replacement therapy have not been reported previously, to the best of our knowledge.
Subtle translocation (18;21) confirmed by FISH in a patient with Down syndrome
Authors: Knight L. A. , Yong M.H. , Tan M. , LNg I. S.
Published: July 2010

The patient presented with the typical features of Down syndrome: hypotonia, brachycephaly, flattened occiput, bilateral prominent medical epican‐thic folds, flat nasal bridge, protruding tongue, low‐set dysplastic ears, short broad hands, bilateral clinodactyly and simian crease. The karyotype of this child was originally reported as normal. High‐resolution chromosomes revealed extra material on the long arm of chromosome 18. The mother's karyotype showed a reciprocal translocation between the long arm of 18 and the long arm of 21 at band q23 and q22.1, respectively. FISH performed separately with two different 21q cosmid probes gave two signals on the mother's metaphases and three signals on the prob‐and. These findings confirmed that the proband is trisomic for the long arm of chromosome 21 at loci D21S65 and D21S19.
Rapid detection of a mutation hot‐spot in the human androgen receptor
Authors: Malmgren Helena , Gustavsson Jan , Tuvemo Torsten , Dahl Niklas
Published: July 2010

Mutations of the human androgen receptor gene may disturb sexual development in males, and are inherited as an X‐linked recessive trait. The vast majority of the mutations are familial. We have identified a large kindred with complete androgen insensitivity syndrome (CAIS) without detectable androgen‐binding in genital skin fibroblasts. A single nucleotide substitution (C‐to‐T transition) was identified, resulting in an Arg855 to Cys in the androgen binding domain. To date, four independent CAIS families have been reported with this specific mutation that coincides with the propensity of cytosines at CpG dinucleotides to methylate. An allele‐specific oligo‐nucleotide assay was developed that allowed for the rapid and specific identification of this mutation hot‐spot in individuals with androgen receptor incensitivity syndromes.
Siblings with congenital renal tubular acidosis and nerve deafness
Authors: Stoll C. , Gentine A. , Geisert J.
Published: July 2010

Two siblings (a boy and a girl) had congenital renal tubular acidosis (RTA) with nephrocalcinosis. Hearing loss due to nerve deafness was diagnosed at 13 1/2 and 9 years of age, respectively. The parents, who are second cousins, are healthy. They have another boy who is unaffected. This is in accordance with an autosomal recessive gene. The association of RTA and deafness was first noted by Royer in 1967, and so far some 50 cases have been described. The literature is reviewed.
A case report of 46, XX, del (21)(q22) de novo deletion associated with Imerslund‐Grasbeck syndrome
Authors: Celep Figen , Karagüzel Ahmet , Aynaci F. Müjgan , Erduran Erol
Published: July 2010

We describe a 2‐year‐old female patient who had megaloblastic anaemia caused by selective vitamin B12 malabsorption (Imerslund‐Grasbeck syndrome) and del (21)(q22). To our knowledge, this is the first observation of Imerslund‐Grasbeck syndrome associated with del(21)(q22) in the literature.
Nosology of fetal hypokinesia sequence based on CNS abnormalities: is there an Aase‐Smith syndrome?
Authors: David Albert , Nombalais Marie‐Françoise , Rival Jean‐Marie , Verloes Alain
Published: July 2010

Aase‐Smith syndrome (ASS) is usually defined as a dominantly inherited combination of arthrogryposis, Dandy‐Walker malformation and cleft palate. We describe a sporadic case of foetal akinesia with abnormal fossa posterior, fitting the diagnosis of ASS, and discuss the nosology of this entity among syndromes with distal arthrogryposis. ASS shows a “hybrid” phenotype: adults with mild ASS could be classified as distal arthrogryposis, whereas severely affected newborns overlap with the Marden‐Walker phenotype, which is recessively inherited. The specificity of the disorder comes from the coexistence of both forms in the same pedigree, so that ASS appears impossible to diagnose with certitude in sporadic cases. We suggest that the severe expression of ASS is only the extreme but aspecific expression of a dominantly inherited form of distal arthrogryposis. Implications for genetic counselling in distal arthrogryposis are outlined.
Abnormal extracellular matrix in Ehlers‐Danlos syndrome type IV due to the substitution of glycine 934 by glutamic acid in the triple helical domain of type III collagen
Authors: McGrory J. , Weksberg R. , Thorner P. , Cole W. G.
Published: July 2010

