bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic heterogeneity in Gaucher disease: Physicokinetic and immunologic studies of the residual enzyme in cultured fibroblasts from non‐neuronopathic and neuronopathic patients
Authors: Grabowski Gregory A. , Goldblatt Jack , Dinur Tama , Kruse Joanne , Svennerholm Lars , Gatt Shimon , Desnick Robert J. , Opitz John M. , Reynolds James F.
Published: June 2005

To elucidate the genetic heterogeneity in the three major phenotypic subtypes of Gaucher disease, the residual acid β‐glucosidase in fibroblasts from patients with all three subtypes from different ethnic and demographic groups was investigated by comparative kinetic, thermostability, and immunotitration studies. The kinetic studies delineated three distinct groups (designated A, B, and C) of residual activities with characteristic responses to the enzyme modifiers, taurocholate (or phosphatidylserine), and glucosyl sphingosine (or N‐hexyl glucosyl sphingosine); Group A residual enzymes responded normally to these modifiers. All neuronopathic patients (types 2 and 3) and most non‐Jewish, non‐neuronopathic patients (type 1) had group A residual activities and thus could not be distinguished by their kinetic properties. Group B residual enzymes had markedly abnormal responses to these modifiers. All Ashkenazi and only two non‐Jewish type 1 patients had group B residual activities. Group C residual activity had an intermediate response to all modifiers and represented a single Afrikaner type 1 patient. Pedigree studies indicated that this patient was a genetic compound for the group A (type 2) and group B (type 1) mutations. Thermostability studies showed additional heterogeneity of the residual activities within the three kinetic groups. Group A (type 2) and group B (type 1) enzymes had similarily decreased thermostabilities. In contrast, group A (type 1) residual activities were heterogeneous; three classes of thermostabilities were found among these enzymes: normal, decreased, and increased Immunotitration of equal amonuts of the normal or Gaucher dieseas β‐glucosidase activities with monospecific IgG indicated that the enzyme proteins from most Gaucher disease patients were antigenically altered and/or that large amounts of catalytically abnormal or inactive antigen were present. A decreased amount of antigenically and catalytically normal enzyme was present in a group A, type 1 African black patient, suggesting decreased stability or synthesis of his mutant acid β‐glucosidase. These kinetic, immunologic, and thermostability studies indicated that 1 type (1) Gaucher disease is biochemically heterogeneous and results from at least from distinct allelic acid β‐glucosidase mutations that alter enzyme structuer and/or function, 2 neuronopathic and non‐Jewish non‐neuronopathic phenotypes cannot be distinguished reliably by kinetic analyses alone, and 3) the Ashkenzi type 1 Gaucher disease results from a unique mutation that alters a specific active site domain of acid β‐glucosidase.
Similarity of effects—experimental hyperthermia as a teratogen and maternal febrile illness associated with oromandibular and limb defects
Authors: Superneau Duane W. , Wertelecki Wladimir , Opitz John M. , Reynolds James F.
Published: June 2005

Experimental hyperthermia in pregnancy causes oromandibular and limb anomalies. In humans, hyperthermia has been suspected of being teratogenic. Two patients were investigated; both had limb defects and one had oromandibular anomalies. Their mothers had a febrile illness at about the 10th wk of gestation. The similarity of defects produced by experimental hyperthermia and those reported here is striking.
Chondrodysplasia punctata in an infant with duplication 16p due to a 7;16 translocation
Authors: Hunter Alasdair G. W. , Rimoin David L. , Koch Ulrike M. , MacDonald G. June , Cox David M. , Lachman Ralph S. , Adomian Gerald , Opitz John M. , Reynolds James F.
Published: June 2005

This paper describes a newborn with a number of clinical manifestations compatible with duplication 16p due to a 46, XY, −7, +der (7), t(7;16) (p22;p13) pat karyotype. In addition, the baby had chondrodysplasia punctata, whose distribution of lesions did not match any of the well‐documented forms of these disorders. The baby also had microcornea and lacked a gallbladder, two features, in addition to chondrodysplasia punctata, that have not previously been noted in cases of duplication 16p.
Weaver syndrome with pes cavus
Authors: Farrell Sandra A. , Hughes Helen E. , Opitz John M. , Reynolds James F.
Published: June 2005

Few cases have been described of the Weaver syndrome, an overgrowth syndrome with advanced skeletal age. Here we report bilateral pes cavus in an affected girl.
Variance components analysis of forced expiration in families
Authors: Astemborski J. A. , Beaty T. H. , Cohen B. H. , Opitz John M. , Reynolds James F.
Published: June 2005

Familial aggregation of forced expiration (as measured by forced expiratory volume in 1 sec (FEV1) and the ratio of this to total forced vital capacity (FEV1/FVC) was analyzed in 439 adult members of 108 families ascertained through control patients who had participated in a genetic and epidemiologic study of chronic obstructive pulmonary disease. Residual values for both FEV1 and FEV1/FVC obtained from regression on age, sex, race, and cigarette smoking (and height for FEV1) were used in a variance components analysis to assess the relative importance of genetic and nongenetic factors influencing familial aggregation of pulmonary function among adults.

