bluuebunny/crossref_metadata_2025 huggingface dataset:
Site‐specific reciprocal translocation, t(11;22) (q23;q11), in several unrelated families with 3:1 meiotic disjunction
Authors: Zackai Elaine H. , Emanuel Beverly S. , Optiz John M.
Published: June 2005

We have studied 32 unrelated families with a site‐specific reciprocal translocation between chromosomes 11 and 22 [t(11;22) (q23;q11)]. In translocation heterozygotes 3:1 meiotic segregation occurs and results in abnormal progeny who carry the der(22) as a supernumerary chromosome. Phenotypic findings consistent with 47,XX (or XY), +der(22), t(11;22) include mental retardation, preauricular skin tag and/or sinus, ear anomaly, palate anomaly, micrognathia, congenital heart disease, and genital anomalies in males. The frequency of abortions among offspring of male and female heterozygotes is increased. Segregation analysis shows that the risk for unbalanced offspring to be born to female heterozygotes may be as high as 10%, and that there may be a significant risk to male heterozygotes as well. The overall carrier frequency among progeny of 11;22 translocation carriers is 70.6%. The occurrence of multiple 11;22 translocation events is supported by de novo occurrence of the translocation, familial heteromorphic variants of the der(22), and varied racial and ethnic backgrounds of the families. To our knowledge, with the exclusion of centric fusion translocations, this represents the only example of nonrandom exchange in a constitutional chromosomal rearrangement.
Pentasomy X: Report of patient and studies of X‐inactivation
Authors: Funderburk S. J. , Valente M. , Klisak I. , Opitz John M.
Published: June 2005

A five‐year‐old girl presented with mental retardation (MR), microcephaly, short stature, ptosis, malocclusion, abnormal elbows, fifth finger clinodactyly, joint hyperextensibility in hands and feet, renal hypoplasia, nonobstructive ureteral stasis, pyelonephritis, and renal failure. Five X chromosomes (49,XXXXX) were found in all peripheral blood lymphocytes and skin fibroblasts examined. Xa RBC typing, utilizing serial dilutions of antiserum, gave agglutination at a higher titer than in either Xg(a+) positive parent; the patient's serum IgM was also elevated. These immunological findings imply a lack of dosage compensation and incomplete inactivation of some X‐linked loci.
A previously unreported, dominantly inherited syndrome of shortness of stature, ear malformations, and hip dislocation: The coxoauricular syndrome—autosomal or X‐linked male‐lethal
Authors: Duca Daniela , Panǎ I. , Ciovirnache Martha , Simionesu Ligia , Ispas I. , Maximilian C. , Opitz John M.
Published: June 2005

We reported an apparently previously undescribed syndrome, designated the coxoauricular syndrome, in a mother and her 3 daughter, all of whom shared in variable manner shortness of stature, minor vertebral and pelvic changes, dislocated hip(s), and microtia with corresponding hearing loss. The oldest daughter had coincidental Ullrich‐Turner syndrome with 46,Xdel(X)(q13) chromosome constitution. Inheritance of the trait in this family is dominant, either autosomal or X‐linked, with hemizygote lethality.
Corneal dermoids and short stature in brother and sister—A new syndrome?
Authors: Guízar‐Vázquez J. , Luengas‐Muñoz F. J. , Antillón F. , Opitz John M.
Published: June 2005

We describe 2 sibs; brother and sister, with corneal dermoids and proportionately short stature. It is suggested that this is an autosomal recessive condition.
Familial midgut anomalies—a spectrum of defects due to the same cause?
Authors: Carmi Rivka , Abeliovich Dvorah , Siplovich Leonardo , Zmora Ehud , Bar‐Ziv Jacob , Opitz John M.
Published: June 2005

We report three familial cases with congenital midgut anomalies: a father and his daughter with congenital midgut volvulus and a consequent intestinal obstruction and father's female sib with atresia of the ascending colon. A common hypothetical cause operating at different gestational periods will be discussed along with the possible genetic implications.
Nonprogressive cerebellar disorder with mental retardation and autosomal recessive inheritance in hutterites
Authors: Schurig Verena , Van Orman Alan , Bowen Peter , Opitz John M.
Published: June 2005

We report a nonprogressive neurological disorder in at least 11 Hutterites with healthy but consanguineous parents. In several of the affected, hypotonia was noted at birth. Retarded motor and mental development became apparent during the first year of life. The age of unsupported walking varied from 5–21 years. Consistent signs were unsteady, broadly based gait and stance, exaggerated deep tendon reflexes mainly in the lower limbs, and mild to moderate mental retardation. Variable signs were extensor plantar reflexes (9/11), short stature (–2SD in 8/11), strabismus (7/11), small muscle mass (6/11), mild intention tremor (3/11), cataracts (1/11), and epilepsy (1/11). CAT scans in two affected sisters showed slight enlargement of the fourth ventricle in one and hypoplasia of the cerebellum in both. The disorder is probably the same as that described earlier under the heading, dysequilibrium syndrome.
Resolution of breakpoints in a complex rearrangement by use of multiple staining techniques: Confirmation of suspected 12p12.3 intraband by deletion dosage effect of LDHB
Authors: Magenis E. , Brown M. G. , Chamberlin J. , Donlon T. , Hepburn D. , Lamvik N. , Lovrien E. , Yoshitomi M. , Opitz John M.
Published: June 2005