A unique substitution of glycine 934 by glutamic acid in the triple helical domain of type III collagen was identified in a proband with Ehlers‐Danlos syndrome type IV. The substitution was due to the transition of G 3302 to A in α 1 (III) cDNA which is encoded by exon 46 of COL3A1. It resulted in a severe deficiency of type III collagen in fibroblast cultures and dermis. Dilatation of the endoplasmic reticulum of the dermal fibroblasts was probably due to the failure of these cells to secrete type III collagen molecules containing one or more mutant α 1(III) chains. The dermal collagen fibrils were narrow, but their constituent type III collagen molecules contained predominantly normal α 1(III) chains. As a result, the major effect of the substitution of glycine 934 by glutamic acid was to severely reduce the amount of normal type III collagen available for the formation of heterotypic collagen fibrils in the extracellular matrix.
Recombination between the postulated CCD/MHE/MHS locus and RYR1 gene markers
Authors: Fagerlund T.H. , Islander G. , Ranklev‐Twetman E. , Berg K.
Published: July 2010

Malignant hyperthermia (MH) susceptibility is considered a subclinical myopathy or a pharmacogenetic trait, and is believed to be closely associated with central core disease (CCD). Data support the notion that MH susceptibility is heterogeneous, with the ryanodine receptor 1 (RYR1) locus on chromosome 19 being one locus harboring a gene that can cause MH susceptibility. The gene for CCD is believed to reside in the locus on chromosome 19. In the family presented here, a girl has CCD, and several close relatives are MH susceptible (MHS). DNA studies conducted on available family members uncovered recombination between the MH susceptibility locus and RYR1 markers. Consequently, if one postulates that the CCD gene in this family resides in the same locus as the MH susceptibility gene, an additional CCD locus different from the RYR1 locus must also be postulated.
The apolipoprotein E gene in Binswanger's disease and vascular dementia
Authors: Higuchi Susumu , Arai Hiroyuki , Nakagawa Takuma , Muramatsu Taro , Sasaki Hidetada , Trojanowski John Q.
Published: July 2010

We investigated the polymorphism of the apolipoprotein E (ApoE) gene using a PCR‐RFLP method in patients with Binswanger's disease (BD), non‐BD vascular dementia, or Alzheimer's disease (AD). The frequency of the e4 allele of the ApoE (ApoE4) in BD patients and non‐BD vascular dementia patients did not differ from that observed in the non‐demented elderly controls, but it was significantly lower than the frequency in AD patients. These results and other recent observations suggest that one or more factors other than the ApoE gene contribute to the pathogenesis of dementia in BD and non‐BD vascular dementia.
Outcomes and process in genetic counselling
Authors: Clarke Angus , Parsons Evelyn , Williams Allison
Published: July 2010

Although it may be simple to evaluate some elements of clinical genetics, it is difficult to evaluate genetic counselling. We review previous studies of the outcomes of genetic counselling; although the methods used may be valid in research studies, there are practical and ethical difficulties in applying them to the measurement of clinical effectiveness in standard practice. No simple measures of outcomes would be suitable. Research evidence will be helpful in deciding what services it is appropriate to offer, and the quality of a service can then be assured by assessing the quality of the clinical process in three ways: 1) adherence to agreed protocols and standards of care; 2) peer review and audit of clinical activity; and 3) ongoing review of the satisfaction of clients and referring physicians with the service. The assessment of client satisfaction will need to be a sophisticated form of retrospective satisfaction with the service provided, and such a scheme has yet to be fully developed.
Rett syndrome in Northern Tuscany (Italy): family tree studies
Authors: Pini Giorgio , Milan Mario , Zappella Michele
Published: July 2010

Four cases of Rett syndrome were ascertained among 19 060 girls born between 1978 and 1990 in a small, defined area of Northern Tuscany (Italy) (prevalence rate of 2.1 per 10 000). A fifth girl with a reported clinical picture of Rett syndrome, born in 1978 and deceased at age 13, was also found. One of the four Rett syndrome cases had a healthy female dizygote twin. Family tree studies going back as far as the 17th century were performed. A number of common ancestors were found in different generations leading to a single family tree encompassing all four Rett syndrome cases. In addition, a Rett girl with preserved speech, born in 1974. was found as part of this family tree. These observations confirm the role of genetic factors in the etiology of Rett syndrome and support the hypothesis that Rett syndrome is a clinically variable phenotype.
Silver‐Russell syndrome and exclusion of uniparental disomy
Authors: Ayala‐Madrigal M. L. , Shaffer L. G. , Ramírez‐Dueñas M. L.
Published: July 2010

