bluuebunny/crossref_metadata_2025 huggingface dataset:
Fetal mortality in sibships with one or more affected members with oral clefts
Authors: Mutchinick Osvaldo , Lisker Rubén , Babinsky Victoria , Santos Miguel Angel , Mejía Francisco , Saavedra Dolores , Villanueva Cristina , Opitz John M. , Reynolds James F.
Published: June 2005

We investigated the fetal mortality in 903 sibships with at least one member having cleft lip with or without cleft palate [CL(P)] and 213 with at least one individual affected with cleft palate (CP) derived from three different data sources in México. The frequency of fetal wastage (abortion and/or Stillbirth) was not increased in sibships where the propositi had cleft lip and palate (CLP) as compared with cleft lip (CL) nor in those where index cases had a bilateral lesion as compared to a unilateral one, nor when the index cases with CL(P) were female rather than males, nor when the index case was a female with bilateral lesion as compared to males with a unilateral one. Similarly fetal mortality was not increased in sibships in which the propositus had CP compared to those in which the index case was a female. These findings are contrary to some reports that claim to support a twothreshold model according to which individuals reaching the first one would be born with an oral cleft, and those reaching the second would be aborted. Our results, together with others, suggest the possibility that liability to oral clefts is independent of liability to fetal wastage.
Infantile polycystic kindney disease: Observations from attempts at prenatal diagnosis
Authors: Luthy David A. , Hirsch Jack H. , Opitz John M. , Reynolds James F.
Published: June 2005

Three successive pregnancies of a couple at risk for infantile polycystic kidney disease were evaluated by sequential ultrasound examinations to attempt prenatal diagnosis of the disorder. The gestational age at which renal sonographic changes were noted varied from 20 to 34 weeks and resulted in both false‐positive and false‐negative diagnoses.
A new X‐linked syndrome with muscle atrophy, congenital contractures, and oculomotor apraxia
Authors: Wieacker Peter , Wolff Gerhard , Wienker Thomas F. , Sauer Michael , Opitz John M. , Reynolds James F.
Published: June 2005

Six men from three generations of one family had manifestations of a possible new syndrome. All had congenital contractures of the feet at birth, a slowly progressive predominantly distal muscle atrophy, dyspraxia of the eye, face, and tongue muscles, and mild mental retardation. The pedigree is compatible with X‐linked recessive inheritance with no detectable manifestations in the obligate carriers. Linkage analysis excludes close linkage with the Xg locus and a polymorphic DNA sequence from the long arm of the X chromosome (DXS17).
Multiple congenital anomalies, mental retardation and hypogonadotropic hypogonadism in a boy with small marker chromosomes
Authors: Copeland Kenneth C. , Hansen Kathryn , Moore Charleen M. , Opitz John M. , Reynolds James F.
Published: June 2005

We report on a mentally retarded boy with hypogonadotropic hypogonadism. He also had a hypoplastic right kidney and right vesicoureteral reflux, blunted calyses of the left kidney, spina bifida occulta, stiff metacarpophalangeal joints, and cataract of the left eye. Chromosome studies showed two marker chromosomes, the larger of which appeared to be a ring chromosome varying greatly in size, while the smaller one remained constant in size. Chromosome abnormalities may be associated with several forms of hypogonadotropic hypogonadism.
Familial Sotos syndrome (cerebral gigantism): Craniofacial and psychological characteristics
Authors: Bale Allen E. , Drum M. Ann , Parry Dilys M. , Mulvihill John J. , Opitz John M. , Reynolds James F.
Published: June 2005

Most reported cases of Sotos syndrome are sporadic, but autosomal dominant and recessive inheritance patterns have been suggested. Ascertainment of a two‐generation family through a 7‐year‐old proposita with a learning disability allowed the relatively unbiased study of two affected relatives.

Developmental delay was not pronounced in the patient's mother or sister; craniofacial characteristics at variance with the characteristic description included acrocephaly and maxillary prominence. Steepness of the anterior cranial base angle and protrusion of the middle and lower face, shown in all three patients by cephalometric radiographs, deserve further evaluation as d agnostic criteria.
Metacarpophalangeal pattern profile analysis in Sotos syndrome
Authors: Butler Merlin G. , Meaney F. John , Kittur Smita , Hersh Joseph H. , Hornstein Lusia , Opitz John M. , Reynolds James F.
Published: June 2005

The metacarpophalangeal pattern profile (MCPP) was analyzed on 16 Sotos syndrome patients. A mean Sotos syndrome profile was produced. Correlation studies confirm clinical homogeneity of Sotos syndrome individuals. Discriminant analysis of Sotos syndrome patients and normal individuals produces a function of two MCPP variables and age, which may provide a useful tool for diagnosis.
Ichthyosis and neutral lipid storage disease
Authors: Williams Mary L. , Koch Thomas K. , O'Donnell James J. , Frost Philip H. , Epstein Lois B. , Grizzard W. Sanderson , Epstein Charles J. , Opitz John M. , Reynolds James F.
Published: June 2005

Four members of a consanguineous middle eastern family had a lipid storage disease characterized by congenital ichthyosiform erythroderma, neurosensory deafness, cataracts, mild myopathy, and leukocyte vacuoles. These patients are similar to several others recently reported and represent a unique disorder of lipid metabolism. The clinical and biochemical manifestations of this lipid storage disease are reviewed. Evidence is presented that the disorder is inherited as an autosomal recessive trait, and that heterozygotes may be detected by the presence of vacuoles within circulating eosinophils.
A taxonomic approach to the del(4p) phenotype
Authors: Preus M. , Aymé S. , Kaplan P. , Vekemans M. , Opitz John M. , Reynolds James F.
Published: June 2005