For both residual FEV1 and residual FEV1/FVC, the “best” model among a series of genetic and nongenetic models was a simple additive genetic model. A modified score test, which is robust to the assumption of multivariate normality, was used to test the significance of these estimated components. Under the most parsimonious model, additive genetic variation accounted for 28% of the variation in residual FEV1 in 108 families and 24% of the variation in residual FEV1/FVC. After outlying individuals were identified by examining goodness‐of‐fit statistics, the simple genetic model still gave the best fit to these data. There was little indication of non‐normality in FEV1 in these families; however, FEV1/FVC did show evidence of non‐normality when examining goodness‐of‐fit statistics. This genetic component contributing to the distribution of forced expiration may be a factor in the familial aggregation of certain respiratory diseases.
Apical hypertrophic cardiomyopathy in a father and daughter
Authors: Malouf Joe , Ratl Habib , Der Kaloustian Vazken M. , Opitz John M. , Reynolds James F.
Published: June 2005

Apical hypertrophic cardiomyopathy is described in a father and his daughter. In both, identical segments of the left ventricle were involved by the hypertrophic process with differing degrees of severity. We suggest that the morphologic findings described are due to a single gene with an autosomal dominant mode of inheritance.
Serum CK‐MB activity in progressive muscular dystrophy: Is it of nosologic value?
Authors: Vainzof Mariz , Zatz Mayana , Otto Paulo A. , Opitz John M. , Reynolds James F.
Published: June 2005

Serum creatine‐kinase (CK) isoenzyme MB was measured in 53 patients affected by different types of myopathies (20 with Duchenne muscular dystrophy (DMD), eight with the Becker form (BMD), ten with the limb‐girdle form (LGMD), six with the facioscapulohumeral form (FSH), and nine affected by polymyositis and in 21 normal control subjects).

The aim of this study was to compare each group with the control individuals and to assess the nosologic value of CK‐MB activity among some clinically similar dystrophies, which may have an important application for genetic counseling.

A statistically significant increased CK‐MB activity was found only in the Duchenne and Becker patients when compared with control persons (p < 0.05).

When the different groups of patients were compared among themselves, no significant difference was found between DMD and BMD or LGMD and polymyositis. However, a significant difference was found between BMD and LGMD.

Based on these data, it is possible, through discriminant analysis, to estimate the relative biochemical probability of an isolated male patient belonging to either group.
Further delineation of the dup(3q) syndrome
Authors: Wilson Golder N. , Dasouki Majed , Barr Mason , Opitz John M. , Reynolds James F.
Published: June 2005

Three patients with duplication of 3q regions ranging from 3q25→qter to the entire long arm provide additional documentation of the dup(3q) malformation syndrome. Data on 40 cases now reported define a characteristic face with hirsutism, synophrys, broad nasal root, anteverted nares, downturned corners of the mouth, micrognathia, and malformed ears recognizable even in the 30‐week fetus and distinct from that of the Brachmann‐de Lange syndrome. Other characteristic anomalies include congenital heart anomalies involving primarily septal defects, hand malformations including simian creases, abnormal dermatoglyphics, clinodactyly or camptodactyly, omphalocele, skeletal anomalies, and genitourinary malformations. Severe mental and growth retardation are common in those patients (64%) who survive the first year. Chromosome study of relatives is extremely important for counseling because only 10 of 40 cases represented de novo duplications.
An autosomal dominant syndrome of characteristic facial appearance, preauricular pits, fifth finger clinodactyly, and tetralogy of fallot
Authors: Jones Marilyn C. , Waldman J. Deane , Opitz John M. , Reynolds James F.
Published: June 2005

This report describes six relatives with a syndrome of mild prenatal‐onset growth deficiency, an altered craniofacial appearance, preauricular pits, and clinodactyly of the fifth finger; three had tetralogy of Fallot. The clinical impact of this condition appears to be related to the severity of the cardiac defect. Autosomal dominant inheritance is implied by the occurence of the disorder in three successive generations with documented male‐to‐male transmission. Recognition of this syndrome is important in counseling families regarding recurrence risk for tetralogy of Fallot.
Syndromes with lissencephaly. II: Walker‐Warburg and Cerebro‐Oculo‐Muscular syndromes and a new syndrome with type II lissencephaly
Authors: Dobyns William B. , Kirkpatrick Joel B. , Hittner Helen M. , Kretzer Frank L. , Roberts Richard M. , Opitz John M. , Reynolds James F.
Published: June 2005

Lissencephaly (smooth brain) is an abnormality of brain development characterized by incomplete neuronal migration and a smooth cerebral surface. At least two distinct pathological types occur, each associated with several recognized syndromes. In this paper, we report on the clinical and pathologic manifestations of four additional patients and classify and delineate three separate disorders with type II lissencephaly. We also report on a previously undescribed abnormality in one of the four patients—dilated rough endoplasmic reticulum cisternae containing an unknown osmiophilic secretory product, probably a glycoprotein.
History and relevance of the Hutterite population for genetic studies
Authors: Hostetler John A. , Opitz John M. , Reynolds James F.
Published: June 2005

The social and cultural origins of the Hutterian Brethren, the most inbred population in North America, are described along with the characteristics that make the group useful for genetic studies. The Hutterites represent a closed population, with high levels of fertility and consanguinity. The group maintains a stable residence pattern and keeps extensive genealogic records. The uniform pattern of communal living, the existence of endogamous subgroups within the population, and an orderly design for colony fission facilitates comparisons rarely found in other accessible populations. This inbred population is useful for detecting new recessively inherited diseases, for advancing our knowledge of the effect of inbreeding, and for analyzing human chromosomal variation. Selected demographic and genetic studies are cited.
Morquio syndrome (MPS IVA) and hypophosphatasia in a Hutterite kindred
Authors: Lowry R. B. , Snyder F. F. , Wesenberg R. L. , Machin G. A. , Applegarth D. A. , Morgan K. , Carter R. J. , Toone J. R. , Holmes T. M. , Dewar R. D. , Opitz John M. , Reynolds James F.
Published: June 2005