Recently, maternal uniparental disomy for the entire chromosome 7 was described in three of 25 Silver‐Russell syndrome sporadic cases, yet the etiology of the remaining cases is unclear. Two cases with Silver‐Russell syndrome and a balanced translocation involving the 17q25 had been reported. We looked for evidence of genomic imprinting due to uniparental disomy 17 in seven patients with sporadic Silver‐Russell syndrome and their parents. Additionally, chromosomes 7, 8, 11 and 20 were studied. Uniparental disomy was ruled out for all these chromosomes in six of seven families; one family was informative only for chromosome 17. Notwithstanding our negative results, it is still possible that uniparental disomy plays a part in this syndrome. A mutation in a Mendelian gene in 17q25 could also account for the Silver‐Russell syndrome etiology.
Tri‐amelia and phocomelia with multiple malformations resembling Roberts syndrome in a fetus: is it a variant or a new syndrome?
Authors: Song Sang‐Yang , Chi Je G.
Published: July 2010

Roberts‐SC phocomelia syndrome is a rare autosomal recessive disorder characterized by morphological anomalies such as limb defects and midfacial clefting, and by premature centromeric division in chromosomal study. Although it has been regarded as a single genetic entity and includes various morphologic defects, babies are being reported nowadays with severe facial defects, tetra‐amelia, and pulmonary abnormality, yet with normal chromosomal findings. We have added a case resembling Roberts syndrome with various congenital anomalies. A gestation with a fetus was terminated at 24 weeks of gestational age because of multiple fetal anomalies. Postmortem examination revealed a severe mid‐facial cleft, tri‐amelia and phocomelia, multiple encephaloceles, protruding and hypoteloric eyes, low‐set ears, atrial septal defect of ostium secundum type, patent ductus arteriosus, bilateral two‐lobed lungs with incomplete location, multiple visceral anomalies, a penis without scrotum, abnormal dermoglyphics, and absence of nipples.
Partial deletion of 18p and partial duplication of 18q caused by a paternal pericentric inversion
Authors: Israëls Trijn , Hoovers Jan , Turpijn Hanne M. , Wijburg Frits A. , Hennekam Raoul C. M.
Published: July 2010

Here we report on a boy with both a partial deletion of chromosome 18p and a partial duplication of chromosome 18q, caused by a paternal pericentric inversion (46, XY, rec(18), dup q, inv(18)(p11.2q21.1)pat). The findings in the patient are compared to those in the literature. The symptoms in the described patient can be explained for the major part by the 18p—and 18q+ syndromes separately. A specific 18p‐/18q+ syndrome cannot be clearly delineated yet. Inspiratory stridor is a symptom that has not been described before in either 18p—or 18q +, but has been found twice before in patients with the combined 18p—/18q+ syndrome.
Increased paternal age in CHARGE association
Authors: Tellier A.L. , Lyonnet S. , Cormier‐Daire V. , de Lonlay P. , Abadie V. , Baumann C. , Bonneau D. , Labrune Ph. , Lacombe D. , Merrer M. Le , Nivelon A. , Philip N. , Briard M. L. , Munnich A.
Published: July 2010

The acronym CHARGE refers to a non‐random clustering of congenital malformations whose cause remains unknown. Here, we report on a series of 41 patients and find a significant increase in mean paternal age of birth of CHARGE patients (33.7±8 years) compared with the control population (30.8±5 years). In contrast, maternal age was not statistically different in patients and controls. These data suggest the possible role of a dominant mutation or, less likely, a subtle chromosomal abnormality in CHARGE association.
Attitudes towards termination for fetal abnormality: comparisons in three European countries
Authors: Drake Harriet , Reid Margaret , Marteau Theresa
Published: July 2010

Attitudes towards termination for a range of genetic conditions were studied in health professionals and lay people in three European countries: Germany, Portugal and the UK. The health professionals consisted of geneticists in all countries and additionally obstetricians from Portugal and the UK. The lay persons consisted of pregnant women, and male and female non‐medical university employees. In all, more than 1,700 study participants completed questionnaires. Overall, health professionals were more likely than the lay persons to report that they would opt for termination following diagnosis of a fetal abnormality. Differences were found between countries and study groups. German respondents were least likely to report that they would undergo termination in the case of a fetal abnormality while Portuguese respondents were most likely to report that they would undergo a termination. Further studies are needed to determine first the extent to which differences between health professionals and lay samples reflect a difference in perception of disability, including tolerance of having a child with a disability; and second, whether such differences result in health professionals presenting termination of pregnancy in a way that is not concordant with patients' value systems.
Maternal non‐recognition of Down syndrome in black South African infants
Authors: Christianson A. L. , Kromberg J. G. R.
Published: July 2010