The findings of 23 patients with the del(4p) phenotype are compared systematically. Three patients with a small deletion evident only on analysis of extended chromosomes have a phenotype comparable to 13 patients with a more extensive chromosomal deletion. Two patients with no detectable deletion also fit into the phenotypic spectrum of patients with del(4p), suggesting the same etiology. Five patients with fewer typical and more atypical findings probably represent a heterogeneous group of other syndromes. Numerical analysis of the phenotype allows one to identify patients who most likely have a deletion requiring a more intensive cytogenetics analysis.
Noonan syndrome: A review
Authors: Mendez Heirie M. M. , Opitz John M. , Reynolds James F.
Published: June 2005

After an introduction dealing with the “historical evolution” of the Noonan syndrome (NS), we try to define the NS phenotype based on clinical descriptions published since 1883. The theories concerning the cause of the NS are discussed fully. The peculiar cardiac involvement deserves especial attention and raises the question of whether the Watson and LEOPARD syndromes are indistinguishable from NS. Finally, the recent contributions to the variability of the NS phenotype (reports on lymphatic dysplasia, partial deficiency of factor XI, malignant hyperthermia, perceptual‐motor disabilities, and endocrine evaluation) are also described.
The role of mesenchyme‐like tissue in the pathogenesis of thanatophoric dysplasia
Authors: Ornoy A. , Adomian G. E. , Eteson D. J. , Burgeson R. E. , Rimoin D. L. , Opitz John M. , Reynolds James F.
Published: June 2005

We have studied the light microscopic, transmission, and scanning electron microscopic (SEM) findings in 13 cases of thanathophoric dysplasia (TD) and 4 control infants. In the TD growth plate, areas with less abnormal cartilage and bone alternated with areas of severely abnormal cartilage and bone. These latter abnormal areas were always found around tongues of apparent mesenchymal tissue that appeared to penetrate from the investing perichondrium and periosteum. The ultrastructure of the less abnormal areas was similar to that of the control infants, including cell and matrix structure as well as mineralization. The abnormal cartilage and bone had many ultrastructural abnormalities that were also found in the adjacent mesenchymal tissue. The mesenchymal cells, adjacent chondrocytes, and osteoblasts contained dilated endoplasmic reticulum and moderately large intracytoplasmic vacuoles. In the area adjacent to the cartilage, the matrix of the apparent mesenchyme contained thin collagen fibers and proteoglycan granules, whereas the matrix adjacent to the bone contained thick bundles of short collagen fibers. The matrix of the surrounding cartilage and bone resembled the adjacent matrix in the mesenchyme. In addition, many vesicular structures or osmiophilic particles were found in the matrix of the mesenchyme and adjacent cartilage and bone. SEM examination showed normal and abnormal bone trabeculae adjacent to each other. In the abnormal trabeculae, there were large, densely packed osteoblastic and osteocytic lacunae. The calcified collagen fibers had a random orientation, in contrast to the longitudinal orientation in the relatively normal bone. Chemical studies of collagen in the metaphyses of bones from five infants with TD showed a small amount of collagen type III (less than 5%), which was not found in three control infants. Thus, a basic pathogenetic mechanism in the skeletal abnormalities of TD appears to be the focal replacement of the growth plate and periosteum by persisting abnormal mesenchymal‐like tissue from which the abnormal bone originates.
Anencephaly in one monoamniotic‐monochorionic twin and encephalocele in the other
Authors: Putz Barbara , Rehder Helga , Opitz John M. , Reynolds James F.
Published: June 2005

This is a report of monoamniotic‐monochorionic (ie, probably MZ) twins, one of which had anencephaly, whereas the co‐twin died of complications of prematurity. Autopsy in this seemingly nonmalformed twin showed a small encephalocele. The literature on MZ twins with discordant anencephaly is often contradictory. It is suggested that this might be due to the difficulty of determining zygosity on the one hand and identifying discordance or concordance on the other. This case is presented as an example of this difficulty; it is discordant with respect to anencephaly, but concordant in the sense of “dysraphic” disturbances.
Familial glioblastoma multiforme without neurofibromatosis
Authors: Chemke J. , Katznelson D. , Zucker G. , Opitz John M. , Reynolds James F.
Published: June 2005

Glioblastoma multiforme is a rapidly growing anaplastic primary tumor of the central nervous system. It is frequently associated with neurofibromatosis or other hamartomatous syndromes, and in such kindreds may be found in several generations. We describe a highly inbred family in which glioblastoma multiforme presents in males only as an isolated central nervous system neoplasm on the right side, without evidence of other underlying genetic disease. It is speculated that in this family the tumor develops as the consequence of an autosomal recessive or an X‐linked recessive mutation. In addition, the gene for cystic fibrosis segregates in this family and an undefined autosomal recessive malformation syndrome was detected.
Anomalies in an infant with Nager acrofacial dysostosis
Authors: Krauss Celeste M. , Hassell Lewis A. , Gang David L. , Opitz John M. , Reynolds James F.
Published: June 2005

