bluuebunny/crossref_metadata_2025 huggingface dataset:
Recent experience in prenatal fra(X) detection
Authors: Jenkins Edmund C. , Brown W. Ted , Krawczun Michael S. , Duncan Charlotte J. , Lele Kusum P. , Cantu Eduardo S. , Schonberg Steven , Golbus Mitchell S. , Sekhon Gurbax S. , Stark Sandra , Kunaporn Suphat , Silverman Wayne P.
Published: June 2005

At least 35 cases of prenatal fra(X) diagnosis have been confirmed and reported. Amniotic fluid, fetal blood and chorion ‐ic villus samples have exhibited fra(X) (q27.3) in cultures from 26 males and 9 females. Here we have detected fra(X) in female and male amniotic fluid specimens, AF1/fra(X),X and AF2/fra(X), Y, respectively, and a male CVS/fra (X), Y1 using both FUdR and excess thymidine (THY) to demonstrate the marker chromosome. Both FUdR and THY detected fra(X) and usually FUdR was superior to THY with the exception of placental cultures. It was important to examine more than one culture per protocol since no fra(X) was observed in one AF2 FUdR culture while another exhibited 19.2% expression. Similarly, confirmation studies in lung fibroblast cultures for AF2 exhibited 4.3% fra(X) in one 1ab while another found negative results. A similar observation in whole blood cultures was also made recently by us. In addition, we have recently experienced our first false negative fra(X), X prenatal diagnosis. We have observed another case where only one cellin 300 exhibited fra(X) where the male fetus was 50% at‐risk and was referred to us after the 20th week of gestation by sonography. On the basis of our experience we recommend the following: (1) the excess THY fra(X) induction system is effective but not superior to FUdR; (2) at least two duplicate cultures per induction system should be analyzed forthe marker chromosome to avoid the possibility of false‐negative diagnosis; (3) where fra(X) is not demonstrated or is present in very low frequencies in CVS and/or amniotic fluid cultures, complementary DNA marker studies and/or fetal blood cultures must be made available; (4) gestational age dating by ultrasonography is recommended as early as possible.
Constitutive fragile sites in fra(X) individuals
Authors: Jenkins Edmund C. , Lele Kusum P. , Krawczun Michael S. , Gross Anne C. , Duncan Charlotte J. , Brown W. Ted
Published: June 2005

Recently, it was proposed that the constitutive fragile site at 3p14 be used as an “internal control” to indicate the effectiveness of the FUdR fragile site induction system. We have tested this hypothesis by determining the frequency of constitutive fragile sites at 1p31, 3p14, and 16q23 in cultures from 42 known fra(X) individuals. At least 50 cells were analyzed from each case. Seventy‐four percent (31/42), 95% (40/42) and 90% (38/42) of the fra(X) individuals exhibited frequencies of <4% at constitutive fragile sites 3p14, 1p31 and 16q23, respectively. Of the 42 individuals tested, 12 or 28.6% showed no fragility at any of the 3 sites studied. On the other hand, at least one constitutive fragile site was observed in 50 cells studied from over 70% of the 42 people studied. It is suggested that “positive controls” continue to be used, while at the same time recording all fragile sites to identify a combination of constitutive fragile sites that may serve as an internal control indicator, and that DNA marker studies be used to complement cytogenetic testing.
Is there a fragile(X) negative Martin‐Bell syndrome?
Authors: Thode A. , Laing S. , Partington M. W. , Turner G.
Published: June 2005

During the course of the preventative screening program for the fra(X) syndrome, we identified 32 men with the phenotype but who were fra(X) negative. These were reviewed and none fitted the full criteria, so we were unable to confirm the existence of the fra(X) negative Martin‐Bell syndrome. The literature and 4 families previously thought to have the fra(X) negative Martin‐Bell syndrome were also reviewed. We were unable to make a concrete diagnosis of the fra(X) negative Martin‐Bell syndrome.
Linkage studies with the gene for an X‐linked syndrome of mental retardation, microcephaly and spastic diplegia (MRX2)
Authors: Sutherland G. R. , Gedeon A. K. , Haan E. A. , Woodroffe P. , Mulley J. C.
Published: June 2005

A family in which a gene (MRX2) is segregating for an X‐linked syndrome of mental retardation, short stature, microcephaly, brachycephaly, spastic diplegia, small testes and possible intra‐uterine growth retardation is described. There are 7 clearly affected males and one possibly affected infant in the family. The obligate carriers are normal. Linkage studies show a suggestion of linkage to loci near the centromere. The maximum lod score was 2.10 at =0.11 for DXYS1, assuming the possibly affected male carried the MRX2 gene. There were lower lod scores suggestive of linkage with DXS7 (=0.14; Ẑ=1.29) and DXS94 (=0.11; Ẑ=1.22).
A family with the Coffin Lowry syndrome revisited: Localization of CLS to Xp21‐pter
Authors: Partington M. W. , Mulley J. C. , Sutherland G. R. , Thode A. , Turner G.
Published: June 2005

We revisited a family with the Coffin‐Lowry syndrome (CLS) first reported by Procopis and Turner in 1972. Twelve affected members are now known in 3 generations of which 9 were seen personally. DNA marker studies supported X‐linkage with localization of CLS to Xp near DXS43 at p22.2‐22.1 (θ = 0.001, Z = 2.71). Such linkage is reinforced by positive lod scores for DXS28 (θ = 0.00, Z = 0.90) and for DXS84 (θ = 0.09, Z = 1.56). Recombination with DXS84 and DXS164 places CLS distal to DMD in Xp21–pter.
Probable localisation of the Coffin‐Lowry locus in Xp22.2‐P22.1 by multipoint linkage analysis
Authors: Hanauer A. , Alembik Y. , Gilgenkrantz S. , Mujica P. , Nivelon‐Chevallier A. , Pembrey M. E. , Young I. D. , Mandel J. L.
Published: June 2005

The Coffin‐Lowry syndrome (McKusick No. 30360) is a rare genetically transmitted disorder characterized by severe mental retardation, “coarse” facial appearance, thick soft skin, tapering fingers, and progressive skeletal abnormalities. X‐linked inheritance is implied since the males are severely affected with variably mild manifestations in carrier women. We have performed a linkage analysis with many X‐linked RFLP markers in 4 families. Positive two‐point lod scores were obtained with DXS28 (z(θ) = 2.00 at θ = 0.05) and DXS41 (z(θ) = 1.26 at θ = 0.10).