Down syndrome (DS), one of the commonest causes of mental retardation in Caucasoids, has only rarely been described in Africa. In previous studies it was suggested that there may be clinical difficulties in making the diagnosis in African neonates. In the present study data were collected by means of a questionnaire administered partly before and partly after a genetic counselling session, to 35 mothers of African infants with DS. The results show that 83% of these mothers did not recognise any facial difference between their affected infant and other normal infants and 57% did not observe any other physical differences. After counselling, 40% of the sample still did not accept that their infant was different from other newborns. Only one mother was aware of infants with similar characteristics. These findings suggest that if mothers themselves cannot see the differences between their DS children and normal children, clinical diagnosis based on physical stigmata may be difficult. Furthermore, acceptance of the diagnosis may be retarded until delayed milestones can be observed in the affected infants.
How often has Lp(a) evolved?
Authors: Lawn Richard M.
Published: July 2010

The lipoprotein Lp(a) is associated with increased risk of atherosclerosis and myocardial infarction in humans. Lp(a) is mostly confined to primate species, due to the limited phylogenetic distribution of its distinguishing protein component, apolipoprotein(a) which is a close homolog of plasminogen. The known properties of Lp(a) are reviewed here. Many of these derive from the ability of Lp(a) to bind to the same substrates as plasminogen. A possible new animal model of Lp(a) is the hedgehog, which contains an Lp(a)‐like particle that is the apparent product of independent evolution of a multi‐kringle, apolipoprotein(a)‐like protein by duplication and modification of portions of the hedgehog plasminogen gene.
Two novel mutations in the LDL receptor gene: common causes of familial hypercholesterolemia in a Spanish population
Authors: Cenarro A. , Jensen H. K. , Civeira F. , Casao E. , Ferrando J. , González‐Bonillo J. , Pocovi M. , Gregersen N.
Published: July 2010

In our investigation of the LDL receptor gene in 30 Spanish patients, who were clinically diagnosed as heterozygous FH and were unrelated, we have applied single strand conformation polymorphism (SSCP) analysis and solid‐phase sequencing. We identified two novel pathogenic mutations accounting for one third of the FH in this patient sample. Six patients were found to have a G to T substitution at nucleotide position 91 in exon 2 that results in a stop codon, E10X. Four patients were found to have a G deletion at nucleotide 518 in exon 4, causing a translational frameshift and a stop codon, 518delG. We have developed two polymerase chain reaction (PCR) based assays to detect easily these two mutations in all the available family members. We found fourteen E10X mutation carriers and eighteen 518delG mutation carriers. There was no statistically significant difference in mean lipid levels between carriers of these two mutations. Furthermore, haplotype analysis revealed that all E10X mutation carriers had the allele determined by TaqI‐, Stul+, Avall+, Ncol‐ and all 518delG mutation carriers had the haplotype TaqI‐, Stul+, Avall‐, NcoI+. This indicates that both mutations may have been inherited from common ancestors, respectively.
A comparative study of X‐inactivation in Rett syndrome probands and control subjects
Authors: Webb T. , Watkiss E.
Published: July 2010

X‐inactivation has been studied in a series of monozygotic female twins and their female relatives by a PCR method which detects methylation at the androgen receptor locus (HUMARA). The results obtained are compared to those from an earlier study employing probe M27β which detects locus DXS255. Analysis of X‐inactivation in girls with Rett syndrome and their mothers by four different methods did not indicate a direct relationship between non‐random inactivation of the X‐chromosome and the presence of the disease with the exception that any skewing detected in the probands tended to favour the preferential inactivation of the paternally inherited X‐chromosome. No evidence for the involvement of uniparental disomy in the etiology of the disease was found.
Multiple congenital malformations in an infant prenatally diagnosed with mosaicism for dup(1q) and del(Xq)
Authors: Wells Steven R. , Kuller Jeffrey A. , Rao Kathleen W. , Aylsworth Arthur S.
Published: July 2010

After ultrasound diagnosis of a fetus with severe hydrocephalus and Dandy‐Walker malformation, amniocentesis revealed chromosomal mosaicism for dup(1q) and del(Xq). The neonate had dysmorphic facial features, vertebral abnormalities, and pulmonary hypoplasia, and expired shortly after birth. This report confirms the poor prognosis reported for partial trisomies involving the long arm of chromosome number 1.
Bloom's syndrome. XIX. Cytogenetic and population evidence for genetic heterogeneity
Authors: German James , Ellis Nathan A. , Proytcheva Maria
Published: July 2010