We report on an infant with Nager acrofacial dysostosis, laryngeal and epiglottic hypoplasia, abnormal septation of the right middle lobe of the lung, hypoplastic right first rib, and dislocation of the right hip. These findings suggest the possibility that patients with the Nager syndrome may have other developmental defects in addition to the facial and acral anomalies associated with this syndrome.
Krabbe disease: Increased incidence in a highly inbred community
Authors: Zlotogora J. , Regev R. , Zeigler M. , Iancu T. C. , Bach G. , Opitz John M. , Reynolds James F.
Published: June 2005

Krabbe disease (globoid cell leukodystrophy) was found with very high incidence (6/1,000 live births) in a large Druze kindred in Israel. The clinical data on 12 of the affected children demonstrated clinical variability even though these children are homozygous for the same mutation by descent from a common ancestor.
The Greig cephalopolysyndactyly syndrome: Report of a family and review of the literature
Authors: Gollop Thomaz Rafael , Fontes Luiz Roberto , Opitz John M. , Reynolds James F.
Published: June 2005

The Greig cephalopolysyndactyly syndrome in characterized by a set of craniofacial defects (macrocephaly, broad nasal root) leading to peculiar facial appearance, postaxial (occasionally preaxial) polydactyly of hands, preaxial (rarely postaxial) polydactyly of feet, and syndactyly of fingers and toes. Occasionally other skeletal or nonskeletal defects are present. This is an autosomal dominant trait with complete penetrance and variable expressivity. Prognosis for mental and physical development of the affected patients is good, surgery being indicated primarily for aesthetic and functional correction of polydactyly and syndactyly. We report on a Brazilian family in whom the mother and two of three sons were affected.
Johanson‐Blizzard syndrome with normal intelligence
Authors: Moeschler John B. , Lubinsky Mark S. , Opitz John M. , Reynolds James F.
Published: June 2005

We report a brother and sister with apparent Johanson‐Blizzard syndrome and normal intelligence. There is a wide range of intellectual abilities of persons with Johanson‐Blizzard syndrome. No phenotypic predictors of ultimate intellectual function were found in the literature.
Pregnancy in a woman with the Brachmann‐de Lange syndrome
Authors: Mosher Gayle A. , Schulte Raymond L. , Kaplan Phoebe A. , Buehler Bruce A. , Sanger Warren G. , Opitz John M. , Reynolds James F.
Published: June 2005

We present the first reported pregnancy in a woman with the Brachmann‐de Lange syndrome. This 24‐year‐old primagravid woman was originally seen at 13 weeks of pregnancy with manifestations consistent with this diagnosis. High‐resolution chromosome studies, performed on lymphocytes, showed a normal 46,XX chromosome constitution. Because of the stage of pregnancy at which she presented, a genetic amniocentesis was simultaneously performed for chromosome analysis on the fetal cells, which were also normal (46,XX). The uncomplicated pregnancy was monitored carefully and at 37 1/2 weeks of gestation she delivered a clinically normal‐appearing female infant.
Brachmann‐de Lange syndrome: Evidence for autosomal dominant inheritance
Authors: Robinson Luther K. , Jones Kenneth Lyons , Wolfsberg Eric , Opitz John M. , Reynolds James F.
Published: June 2005

We have evaluated a family in whom a mildly affected mother and her two severely affected sons have manifestations of the Brachmann—de Lange syndrome suggesting that some cases of this disorder are inherited in an autosomal dominant fashion. Documentation of the clinical phenotype in two generations of this family permits further delineation of the phenotypic spectrum of the disorder. The fact that most affected patients represent sporadic cases in otherwise normal families might represent the inability of severely affected individuals to reproduce.
The natural history of familial hypopituitarism
Authors: McArthur Robert G. , Klassen John , Morgan Kenneth , Phillips John A. , Bala Marvin , Opitz John M. , Reynolds James F.
Published: June 2005

Familial hypopituitarism in the Hutterite Brethren is an autosomal recessive disorder involving sequential loss of anterior pituitary tropic hormones. Five individuals from two closely related families have been followed for 19 years. Both families are well integrated into the Hutterite community. Three sibs elected not to be treated with growth hormone and sex steroids. These sibs developed growth hormone and gonadotropin deficiency in the first decade of life, with subsequent loss of TSH function and finally ACTH deficiency in the third decade. The pattern of hormone loss differed in the second family, in that deficiency of growth hormone, gonadotropins, and TSH was evident in the first decade. A third family has been reported to have the same disorder and is from a different endogamous subdivision from that of the two families described here. Genealogical analysis of the three families shows that there are four ancestral couples common to the six parents. Thus all affected individuals are likely to be identical by descent for the same ancestral allele. The gene for hypopituitarism is not closely linked to the gene for growth hormone nor to the HLA region.
I. Familial hypercholesterolemia with “normal” cholesterol in obligate heterozygotes
Authors: Nora James J. , Lortscher Randall M. , Spangler Richard D. , Bilheimer David W. , Opitz John M. , Reynolds James F.
Published: June 2005

We have investigated the family of a 15‐year‐old proposita with a homozygous, receptor‐defective, familial hypercholesterolemia and found that her consanguineous, obligate heterozygous parents have “normal” cholesterol levels and a family history of unusual longevity. Documentation of paternity and the presence of the heterozygous biochemical disorder in the parents is firm. The implications are that, at least in this family, relatively low serum cholesterol and high levels of HDL cholesterol are protective against the risks associated with having a mutant allele for heterozygous familial hypercholesterolemia.
Animal model: Light and electron microscopy of hepatocytes of cats with Chediak‐Higashi syndrome
Authors: Hargis Ann M. , Prieur David J. , Opitz John M. , Reynolds James F.
Published: June 2005