We performed a 5‐point linkage analysis using the LINKMAP program assuming that DXS16 and DXS43 are a single locus and using the following fixed map (distances in centimorgans): DXS85 ‐ 18cM ‐ (DXS16, DXS43) ‐ 13cM ‐ DXS41 ‐ 5cM ‐DXS28.

This gave a multipoint lod score of 3.41 for a localisation in Xp22.2‐p22.1, between DXS43 and DXS41.
Fragile X syndrome: Linkage analysis in black and white populations
Authors: Schwartz C. E. , Phelan M. C. , Brightharp C. , Pancoast I. , Howard‐Peebles P. N. , Thibodeau S. , Brown W. T. , Jenkins E. C.
Published: June 2005

Eleven white families and 10 black families have been studied to detect racial differences in the linkage of DNA markers flanking the fragile X site (FRAXA). The differences in the recombination fractions for F9‐FRAXA and DX13‐FRAXA were not significant. The pair St14‐FRAXA exhibited no difference between the two groups. Although the sample size was small, it would appear that these DNA markers can be used in black persons for prenatal diagnosis and genetic counseling. A larger group of families would be necessary to determine if 4D8 and cX55.7 will be equally useful since these appear to have lower heterozygote frequencies in the black population.
Pulsed‐field gradient‐gel studies around the fragile site
Authors: Dobkin Carl S. , Brown W. Ted
Published: June 2005

Using pulsed‐field gradient‐gel electrophoresis (PFGE) we compared two fragile X (fra(X)) chromosomes from individuals in families that exhibit linkage heterogeneity between fra(X) and coagulation factor IX (F9). The analysis of very large restriction fragments indicated that there is a structural difference in the interval between fra(X) and F9 near the locus DXS105. Differences were observed in the Sfi I partial digestion analysis and in the Mlu I pattern of the DXS105 region. Digestion with Nru I and Sst II also showed differences between these alleles. The analyses suggest that the alleles differ in a region of >200 kb. Analysis of other normal and fra(X) chromosomes will be necessary to determine whether the observed difference is a normal population variant or if it may be resonsible for the linkage heterogeneity observed between these loci.
Cytogenetic and physical mapping in the region of the X chromosome surrounding the fragile site
Authors: Nguyen Catherine , Mattei Marie‐Geneviève , Rey Juan Antonio , Baeteman Marie‐Antoinette , Mattei Jean‐François , Jordan Bertrand R.
Published: June 2005

Seven DNA probes have been mapped within the Xq27‐Xq28 region using in situ hybridization, in some cases on chromosomes expressing the fragile site to enhance the resolution. To complement these studies and investigate the relationship between genetic, cytogenetic and physical distance some of these probes were used for large scale mapping using pulsed field gels. Physical linkage was demonstrated between two loci, F9 and MCF2, which are separated by less than 270 kb, and a restriction map extending over 1,300 kb has been generated.
Investigation of the segregation of the fragile X mutation in daughters of obligate carrier women
Authors: Sherman S. L. , Turner G. , Robinson H. , Laing S.
Published: June 2005

Two reports have suggested that over 50% of the offspring of obligate carrier women receive the mutation for the fra(X) or the Martin‐Bell syndrome [Webb et al, 1986; Fryns, 1984]. Such a segregation distortion is difficult to assess for the fra(X) syndrome because of incomplete penetrance, variable expression and probable ascertainment biases. We have attempted to evaluate this possible segregation distortion in daughters of obligate carriers in a large sample of sibships ascertained in a survey of New South Wales, Australia. We used two definitions of expression: 1) presence of fra(X) positive cells if daughters were tested cytogenetically, and 2) mental impairment if daughters were not tested cytogenetically. The segregation frequency was estimated in different types of sibships of obligate carriers based on the way they were ascertained. This was done in order to have an internal check on possible ascertainment biases. Among the 189 cytogenetically tested daughters, 81 were fra(X) positive. Among the 97 untested daughters, 24 were mentally impaired in some way. Therefore, the segregation frequency as defined by fra(X) expression and/or mental impairment was 37%. Thus, no evidence was detected for segregation distortion. These data were significantly different than those collected by Webb et al {1986} and scored by the same method as the present data set.
Screening developmentally disabled male populations for fragile X: The effect of sample size
Authors: Fisch Gene S. , Cohen Ira L. , Jenkins Edmund C. , Brown W. T.
Published: June 2005

The fra(X) or Martin‐Bell syndrome is the most common cause of inherited mental retardation (MR) in males. It is also associated with a variety of unusual behavioral and developmental disorders. Recent studies found great variability in the estimated strength of association between “autism” and the fra(X) syndrome, but not between MR and fra(X). We examined 31 studies which investigated the association of fra(X) syndrome with either MR or “autism” and found that the conclusions of those researchers could be significantly affected by sample size. Different behavioral and cytogenetic protocols will also influence the strength of association between fra(X) and autism.
Fragile X syndrome: A hypothesis regarding the molecular mechanism of the phenotype
Authors: Warren Stephen T.
Published: June 2005