A patient is described who has Morquio syndrome (MPS IVA). He is a member of the Hutterite Brethren and genealogic analysis discloses a high inbreeding coefficient for the proband. The proband's sibship is segregating two autosomal recessive disorders, ie, MPS IVA and infantile hypophosphatasia. Two other families each have one or the other of these diseases but not both. The three families are distantly related.
Hutterite cerebro‐osteo‐nephrodysplasia: Autosomal recessive trait in a Lehrerleut Hutterite family from Montana
Authors: Opitz John M. , Lowry R. Brian , Holmes T. Mary , Morgan Kenneth , Reynolds James F.
Published: June 2005

We are reporting on two Lehrerleut Hutterite sisters who have a syndrome of 1) congenital shortness with mild spondylorhizomelic dwarfism; 2) later failure to thrive, ie deceleration of weight gain presumably due to CNS‐based severe feeding problems; 3) a CNS defect, probably developmental (not biochemical) with normal prenatal brain growth but later deceleration from 50th to 2nd centile associated with severe mental retardation and decorticate disturbances of neurologic function; and 4) possible renal involvement with terminal nephrotic syndrome.

This seems to be a previously undescribed pleiotropic autosomal recessive trait.
Congenital contractures, edema, hyperkeratosis, and intrauterine growth retardation: A fatal syndrome in hutterite and mennonite kindreds
Authors: Lowry R. B. , Machin G. A. , Morgan K. , Mayock D. , Marx L. , Opitz John M. , Reynolds James F.
Published: June 2005

We present clinical findings in infants from three kindreds (two Hutterite and one Mennonite) with an apparently unique, fatal disorder. The major manifestations consist of severe intrauterine growth retardation, congenital contractures, and tense skin which is easily eroded. The skin is tightly drawn over the face, giving an abnormal appearance consisting of a narrow, pinched nose, small mouth, limited jaw mobility, and ectropion (in one). One infant had first‐degree hypospadias. Apart from this, there were no organ malformations and the infants did not have hydrops. Histologically, the skin showed hyperkeratosis. It is postulated that this is a tissue dysplasia and that all of the clinical effects are secondary. The disorder appears to be an autosomal recessive trait. The two Hutterite families are from different endogamous subdivisions. They are related as fourth cousins onceremoved and fifth cousins in multiple ways through the six nearest common ancestors of all four parents. There are 25 founders (11 couples and three individuals) who are common ancestors. We computed the probability of joint descent of the four alleles in each pair of parents and in a sample of Alberta Hutterite couples, assuming that each of the common founders in turn was the original carrier. For an allele from one particular founder couple, there is a relatively greater probability of identity by descent for each pair of parents than on the average for other couples of the same endogamous subdivision.
II. Clinical studies in a kindred with a kinetic LDL receptor mutation causing familial hypercholesterolemia
Authors: Bilheimer David W. , East Cara , Grundy Scott M. , Nora James J. , Opitz John M. , Reynolds James F.
Published: June 2005

We have studied a family carrying a variant of the class 2 mutation of familial hypercholesterolemia (FH) in which there is unusual longevity and in which obligate heterozygotes did not express constant or statistically significant hypercholesterolemia. The heterozygotes have the same kinetic defect in the processing of low density lipoprotein (LDL) receptors in their fibroblasts and the reduced fractional catabolic rate for apoLDL that is characteristic of other patients with heterozygous FH. However, their plasma lipid and lipoprotein levels are not as strikingly abnormal because they have normal or near normal rates of apoLDL synthesis.
Deletion of the distal long arm of chromosome 1: A definable syndrome
Authors: Johnson Virginia P. , Heck Louis J. , Carter Guy A. , Flom Jon O. , Opitz John M. , Reynolds James F.
Published: June 2005

Based on analysis of 15 cases, there appears to be a characteristic facial appearance and pattern of associated malformations that would allow clinical delineation of deletion of the distal bands of 1q. Characteristic manifestations include round face with prominent “cupid's bow” and downturned corners of the mouth, thin vermilion borders of lips, long upper lip with smooth philtrum, short and broad nose, epicanthal folds, apparently low‐set ears, micrognathia, microcephaly, abnormal hands and feet, variable cardiac, genital, and other anomalies, moderate to severe mental retardation, and growth retardation. The deletion includes 1q42 or 1q43→qter and was a de novo defect in nine of 15 cases.
Epidemiology of neural tube defects in South America
Authors: Castilla Eduardo E. , Orioli Iěda M. , Opitz John M. , Reynolds James F.
Published: June 2005