A complex de novo translocation was found in leukocytes and fibroblasts from a boy with mental retardation and minor abnormalities. The 45,XY chromosome constitution found in all cells was initially interpreted from routine G‐ and Q‐banding techniques as a balanced translocation of part of the short arm of 12 to the short arm of 15 and of the long arm of 21 to the short arm of 12. With additional staining techniques and use of prometaphase chromosome preparations, it was determined that the distal portion of band 12.3 of the short arm of chromosome 12 was missing from the 12/15 and the 12/21 translocation chromosomes. This interpretation was confirmed by a decreased concentration of the LDH‐B subunit in lactate dehydrogenase isozymes of the patient's fibroblasts, consistent with his being hemizygous for the LDHB locus.
Wiedemann‐Beckwith syndrome: Autosomal‐dominant inheritance in a family
Authors: Best Lyle G. , Hoekstra Ronald E. , Opitz John M.
Published: June 2005

We report four additional cases of Wiedemann‐Beckwith syndrome (WBS): A mother, her brother, and two of her children (half‐sibs). Theories of the genetic transmission of the WBS are reviewed. The trait in this family appears to be an autosomal‐dominant with variable expressivity. A theory of delayed mutation of an unstable premutated gene is discussed and an interpretation and observations are offered which could alter slightly the expected pattern of inheritance. Eighty‐eight other family members were screened for evidence of WBS and noteworthy findings are presented.
Differential diagnosis of hydrops fetalis
Authors: Machin G. A. , Opitz John M.
Published: June 2005

Apart from isoimmunization, a number of conditions may present as hydrops fetalis and now account for a large proportion of hydropic infants. A large differential diagnosis must be considered when investigating the hydropic fetus and placenta while in utero, in the neonatal period, and at autopsy. An investigative protocol is proposed.
Unusual mosaicism of De novo structural abnormalities and ocular anomalies in a male with 13 trisomy syndrome
Authors: Reardon P. C. , Greenstein R. M. , Howard R. O. , Gianacopolos E. K. , Breg W. R. , Opitz John M.
Published: June 2005

A boy with the 13 trisomy syndrome was found to have a unique form of mosaicism in which each of the two cell lines had different structural rearrangements. The predominant cell line was partially trisomic for the distal portion of the long arm of chromosome 13, while the minor cell line was trisomic for all of the long arm of 13. The patient is also unusual because he had congenital glaucoma and was still alive at 10 years.
A Study of mitosis, meiosis, histology, and scanning electron microscopic details of spermatogenesis in an infertile male with probable 46,XY/47,XXY germinal mosaicism
Authors: Rajendra Barathur R. , Lee Ming‐liang , Amorosa Louis , Sciorra Leonard J. , Opitz John M.
Published: June 2005

A 29‐year‐old infertile man with mild eunuchoid body proportions and unilateral gynecomastia with a low sperm count had normal chromosomes in lymphocytes and skin fibroblasts. Serum testosterone, urinary ketosteroid, and follicle‐stimulating hormone levels were normal, but serum prolactin, luteinizing hormone, and estrogen levels were above normal. Testicular biopsy showed hypocellularity, a pacuity of maturing sperm, and increased lipid content in early spermatogonia. Cytogenetic analysis of the testicular material showed probable 46,XY/47,XXY mosaicism in spermatogonial cells. None of the cells in diakinesis and metaphase I showed the extra‐X as a univalent, and 50% of the cells in diakinesis were hypodiploid with intact XY bivalents. Further analysis of spermatogenesis revealed polymorphic dyads, triads, tetrads, and uncleaved meiotic products of first and second meiosis. Sex chromatin studies of testicular cells showed that 20% of the cells were X‐chromatin positive. Scanning electron microscopic study of sperm revealed a wide range of polymorphisms, with some uncleaved meiotic products maturing into double‐headed and double‐tailed sperm or sperm with bulbous middle pieces or protrusions. A cyto‐genetic basis for the origin of these abnormalities is presented.
A sixth report (eighth case) of craniosynostosis‐radial aplasia (Baller–Gerold) syndrome
Authors: Pelias Mary Z. , Superneau Duane W. , Thurmon Theodore F. , Opitz John M.
Published: June 2005

We report a patient with craniosynostosis, radial aplasia, imperforate anus, and several associated congenital anomalies. It is concluded that she has the Baller‐Gerold syndrome. Parental consanguinity supports the suggestion that this condition is inherited in an autosomal recessive manner.
Genetics of red cell COMT activity: Analysis of thermal stability and family data
Authors: Spielman Richard S. , Weinshilboum Richard M. , Opitz John M.
Published: June 2005

Previous studies have shown that the activity of human red cell catechol‐O‐methyltransferase (RBC COMT) is significantly correlated in sibs, that the population distribution is bimodal, and that RBC COMT from individuals with low activity is more thermolabile than that from individuals with high activity.