Among all the human chromosomal fragile sites currently recognized, the fragile site mapping to Xq27.3 is the only one associated with an abnormal phenotype. This phenotype, referred to as the Martin‐Bell or fragile X syndrome, has mental retardation as its most important manifestation. We propose that this site is associated with an abnormal phenotype due its location on the X chromosome, particularly it's proximity to the q telomere. Thus, if an in vivo break should occur with loss of Xq28 in the fra(X) male, the cell would be nullisomic for the genes distal to the fragile site. Similarly, a female cell would be functionally nullisomic if the break occurred on the active X. Breakage and loss of genetic material at other fragile sites either would have no impact due to complementation by homologous genes or would be lethal if X‐linked with a significant deletion (i.e. fra(Xq22)). This leads to the proposal that the fragile X syndrome is due to mosaic nullisomy of distal genes. We describe below the implications of this model and a means to test this hypothesis.
Fragile X expression in Martin‐Bell syndrome, intellectually normal individuals, and neoplasia, interpreted by a viral hypothesis
Authors: Shabtai Fiorella , Hart Jacob , Klar Dvora , Bichacho Shlomo , Halbrecht Isaac
Published: June 2005

We present data on fragile X expression in lymphocytes obtained from the following patients: a university student, an infertile couple, 6 of 22 prostatic cancer patients, a meningioma patient, and members of families with meningioma and familial gliomas. All patients were of normal intelligence. In addition, we report 3 cases of central nervous system (CNS) tumors in more typical fragile X families.

We suggest that the fragile X expression as well as the clinical findings may be caused by a viral (or similar) infection. The virus may require a receptor protein coded by one allele of a gene on the X chromosome.
Prenatal diagnosis of deletion 17p13 associated with DiGeorge anomaly
Authors: Greenberg Frank , Courtney Kristine B. , Wessels Robert A. , Huhta James , Carpenter Robert J. , Rich Donna C. , Ledbetter David H. , Opitz John M. , Reynolds James F.
Published: June 2005

A fetus, subsequently shown to have the deletion 17p13, was detected at 30 weeks' gestation because of multiple anomalies and polyhydramnios on ultrasonography. The fetus died and was born at 34 weeks of gestation. Pathologic examination showed intrauterine growth retardation, double outlet right ventricle (a conotruncal cardiac defect), and thymic hypoplasia suggesting partial DiGeorge anomaly. To our knowledge, DiGeorge anomaly has not been reported previously in conjunction with del(17p) nor in the Miller‐Dieker syndrome. Since this deletion is the largest deletion of distal 17p observed so far, one explanation for this association may be the presence of a gene on proximal 17p for neural crest development.
Sensorineural deafness, hypospadias, and synostosis of metacarpals and metatarsals 4 and 5: A previously apparently undescribed MCA/MR syndrome
Authors: Pfeiffer R. A. , Kapferer L. , Opitz John M.
Published: June 2005

We report on a young man with a syndrome of mental retardation, abnormalities of the brain, sensorineural deafness, hypospadias, bilateral synostosis of the 4th and 5th metacarpals and metatarsals, and abnormal dermatoglyphics. This appears to be a previously undescribed MCA/MR syndrome.
Complex de novo rearrangement involving four chromosomes and ten break points with interstitial deletions and duplication
Authors: Muneer Razia S. , Himes Jeannie , Rennert Owen M. , Opitz John M. , Reynolds James F.
Published: June 2005

We describe an unusual de novo case of two interstitial deletions (5q22→5q31; 9p13→9q22) and one duplication (9q22→9q34) resulting from a 10–breakpoint, complex chromosome rearrangement of chromosomes 1, 5, 8, and 9 in a profoundly retarded woman.
Inherited lysosomal storage disease associated with deficiencies of β‐galactosidase and α‐neuraminidase in sheep
Authors: Ahern‐Rindell Amelia J. , Prieur David J. , Murnane Robert D. , Raghavan Srinivasa S. , Daniel Peter F. , McCluer Robert H. , Walkley Steven U. , Parish Steven M. , Opitz John M. , Reynolds James F.
Published: June 2005

Histopathologic, ultrastructural and Golgi impregnation studies disclosed lesions characteristic of a neuronal lysosomal storage disease in related sheep with onset of neurologic signs at 4–6 months. Biochemical and enzymatic evaluation disclosed storage of GM1 ganglioside, asialo‐GM1, and neutral long chain oligosaccharides in brain, urinary excretion of neutral long chain oligosaccharides, and deficiencies of lysosomal β‐galactosidase and α‐neuraminidase. Retrospective and limited prospective genetic studies suggested autosomal recessive inheritance. A gene‐dosage effect on β‐galactosidase levels was documented in fibroblasts from putative heterozygous sheep. Fibroblasts from affected sheep did not have increased β‐galactosidase activity after incubation with the protease inhibitor, leupeptin. In some aspects this disease is similar GM1 gangliosidosis, but is unique in that a genetic defect in lysosomal β‐galactosidase may cause the deficiency of lysosomal α‐neuraminidase.
Dandy‐Walker malformation in Ellis‐van Creveld syndrome
Authors: Zangwill Kenneth M. , Boal Danielle K. B. , Ladda Roger L. , Opitz John M. , Reynolds James F.
Published: June 2005