We present data from the Latin American Collaborative Study of Congenital Malformations (ECLAMC) on prevalence rates and etiologic factor associations in neural tube defects. Two series of data are analyzed: the A series, including 740, 139 consecutive infants born in the 1967–1979 period suitable for secular trend analysis and case‐control study of risk factors; and the B series, including 255, 834 consecutive stillborn and liveborn infants of the 1980–1982 period suitable for prevalence rate analysis. Anencephaly was registered in 6.0/10,000 births, spina bifida aperta in 6.2/10,000 births, and cephalocele in 2.4/10,000 births. A stable secular trend was observed for the frequency of all three neural tube defect types. Spina bifida was more frequent in Chile than in the rest of South America. No differences in prevalence rates were seen between tropical and non tropical areas. Parental consanguinity and environmental prenatal factors including maternal illnesses, drug intake, and radiation exposure were found in association with anencephaly and spina bifida.
Heterozygous cystinuria and urinary lithiasis
Authors: Giugliani Roberto , Ferrari Iris , Greene Lewis J. , Opitz John M. , Reynolds James F.
Published: June 2005

Cystinuria is a recessively inherited transport disorder, with at least three mutant alleles (I, II, and III) demonstrable. I/I, II/II, and III/III homozygotes and I/II, I/III, and II/III compound heterozygotes (cystinuric patients) have high urinary concentrations of cystine, lysine, arginine, and ornithine and frequently form cystine stones. +/I heterozygotes (nondetectable) are phenotypically normal, whereas +/II and +/III heterozygotes (detectable) show variable increases in urinary cystine and lysine concentration and at times increases in urinary arginine levels. The objectives of the present study were to determine the frequency of +/II heterozygotes among stone‐forming and nonstone‐forming individuals from the same region of Brazil and to evaluate the possible relationship between heterozygous cystinuria and urinary lithiasis.

When urine samples from 5,150 individuals (5,000 nonstone‐forming individuals and 150 stone‐forming individuals) were screened by the qualitative cyanidenitroprusside cystine test, by thin‐layer amino acid chromatography, and by quantitative amino acid determination by ion‐exchange chromatography, 32 +/II or +/III heterozygotes (26 nonstone‐forming and six stone‐forming individuals) were detected. The frequency of detectable heterozygotes among the stone‐forming individuals (1:25) was significantly higher than that among nonstone‐forming individuals (1:104), which provides additional evidence that heterozygosity for +/II and +/III cystinuria is a risk factor in the formation of urinary stones. No significant difference was detected in urinary cystine concentration or in terms of the various characteristics of urolithiasis when stone‐forming heterozygotes were compared to nonstone‐forming heterozygotes. These data suggest that the tendency towards stone‐forming among heterozygotes is probably owing to a complex and multifactorial mechanism.
Segregation patterns and phenotypes of unbalanced offspring in a large family with (10;18) chromosome translocation
Authors: Bernstein Reneé , Pinto Maximina R. , Kromberg Jennifer , Wagner Joan , Jenkins Trefor , Opitz John M. , Reynolds James F.
Published: June 2005

We describe a large family in whom a balanced 10;18 chromosome translocaton is segregating through five generations. Six severely mentally retarded relatives and an abnormal fetus further define the phenotypic expression of dup (18q21 → qter). Other segregants detected prenatally included a fetus with deletion 18q21 → qter and two fetuses with dup(18pter → q21) owing to tertiary trisomy. One of the latter also had an extra X chromosome; this might be another example of possible nonhomologous pairing in man.
Histologic and ultrastructural studies on the mineralization process in hypophosphatasia
Authors: Ornoy Asher , Adomian Gerald E. , Rimoin David L. , Opitz John M. , Reynolds James F.
Published: June 2005

Chondroosseous tissue from six infants with infantile hypophosphatasia and six control infants were studied by light, transmission, and scanning electron microscopy. Alkaline phosphatase histochemical reaction of the growth plate was studied in two infants and was greatly reduced when compared to two control infants. Hypertrophic chondrocytes were increased in number with persisting cartilage islets in the metaphysis. In five of the six cases studied, chondrocytes and intercartilagenous intercellular chondroid matrix appeared ultrastructurally normal. Matrix vesicle distribution was similar to that of control subjects, but they were associated with few mineral crystals. In two infants, the matrix vesicles were alkaline phosphatase nonreactive. In the calcifying zone of the growth plate and in the newly formed metaphyseal trabecular bone, cartilagenous calcospherites often were small and the orientation of crystals was nonradial when compared to that of control infants. The mineralization of diaphyseal bone appeared normal. It seems that matrix vesicles are present in hypophosphatasia and that the impaired mineralization of cartilage is due primarily to the deficiency of alkaline phosphatase. In spite of the lack of alkaline phosphatase, secondary mineralization of bone which is not mediated by matrix vesicles was normal.
Planning a statewide genetic screening program: Defining program functions to achieve desired outcomes
Authors: Harris Mary S. , Carriere Andree R. , Opitz John M. , Reynolds James F.
Published: June 2005

When responsibility for administering the Genetic Screening Program in Georgia was transferred from an academic institution to state authority in 1982, the need was identified to reassess program planning. Accordingly, a cooperative effort was initiated between the Director of the Genetic Screening Program and representatives of the Centers for Disease Control to define desired program outcomes and the functions that should be performed to achieve these outcomes.

This cooperative effort resulted in the development of specific and measurable outcomes for Georgia's Genetic Screening Program. These desired outcomes indicate the degree of reduction in morbidity and mortality associated with genetic diseases the Program is expected to achieve within a specified period of time. The major actions that should be taken to achieve these outcomes were also identified and delineated in sequence using flowchart format.