Cats with a condition resembling human Chediak‐Higashi syndrome (CHS) are the most recently described of five species of animals with similar syndromes. In this study, hepatocytes of cats with CHS were examined by light microscopy, histochemistry, and transmission electron microscopy. Enlarged cytoplasmic granules, morphologically consistent with lysosomes, were present in many of the CHS cat hepatocytes. The enlarged lysosomes were generally larger and more numerous in centrilobular hepatocytes and were generally larger in older cats. The lesions were similar to those reported in other species with CHS suggesting that CHS cats are a valid animal model of human CHS.
Thanatophoric dysplasia: Fetal manifestations and prenatal diagnosis
Authors: Elejalde B. Rafael , De Elejalde Maria Mercedes , Opitz John M. , Reynolds James F.
Published: June 2005

This paper describes two fetuses with thanatophoric dysplasia (TD) diagnosed in utero by ultrasonography. The fetuses were found to have severely short (< 3rd centile), mildly bowed bones in one of them at 20 weeks and straight bones in the other at 34 weeks; bell‐shaped chest; abnormal ribs (broadened and flattened at their ends); severe lung hypoplasia; hypoplastic, round‐shaped vertebral bodies with hypoplastic arches; abnormally small pelvic bones, phalanges, metacarpals, and metatarsals. There was also an incipient “cloverleaf” skull deformity produced by fused posterior sagittal and lambdoidal sutures in the 20‐week fetus and a definitive cloverleaf skull with communicating hydrocephaly in the 34‐week fetus. The autopsies did not show any other abnormality. By xeroradiography after delivery, marked abnormalities of the endochondral and perichondral bone structures could be demonstrated in the 20‐week fetus but not in the 34‐week fetus. They appear to constitute two different conditions. These cases are good examples of the possibilities brought by ultrasound to the analysis of the fetal phenotype in utero.
On monitoring the multiply malformed infant. I: Case‐finding, case‐recording, and data handling in a Latin American program
Authors: Castilla Eduardo E. , Lopez‐Camelo Jorge S. , Orioli Lěda M. , Opitz John M. , Reynolds James F.
Published: June 2005

The methods used by the Latin American Collaborative Study of Congenital Malformations (ECLAMC) for monitoring the birth prevalence of multiply malformed infants are based on a clinical‐epidemiological approach oriented to the early detection of teratogenic agents. They consist of three steps: 1) the analysis of observed vs expected rates of all congenital anomalies (CA), including their isolated and associated forms; 2) the same type of analysis applied to each multiple congenital anomaly (MCA) pattern; and 3) a clinical case presentation reserved only for those considered as true MCA because of presence of three or more independent CA.

During the period 1982–1983 299,231 infants were examined. Multiply malformed infants, excluding Down syndrome cases, were born at a rate of 4/10,000, 40% having syndromes (two or more interrelated CA), 30% anomaly pairs, ie, two independent CA, and 30% true MCA cases. In a program with 150,000 births per year, as in ECLAMC, this means about five true MCA cases per week, a number easily handled individually on a clinical basis.
Partial fra(X) phenotype with megalotestes in fra(X)‐negative patients with acquired lesions of the central nervous system
Authors: Fryns Jean‐Pierre , Dereymaeker Annemie , Hoefnagels Margot , Volcke Philip , Van den Berghe Herman , Opitz John M. , Reynolds James F.
Published: June 2005

We describe 3 men with acquired lesions of the central nervous system (one male with tumor of the third ventricle, two males with peri‐ or postnatal accidents). In all three patients macroorchidism was associated with facial characteristics similar to those found in fra(X) males, but they were fra(X)‐negative.

The finding of megalotestes associated with a partial fra(X) phenotype in the present patients and, more particularly, the documentation of a hypothalamic tumor in the first patient, suggests that a specific hypothalamic lesion in fra(X) malesis responsible for some of their manifestations.
Cerebral gigantism (Sotos syndrome) in two patients with fra(X) chromosomes
Authors: Beemer Frits A. , Veenema Henk , de Peter Johanna M. , Opitz John M. , Reynolds James F.
Published: June 2005

Two boys were studied who had a large size at birth and/or overgrowth, unusual length, large head circumference and minor anomalies, mainly facial. Their mental development appeared mildly retarded. A clinical diagnosis of cerebral gigantism (Sotos syndrome) was made. However, subsequent chromosome studies (medium 199, with 5% fetal calf serum) showed fra(X) (q27) in 4 and 6% of cells, respectively. These observations give evidence for genetic heterogeneity in cerebral gigantism. Fra(X) studies are recommended in all cases of cerebral gigantism (Sotos syndrome).
Folic acid treatment in males and females with fragile‐(X)‐syndrome
Authors: Froster‐Iskenius U. , Bödeker K. , Oepen T. , Matthes R. , Piper U. , Schwinger E. , Opitz John M. , Reynolds James F.
Published: June 2005

Ten males with the fragile X (fra(X)) syndrome were treated with folic acid (10 mg/day) for 4 months in a double‐blind design study. To eight heterozygotes with mental impairment and fra(X), folic acid was given for 4 months (10 mg/day) in an effortto study possible beneficial effects of folic acid. Psychological and cytogenetic testing were carried out during the trial. There was no improvement in concentration, fine motor co‐ordination, or comprehension in the adult male and female patients of the study. One patient showed improvement under a control medications. In the females, improvement was seen only in the youngest patient, a 5‐year‐old girl. Folate treatment does not seem to be effective in fra(X) adults, but may have some effect in children of both sexes with the disorder.