We report on 2 Old Order Amish patients with Ellis‐van Creveld (EvC) syndrome and the Dandy‐Walker malformation; a similar case is noted in the literature. Pedigree analysis of our patients documents extensive inbreeding in successive generations. Considering the rarity of EvC syndrome and Dandy‐Walker malformation as isolated malformations, the appearance of both in our 2 patients plus the patient in the literature suggests that Dandy‐Walker malformation may be a manifestation in the EvC syndrome. However, in this isolate the coincidental occurrence of 2 rare recessive traits cannot be excluded.
Probable metachromatic leukodystrophy/pseudodeficiency compound heterozygote at the arylsulfatase A locus with neurological and psychiatric symptomatology
Authors: Hohenschutz Ch. , Friedl W. , Schlör K.‐H. , Waheed A. , Conzelmann E. , Sandhoff K. , Propping P. , Neri Giovanni , Reynolds James F.
Published: June 2005

Metachromatic leukodystrophy (MLD) is an autosomal recessive progressive demyelination disorder caused by the deficiency of arylsulfatase A (ASA). However, there exist individuals with low ASA activity without clinical symptoms. This state is described as ASA pseudodeficiency (PD).

A number of patients with low ASA activity and various neuropsychiatric symptoms have been observed. It is controversial to what extent low ASA activity predisposes for neurological and/or psychiatric symptomatology. Therefore, persons with low ASA activity who were collected from a large‐scale screening among neuropsychiatric patients and healthy controls are presently being extensively evaluated using biochemical, genetic, and clinical methods. Here we present a female patient, who had been first hospitalized with the diagnosis encephalomyelitis disseminata. Her ASA activity determined in fibroblast extracts is intermediate between adult MLD and PD. Sulfatide degradation in cultured fibroblasts is diminished. The subunit pattern obtained after SDS‐polyacrylamide gel electrophoresis and immunoblotting was determined in the index patient and 2 sibs. It is compatible with a compound genotype ASA−/ASAp in the index case. It appears probable that in this patient low ASA activity leads to the accumulation of sulfatide and either causes the appearance of neuropsychiatric symptoms or at least contributes to the demyelination process.
Juvenile myoclonic epilepsy (JME) may be linked to the BF and HLA loci on human chromosome 6
Authors: Greenberg David A. , Delgado‐Escueta Antonio V. , Widelitz Heidi , Sparkes Robert S. , Treiman Lucy , Maldonado Hector M. , Park Min S. , Terasaki Paul I. , Opitz John M. , Reynolds James F.
Published: June 2005

Although certain forms of epilepsy have long been suspected to be inherited, heterogeneity has made it difficult to find the genes responsible for any subtypes. We found that families ascertained through patients with juvenile myoclonic epilepsy show linkage with the BF and HLA loci on human chromosome 6. There is some evidence that the locus may be outside the HLA complex and no evidence as yet of an association with any allele of the HLA complex.
The impact of MSAFP screening on genetic services, 1984–1986
Authors: Greenberg Frank , Opitz John M. , Reynolds James F. , Greenberg Frank
Published: June 2005

The impact of maternal serum alpha‐fetoprotein (MSAFP) screening on genetic centers was investigated by a questionnaire mailed to 220 genetic centers in the United States. Eighty‐four (38%) of centers responded to the questionnaire; of these (34%) were adequate for analysis. About 33% of the programs performed their own MSAFP testing. Approximately 70% of centers used 2.5 times the median (MoM) as a cutoff for MSAFP elevations and approximately 75% of centers used a sliding cutoff for low MSAFP based on both maternal age and the multiple of the median.

Between 1984 and 1986, the total number of women screened by the reporting centers increased by about 4.7 fold. The percentage of women seen in their centers for prenatal counseling due to high or low MSAFP levels increased from 1.3% in 1984 to 13.1% in 1986.

The percentage of prenatal diagnoses utilizing amniocentesis for high or low MSAFP increased from 3% in 1984 to 10% in 1986.

During this period, 76 cases of Down syndrome were detected based on low MSAFP; this represents 1.7% of amniocenteses for low MSAFP.

These data demonstrate a significant increase in the number of women seen for prenatal counseling and amniocentesis at the reporting genetic centers and is likely to represent a similar trend at all genetic centers. The impact of high MSAFP screeing for neural tube defects and low MSAFP screening for Down syndrome is likely to increase over the coming years and genetic programs should prepare for the increasing utilization of services necessary to handle women with high and low MSAFP levels.
Assessment of reproductive risk and intentions by mothers of children with hemophilia
Authors: Kraus Elissa M. , Brettler Doreen B. , Opitz John M. , Reynolds James F.
Published: June 2005

Thirty‐five mothers of children with hemophilia were studied in order to ascertain the impact of hemophilia on family planning. Attitudes about reproductive risks and prenatal diagnosis were also examined. The most important factors influencing family planning in this group were parental fulfillment and availability of medical care and education for their affected child. Although 79% of mothers viewed their reproductive risk as moderate to very high, 57% indicated that their reproductive plans had not changed even with this knowledge. While 43% of the group would consider prenatal diagnosis, only 17% would terminate a pregnancy if the fetus was found to have hemophilia. Of those interested in prenatal diagnosis, the majority were interested in knowing if the fetus was affected but would not consider termination of the pregnancy. The majority of mothers in the group did not view having a child with hemophilia as an insurmountable burden on their lives. Therefore, the disease appeared to have little impact on family planning.
Genetic and environmental components of serum creatine kinase (CK) and pyruvate kinase (PK) in normal twins: Implication for genetic risks estimates in Duchenne muscular dystrophy carriers
Authors: Rapaport Debora , Colletto Gloria M. D. D. , Zatz Mayana , Opitz John M. , Reynolds James F.
Published: June 2005