Cells with abnormally high rates of sister‐chromatid exchange (SCE) are uniquely characteristic of Bloom's syndrome (BS). However, in one in five persons a minor population of cells with a low‐SCE phenotype circulates in the blood. The origin and significance of the low‐SCE cells in BS have never been understood, although they are assumed to arise by somatic mutation. In the present investigation, the enigmatic high‐SCE/low‐SCE mosaicism was investigated by comparing the incidence in several subpopulations of persons in the Bloom's Syndrome Registry who exhibit the two types of cells, and a striking negative correlation emerged: in persons with BS whose parents share a common ancestor, the case in approximately half of registered persons, low‐SCE cells are found only rarely; conversely, the mosaicism occurs almost exclusively in persons with BS whose parents are not known to share a common ancestor. Because those who share a common ancestor are predominantly homozygous‐by‐descent at the mutated BS locus, the negative correlation is interpreted to mean that the emergence of low‐SCE cells in BS in some way depends on the pre‐existence of compound heterozygosity. A corollary to this is that BS is genetically heterogeneous.
Cohen syndrome: the clinical symptoms and stigmata at a young age
Authors: Fryns Jean‐Pierre , Legius Eric , Devriendt Koen , Meire Françoise , Standaert Lieve , Baten Emiel , Van den Berghe Herman
Published: July 2010

We present the clinical findings and follow‐up data of four female children with Cohen syndrome, two sisters and one pair of dizygotic female twins. The most characteristic findings from birth on were as follows:

Low‐normal growth parameters at birth.

Mild hypotonia and evidence of progressive microcephaly with narrow forehead in the first year of life.

Neutropenia was present from the beginning, remained unchanged over the years and is not associated with higher susceptibility to infections.

Autistic behavior and severe psychomotor retardation up to the age of 2 years. At that age the ocular anomalies with high‐grade myopia and chorioretinal dystrophy were diagnosed. Correction of the myopia resulted in a marked catch‐up in psychomotor development.

After the age of 6 years facial stigmata became more evident with short philtrum of the upper lip and broad and large upper incisors.

Tendency to truncular obesity with rest hypotonia and poor muscle development after the ages of 6 to 8 years.

The clinical findings and follow‐up data in the present four children with Cohen syndrome illustrate that the diagnosis of Cohen syndrome in infancy is very difficult.
Coexistence of gene mutations causing Fabry disease and Duchenne muscular dystrophy in a Japanese boy
Authors: Takenaka Toshihiro , Sakuraba Hitoshi , Hashimoto Kiyoshi , Fujino Osamu , Fujita Takehisa , Tanaka Hiromitsu , Suzuki Yoshiyuki
Published: July 2010

Both Fabry disease and Duchenne muscular dystrophy were confirmed by gene analysis in a Japanese boy. He developed muscle weakness at 4 years of age. A muscle biopsy revealed lamellar inclusion bodies in vascular endothelial cells in addition to myopathic changes with negative dystrophin staining. The myopathic symptoms progressed, and he died of pneumonia at 24 years of age. No clinical manifestations of Fabry disease were observed except for hypohidrosis and angiokeratoma. However, glycolipid accumulation was found in biopsied renal tissue. Molecular analysis demonstrated two gene mutations; a novel single‐base deletion in exon 3 of the α‐galactosidase gene, and a dystrophin gene deletion extending from exon 46 to exon 50. His mother was confirmed to be heterozygous for both gene deletions.
A mild form of Roberts/SC phocomelia syndrome with asymmetrical reduction of the upper limbs
Authors: Concolino D. , Sperlì D. , Cinti R. , Strisciuglio P. , Andria G.
Published: July 2010

Roberts syndrome is a rare autosomal recessive condition characterized by growth retardation, cranio‐facial abnormalities and symmetrical limb reduction of variable severity. Most patients with Roberts syndrome show a typical cytogenetic finding known as “Roberts syndrome effect”. We describe a 4‐month‐old patient with a mild form of this syndrome, who presented with an asymmetrical reduction of the right upper limb.
Interstitial 6q deletion and Prader‐Willi‐like phenotype
Authors: Stein Constance K. , Stred Susan E. , Thomson Laura L. , Smith Frank C. , Hoo Joe J.
Published: July 2010

A third case of an interstitial deletion of the long arm of chromosome 6 with clinical features mimicking Prader‐Willi syndrome (PWS) is presented. Although preliminary clinical evaluation in each case suggested PWS, further review revealed that the features in all three cases are not completely compatible with the characteristic findings in Prader‐Willi syndrome. Furthermore, the deletions in the three cases do not show a consistent region of overlap. Consequently, no particular band or region in 6q can be defined as associated widi obesity. However, our findings confirm the suggestion of Villa et al. in 1995, that individuals with a PWS phenotype who are cytogenetically and molecularly negative for a deletion of 15q11‐q13 should be examined for a deletion of 6q.
Fibular dimelia and mirror foot without associated anomalies
Authors: Bayram Hüseyin , Herdem Mustafa , Temoçin A. Kübra
Published: July 2010