Cytogenetic studies using peripheral lymphocytes showed that the fra(X) frequency decreased significantly (t = 0.00856; 1% level) only in cells cultured in a folic acidfree medium but not in cells cultured in a medium with added antifolate (methotraxate). This shows a “contamination effect” of folate‐free culture medium after oral folic acid treatment of these patients. The decrease of fra(X) involves primarily the early‐replicating X when culturing with folic acid‐free medium. A synergistic suppression effect of “external folate” and BrdU is the most likely explanation of this phenomenon.
Assessment of behavior change in a fragile‐X syndrome male treated with folic acid
Authors: Wells Thomas E. , Madison Lynda S. , Opitz John M. , Reynolds James F.
Published: June 2005

The effects of folic acid treatment were assessed in a 7‐year‐old boy with Fragile‐X (fra(X)) syndrome utilizing a within‐subject experimental design. Dependent variables consisted of classroom behavior, activity level/impulsiveness, and attentiveness. While improvements in all dependent variables were observed during folic acid treatment in comparison to initial baseline/placebo conditions, these changes were maintained in a final return to the placebo condition. These results do not support unequivocally the effectiveness of folic acid treatment. Folic acid treatment may have facilitated behavior changes that were then maintained by natural contingencies in the child's environment.
Prenatal diagnosis of the fra(X) syndrome
Authors: Shapiro Lawrence R. , Wilmot Patrick L. , Opitz John M. , Reynolds James F.
Published: June 2005

The fra(X) syndrome is one of the most common causes of mental retardation, and validation of the reliability and feasibility of making the prenatal diagnosis of this disorder is important for genetic counseling and prevention. We have received a total of 74 amniotic fluid specimens for prenatal diagnosis of fra(X) from worldwide sources. Results, were obtained on 68 specimens of which 43 had a documented family history of the fra(X) syndrome. Of the 43 specimens, 23 were male and 4 were prenatally diagnosed as being affected. On the basis of the results, several conclusions follow: (1.) At least 3 different tissue culture methods should be utilized. (2.) At least 150 cells should be scored, preferably 50 from each of 3 different tissue culture methods or 100 from each method if less than 3 methods are used. (3.) While the test‐appears to be reliable, it should still be considered to be experimental until larger numbers are obtained with completed follow‐up of cases.
Fragile X expression increased by low cell‐culture density
Authors: Krawczun Michael S. , Lele Kusum P. , Jenkins Edmund C. , Brown W. Ted , Opitz John M. , Reynolds James F.
Published: June 2005

The effect of cell density on expression of fra(X) was studied. A. lymphoblast cell line from one fra(X) individual and whole blood from another individual was tested at various cell densities using RPMI‐1640 with FudR (0.1 μM) 24 hrs before harvest. Densities from 0.25×105 to 2×106 cells/Ml were tested. Chromosomes were G‐banded and analyuzed for fra(X) frequency. Increased density caused fra(X) frequency to decline in lymphoblasts and whole blood. In the established line low density fra(X) frequency was 51.2% and decreased to 6.5% at the high density. In blood fra(X) frequency was 34.7% at low density and decreased to 18% fra(X) in high density. We suspect that of the FUdR effect may explain the results. Our results suggest that to maximize fra(X) frequency, clutures should be inititated at low density. This may be important in analysis female carriers, and obligate nonpenetrant males.
Fragile X chromosome frequency is consistent temporally and within replicate cultures
Authors: Jenkins Edmund C. , Kastin Bruce R. , Krawczun Michael S. , Lele Kusum P. , Silverman Wayne P. , Brown W. Ted , Opitz John M. , Reynolds James F.
Published: June 2005

Fragile X frequencies differ widely between different fra(X)‐positive individuals. The basis for this variation is unknown, but may reflect genetic differences or unknown environmental factors. To determine more fully the individual and familial variation in fra(X) frequencies, we studied 15 individuals. The present study showed that fra(X) frequency, with few exceptions, was consistent for the same individual both over time and within replicate cultures. This confirms previous observations by others on the consistency of fra(X) expression by others, and indicates the extent of expected variability within replicate cultures. Consideration of this variability should enable improved fra(X) identification.
The fragile X in cattle
Authors: Uchida Irene A. , Freeman Viola C. P. , Basrur Parvathi K. , Opitz John M.
Published: June 2005

In search of an animal model for the human fragile X syndrome, the chromosomes of Holstein cows were examined. This breed was chosen because of previous studies on the baldy calf syndrome. An achromatic gap was observed at a specific site on the X chromosome closer to the centromere than that identified in humans. This unstained gap was found in 3%–4% of cells of the following four animals: an affected calf, her sister, their mother, and an unrelated Holstein cow. The bovine fragile X may not be analogous to the human fragile X but its location may be important as a genetic marker in linkage studies involving the loci for hypoxanthine phosphoribosyltransferase (HPRT) and glucose‐6‐phosphate dehydrogenase (G‐6‐PD).
Prevalence of the fragile‐X syndrome in mentally retarded boys in a Swedish county
Authors: Gustavson Karl‐Henrik , K:son Hans Blomquist , Holmgren Gösta , Opitz John M. , Reynolds James F.
Published: June 2005

In an etiological study of an unselected series of mentally retarded children (IQ < 70) born 1959‐1970 in a northern Swedish county, 12 of 205 boys (5.9%) were found to have a fragile site on the distal end of the C‐chromosome (fra(X)(q27)). The incidence of the fra(X) syndrome was calculated to be 1:1500 boys in this county. If this is true for the whole of Sweden, 30–40 new cases of the fra(X) syndrome should be born yearly in Sweden. This must be considered a minimum figure, since a certain proportion of individuals with fra(X) are not observed in groups of mentally retarded patients.