The serum activity of creatine kinase (CK) and pyruvate kinase (PK) was measured in 98 pairs of same‐sex Brazilian twins. The purpose of this study was to estimate the genetic and environmental components of serum activity levels for both enzymes. Heritabilities were estimated separately by path analysis in each sex. The results showed that CK and PK activities are under genetic control in normal males and females. Environmental components were not statistically significant for CK or PK. The genetic components of both enzymes estimated in females has implications in the calculation of genetic risks for Duchenne muscular dystrophy carriers.
Lid agenesis‐macrostomia‐psychomotor retardation‐forehead hypertrichosis—A new syndrome?
Authors: Cesarino E. J. , Pinheiro Marta , Freire‐Maia Newton , Meira‐Silva M. C. , Opitz John M. , Reynolds James F.
Published: June 2005

We describe a boy with bilateral lid agenesis and total keratinization of cornea and conjunctiva, macrostomia, psychomotor retardation, forehead hypertrichosis, ocular hypertelorism, thin lips, abnormal auricles and nose, skin alterations, and other findings. Differential diagnosis with ablepharon‐macrostomia syndrome is presented. Cause is unknown.
Selective termination of multiple gestations
Authors: Golbus Mitchell S. , Cunningham Nona , Goldberg James D. , Anderson Robert , Filly Roy , Callen Peter , Opitz John M. , Reynolds James F.
Published: June 2005

Twenty‐two selective terminations in multiple gestations were performed by a number of different methods. In 17 dichorionic pregnancies there was a successful delivery in surviving singletons or twins. In five monochorionic pregnancies undergoing selective termination there was a successful delivery in only one and a pregnancy loss in the other four. Six of the 18 delivered pregnancies were complicated by premature labor and delivery. Among the several methods used for selective termination, intracardiac potassium chloride injection appears to be the procedure of choice in dichorionic pregnancies.
Fechtner syndrome: Clinical and genetic aspects
Authors: Gershoni‐Baruch R. , Baruch Y. , Viener A. , Lichtig C. , Opitz John M. , Reynolds James F.
Published: June 2005

Fechtner syndrome, a variant of Alport syndrome, was first reported by Peterson et al. [1985]. It is characterized by nephritis, hearing loss, eye abnormalities, macrothrombocytopenia, and leucocyte inclusions, present in varying combinations in several members of the same family. This is the second family reported; 16 relatives are affected. The clinical manifestations of the syndrome are delineated. The pattern of inheritance is autosomal dominant. The hematologic abnormalities are similar to those detected in May Hegglin anomaly. They are present in every affected relative and may be present at birth. The feasibility of prenatal diagnosis is discussed.
Preliminary communication: Neuroanatomical variations of the posterior fossa in men with the fragile X (Martin‐Bell) syndrome
Authors: Reiss Allan L. , Patel Shilpesh , Kumar Ashok J. , Freund Lisa , Opitz John M. , Reynolds James F.
Published: June 2005

Four men with fragile X (fra (X)), or Martin‐Bell, syndrome were studied by magnetic resonance imaging (MRI) to determine whether detectable abnormalities of the cerebellum were present. The cerebellum was chosen because of the apparently increased tendency for fra (X) patients to demonstrate autistic behavior and accumulating evidence implicating cerebellar abnormalities in autism. Compared with a control group of four normal men, fra (X) patients had a significantly decreased area of the cerebellar vermis, particularly the posterior portion, on planimetric analysis in the midsagittal plane. The pons and fourth ventricular areas also were decreased and increased, respectively, in the fra (X) men. Neuroanatomical and animal research increasingly implicates the cerebellar vermis as an important component in functional brain systems subserving sensory and motor integration, learning, and modulation of affect, motivation, and social behavior. Thus, vermis dysfunction could account for many of the behavioral and cognitive abnormalities observed in fra (X) males, particularly those which overlap with the behavioral syndrome of autism.
Complex chromosomal rearrangement in a woman with multiple miscarriages
Authors: Kausch Katrin , Haaf Thomas , Köhler Julia , Schmid Michael , Neri Giovanni , Reynolds James F.
Published: June 2005

We report on a 23‐yr‐old healthy female with repeated miscarriages and a de novo complex chromosomal rearrangement (CCR) involving chromosomes 1, 2, 5 and 11 with 5 breakpoints. A review of cases reported in the last five yr is provided.
Idiopathic extrahepatic biliary atresia: Recurrence in sibs in two families
Authors: Cunningham Michael L. , Sybert Virginia P. , Opitz John M. , Reynolds James F.
Published: June 2005

Since 1855, 11 instances of familial extrahepatic biliary atresia (EHBA) have been described. Genetic, environmental, vascular, and infectious causes for this disorder have been proposed. We report on 2 families each with 2 sibs with EHBA. We suggest that a genetic susceptibility to an environmental insult to the biliary tree may be responsible for the genesis of this disease.
Martin‐Bell syndrome in Greece, with report of another 47,XXY fragile X patient
Authors: Mavrou Ariadni , Syrrou Maria , Tsenghi Christine , Agelakis Manthos , Youroukos Sotiris , Metaxotou Catherine , Opitz John M. , Reynolds James F.
Published: June 2005

A cytogenetic investigation was carried out among 200 mentally retarded boys in Greece for the detection of the fragile X [fra(X)] syndrome. Thirteen patients were found to carry fra(X) (6.5%). Of those, six boys had a history of familial X‐linked mental retardation, two had the phenotype of the Martin‐Bell syndrome, four had only mental retardation of unknown etiology, and one was a mentally retarded patient with Klinefelter syndrome. The remaining 187 boys were fra(X) negative. Our findings emphasize the importance of early identification of this syndrome in the diagnosis and prevention, through proper genetic counselling, of mental retardation.
Metacarpophalangeal pattern profile analysis in fragile X syndrome
Authors: Butler Merlin G. , Fletcher Mark , Gale David D. , Meaney F. John , McLeod D. Ross , Fagan Joel , Carpenter Nancy J. , Opitz John M. , Reynolds James F.
Published: June 2005