Fibular dimelia with mirror foot is a rare anomaly that may be associated with additional anomalies such as ulnar dimelia, facial abnormalities and sacrococcygeal teratoma. We report a female child with unilateral tibial aplasia, ipsilateral duplication of fibula and calcaneus, and mirror Polydactyly of the foot without associated abnormalities.
Alopecia‐mental retardation syndrome associated with convulsions and hypergonadotropic hypogonadism
Authors: Devriendt Koenraad , Van den Berghe Herman , Fryns Jean‐Pierre
Published: July 2010

We report two brothers with congenital total alopecia, mental retardation, childhood convulsions and hypergonadotropic hypogonadism. This association has not previously been reported and probably represents a new autosomal recessive condition.
Homozygosity and heterozygosity for the transthyretin Leu64 mutation: clinical, biochemical and molecular findings
Authors: Ferlini Alessandra , Salvi Fabrizio , Uncini Antonino , El‐Chami Jasmin , Winter Pia , Altland Klaus , Repetto Monica , Littardi Massimo , Campoleoni Andrea , Vezzoni Paolo , Patrosso Maria Cristina
Published: July 2010

Transthyretin gene point mutations cause hereditary amyloidosis with an autosomal dominant pattern of inheritance. The disease usually manifests itself in heterozygous patients, although a few homozygotes have been reported. We describe two unrelated patients carrying the Leu64 mutation, one of whom presents a homozygous genotype (Family B). Homozygosity was confirmed by sequence analysis, RG‐PCR and double one‐dimensional electrophoresis of the plasma protein. Although the clinical picture of the homozygous patient of Family B was more severe than that shown by the heterozygous members of Family A, the variability often displayed by FAP patients does not allow any firm conclusion about the role of homozygosity in the seriousness of the disease.
Generalized osteoporosis in a patient with oculocutaneous hypopigmentation syndrome (OOCHS), without cerebral defects A new syndrome?
Authors: Hernández A. , Nazará Z. , Reynoso M. C. , Sarralde A. , Bobadilla L. , Fragoso R.
Published: July 2010

An 8‐year‐old male patient presented a unique pattern of congenital anomalies. Prominent findings included a combination of severe osteoporosis and congenital oculocutaneous hypopigmentation. The patient may represent a hitherto undescribed syndrome of unknown etiology.
G542X mutation in Mexican cystic fibrosis patients
Authors: Villarreal Maria Teresa , Chávez Margarita , Lezana José Luis , Cuevas Francisco , Carnevale Alessandra , Códova Emilio , Ma Rosa , Angel Del , Orozco Lorena
Published: July 2010

We analyzed the frequency of the G542X mutation in a sample of 76 Mexican cystic fibrosis patients and the genotype‐phenotype correlation. The mutation was screened using PCR‐mediated site‐directed mutagenesis, and was present on 7.2% of the CF chromosomes. This frequency is significantly higher than the worldwide frequency according to the Cystic Fibrosis Genetic Analysis Consortium (3.4%, p<0.01), and similar to that reported in Spain (8%), which is in accordance with the ethnic origin of the Mexican population. All patients carrying G542X on at least one allele had mild to moderate pulmonary disease. In patients with hepatobiliary involvement, the frequency of G542X chromosomes was higher than the frequency of the mutation in all the Mexican CF chromosomes.
Neuropsychological aspects of Marfan syndrome
Authors: Lannoo E. , Paepe A. De , Leroy B. , Thiery E.
Published: July 2010

We evaluated the neuropsychological status of 13 adult patients with Marfan syndrome. All subjects were administered the same neuropsychological test battery that included nine measures covering a broad range of cognitive abilities such as attention and concentration, learning and memory, and verbal and non‐verbal abilities. Compared to a control group of 13 normal healthy subjects matched for sex, age and verbal intelligence, Marfan patients only performed significantly worse on tests measuring sustained visual attention and visuoconstruction. Although these tests use visual material and depend on visual perception and processing, the visual acuity problems associated with the syndrome could not explain these differences, nor could the use of beta‐blocking medication or the presence of joint hypermobility. The findings suggest that problems with sustained visual attention and visuoconstruction may be present in Marfan syndrome over and above visual acuity problems and other phenomena associated with the disease. Further research on the neuropsychological aspects of Marfan syndrome is needed, using larger patient groups and more adequate control groups such as non‐affected siblings and matched controls with similar visual impairment.
Identification of two apolipoprotein variants, A‐I Karatsu (Tyr 100 → His) and A‐I Kurume (His 162 → Gin)
Authors: Moriyama Kengo , Sasaki Jun , Matsunaga Akira , Takada Yoichi , Kagimoto Masaaki , Arakawa Kikuo
Published: July 2010