These explicit descriptions of desired program outcomes and the functions necessary to achieve these outcomes provide the Genetic Screening Program Director with a valuable resource to use in planning program activities and assessing the extent to which the Program is successful in achieving its overall goal of reducing morbidity and mortality associated with genetic diseases.
Unusual facial appearance, microcephaly, growth and mental retardation, and syndactyly. A new syndrome?
Authors: Filippi G. , Fraser F. Clarke , Perus Marilyn
Published: June 2005

A syndrome with similarities to blepharo‐naso‐facial and KBG syndromes is described, indicating some important differences.
Dermatoglyphic indices of males with the fragile X syndrome and of the female heterozygotes
Authors: Simpson Nancy E. , Opitz John M. , Reynolds James F.
Published: June 2005

Indices for males with the fragile X [fra(X)] syndrome and for the female heterozygotes have been established. The indices were based on the increased frequencies of whorls and radial loops on the third digits of affected males and heterozygous femal increased frequency of arches on the third digits of the affected males, and an excess of low ab ridge counts and abnormal palmar creases, particularly the Sydney crease, in both sexes. The indices were calculated using the logN odds ratio based on the frequencies of the above dermatoglyphics and palmar creases in 47 males with the syndrome compared to 497 male controls and 36 heterozygous females compared to 493 female controls. The indices had similar distributions in males and females. Seventy per cent of males with the syndrome and 67% of female heterozygotes had an index ≥ +0.5. Thirty‐one per cent of female heterozygotes who had both the dermatoglyphic index calculated and their chromosomes examined under appropriate conditions for the fra(X) site had an index < +0.5 and had less than 2% fragile sites (most had none). However when the two tests were considered together, only 4/35 (11%) of the heterozygotes would not have been identified using the two criteria. The data suggest that the dermatoglyphic index is a helpful adjunct test with chromosome analysis for the identification of fra(X) heterozygotes.
Oral findings in fragile X syndrome
Authors: Shellhart W. Craig , Casamassimo Paul S. , Hagerman Randi J. , Belanger Gary K. , Opitz John M. , Reynolds James F.
Published: June 2005

This study compares the oral findings in fragile X syndrome individuals to those of normal age‐matched patients. Sixteen fra(X) males (mean age 22 10/12 years) had a low caries rate (decayed, missing and filled surfaces (DMFS) = 12.3) and minimal intraoral hard or soft tissue disease. Rate of malocclusion, as determined by the first permanent molar classification of Angle, was not significantly different from that of matched subjects. Fra(X) subjects had a significantly higher occurrence of malocclusion as compared to matched subjects using crossbite and openbite as criteria. Palatal dimensions of fra(X) subjects did not differ significantly from those of the matched sample. The fra(X) males also demonstrated significantly more severe occlusal wear of their teeth than the matched sample.
Speech disturbances (cluttering) in mildly impaired males with the Martin‐Bell/fragile X syndrome
Authors: Hanson Donna M. , Jackson Alfred W. , Hagerman Randi J. , Opitz John M. , Reynolds James F.
Published: June 2005

The language characteristics of fra(X) males (n = 10) with an IQ ≥ 70 were evaluated. Language testing demon strated relatively stronger receptive vocabulary skills compared to weak auditory memory and processing skills. A characteristic speech and language disturbance, cluttering, was present in 9 of the 10 study patients. Their speech was characterized by a fast and fluctuating rate of speech, and repetitions of sounds, words or phrases. Other aspects of cluttering including attentional problems, hyperactivity, motor delays and reading difficulties are commonly seen in the fra(X) syndrome. Cluttering may be helpful in identifying the fra(X) syndrome in a male who is not retarded.
Metaphyseal dysostosis and congenital nystagmus in a male infant with the fragile X syndrome
Authors: Williams Charles A. , Cantú Eduardo S. , Frías Jaime L. , Opitz John M. , Reynolds James F.
Published: June 2005

A 14‐month‐old male with congenital nystagmus, sparse scalp hair, protuberant ears, developmental delay, and radiologic manifestations of mild metaphyseal dysostosis was coincidentally found to have the fra(X) chromosome in 67% of analyzed metaphases. This observation underscores the need for fra(X) analyses in children with developmental deficit of unknown cause.
Gonadal function in men with the Martin‐Bell (fragile‐X) syndrome
Authors: Berkovitz Gary D. , Wilson Don P. , Carpenter Nancy J. , Brown Terry R. , Migeon Claude J. , Opitz John M. , Reynolds James F.
Published: June 2005

We evaluated testicular function in 15 men with the Martin‐Bell (fragile‐X) mental retardation syndrome. Macro‐orchidism was present in all subjects. Their mean serum LH and FSH levels and plasma testosterone and dihydrotestosterone levels were normal. The mean plasma levels of androstenedione, 17‐hydroxyprogesterone, and progesterone were slightly elevated above the normal range, whereas the plasma levels of dehydroepiandrosterone and dehydroepiandrosterone‐sulfate were normal. The response in the levels of plasma testosterone following a 5 day period of hCG stimulation was normal in 8 subjects and there was no abnormal accumulation of androgen precursors. The level of 5α‐reductase activity and androgen receptor binding was normal in genital skin fibroblasts derived from 3 of these patients. The response of gonadotropin secretion to GnRH stimulation was normal in the 8 men who were tested. Therefore, ourdata are consistent with the hypothesis that testicular enlargement in men with the Martin‐Bell syndrome is not mediated by hormonal factors.
Oral folic acid versus placebo in the treatment of males with the fragile X syndrome
Authors: Hagerman Randi J. , Jackson Alfred W. , Levitas Andrew , Braden Marcia , McBogg Pamela , Kemper Melinda , McGavran Loris , Berry Rebecca , Matus Irwin , Hagerman Paul J. , Opitz John M. , Reynolds James F.
Published: June 2005