These observations and additional data from family studies are consistent with the hypothesis that RBC COMT activity is controlled by two alleles at an autosomal locus [Weinshilboum and Raymond, 1977], giving rise to genotypes with different but overlapping activity distributions.

In the present study, this hypothesis has been explored with various types of analyses. Given the assumption of Hardy‐Weinberg genotype frequencies, we find that the population distribution of RBC COMT activity is explained much better by codominant or “intermediate” inheritance than by either dominant or recessive inheritance.

The intermediate genetic model has also been used to analyze the data of Scanlon et al [1979] on thermal inactivation of RBC COMT in a random sample of blood donors. Hypothesis tests based on this analysis confirm the conclusion of Scanlon et al that individuals with different COMT genotypes differ in the thermostability of their RBC COMT.

Using the RBC COMT activities of low‐activity probands and their parents, we have derived the expected distribution of activity among the proband's sibs on the assumption of three genotypes in Hardy‐Weinberg equilibrium in the population. The fit of this expected distribution to that observed is excellent, supporting the genetic model.
Two siblings with unusually mild homozygous β‐thalassemia: A didactic example of the effect of a nonallelic modifier gene on the expressivity of a monogenic disorder
Authors: Prchal Josef , Stamatoyannopoulos G. , Opitz John M.
Published: June 2005

Two adult Black sibs with homozygous β‐thalassemia had severe deficiency of β‐chain production but an unusually mild clinical course and almost normal hematocrit values. Their father had the typical hematological findings of β‐thalassemia trait but the mother, in addition to the β‐thalassemia trait, had elevated F cells (42.2%). Elevated F cells were also present in a hematologically normal sister of the affected providing evidence that a gene for heterocellular hereditary persistence of fetal hemoglobin (HPFH) was also running in this family. The unusually mild clinical course of the two homozygotes is attributed to their inheritance from their mother of the heterocellular HPFH gene. The gene for heterocellular HPFH is nonallelic to the β‐globin locus and apparently acted as a modifier of the homozygous β‐thalassemia phenotype by facilitating F‐cell production and thus diminishing the pathophysiological consequences of the β‐thalassemia defect. The effect of heterocellular HPFH on the expression of homozygous β‐thalassemia or Hb S genotypes is an impressive example of the pathophysiological basis of changes in the expressivity of monogenic disorders due to action of nonallelic modifiers.
Achondrogenesis: A review with special consideration of achondrogenesis type II (langer‐saldino)
Authors: Chen Harold , Liu Charlotte T. , Yang S. Samuel , Opitz John M.
Published: June 2005

We describe two dwarfed infants with large head, short neck and chest, prominent abdomen, and short limbs. Both died neonatally. Radiographic and morphologic characteristics identified the Langer‐Saldino form of achondrogenesis (type II). Review of type II achondrogenesis documented distinctive clinical and anthropometric manifestations (fewer stillbirths, longer survival time and gestational period, larger size of the baby, longer limbs, and characteristic craniofacial features) as compared with type I achondrogenesis (Parenti‐Fraccaro).
dup(4p 15→4pter) in a 19‐year‐old woman resulting from a maternal 4;14 translocation
Authors: Clark Constance E. , Telfer Mary A. , Cowell Henry R. , Kalamchi Ali , Steg Nina L. , Opitz John M.
Published: June 2005

We describe a 19‐year‐old woman who has a duplication of 4p. The karyotype is 46,XX, – 14, + der(14),t(4;14) (p15;p12)mat in lymphocytes and skin fibroblasts. The patient has coarse hair, prominent forehead and tip of nose, coloboma, scoliosis, and mental retardation.
The Weissenbacher–Zweymüller syndrome: Possible neonatal expression of the Stickler syndrome
Authors: Kelly Thaddeus E. , Wells Hugh H. , Tuck Kenneth B.
Published: June 2005

The Robin anomaly is a recognized presenting manifestation of the Stickler syndrome, an autosomal dominantly inherited disorder originally termed “hereditary progressive arthroophthalmopathy.” We report an infant with the Robin anomaly, myopia and dumbbell‐shaped femora and humeri in a family with the Stickler syndrome. This observation suggests that the Weissenbacher‐Zweymüller syndrome is in fact a variant of the Stickler syndrome.
Gastro‐cutaneous syndrome: Peptic ulcer/hiatal hernia, multiple lentigines/café‐aulait spots, hypertelorism, and myopia
Authors: Halal Fahed , Gervais Marc‐H. , Baillargeon Jacques , Lesage Robert , Opitz John M.
Published: June 2005