We identified two apolipoprotein (apo) A‐I variants, using isoelectric focusing gel electrophoresis: apo A‐I Karatsu, which had a relative charge of+ 1 compared to normal apo A‐I4, and apo A‐I Kurume, which had a relative charge of ‐1. Direct sequence analysis of the PCR‐amplified DNA from the proband of apo A‐I Karatsu revealed a single substitution of tyrosine (TAC) for histidine (CAC) at position 100. Sequence analysis of apo A‐I Kurume revealed a single substitution of histidine (CAT) for glutamine (CAG) at position 162. Probands of these two mutants and limited family study showed no accelerated atherosclerosis.
Screening for coeliac disease as a possible maternal risk factor for neural tube defect
Authors: Dickey W. , Stewart F. , Nelson J. , McBreen G. , McMillan S. A. , Porter K. G.
Published: July 2010

Coeliac disease is an important cause of malabsorption, particularly of folic acid, in adults. We investigated the possibility that it might be a maternal risk factor for neural tube defect (NTD)‐associated pregnancy by screening affected mothers using serum endomysial antibody (EmA) which has high sensitivity and specificity for coeliac disease. One (1.6%) of 60 patients was EmA positive and had a diagnosis of coeliac disease confirmed by the finding of villous atrophy on jejunal biopsy. In conclusion, the majority of NTD‐associated pregnancies are not associated with maternal coeliac disease and our study is additional evidence that abnormalities of folic acid metabolism rather than absorption are the most important risk factors for NTD. Further studies are needed to determine whether the coeliac disease prevalence among women with NTD‐affected pregnancy is higher than that of the general population.
Symmetry of neurological signs in Pakistani patients with probable inherited spastic cerebral palsy
Authors: Mitchell Simon , Bundey Sarah
Published: July 2010

Seven Pakistani families are described with children manifesting a spastic cerebral palsy‐like syndrome. One feature common to all affected patients was symmetry of neurological signs. Only one of these families had been offered genetic counselling and fewer than half had undergone clinical investigations. The importance of symmetry of neurological signs is reaffirmed as an indicator of a probable genetic aetiology in children with spasticity. Many families at risk of recurrence are not offered appropriate genetic advice, and some children with potentially diagnosable conditions are given a label of cerebral palsy without investigation of possible underlying inherited disorders.
The role of the apolipoprotein E polymorphism in the prediction of coronary artery disease age of onset
Authors: Moore Jason H. , Reilly Sharon L , Ferrell Robert E. , Sing Charles F.
Published: July 2010

We investigated the role of the apolipoprotein (Apo) E polymorphism in the prediction of CAD age of onset in a sample of unrelated living male (n = 65) and female (n = 54) Caucasian subjects diagnosed with CAD. Cumulative distributions of age at the first diagnosis of CAD were estimated for each Apo E genotype and tested for homogeneity using the log‐rank test. The Apo e33 genotype was used as a reference group for all hypothesis tests. Analyses were performed separately in males and females. We found evidence suggesting that the presence of the Apo s32 genotype in males is associated with a significantly earlier CAD age of onset. These results suggest that the Apo E polymorphism may be a gender‐specific predictor of CAD age of onset.
Genetic variation of the angiotensin‐converting enzyme gene: increased frequency of the insertion allele in Koreans
Authors: Hong S. H. , Kang B. Y. , Park W. H. , Kim J. Q. , Lee C. C.
Published: July 2010

In view of the clinical importance of angiotensin‐converting enzyme (ACE) as a major marker for cardiovascular diseases, we investigated insertion/deletion (I/D) polymorphism of the ACE gene in Koreans. Genotype frequencies were examined by polymerase chain reaction in 171 patients with coronary artery disease (CAD) and 120 healthy subjects. Allele frequencies of ACE polymorphism in Koreans were not significantly different between patient and control groups. In addition, association between ACE genotypes and the number of stenosed coronary arteries was not detected. ACE genotypes in the CAD group were not associated with body mass index and plasma lipid levels. Thus, our results suggest that, at least in Koreans, I/D polymorphism of the gene is unlikely to be a useful marker for CAD subjects. However, the I allele frequency of Koreans (0.58) was higher than that of Caucasian populations (0.47) but lower than that of Samoan (0.91) and Yanomami (0.85) populations. Here, we discuss the clinical and ethnic importance of ACE polymorphism.
An autosomal recessive adducted thumb‐club foot syndrome observed in Turkish cousins
Authors: Dundar Munis , Demiryilmaz Fatma , Demiryilmaz Ilhan , Kumandas Sefer , Erkilic Kuddusi , Kendirci Mustafa , Tuncel Mehmet , Ozyazgan Isilay , Tolmie John L
Published: July 2010