A double‐blind, crossover study of a 10 mg folic acid per day (vs. placebo) treatment was carried out in 25 fra(X)males (ages 1–31 years). Each treatment period lasted 6 months. Before, during and after the study, the patients were assessed blindly with psychological, language and behavioral evaluations, and parent or caretaker reports were collected. Standardized testing did not show statistically significant changes in the group as a whole; psychological testing demonstrated a statistically significant improvement on folic acid in the prepubertal male After undercoding, caretaker or parent reports also demonstrated behavioral improvements in the prepubertal males while being treated with folic acid.
Second trimester prenatal diagnosis of the fragile X
Authors: Tommerup Niels , Aula Pertti , Gustavii Björn , Heiberg Arvid , Holmgren Gösta , von Koskull Harriet , Leisti Jaakko , Mikkelsen Margareta , Mitelman Felix , Nielsen Karen B. , Steinbach Peter , Stengel‐Rutkowski Sabine , Wahlström Jan , Zang Klaus , Zankl Merve , Opitz John M. , Reynolds James F.
Published: June 2005

The fra (X) chromosome was detected in 5 samples of amniotic fluid cells in a series of 23 pregnancies at risk. The prenatal results were confirmed in 2 male abortuses, one with a relatively high and one with a very low frequency of expression in both amniocytes and fetal tissue. In a third male fetus with low expression in amniocytes, the fra (X) was not detected in the fetal tissues tested. In another male with low expression in amniocytes the fra (X) was not detected after birth. In one female with a low expression in amniocytes, a very high frequency (28%) was detected in cord blood after birth. Low expression of the fra(X) was found in a 4‐year‐old normally developed girl, where the prenatal results had been negative. In 4 males and 4 females the negative prenatal diagnoses were confirmed after birth. This study indicates that prenatal diagnosis of the fragile X after amniocentesis may be complicated, either due to technical problems related to the use of amniotic fluid cells, or due to genetic heterogeneity, or both. Part of this heterogeneity could be due to the existence of normal male transmitters. Also, it seems that the frequency of expression in amniocytes from female carriers can not be used for the prediction of the frequency in blood after birth.
Infantile autism and the fragile X. A swedish multicenter study
Authors: Wahlström Jan , Gillberg Christopher , Gustavson Karl‐Henrik , Holmgren Gösta , Opitz John M. , Reynolds James F.
Published: June 2005

In a Swedish multicenter study of 122 cases of infantile autism 16 boys (13%) were found to be fragile (X)(q27) positive. None of the 21 girls studied were fragile (X) positive.
Effects of nucleotides on expression of the folate sensitive fragile sites
Authors: Sutherland Grant R. , Baker Elizabeth , Opitz John M. , Reynolds James F.
Published: June 2005

Further studies on the effect of nucleotides upon expression of the folate sensitive fragile sites have confirmed that high concentrations of thymidine (300 mg/l) but not BrdU (600 mg/l) induce these fragile sites. Induction by thymidine can be supressed by addition of cytidine in a dose response manner. Studies on other nucleotides suggest that guanosine, but not adenosine or cytidine, can induce the fragile sites. The previously hypothesised model for the DNA at a fragile site as a naturally occurring polypurine/polypyrimidine sequence which becomes amplified is further developed.
Clinical implications and classification of the constitutive fragile sites
Authors: Daniel Art , Opitz John M. , Reynolds James F.
Published: June 2005

Constitutive fragile sites (c‐fra) comprise the more prevalent but less recognised suite of fragile sites in eukaryotes. They differ from the heritable (rare) suite of fragile sites (h‐fra) in several significant ways. In the present report, data concerning the c‐fra so far recognised are reviewed in connection with their origin, classification, use as positive controls for cell culture conditions inducing the fra(X), and their presumptive relationships to the characteristic breakpoints in the neoplasias and in constitutional chromosome rearrangements.
Fragile X: Carrier detection in pregnancy
Authors: Tommerup Niels , Holmgren Gösta , Steinbach Peter , Opitz John M. , Reynolds James F.
Published: June 2005

The expression of the fragile X in 9 pregnant women (4 obligate carriers and 5 carriers at risk) was not significantly different from the expression observed either before or after pregnancy in the same individuals. Hence, carrier diagnosis during pregnancy seems to be as reliable as in non‐pregnant women.
Frequency of tri‐ or multiradial configurations in fragile X identification
Authors: Jenkins Edmund C. , Duncan Charlotte J. , Krawczun Michael S. , Berns Lisa M. , Sanz Maureen M. , Brown W. Ted , Opitz John M. , Reynolds James F.
Published: June 2005

Using the FUdR system for fragile X induction, we have observed no triradial or bisatellited configurations at fra (X)(q27.3) in over 5,000 fra(X) chromosomes examined from over 150 fra(X) individuals. Based on our observations, and those of Turner and Jacobs (1983) and Daniel et al (1984), we hypothesize that triradial configurations may not occur at Xq27 with FUdR induction. To test this hypothesis we cultured whole blood simultaneously in parallel folate‐deficient and FUdR fra(X) induction systems, and systematically examined fra(X) chromosomes for triradials. Neither autosomes nor X chromosomes exhibited any apparent triradial figures in the FUdR system, while 1.4% of the fra(X) chromsomes in TC 199 exhibited a triradial. Also we observed one autosomal triradial at 4q35. We conclude that triradial configurations, occur in low frequencies in the folate deficient system and seldom if ever in the FUdR system.
Fragile X mental retardation: Prevalence in a group of institutionalized patients in Italy and description of a novel EEG pattern
Authors: Sanfilippo S. , Ragusa R. M. , Musumeci S. , Neri G. , Opitz John M. , Reynolds James F.
Published: June 2005