Next to trisomy 21, the fragile X syndrome is the most common specific cause of mental retardation among mentally retarded boys in Sweden.
An assessment of the use of flanking DNA markers for fra(X) syndrome carrier detection and prenatal diagnosis
Authors: Forster‐Gibson Cynthia J. , Mulligan Lois M. , Simpson Nancy E. , White Bradley N. , Holden Jeanette J. A. , Opitz John M. , Reynolds James F.
Published: June 2005

One hundred and three individuals in ll unrelated families with the fragile‐X [fra(X)] syndrome were tested for polymorphisms identified bhy probes flanking the fra(X) site at Xq27.3 Two probes distal and 2 proximal to the fra(X) site were used. Thirteen known female carriers were analyzed retrospectively. DNA markers gave probabilities of carrying the mutation of 99% in 1 female, 89% in 8 females, and 10–55% in the other 4 females. We also estimated the probability of having inherited the mutation for 16 individuals of unknown fra(X) status using DNA markers and corrections for imcomplete penetrance. the DNA marker test gave risks for females of 1–6% (7 females), 15% (1 female), and 97% (1 female). In males the risks were 1–3% (6 males) and 91% (1 male). In 3 families, DNA marker data were used to calculate probabilities of ≥98.5% that transmission of the fra(X) mutation had occurred through normal males. In the retrospective studies, only 1 of 7 retarded males could have been diagnosed prenatally as having the fra(X) mutation with a probability of 99% DNA maker analysis was uninformative in 5 of these males. When fra(X) carrier status cannot be established by chromosome analysis, DNA maker studies provide an alternative test that can be used to calculate individual risks more precisely. However, linkage analysis of the probe loci in these 11 families suggests that the recombination frequency between the fra(X)locus and the factor IX gene (F9) and DXS52 may be greater than previously suggested. Until the true recombination frequencies are established and the question of heterogeneity among families is fully analyzed, caution in using DNA markers as a predictive is advised.
Speculation on the role of transposable elements in human genetic disease with particular attention to achondroplasia and the fragile X syndrome
Authors: Hoegerman Stanton F. , Rary Jack M. , Opitz John M. , Reynolds James F.
Published: June 2005

We suggest that mutations for fragile X‐positive Martin‐Bell syndrome, and prehaps also for achondroplasia, may result from the insertion of transposable elements (TE's). Loss of genetic function could result from either the insertion of TE's within or adjacent to a normal chromosmal gene or, in the case of fragile X, from the loss of genes distal to the site of TE insertion following subsequent TE excision without ligation of the resulting discontinuity.

The phenotypically and often cytogenetically normal transmitting males in fragile X peidgress are interpreted not as “nonpenetrant” transmitters of a fully formed fragile X but rather as transmitters of some or all of the factors necessary for necessary for TE insertion at Xq27. We consider it likely that such insertion frequently first occurs, both in some and especially in the germline, in their daughters.

Our models predict that father to son transmission of causative factors would be a common occurrence in fragile X pedigrees. The absence of documented father to son transmission either points to a flaw in the models or reflects systematic bias in the collection of pedigree information.
Recombination and amplification of pyrimidine‐rich sequences may be responsible for initiation and progression of the Xq27 fragile site: An hypothesis
Authors: Nussbaum Robert L. , Airhart Susan D. , Ledbetter David H. , Opitz John M. , Reynolds James F.
Published: June 2005

Hypothesis: A pyrimidine‐rich sequence (PRS) of DNA is present as a normal sequence in the q27 band of the human X chromosome. Under conditions of pyrimidine nucleotide triphosphate deprivation during S phase, deoxyuridine monophosphate is misincorporated and has to be excised during G2 by DNA mechanisms. When a simple PRS is present on both homologous X chromosomes during oogenesis, PRS may undergo amplification through non‐homologous crossing‐over ot produced the initial lesion of the fragile (X). Carriers of such initial lesions will be unaffected transmitting females or males. When an X chromosome bearing such an initial lesion is itself paired with a homologous X carrying a simple PRS during oogenesis, a much higher rate of non‐homologous crossing‐over may occur resulting in progression to an even longer stretch of pyrimidine rich DNA in this region; the increased length of PRS through amplification makes the region too long to be repaired during G2 and allows it to be seen as a fragile site in metaphase chromosome preparations. Furthermore, this amplified lesion may interfere with transcription of one or more genes in this region and produce the phenotype of the Martin‐Bell syndrome.
Univariate and bivariate analyses of cholesterol and triglyceride levels in pedigrees
Authors: Boehnke Michael , Moll Patricia P. , Lange Kenneth , Weidman William H. , Kottke Bruce A.
Published: June 2005

A multivariate normal model for pedigree analysis is applied to fasting total serum cholesterol and total serum triglyceride measurements on 771 individuals in 95 pedigrees from Rochester, MN. Univariate and bivariate analyses are carried out to determine to what extent the aggregation and coaggregation in families of these two traits may be attributed to shared genetic and environmental factors. Pedigrees were ascertained through a sample of schoolchildren enriched for those with serum cholesterol levels in the highest and lowest deciles of their age‐ and sex‐specific distributions. Ascertainment is corrected for by conditioning the likelihood on the trait values of the probands.