We analyzed the metacarpophalangeal pattern profile (MCPP) on 18 male individuals from 16 families with fragile X—fra (X), or Martin‐Bell—syndrome and calculated a mean syndrome profile. Fourteen of 18 individuals with fra (X) syndrome had significant positive correlations which indicated clinical homogeneity. Discriminant analysis of individuals with fra (X) syndrome compared with a sample of normal individuals produced a correct classification rate of 88% based on a function of 3 MCPP variables that may provide a useful tool in screening individuals for the fra (X) syndrome. Discriminant and correlation analyses of individuals with Sotos sequence and individuals with fra (X) syndrome did not identify MCPP similarities. Therefore, there was no MCPP evidence in our study of patients with Sotos sequence and fra (X) chromosome expression.
Balanced X;15 translocation 46,X,t(X;15)(q21;q23) associated with primary amenorrhea
Authors: Ji Xue‐Wen , Chen Xiao‐Yi , Tan Jun , Liang Hong , Opitz John M. , Reynolds James F.
Published: June 2005

Cytogenetic studies on a woman with primary amenorrhea showed an X;15 translocation, karyotype 46,X,t(X;15)(q21;q23). Fifteen percent of the buccal cells showed a normal‐sized sex chromatin body. The normal X chromosome was uniformly inactivated. Many balanced X;15 translocations have been reported; however, breakpoints in our patient differ from those reported previously. This case also supports earlier evidence that ovarian development fails when the breakpoint of the X chromosome is in the region X q13‐q25 or q13‐q27.
Greig cephalopolysyndactyly syndrome: A possible mouse homologue (Xt‐extra toes)
Authors: Winter Robin M. , Huson Susan M. , Prieur David J. , Reynolds James F.
Published: June 2005

Greig cephalopolysyndactyly syndrome is an autosomal dominant form of complex polydactyly in man. Attention is called to the evidence that, on both morphological and comparative gene mapping grounds, this defect is homologous to Xt‐extra toes in the mouse. The pattern of polydactyly in both species is very similar. In addition, both conditions probably map close to the T‐cell receptor gamma polypeptide at 13 A2–3 in mouse and 7p15 in humans.
Chromosomal localisation of a developmental gene in man: Direct DNA analysis demonstrates that Greig cephalopolysyndactyly maps to 7p13
Authors: Brueton Louise , Huson Susan M. , Winter Robin M. , Williamson Robert , Opitz John M. , Reynolds James F.
Published: June 2005

Greig cephalopolysyndactyly syndrome (GCPS) is a rare autosomal dominant form of complex polydactyly. GCPS has been tentatively assigned to chromosome 7 on the basis of association of the condition with balanced translocations involving the short arm of chromosome 7 (7p13) in two families. Seven GCPS pedigrees with no chromosome abnormality were studied, and linkage was demonstrated between. GCPS and the DNA sequence coding for the receptor for epidermal growth factor (localised to 7p12–13) (Z. = 3.17; 0 = θ).
Thanatophoric dysplasia: An autosomal dominant condition?
Authors: Martínez‐Frías M. L. , Ramos‐Arroyo M. A. , Salvador J. , Opitz John M. , Reynolds James F.
Published: June 2005

We present 13 cases of thanatophoric dysplasia collected in the Spanish Collaborative Study of Congenital Malformations from a total population of 517,970 births. The incidence (live and stillbirth) was 2.7 per 100,000 births. All cases were sporadic, and there was no evidence of parental consanguinity. Parental age was significantly higher as compared with control parents. These findings suggest the occurrence of autosomal dominant mutation, with an overall mutation rate of 1.34 × 10−5 in our population, which is close to that observed in achondroplasia.
Deletion 9p, duplication 18q in two sisters resulting from a maternal (9;18) (p22;q21.3) translocation
Authors: Tayel Shawky M. , Kurczynski Thaddeus W. , Casperson Susan , McCorquodale Maureen M. , Opitz John M. , Reynolds James F.
Published: June 2005

We have studied two sisters with partial deletion 9p and partial duplication 18q resulting from adjacent 1 segregation of a maternal translocation (9;18) (p22;q21.3). The clinical manifestations identified in our patients were compared with those reported in the literature for 9p− and 18q + patients involving approximately the same amount of genetic material. There was relatively greater similarity with the 9p− syndrome than with dup (18q) syndrome, but typical characteristics of both conditions were lacking.
Ocular hypotelorism, submucosal cleft palate, and hypospadias: A new autosomal dominant syndrome
Authors: Schilbach U. , Rott H.‐D. , Neri Giovanni , Reynolds James F.
Published: June 2005

A syndrome characterized by ocular hypotelorism, submucosal cleft palate, and hypospadias in males was found in ten relatives over five generations of a family. Other anomalies are blepharophimosis, upslant of palpebral fissures, and a tendency to cutaneous syndactyly of 3rd and 4th fingers as well as 2nd and 3rd toes. Autosomal dominant inheritance is likely.
Carrier detection in hemophilia A: ABO blood group, multiple measurements, and application of logistic discrimination
Authors: Percy M. E. , Rusk A. C. M. , Garvey M. B. , Freedman J. J. , Teitel J. M. , Blake P. , Carter C. , Andrew M. , Johnson M. , Inwood M. , Andrews D. F. , Brasher P. M. A. , Opitz John M. , Reynolds James F.
Published: June 2005

In healthy 20‐ to 50‐year‐old women, the ABO blood group has a significant effect on levels of von Willebrand factor (VWF:Ag, formerly VIIIR:Ag) and on factor VIII activity (F.VIII:C). However, there is no significant effect of ABO group or subject age on the ratio loge (F.VIII:C/VWF:Ag). Multiple measurements of the “ratio” on possible carriers of hemophilia A may be combined with pedigree information using logistic discrimination to yield final risk assessment. To reduce misclassification of carriers as normal women, a lower limit, specified by the logistic model, is set on the logistic carrier probabilities.