We report the familial occurrence in a French Canadian family of peptic ulcer/hiatal hernia, multiple lentigines/café‐au‐lait spots, apparent hypertelorism, and myopia caused by a pleiotropic autosomal dominant gene with high penetrance and variable expressivity. Other probable but rarer components of the syndrome include ischemic heart disease, congenital heart disease, and maturity onset diabetes. Symptoms of peptic ulcer/hiatal hernia usually started in the second or third decade and were associated, at least in some examined individuals, with relatively increased acid secretion and abnormal dermatoglyphics.
Brief clinical report and review: The Marden‐Walker syndrome
Authors: Jaatoul Nadia Y. , Haddad Nadra E. , Khoury Leila A. , Afifi Adel K. , Bahuth Nadia B. , Deeb Mary E. , Mikati Mohammad A. , Der Kaloustian Vazken M.
Published: June 2005

We have studied a sibship with one confirmed and three probable cases of the Marden‐Walker syndrome (MWS). Our patient had the major manifestations of blepharophimosis and squint; narrowly arched palate with micrognathia; small mouth and mouth‐breathing; facial deformities and distortions; congenital muscle weakness with resulting scoliosis; mild pectus excavatum; camptodactylies and hip and finger joints subluxation. In addition, he had small, apparently low‐set and slightly malformed auricles with a unilateral preauricular tag. However, he had no apparent renal or cardiovascular involvement.

Results of CPK, EMG, and of histochemical, light microscopic, and ultrastructural studies of muscle biopsy do not suggest a primary myopathy but rather CNS related weakness/hypotonia with small muscle mass and hypoactive DTRs. This pathogenetic hypothesis is confirmed by the presence of severe mental retardation and minor brain changes suggesting cortical atrophy. In five previously reported cases there has been microcephaly. Phenotype analysis does not convince that the MWS is a true malformation syndrome, but rather hints at the possibility of a congenital metabolic dysplasia. Genetic analysis demonstrates autosomal‐recessive inheitance in this and two other instances; primarily sporadic occurrence leaves open the possibility of genetic heterogeneity.
Neural tube defects in france: Segregation analysis
Authors: Demenais F. , Le Merrer M. , Briard M. L. , Elston R. C.
Published: June 2005

Segregation analysis was performed on a subset of a large body of French data comprising 298 nuclear families. Two models were used in this analysis: the transmission probability model [Elston and Stewart, 1971; Elston, 1981] and the mixed model [Morton and MacLean, 1974]. Both models are consistent with familial aggregation of neural tube defects, in this sample, being due to either the segregation of a recessive major gene or a sibling environmental effect, or both factors. In each case, other environmental factors are also involved. These results were compared to the findings of other studies and discussed in respect to the diversity of the epidemiological features displayed by different populations. Some observations of vertical transmission in a British study and the proportion of affected first cousins, in both France and Great Britain, lead us to reject a possible absence of transmission. We propose a monogenic component with a large influence of environmental factors, some of which may be common to sibs, to explain the occurrence of neural tube defects in this sample.
DNA replication sequence in a dicentric (functionally monocentric) X chromosome formed by the joining of two X chromosomes at region p22
Authors: Yu C. W. , Priest J. H. , Byrd J. R. , Opitz John M.
Published: June 2005

In this study we used densitometry to evaluate DNA replication kinetics in a rearranged chromosome formed by the joining of two X chromosomes at region p22. No 45X mosaicism is present in peripheral blood or fibroblast cultures. The patient has primary amenorrhea, short stature, and gonadal dysgenesis. The sequence of replication in the majority of cells is p11, q11, q13, q22–24, q12, p22, q26, q28, q27, q25, and p21, q21. Thus p11 is the earliest region to replicate, and q21 is the last. In 66% of 127 cells analyzed, the replication pattern is asymmetric, and bands q12, q26, and q28 are most likely to be out of phase on the two sides of the breakpoint. We find that band p22 has a delay of replication compared to an abnormal X derived from two X chromosomes joined at the q23 region previously reported by us. Structural rearrangement may therefore delay replication in the region of the break.
The nasopalpebral lipoma‐coloboma syndrome: A new autosomal dominant dysplasia‐malformation syndrome with congenital nasopalpebral lipomas, eyelid colobomas, telecanthus, and maxillary hypoplasia
Authors: Penchaszadeh Victor B. , Velasquez Darlin , Arrivillaga Ramon , Opitz John M.
Published: June 2005

We describe a new autosomal dominant dysplasia‐malformation syndrome from eight affected individuals in three generations of a Venezuelan family. It is characterized by congenital symmetrical upper lid and nasopalpebral lipomas, bilateral symmetrical upper and lower palpebral colobomas located at the junction of the inner and middle thirds of the lids, telecanthus, and maxillary hypoplasia. Affected individuals have a broad forehead, widow's peak, abnormal pattern of eyebrows and eyelashes, and maldevelopment of the lacrimal punctae. Interorbital distance is normal, but interpupillary distance is increased due to divergent strabismus originating from visual interference from inner canthal masses. Persistent epiphora, conjunctival hyperemia, and corneal (and less frequently lens) opacities are a secondary consequence of the defect of the lacrimal punctae and the inability to close the lids completely. The syndrome has complete penetrance and a rather narrow range of expressivity. The primary defect could involve a dysplasia of adipose tissue leading to nasopalpebral and upper lid lipomas during embryogenesis, with the rest of the malformations being secondary to interference of morphogenesis of the mid‐upperface developmental field from the lipomatous hamartomas. Alternatively, a central rather than a peripheral mechanism of malformation might be considered, such as defective migration of neural crest cells.
Occurrence of cyclopia, myelomeningocele, deafness, and abducens paralysis in siblings
Authors: Burck Uta , Held Karsten R. , Kitschke Hans‐J. , Opitz John M.
Published: June 2005