We have studied the prevalence of the fra(X) and of the autosomal fragile sites fra(10) (q25) and fra(16) (q22) in patients from an institute for the mentally retarded in Italy. We found six cases (1.9%) of fra(10) (q25) and 9 (2.9%) of fra(16) (q22). The study of the fra(X) was restricted to a subgroup of 91 males who did not have other chromosome anomalies or variants, and led to the discovery of 4 fra(X) cases. These 4 had the Martin‐Bell syndrome; 3 of them were epileptic and had a characteristic EEG pattern originating during sleep from the temporal lobe not previously described in fra(X) mental retardation.
DNA studies of X‐linked mental retardation associated with a fragile site at Xq27
Authors: Davies Kay E. , Opitz John M. , Reynolds James F.
Published: June 2005

X‐linked mental retardation associated with expression of a fragile site at Xq27.3 has attracted much interest because transmission can occur through phenotypically normal males. Several theories have been proposed to explain the segregation pattern. Linkage analysis in affected families indicates a high frequency of recombination around this site in some families, although in others the genetic relationships are quite different and closer linkage between bridging markers is suggested. The problems associated with the clinical and cytogenetic analyses of this fascinating disorder await the results of detailed molecular approaches.
Inheritance of fragile X syndrome: An hypothesis
Authors: Friedman J. M. , Howard‐Peebles Patricia N. , Opitz John M. , Reynolds James F.
Published: June 2005

The fragile X (fra(X), or Martin Bell‐MB) syndrome is considered an X‐linked recessive trait. However, clinically normal male transmitters of the condition have been observed occasionally. The occurrence of “carrier” males and the observation of other unusual genetic characteristics in the MBS suggest that this condition is not a standard X‐linked recessive trait. We propose that the MBS is due to a transposible genetic element which can exist in 3 different chromosomal states and effect 2 different extrachromosomal environments. This model can account for the peculiar genetic behavior of the fragile X syndrome.
Maternal effect on intelligence in fragile X males and females
Authors: van Dyke Daniel L. , Weiss Lester , Opitz John M. , Reynolds James F.
Published: June 2005

If the mother is the fragile X gene carrier, her daughters (and sons) with the mutation are at high risk of mental retardation. If the father is the (clinically unaffected) carrier, his daughters are normal. This is strong evidence for a maternal effect. The decreased penetrance and variable expressivity in fra(X) offspring of carriers could be related, at least in part, to variabile expression or availability of some meternal factor between pregnancies.

We hypothesize a maternal effect in fra(X), with variability in intelligence of heterozygotes and hemizygotes mediated mainly by the maternal uterus or placenta by virtue of different patterns of lyonization in those tissues between pregnancies. If the mother is a carrier, the matenal placenta could develop with a skewed proportion of the normal or the fra(X) genetically active. Each female or male embryo could be exposed to very different enviroments with respect to genetic activity fo the fra(X) chromosome, depending on the site of implantation within the uterus. If the father contributes the fra(X), the intrauterine enviroment is invariably normal and so are the daughters. Modifiers of the intrauterine effect could include lyonzation patterns in tissues of the carrier fetus, and preferential inactivation of the paternal X in extra‐embryonic tissues. The ultimate phenotype of the developing heterozygote and hemizygote may be determined by a threshold effect and interaction between the maternal genotype, the placental genotype, and the fetal genotype. The possibility of maternal effects is testable and has implications for treatment.
Familial Miller‐Dieker syndrome associated with pericentric inversion of chromosome 17
Authors: Greenberg Frank , Stratton Robert F. , Lockhart Lillian H. , Elder Frederick F. B. , Dobyns William B. , Ledbetter David H. , Opitz John M. , Reynolds James F.
Published: June 2005

Recently it has been shown that most cases of the Miller‐Dieker syndrome (MDS) are caused by deletion 17p13.3. All familial cases have been associated with a balanced reciprocal translocation in a carrier parent and unbalanced translocations in their affected offspring. We report a new case of familial MDS in whom the mother carries a pericentric inversion of chromosome 17. She has had two children with MDS, one of whom was shown to carry a recombinant 17 consisting of dup(17q) and del(17p). The high frequency of familial MDS and its consistent association with balanced chromosomal rearrangements in one of the parents makes it important to do high‐resolution chromosome analysis on all patients with MDS and possibly all patients with lissencephaly. Finding a familial balanced rearrangement makes prenatal diagnosis of this condition feasible.
Interstitial deletion of the long arm of chromosome 1 [del(1)(q32q42)]
Authors: Al‐Awadi S. A. , Farag T. I. , Usha R. , El‐Khalifa M. Y. , Sundareshan T. S. , Al‐Othman S. A. , Opitz John M. , Reynolds James F.
Published: June 2005