In this study, the proportion of blood group A for a population of obligate carriers was significantly higher than that expected for the general population (60% vs. 42%); for a population of control women it was lower than expected (22.5 vs. 42%). The effect for the carriers came primarily from daughters of affected fathers, as 81.3% were of blood group A. These observations indicate that a “universal” discriminant should be applied with caution.
Hepatocellular carcinoma in a child with familial Russell‐Silver syndrome
Authors: Chitayat David , Friedman Jan M. , Anderson Linda , Dimmick James E. , Opitz John M. , Reynolds James F.
Published: June 2005

We describe a 4‐year‐old boy with Russell‐Silver syndrome (RSS) found to have hepatocellular carcinoma. The brother of this child also had manifestations of RSS. This is the third malignancy and the first hepatocellular carcinoma described in a patient with RSS. The coexistence of hepatocellular carcinoma and RSS may be completely fortuitous; however, the known association of liver cancer with growth abnormality and hemihypertrophy, findings also present in RSS, suggest that these disorders may be related.
Late onset scleroatonic familial myopathy (Ullrich disease): A study of two sibs
Authors: Ricci Enzo , Bertini Enrico , Boldrini Renata , Sabatelli Mario , Servidei Serenella , Mazziotta Mercedes R. M. , Bosman Cesare , Tonali Pietro , Neri Giovanni , Reynolds James F.
Published: June 2005

We report on sibs with scleroatonic familial myopathy (Ullrich disease). Muscular weakness was of relatively late onset in relation to other cases reported in the literature. Short stature and moderate growth hormone deficiency were noted during follow‐up. Differential diagnosis with other neuromuscular disorders, particularly rigid spine syndrome, is discussed.
Juvenile polyposis: A case with early presentation and death attributable to adenocarcinoma of the pancreas
Authors: Walpole Ian R. , Cullity Garry , Opitz John M. , Reynolds James F.
Published: June 2005

A male child who first presented in the second year of life demonstrated all the recognized clinicopathological manifestations of juvenile polyposis with associated birth defects. Subsequent death at age 19 years from adenocarcinoma of the pancreas further broadens the recognized spectrum of possible sequelae in this disorder and is in keeping with current hypotheses of inherent cancer potential throughout the polyposis syndromes.
A new Spanish family with Hb Louisville
Authors: Villegas A. , Malcorra J. J. , Balda I. , Calero F. , Porres A. , Alvarez‐Sala J. L. , Espinós D. , Opitz John M. , Reynolds James F.
Published: June 2005

The clinical, hematological, and biochemical characteristics of a new family with heterozygous hemoglobin (Hb) Louisville are described. The family showed a decrease in both oxygen affinity and cooperativity with the normal Bohr effect. This family has the greatest number of affected members reported to date. Among the descendants, two first cousins (III‐10 and III‐11), both of whom are affected by the heterozygous trait of Hb Louisville, had had three abortions of undetermined causes.
Autosomal dominant hypoparathyroidism with intracranial calcification outside the basal ganglia
Authors: McLeod D. Ross , Hanley David A. , McArthur Robert G. , Opitz John M. , Reynolds James F.
Published: June 2005

We describe a family with autosomal dominant hypoparathyroidism. The 3 affected individuals had no detectable serum parathyroid hormone on radioimmunoassay. The propositus presented with seizures and on CT scan had bilateral basal ganglion calcification and calcification in the frontal lobes. His similarly affected mother had even more intracerebral calcification. The latter manifestation has not been described previously in autosomal dominant hypoparathyroidism.
A man with isochromosome Xq Klinefelter syndrome with lack of height increase and normal androgenization
Authors: Richer Claude‐Lise , Bleau Gilles , Chapdelaine Alcide , Murer‐Orlando Manuela , Lemieux Nicole , Cadotte Marcel , Opitz John M. , Reynolds James F.
Published: June 2005

We report on a patient with Klinefelter syndrome (KS) and the homogeneous aneuploidy 47,Xi(Xq)Y, or male trisomy Xq. He had many characteristics of classical KS: small testes, azoospermia, elevated FSH and LH, average intelligence, and normal androgenization, but his stature was not increased, compared with his father's and brothers'. The i(Xq), found in all cells analyzed, was late‐replicating, monocentric, and also asymmetric for the RBG‐banding of the two arms, indicating a different chronology of DNA synthesis in each arm. When indicated, in the seven previously reported cases, the level of plasma testosterone was always subnormal; it was normal (650 ng/100 ml) in our patient, who had normal masculinization. Thus the level of testosterone among patients with KS is not necessarily lower with an extra Xq. Furthermore, the sharp contrast in the height of KS patients with or without an i(Xq) is striking. It appears definitely possible to associate the isochromosome Xq Klinefelter syndrome with a lack of height increase.
Etiologic heterogeneity in dyskeratosis congenita
Authors: Pai G. Shashidhar , Morgan Samuel , Whetsell Carl , Opitz John M. , Reynolds James F.
Published: June 2005