Male and female cousins, the offspring of consanguineous Turkish parents, have been affected by a hitherto unreported combination of problems comprising moderate to severe psychomotor developmental delay, ocular anterior chamber abnormality, facial dysmorphisms (broad, bossed forehead, late‐closing fontanelle, telecanthus, downslanting palpebral fissures, posteriorly rotated ears, downturned angles of mouth), arachnodactyly and distal arthrogryposis with severely adducted thumbs and club feet. This striking phenotype has some similarities with the multiple pterygium syndrome (Escobar syndrome), but it most likely represents a distinct condition caused by an autosomal recessive gene defect.
Two mosaic‐YY males carrying asymmetric Y chromosomes
Authors: Zelante L. , Dallapiccola B. , Calvano S. , Memeo E. , Gasparini P. , Simi P. , Rossi S. , Finelli P. , Rocchi M. , Archidiacono N.
Published: July 2010

Two patients were referred because of oligospermia and azospermia, respectively. Karyotypic analysis revealed two mosaic‐YY males carrying asymmetric Y chromosomes. To our knowledge, no instance of double unequal Y chromosomes has been reported so far in human males. Results of fluorescent in situ hybridization (FISH) studies in spermatozoa from one of these patients revealed a significantly high number of hyperaploid spermatozoa.
Paracentric inversion of chromosome 9 with schizoaffective disorder
Authors: Inayama Yasuhiro , Yoneda Hiroshi , Fukushima Kentaro , Sakai Jun , Asaba Hiroyuki , Sakai Toshiaki
Published: July 2010

A 36‐year‐old man with schizoaffective disorder was found to have a de novo 46 XY inv (9) (q31.2q34.3). Phenotypical abnormalities are short stature, depressed nasal bridge, hypertelorism and slender shoulders. Paracentric inversion of chromosome 9 is a rare chromosome aberration. This case suggests a new candidate region related to schizoaffective disorder.
Congenital intractable diarrhea of infancy in Iraqi Jews
Authors: Straussberg Rachel , Shapiro Rivka , Amir Jacob , Yonash Anita , Rachmel Avinoam , Bisset William M. , Varsano Itzhak
Published: July 2010

We report on five patients who presented with intractable diarrhea starting during the first days of life. The patients belonged to four families of Iraqi Jewish origin. Autosomal recessive inheritance is suggested by parental consanguinity in three families and recurrence in another sib in one family. The patients were all born after uneventful pregnancy and labor, with birth weight in the normal range. There were no dysmorphic features. Three patients were breast fed. Diarrhea started between the first and eighth day of life. Diarrhea was of the secretory type. No pathogen was cultured from the stool. Jejunal biopsies performed on all patients ranged from normal to severe partial villous atrophy. The patients received different drug regimens with no beneficial effect and all are dependent on TPN. These findings and the common ethnic origin of the patients suggest that these patients have the same syndrome of congenital intractable diarrhea. No similar cases are known in other ethnic groups in Israel, suggesting a possibility of high gene frequency among the Jews of Iraqi origin.
Clinical variability of tetrasomy 12p
Authors: Schaefer G. B. , Jochar A. , Muneer R. , Sanger W. G.
Published: July 2010

We describe five patients with tetrasomy 12p (one previously reported). These patients exhibit a very wide range of phenotypic features from that of classic Pallister‐Killian syndrome to only mild learning disabilities with pigmentary skin changes. As such, these cases highlight the fact that tetrasomy 12p [i(12p)] and Pallister‐Killian syndrome are not synonymous, although this combination of genotype and phenotype is often seen. This information is especially important in prenatally ascertained i(12p). The full spectrum of phenotypic possibilities associated with this chromosome aneuploidy should be discussed in prenatal counseling.
Genetic mapping using fluorescent quantification of allele frequencies in pooled DNA loaded by solid support
Authors: Graff Caroline , Persson Anja , Ulfendahi Per Johan , Wahlberg Johan , Wadelius Claes
Published: July 2010

An efficient and labour‐saving method for fragment analysis in linkage studies using biotinylated primers and streptavidin‐coated combs is presented. The level of streptavidin attached to the combs was used to control the amount of immobilised material. Thus, the need for titration of PCR products to fit the dynamic range of the sequencer was reduced. The method was used to investigate the possibility of quantitating allele frequencies in pools of DNA from family members with the autosomal dominant eye disorder Best's macular dystrophy. The method allowed the detection of one unique allele in a background of 39 other alleles. Using independent datasets, it was further found that the method was able to detect distorted allele frequencies in affected individuals of one family as compared to reference individuals, for markers located more than 30 cM from the disease locus. It was found that this procedure is a powerful alternative to conventional linkage analysis and the method may prove useful in a genome scan for genes involved in complex disorders.