As holoprosencephaly without chromosome defect may be associated with other CNS‐related anomalies such as mental retardation, mental illness, facial paralysis, endocrine disorders, deafness, spina bifida, and myelomeningocele, we present a family in which one girl had a myelomeningocele, a brother had orbital hypotelorism, facial and cerebral asymmetries, cerebral palsy, abducens paralysis, and inner ear deafness. A 3rd pregnancy was terminated at 16 weeks; the fetus had cyclopia. A common cause is discussed in these cases and in those families in which holoprosencephaly and additional malformations occur among different generations.
The fragile X chromosome: Current methods
Authors: Hecht Frederick , Jacky Peter B. , Sutherland Grant R.
Published: June 2005

At the International Congress of Human Genetics (Jerusalem, September, 1981) a Workshop was held on the fragile X chromosome; it was entitled “The Fragile X Chromosome: Current Methods.” It was to focus on laboratory methods required to detect or to enhance the detection of the fragile X.

The fragile site on the X chromosome is one of 13 proven fragile sites known in humans. (A diagram of these sites is provided.) The fragile site on the X is sensitive to the concentration of folic acid in the medium in which cells are cultured. Cytologically, gaps and breaks are increased at the X fragile site, which is located at band Xq27–28. To enhance expression in lymphocytes, prolongation of culture time to 96 hours, elevation of the pH, diminution of the colcemid effect, and air drying of slides are helpful. The need for methionine in low‐folate media can be overridden by the addition of fluorodeoxyuridine (FUdR). Detection of the fragile X in males requires meticulous attention to methods of lymphocyte culture and metaphase preparation and then the examination of a sufficient number of mitoses, eg, 50–100 metaphases per individual. Detection of the fragile X in female carriers is often more difficult. Uniform detection of all obligate female carriers has not been achieved. Difficulty may correlate with increasing age or intelligence of females.

Key methodologic advances with the fragile X include the addition of methotrexate, trifluorothymidine or, especially of FUdR to the culture medium. FUdR, for example, is helpful in demonstrating the fragile X in lymphoblastoid cell lines and fibroblasts. Both of these cell types now represent an opportunity to study the biochemistry of the fragile X.

The success of the FUdR technique with skin fibroblasts heralds the feasibility of demonstrating the fragile X chromosome in cultured amniocytes. Since the Workshop, it has been reported that with FUdR the fragile X could in fact be detected in 46,XY amniotic fluid cells.
Studies of microcephalic primordial dwarfism I: Approach to a delineation of the seckel syndrome
Authors: Majewski F. , Goecke T. , Opitz John M.
Published: June 2005

The literature dealing with the Seckel syndrome is discussed critically. Some 60 patients have been published as having the Seckel syndrome. The diagnostic criteria proposed by Seckel are met by only 1/3 of these. It seems evident that this “syndrome” is a heterogeneous group of microcephalic primordial dwarfism. An approach to the delineation of the Seckel syndrome is given.
Studies of microcephalic primordial dwarfism III: An intrauterine dwarf with platyspondyly and anomalies of pelvis and clavicles—osteodysplastic primordial dwarfism type III
Authors: Majewski F. , Stoeckenius M. , Kemperdick H. , Opitz John M.
Published: June 2005

We report a male infant with intrauterine growth retardation (IUGR) with alopecia, microcephaly, receding forehead and chin, large eyes, and large prominent nose. Roentgenographic examination showed platyspondyly, “dysplasia” of pelvis, elongated clavicles, and enlargement of proximal femora, clearly separating this condition from all presently known types of microcephalic IUGR.
Ring chromosome 6: Case report and review
Authors: Nishi Yoshikazu , Yoshimura Osamu , Ohama Koso , Usui Tomofusa , Opitz John M.
Published: June 2005

A ring chromosome 6 was identified in an apparently healthy girl with short stature and microcephaly. Of 100 peripheral lymphocyte metaphases analyzed, chromosome 6 was replaced in 73% by a monocentric ring chromosome, in 10% by a dicentric, in 1% by a tricentric, and 3% by two rings. Thirteen other cells were 45,XX, −6, which may represent 46,XX,r(6)/45,XX, −6 mosaicism. The breakpoints were located on bands p24 or p25 and q26 or q27. Eight other patients with a ring chromosome 6 have been reported. The most characteristic findings in subjects with a ring chromosome 6 are mental retardation and eye and ear abonormalities, none of which were present in our patient.
The implications of S‐phase exchanges for the mechanisms of radiosensitivity in trisomy 21
Authors: Athanasiou K. , Bartsocas C. S. , Opitz John M.
Published: June 2005