Univariate results confirm the findings of previous studies indicating that familial aggregation of serum cholesterol and triglyceride levels is due both to shared genes and to shared environmental factors. Results of the bivariate analyses suggest that the coaggregation of cholesterol and triglyceride levels in these families is strongly influenced by both shared genes (pleiotropy) and shared environmental factors. These findings are consistent with our understanding of lipid metabolism and of specific environmental factors known to influence both traits.
Clinical and cytogenetic survey of 39 individuals with Prader‐Labhart‐Willi syndrome
Authors: Butler Merlin G. , Meaney F. John , Palmer Catherine G. , Opitz John M. , Reynolds James F.
Published: June 2005

In a clinical and cytogenetic survey of 39 individuals with Prader‐Labhart‐Willi syndrome (PLWS) (23 males and 16 females ranging in age from 2 weeks to 39 years), an interstitial deletion of chromosome 15 (breakpoints q11 and q13) was identified in21 cases and apparently normal chromosomes in the remainder. Studies of parental chromosome 15 variants showed that the del[15q] was paternal in origin, although chromosomes of both parents were normal. All chromosome deletions were de novo events. Possible causes for the chromosome deletion and the role of chromosome rearrangements in individuals with PLWS are discussed. Clinical characteristics of the, deletion and nondeletion groups were recorded and compared with 124 individuals reported in the literature. Individuals with the chromosome deletion were found to have lighter hair, eye, and skin color, greater sun sensitivity, and higher intelligence scores than individuals with normal chromosomes. Correlation studies of metacarpophalangeal pattern profile variables and dermatoglyphic findings indicate apparent homogeneity of the deletion group and heterogeneity of individuals with PLWS and normal chromosomes.
Trisomy 14 mosaicism in a liveborn male: Clinical Report and review of the literature
Authors: Kaplan Lawrence C. , Wayne Alan , Crowell Stephen , Latt Samuel A. , Opitz John M. , Reynolds James F.
Published: June 2005

We present the history and results of chromosome analysis of a liveborn male with mosaic trisomy 14 who was initially evaluated for a congenital heart defect. His chromosome complement was 46,XY/47,XY, + 14. The phenotype of the patient is similar in many respects to that of females previously reported with mosaic trisomy 14, whereas the patient's micropenis and cryptorchidism are consistent with findings in males with dup(14q).
Diagnosis of chromosome 3 duplication q23→qter, deletion p25→pter in a patient with the C (trigonocephaly) syndrome
Authors: Preus Marilyn , Vekemans Michel , Kaplan Paige , Reynolds James F.
Published: June 2005

The cells of a deceased patient previously reported to have the C (trigonocephaly) syndrome were reinvestigated because his phenotype resembled that of a patient with a duplication‐deficiency of chromosome 3. This diagnosis was confirmed using fibroblasts grown from frozen cells, and his mother was shown to carry an inversion of chromosome 3 in her peripheral blood leukocytes.

His findings are compared to those of another patient with the C trigonocephaly syndrome with normal chromosomes and to others from the literature. At least one other patient from the literature has a phenotype compatible with “3q duplication syndrome”.
Chromosome deletion 1q42‐43
Authors: Watson Michael S. , Gargus J. Jay , Blakemore Karin J. , Katz Sanford N. , Breg W. Roy
Published: June 2005

We report on a newborn male and a female of 3 years 9 months with de novo 1q42 or 43‐qter deletions. These cases are compared with ten other reported cases.
Routine amniotic fluid alphafetoprotein assay: Experience with 40,000 pregnancies
Authors: Crandall Barbara F. , Matsumoto Myles , Opitz John M. , Reynolds James F.
Published: June 2005

Of 40,000 initial amniotic fluid samples, 0.7% had an alphafetoprotein (AFP) level ⩾ +3 standard deviations above the mean. The risk of an open neural tube defect (NTD) or other serious fetal abnormality was 61% when AFP levels measured ⩾ +3 and 87% for levels ⩾ +5 standard deviations. If the acetylcholinesterase (AChE) was positive, this risk was 84% and 95% for AFP levels of ⩾ +3 and ⩾ +5 SD, respectively, and 29% and 62% for the same levels if the AChE was negative. If the second amniocentesis AFP was also ⩾ +3, the risk of an abnormality was 96%. In this series, there were 93 open neural tube defects, and all were identified. The true false‐positive rate was 1 per 13,000 of the cases screened. The recurrence risk for an NTD was 1.8%, and the incidence of NTDs in women having amniocentesis only for maternal age was 1.5 per 1,000.
The genetics of quantifiable homeostasis: I. The general issues
Authors: Murphy Edmond A. , Trojak Joseph L. , Opitz John M. , Reynolds James F.
Published: June 2005