A severely malformed girl died 7 days after birth and was found to have de novo interstitial deletion of 1q (1q32 → 1q42). Clinical abnormalities included microcephaly, encephalocele, small eyes with unilateral esotropia, hypertelorism but small prominent nose, highly arched palate, micrognathia, abnormal cry, apparently abnormal low‐set ears, short neck with low posterior hair line, narrow shoulders, congenital heart defect, hypoplastic nails, overlap of toes with flat feet, and single umbilical artery.
Diploid‐triploid mosaicism: Report of necropsy findings
Authors: Pettenati Mark J. , Mirkin L. David , Goldstein David J. , Opitz John M. , Reynolds James F.
Published: June 2005

This is the first report of necropsy findings associated with diploid‐triploid mosaicism. The important pathological findings are presented and compared to those of pure triploidy and those noted in noninvasive studies of diploid‐triploid mosaics. The clinical findings in this patient are compared with those of other reported cases.
Syndrome of short stature, microcephaly, mental retardation, and multiple epiphyseal dysplasia—Lowry‐Wood syndrome
Authors: Nevin Norman C. , Thomas Paul S. , Hutchinson Jill , Opitz John M. , Reynolds James F.
Published: June 2005

We describe a brother and a sister with a syndrome of short stature, microcephaly, mental retardation, and multiple epiphyseal dysplasia. The parents were normal. This appears to be the second example of the syndrome first described by Lowry and Wood [1975] in two boys who had epiphyseal dysplasia, short stature, microcephaly, and nystagmus; one of these patients was mildly mentally retarded. The Lowry‐Wood syndrome probably is an autosomal recessive trait.
The Wiedemann‐Beckwith syndrome: Pedigree studies on five families with evidence for autosomal dominant inheritance with variable expressivity
Authors: Niikawa Norio , Ishikiriyama Satoshi , Takahashi Satoshi , Inagawa Akira , Tonoki Hidehumi , Ohta Yachio , Hase Naoki , Kamei Tsutomu , Kajii Tadashi , Opitz John M. , Reynolds James F.
Published: June 2005

We describe 18 individuals from five unrelated families with various manifestations of the Wiedemann‐Beckwith syndrome. Pedigree analysis was performed on the 5 families and on another 19 families in the literature, each of which included more than one affected person. The following findings were obtained: (1) the clinical manifestations among the affected individuals were highly variable—those obvious in infancy tended to become less distinct with increasing age; (2) the syndrome was transmitted directly and vertically through three generations in four families, and through two generations in seven families; (3) male‐to‐male transmission was noted once; (4) the sex ratio in the affected individuals was not significantly different from 1; (5) the segregation ratio of the trait among the sibs of the probands was 0.571 ± 0.066; (6) the affected+carrier/normal ratio was one among the offspring of the affected individuals and obligate carriers; (7) phenotrance (the expected presence of the trait in a generation) of the syndrome in the sibship of probands was complete, whereas that in earlier generations appeared low. The discrepancy is attributable to the lessening of the clinical features with increasing age as well as to a possibly less aggressive search for abnormalities in older generations. These findings indicate that the syndrome is an autosomal dominant trait with variable expressivity.

High‐resolution chromosome banding analysis in seven affected individuals and their respective parents showed no abnormalities.
Hexosaminidase A deficiency in adults
Authors: Navon Ruth , Argov Zohar , Frisch Amos , Opitz John M. , Reynolds James F.
Published: June 2005

Deficiency of hexosaminidase A (Hex A) in adults was found in 15 individuals from nine unrelated Ashkenazi families; 14 individuals had neurological symptoms, one was clinically intact. Clinical, biochemical and genetic findings are reported and compared to previously reported cases.

The clinical picture varied between and within families and included spinocerebellar, various motor neuron and cerebellar syndromes. Psychosis appeared in 30% of cases. Involvement of three generations was recorded in one family. The phenotype appears too variable to serve as a basis for genetic classification. The level of Hex A activity in serum, leukocytes, and fibroblasts of all 14 patients was in the range of Tay‐Sachs disease (TSD) homozygotes when measured by the routine heat‐inactivation method. More sensitive and direct methods detected some residual activity. Cultured skin fibroblasts of patients synthesize the α and β chain precursors of Hex A of the same molecular weight as that synthesized by normal fibroblasts. However, the amount of the α chain precursor is greatly reduced. Mature chains were not detected. The one healthy adult we studied displayed a nonuniform distribution of Hex A; while it lacked activity in the serum it had intermediate activity in fibroblasts and leukocytes.
Achondrogenesis II–hypochondrogenesis: Variability versus heterogeneity
Authors: Borochowitz Zvi , Ornoy Asher , Lachman Ralph , Rimoin David L. , Opitz John M. , Reynolds James F.
Published: June 2005

Recently hypochondrogenesis was described as a form of neonatally lethal dwarfism said to resemble spondyloepiphyseal dysplasia congenita radiographically and achondrogenesis II morphologically. Because of the difficulty in distinguishing radiographically between mild achondrogenesis II and severe hypochondrogenesis, we performed a clinical, radiographic, and morphologic study of 24 cases originally classified as either achondrogenesis II or hypochondrogenesis, in an attempt to distinguish between heterogeneity and clinical variability. Review of the radiographic findings in these cases show a fairly continuous spectrum of bony defects, rather than two distinct radiographic syndromes. Chondro‐osseous histology and ultrastructure was similar in all cases regardless of severity and was characterized by hypervascularity and hypercellularity of the cartilage with multiple small, round dilated cysternae of rough endoplasmic reticulum. These findings suggest that hypochondrogenesis and achondrogenesis type II represent a spectrum with marked phenotypic variability.