Human lymphocytes obtained from four patients with Down syndrome and from two normal individuals were irradiated with X‐rays during their S phase and examined for chromatid type aberrations. It is suggested that the significantly increased frequency of asymmetrical chromatid interchanges found in trisomic cells is related to an altered DNA repair system. This altered repair system is probably responsible for the increased frequency of chromosome aberrations that can be induced in these cells by x‐rays and the increased tendency for leukemia observed in Down syndrome as well.
The role of Yp in sex determination: New evidence from X/Y translocations
Authors: Zuffardi Orsetta , Maraschio Paola , Lo Curto Franco , Müller Ulrich , Giarola Arturo , Perotti Lisa , Opitz John M.
Published: June 2005

A 33‐year‐old man had azoospermia and tubular atrophy as in the Klinefelter syndrome but short stature. He had a 46,X,t(X/Y) (Xqter→p22.3::Yp11→Yqter) translocation and was H‐Y antigen‐positive. This excludes one of the genes controlling H‐Y antigen from the terminal portion of the short arm of the Y chromosome. This case and the two similar ones in the literature indicate that the proximal Yp portion is required for the differentiation of a male gonad. The pattern of X inactivation was random in the patient's fibroblasts, whereas in the lymphocytes the translocated chromosome was preferentially inactivated; comparison with other cases shows that the quantity of Y chromosome material involved in these translocations does not influence the X inactivation patterns. In the three cases with this dicentric translocation the X chromosome centromere is consistently the active one. Our case indicates that the choice of which centromere is inactivated is independent of the replication pattern of the X chromosome. Our patient and a few other relevant cases from the literature confirm that factors controlling height are located on the distal portion of Xp and of Yp.
The effects of long‐term fetal constraint in vitro on the cranial base and other skeletal components
Authors: Jaskoll Tina , Melnick Michael
Published: June 2005

Recently it was suggested that some cases of premature closure of the sagittal suture in humans may be due to fetal head constraint. Using various modifications of the procedure for long‐term shell‐less cultivation of chick embryos, we sought to test the hypothesis that fetal head constraint may result in abnormalities of the cranial base and other skeletal structures of the head. Our experiments with various sized containers demonstrate that fetal constraint is associated with both deformation and malformation of the craniofacial skeleton, including the cranial base, squamosal, columella (stapes), and mandible. The severity of both deformation and malformation appears to be a function of the degree of fetal constraint. If, as some suggest, abnormality of the cranial base is the primary anomaly in craniosynostosis, then our results tend to support the fetal constraint hypothesis as one explanation of simple craniostenosis.
Power of the affected‐sib‐pair method to detect disease susceptibility loci of small effect: An application to multiple sclerosis
Authors: Suarez Brian , O'Rourke Dennis , Van Eerdewegh Paul , Opitz John M.
Published: June 2005

The distribution of marker locus identity‐by‐descent scores in affected sib pairs provides a powerful tool for detecting the presence of a linked non‐Mendelian disease susceptibility locus. This basic approach is here extended to include a trio of sibs. A special type of sib trio consisting of two affected and one unaffected sib is investigated. It is shown that compared to affected‐sib‐pairs, trios with the above configuration are less efficient in detecting the presence of a linked disease susceptibility locus.

When the generalized two‐allele single locus model is fitted to sib pairs affected with multiple sclerosis, an estimate of the recombination fraction of 0.21 between the putative disease susceptibility locus and the HLA complex is obtained. However, this transmission model is deemed inadequate since a recombination fraction this large is inconsistent with the variety of HLA associations observed at the population level.
Not all cystic hygromas occur in the Ullrich‐Turner syndrome
Authors: Cowchock F. Susan , Wapner Ronald J. , Kurtz Alfred , Chatzkel Sherrie , Barnhart Jay S. , Lesnick Dianna C. , Opitz John M.
Published: June 2005

We report two sib fetuses with nuchal systic hygroma and cleft palate. This condition is probably recessively inherited as the parents have normal chromosomes (G‐banded) and the fetuses were of opposite sex. Nuchal cystic hygroma is a nonspecific malformation, which reflects a delay in development of the connection between the jugular lymph sacs and the internal jugular vein. This fetal malformation and its equivalent in the adult, neck webbing, has been reported to be a part of a variety of genetic malformation syndromes. Some suggestions for counseling parents of an affected fetus are made: If the chromosome karyotype of an affected fetus is unknown, ultrasound examination, rather than AFP studies, is suggested for future pregnancies.
Sacroiliitis in the old order Amish
Authors: Arnett Frank C. , Enlow Roger W. , Bias Wilma B. , Opitz John M.
Published: June 2005