Some fundamental issues in developing the quantitative genetics of heritable traits are addressed. Such a trait must be capable of being represented as a quantity. Choice of the metric can be satisfactorily made only in the light of some insight into the nature of the trait and what its revealing characteristics may be. This insight is likely to change as more is known about the process, so the form and detail of the analysis is not static but perhaps continually evolving. Much has been made out of sample means and, at a more sophisticated level, Galton‐Fisher theory (the analysis of the first two moments of multivariate Gaussian variates). However, at least some processes seriously violate the assumptions underlying that theory. One such group comprises traits in which the means are unvarying and the genetic message lies in other aspects of the distribution; in these circumstances the standard summary statistics such as heritability, regression, and correlation may be totally uninformative, distracting, or even misleading. This paradox is illustrated by reference to homeostasis, where the Mendelian component lies, not in the mean, but in the degree of laxity of control. Since estimating higher moments is notoriously imprecise, the suggested remedy is the familiar and commonsense one of exploring the genetics of the intermediate states and underlying mechanisms and not only that of the resultant (“bottom‐line”) phenotype. In our chosen problem, the task of relating the outcome to the basic mechanism of inheritance calls for a detailed understanding of the homeostasis involved.
Ring chromosome 18 in a mother and son
Authors: Donlan Michael A. , Dolan Cynthia R. , Opitz John M. , Reynolds James F.
Published: June 2005

Inheritance of ring chromosomes is reported infrequently. We report on a mother and her son both with a ring 18 chromosome, and describe the associated manifestations. The son had microcephaly, ptosis, short stature, and mental retardation; the mother was mentally retarded and had a similar facial appearance.
A patient with dup(10p)del(8q) and pendred syndrome
Authors: van Wouwe J. P. , Wijnands M. C. , Mourad‐Baars P. E. C. , Geraedts J. P. M. , Beverstock G. C. , van de Kamp J. J. P. , Opitz John M. , Reynolds James F.
Published: June 2005

We report on a severely retarded girl with multiple congenital anomalies. Chromosome studies showed a der (8) chromosome with dup(10p) and deficiency for a small distal segment of 8q. Her father proved to be carrier of a de novo balanced translocation between chromosome 8q and 10p. At 1 year the patient was also found to have the Pendred syndrome, an autosomal recessive defect in thyroid organification. The concurrence of chromosome anomalies and single gene disorders might not be too rare, but can be easily overlooked. Yet there are important consequences for genetic counseling. Moreover, recognition of these concurrences may help gene mapping.
A bayesian method for the estimation of penetrance: Application to mandibulofacial and frontonasal dysostoses
Authors: Rogatko André , Pereira Carlos A. B. , Frota‐Pessoa Oswaldo , Opitz John M. , Reynolds James F.
Published: June 2005

We describe a Bayesian method of estimating penetrance from genealogical data. It consists of calculating the likelihood of the data alone to make inferences about penetrance without sample space considerations. The method is applied to mandibulofacial dysostosis giving a penetrance of 0.908 with 0.95 credible interval of [0.809; 0.972] and to frontonasal dysostosis giving a penetrance of 0.670 with 0.95 credible interval of [0.457; 0.851].
Suicide and attempted suicide in Huntington disease: Implications for preclinical testing of persons at risk
Authors: Farrer Lindsay A. , Opitz John M. , Reynolds James F.
Published: June 2005

Suicide behavior in Huntington disease (HD) was assessed by examining the proportion of deaths attributed to suicide among 452 deceased individuals with HD and the number and pattern of attempted suicides among a total population of 831 HD patients from the National Huntington Disease Research Roster. It was found that 5.7% of deaths among affected persons resulted from suicide and 27.6% of patients attempted suicide at least once. Comparison of this group with the general population indicated that the proportion of deaths due to suicide among persons with HD is almost four times greater than the corresponding proportion for the U.S. Caucasian population. Age at onset of HD was not significantly different between HD suicide and non‐suicide patients, although suicide occurred more frequently in the early to middle stages of the illness. The ''success'' rate among HD suicide attempters did not differ from the general population rates in several western European countries. The relatively high suicide and attempted suicide rates in HD indicate that thorough psychological testing of at‐risk persons and extensive patient support systems must be integral components of a program to identify HD gene carriers using a genetic marker.
De novo partial duplication of 17p [dup(17)(p12→p11.2)]: Clinical report
Authors: Magenis R. Ellen , Brown Michael G. , Allen Leland , Reiss Jacob , Opitz John M. , Reynolds James F.
Published: June 2005

Duplication of band p11.2 and a small proximal portion of band p12 of chromosome 17 was noted in an infant with unusual facial appearance and left calcaneovalgus deformity. Developmental delay was documented over time. Only one other similar case has been found in the literature, but deletion of the same region is known in nine recently described cases [Smith et al, 1986]. This suggests that abnormalities of this small region of 17p are relatively common and only recently detectable with modern high‐resolution techniques.
Nonsyndromal anencephaly: Possible autosomal recessive variant
Authors: Farag Talaat I. , Teebi Ahmad S. , Al‐Awadi Sadika A. , Opitz John M. , Reynolds James F.
Published: June 2005

The recurrence of anencephaly in families has been explained on a multifactorial basis. We present two unrelated families with three sibships of several nonsyndromal anencephalics including two pairs of concordantly affected like‐sex twins. A rare autosomal recessive variant is proposed and inheritance is discussed in view of parental consanguinity among the two affected sibships in one family.
Interstitial deletion of the short arm of chromosome 3 (3p14)
Authors: Short M. Priscilla , Shah Kumudini D. , Djamdjian Siranoush , Dische M. Renata , Gilbert Fred , Opitz John M. , Reynolds James F.
Published: June 2005

Deletions of 3p usually involve the terminal portion (3p25). An interstitial deletion of a proximal 3p segment (3p14) was detected at amniocentesis. The clinical and cytogenetic characteristics of this case and of three previously published cases are reviewed. Cardiovascular and gastrointestinal malformations have not been reported before in association with this particular chromosome abnormality.