Most patients with dyskeratosis congenita [DC or Zinsser‐Cole‐Engman syndrome] are males hemizygous for an X‐linked recessive mutation. However, one or more autosomal form(s) of DC may exist. We have studied a 6‐year‐old black girl with the characteristic triad of nail dystrophy, cutaneous and mucosal pigmentary changes, and bone marrow failure. Severe microcephaly, mental retardation, cerebellar hypoplasia, and purple discoloration of the tongue were other manifestations not usually seen in DC. Comparison of our patient's phenotype with that of 5 other sporadic and 10 familial cases of DC in females showed that the autosomal and X‐linked phenotypes are not distinguishable in the absence of a suggestive pedigree pattern. Additional cases of DC need to be studied to better elucidate the apparent causal heterogeneity in this syndrome.
Impaired spermatogenesis is not an obligate expression of receptor‐defective androgen resistance
Authors: Pinsky Leonard , Kaufman Morris , Killinger Donald W. , Opitz John M. , Reynolds James F.
Published: June 2005

We are studying a man who presented at age 21 years with severe extragenital subvirilization despite high‐normal to above‐normal levels of plasma testosterone for at least 5 years. At puberty, his penis, scrotum, and testes matured normally, and he did not develop gynecomastia; however, his voice, muscularity, and facial, sexual, and body hair remained immature. A 2.5‐ml ejaculate yielded normal results for sperm density, morphology, and motility. Because persistent undervirilization was emotionally disabling, he has received pharmacologic doses of testosterone enanthate intramuscularly for 3.5 years. The treatment has improved his virilization and masculine self‐image substantially, and his semen analysis has remained well within the normal range. The androgen receptor in his genital skin fibroblasts has a distinctively mutant phenotype: it has a low affinity (increased apparent equilibrium dissociation constant, Kd) for 5α‐dihydrotestosterone and two synthetic androgens, mibolerone (MB) and methyltrienolone (MT), and its binding capacity (Bmax) is normal for the other two ligands, but questionably low for MT. In addition, it up‐regulates its activity normally in response to prolonged incubation with androgen, and its androgen‐receptor complexes are not thermolabile. Our study of this man permits two conclusions: impaired spermatogenesis is not the irreducible expression of receptor‐defective androgen resistance in man; and androgen pharmacotherapy may be remedial for those in whom extragenital subvirilization is emotionally costly and subnormal spermatogenesis is not an inevitable side effect of such therapy.
Autosomal dominant inheritance of small kidneys
Authors: Kaplan Bernard S. , Milner Lawrence S. , Jequier Sigrid , Kaplan Paige , De Chadarevian Jean‐Pierre , Opitz John M. , Reynolds James F.
Published: June 2005

We report herein bilateral small kidneys found in a mother and her two sons. This was associated with slowly progressive chronic renal failure. None of the patients had any of the associated clinical manifestations of recognized syndromes in which there is autosomal dominant inheritance of bilateral small kidneys (e.g., branchio‐oto‐renal syndrome). Nor did they have the clinical symptoms commonly associated with medullary cystic kidney‐juvenile nephronophthisis. However, there were some manifestations that have been reported in familial hypoplastic kidneys with glomerular cysts. Without wanting to claim that this is a “new” syndrome, we are, however, unaware of any reports describing a similar kindred. The importance of this report stems mainly from the fact that a woman with mild to moderate stable chronic renal failure associated with, or caused by, bilateral small dysplastic kidneys gave birth to two sons with the same problem.
Mutation rate estimates are not compatible with autosomal dominant inheritance of the dysplastic nevus “syndrome”
Authors: Traupe Heiko , Macher Egon , Hamm Henning , Happle Rudolf , Opitz John M. , Reynolds James F.
Published: June 2005

Dysplastic nevi represent precursor lesions harboring an increased risk of evolving into melanoma. Their association with familial melanoma is usually considered a monogenic syndrome with autosomal dominant transmission. To test this concept we estimated the mutation rates. When derived directly from the sporadic occurrence of the trait, the mutation rate is exceedingly high (0.9%–2.5%), whereas, as estimated with the aid of Haldane's formula it would be 0.007% to 0.02%. Accordingly, newly arising mutation would out‐number eliminated mutations by 100:1. Even if only 80% of all old mutations are passed onto the next generation, this ratio of 100:1 would rapidly change. After only a few generations, 10% of the world population should be affected with the dysplastic nevus “syndrome”. The apparent lack of a genetic equilibrium between newly arising and eliminated mutations is not compatible with autosomal dominant inheritance of the dysplastic nevus “syndrome”.
Holoprosencephaly, ear abnormalities, congenital heart defect, and microphallus in a patient with 11q–mosaicism
Authors: Helmuth Robin A. , Weaver David D. , Wills Edward R. , Opitz John M. , Reynolds James F.
Published: June 2005

We report on a newborn male with deletion of part of 11q, the 27th reported case. Our patient had some of the clinical characteristics of the 11q–syndrome, but his male gender, liveborn status, q21 breakpoint, and mosaicism were unusual. In addition, he demonstrated holoprosencephaly, with cyclopia and arhinencephaly, manifestations previously unreported in the 11q–syndrome. We discuss the above points and review the literature on 11q–.
Atrial septal defect, ventricular septal defect, and coarctation of the aorta in sibs: An autosomal recessive disorder?
Authors: Nordenberg Dale F. , Hanna Brian , Fouron Jean‐Claude , Der Kaloustian Vazken M. , Opitz John M. , Reynolds James F.
Published: June 2005

We report on two sisters with secundum atrial septal defect, perimembranous ventricular septal defect, and coarctation of the aorta. Identical anatomical malformations were verified by echocardiography and at operation. No other affected relatives were identified. We suggest that this is a specific, possibly recessively inherited type of complex cardiac malformation.