In a study designed to clarify the relationship of HLA‐B27 and sacroiliitis, 45 members of seven Old Order Amish families were thoroughly evaluated for sacroiliitis. The primary study group was three sibs who carried HLA‐B27 and three of their other sibs who inherited the alternate non‐B27 haplotype, their spouses and offspring. The seventh B27 positive family was more distantly related. The study was undertaken with no prior knowledge of disease in these families. These families represented all the B27‐positive subjects who had been ascertained up to the time the study began. In these selected families, 24% of the members were found to have sacroiliitis, irrespective of whether they were B27 positive. Analysis of the relevance of HLA to disease in this kindred was confounded by the presence of Bw39 and B17, antigens associated with psoriatic arthritis. However, not all B27‐negative cases possessed one or both of these specificities. Rather than clarifying the relationship of B27 to disease, this study, in a highly consanguineous kindred, indicated that other nonlinked loci may be epistatic to B27, that other HLA alleles may be involved, or that certain causes are more prevalent in the Amish than in the non‐Amish population.
Does unequal crossing over contribute to the mutation rate in Duchenne muscular dystrophy?
Authors: Winter R. M. , Pembrey M. E. , Opitz John M.
Published: June 2005

In order to explain the high mutation rate in Duchenne muscular dystrophy (DMD), together with the apparent equal incidence of new mutations in sperms and ova, which is unusual when compared with other X‐linked conditions, it is postulated that a significant proportion of new mutations in DMD are caused by unequal crossing over in females at meiosis. If this is true, then there are important consequences for the strategy of research into the molecular basis of DMD.
A five‐generation family with sacral agenesis and spina bifida: Possible similarities with the mouse T‐locus
Authors: Fellous M. , Boué J. , Malbrunot C. , Wollman E. , Sasportes M. , Van Cong N. , Marcelli A. , Rebourcet R. , Hubert Ch. , Demenais F. , Elston R. C. , Namboodiri K. K. , Kaplan E. B. , Fellous M. , Opitz John M.
Published: June 2005

In man, a malformation that recalls some of the defects associated with T/t mutants in the mouse is sacral agenesis. We report on a family with a high incidence of sacral malformation, ranging from a complete absence of the sacrum (SA), with or without spina bifida aperta, to a spina bifida occulta (SBO) that could only be detected by x‐ray. The condition appeared in a man with four children who were all affected, and thereafter, to varying degrees, in 17 of his 28 descendants.

Segregation analysis has been performed in this family, using the Elston and Stewart transmission probability model [1971]. The two traits (SA and SBO) were first studied separately and then together. A fully penetrant major dominant gene is shown to cause SA. When the phenotypes SA and SBO are considered together, Mendelian transmission is rejected. This could be explained genetically by two alternative hypotheses: genetic heterogeneity or a dominant major gene transmitted in excess by heterozygotes (τAa A = 0.896), suggesting a segregation distortion property of an allele at a T‐like locus.

In the mouse, the T‐locus is linked to the major histocompatibility complex H‐2. Thus linkage was investigated between this assumed major SA gene and five polymorphic markers, especially those located on chromosome 6 (PGM3 and HLA). When SA is studied, none of the lod scores are significant. However, when SA + SBO are examined together a high lod score is obtained with PGM3 under the hypothesis of no sporadic cases (lod score = 1.85 at a recombination fraction of 0.087 ± 0.084).

Although similarities with a T‐locus (segregarion distortion, possible linkage with PGM3) appear in this pedigree, genetic heterogeneity of SA cannot be excluded.
Duchenne muscular dystrophy carrier detection using logistic discrimination: Serum creatine kinase, hemopexin, pyruvate kinase, and lactate dehydrogenase in combination
Authors: Percy Maire E. , Andrews David F. , Thompson Margaret W.
Published: June 2005

In the absence of an unambiguous test for identifying Duchenne muscular dystrophy (DMD) heterozygotes, methods are needed for combination of the results of individually equivocal tests as effectively and rationally as possible. We used logistic discrimination to assess the effectiveness of measurements of serum creatine kinase, hemopexin, pyruvate kinase, and lactate dehydrogenase alone and in various combinations in identifying DMD carriers. We analyzed 127 serum samples from 63 normal female controls (20–40 years old) and 67 from 38 obligate DMD carriers. The best two tests to use in combination were creatine kinase and hemopexin, and these two, with lactate dehydrogenase, were the best three. Use of all four tests was significantly better than any two or three. At the 95% level (with 5% of controls misclassified), 54% of the carriers were identified by CK alone, whereas 88% were identified by means of the four tests. Although a small proportion of known carriers still cannot be identified, application of the four tests to a group of 45 possible carrier mothers of isolated cases of DMD resolves the population into fairly discrete “normal” and “abnormal” subgroups. Thus, if bias of selection can be eliminated, application of logistic discrimination may permit a direct estimate of the proportion of mothers of affectecd boys who are homozygous normal.
A lethal, larsen‐like multiple joint dislocation syndrome
Authors: Chen Harold , Chang Chung‐Ho , Perrin Eugene , Perrin Jane , Opitz John M.
Published: June 2005

We describe here two isolated cases of lethal, Larsen‐like multiple joint dislocation syndrome. Death occurred shortly after birth with pulmonary insufficiency due to tracheomalacia and/or lung hypoplasia. Both had abnormal dermal collagen bundles. In one case, histochemical studies showed abnormal cartilagenous matrix and striking deficiency in the dense collagen bundles of joint capsules; electron‐microscopic studies of the hyalin cartilage of the trachea documented a relative increase of the small, short fibers with decrease of the matrix collagen fibers. This study confirms that this Larsen‐like syndrome is a disorder of connective tissue, possibly involving dysmaturity of the collagen fibers, with a predilection for joint capsules and tracheal cartilage. This lethal condition is characterized by pulmonary insufficiency, tracheomalacia, and collagen fiber dysmaturity.
Theory of genetic counseling for rare recessive traits with consanguinity
Authors: Murphy Edmond A. , Rosell Magdalena I. , Rosell E. Manuel
Published: June 2005

The theory of assessing genetic risk for rare autosomal recessive traits in the face of extensive consanguinity is explored. A general lemma is proved that justifies the partition of posterior probability and recursive incorporation of it, as a means of reducing the logic of analysis to steps of manageable complexity: the conditions are that either the components should be independent or that each component, as it is added, is conditioned on the occurrence of all earlier components. An example is given of a pedigree in which the tracing of a gene by the method of expected proportions is misleading, and another that points up the importance of the posterior information. Four classes of patterns are identified and appropriate methods devised for handling them: the single consanguineous loop, multiple mutually‐external loops, nested loops, and multiple closures. The latter problem may be treated in general by the use of truncated generating functions, with or without the use of matrix methods.
Sib risks for nonspecific mental retardation in British Columbia
Authors: Herbst Diana S. , Baird Patricia A. , Herrmann Jürgen
Published: June 2005

Cases of nonspecific mental retardation (MR) born in British Columbia between 1952 and 1970 ascertained through the British Columbia Health Surveillance Registry were linked by birth registration number to family sibships from computer‐linked groupings of birth and marriage records in British Columbia. It was possible to retrieve family information for 97% of the cases by this method.

Because of good ascertainment and relatively large sample size, the 1952–1965 birth cohort comprising 2,209 index cases was selected for calculations of overall risks and recurrence risks to sibs categorized by sex, MR level, associated neurological disability, and singleton versus multiple birth. The overall risk of affected individuals among all sibs was 4.4 ± 0.6%, which was about ten times greater than the minimum population incidence of nonspecific MR. The risk among subsequent sibs of the first affected case in a family was 3.7 ± 0.8%. These risks varied depending on sex, MR level, and whether the mental retardation was associated with hydrocephalus, microcephalus, cerebral palsy, or epilepsy. The recurrence risk after two affected individuals was 12 ± 7% – about three times greater than after one affected individual. Even though the frequency of MR is greater among twins than in the overall population, the recurrence risk of nonspecific MR was not significantly different for index cases from either singleton or multiple births.
Cockayne syndrome with early onset of manifestations
Authors: Moyer Donna B. , Marquis Paul , Shertzer Mark E. , Burton Barbara K. , Opitz John M.
Published: June 2005

The Cockayne syndrome is an autosomal recessive syndrome of growth failure and characteristic physical and pathological changes. Typically the disorder becomes manifest in the second year of life; growth and development are normal during the first year. We report presumably monozygotic twins with otherwise classic Cockayne syndrome but with a prenatal onset. Several previously described cases seem to represent a similar form of Cockayne syndrome with early onset of growth failure and development delay.
The greig cephalopolysyndactyly syndrome in a canadian family
Authors: Chudley Albert E. , Houston C. Stuart , Opitz John M.
Published: June 2005

A father and his son and daughter had preaxial and postaxial polydactyly, syndactyly, and craniofacial changes including macrocephaly and were diagnosed as having the Greig cephalopolysyndactyly syndrome. Additional defects in the father and other reportedly affected relatives were inguinal hernias and camptodactyly.
A clinical syndrome associated with dup(5p)
Authors: Carnevale Alessandra , Hernández Marisela , Limón‐Toledo Irma , Frías Sara , Castillo Julieta , Del Castillo Victoria , Opitz John M.
Published: June 2005

We report two cases of dup(5p), both the consequence of an unbalanced segregation of a balanced translocation. Our cases and those previously published suggest that dup(5p) when involving at least a portion of band 5p13 results in a recognizable clinical syndrome of congenital malformations, mental retardation, and growth failure. Although the size of the trisomic segment is different, the patients have a similar phenotype.
Posterior shoulder girdle abnormalities with absence of pectoralis major muscle
Authors: Hegde H. R. , Shokeir M. H. K. , Opitz John M.
Published: June 2005

We have reviewed 12 consecutively ascertained individuals with unilateral absence of the sterno‐costal head of the pectoralis major muscle and have studied associated abnormalities of the posterior shoulder girdle and their frequency and extent as contrasted with that of the symbrachydactyly. We found certain previously unreported associations of skeletal and renal anomalies in these individuals. We review various speculations regarding the possible causes of the Poland anomaly.
Attitudes regarding utilization of artificial insemination by donor in Huntington disease
Authors: McCormack Michael K. , Leiblum Sandra , Lazzarini Alice , Karp Laurence E. , Optiz John
Published: June 2005

We report on a study of attitudes toward artificial insemination by donor (AID) of persons at risk for Huntington disease (HD). The subjects of the study were 91 at risk persons and 68 matched controls. Both groups were divided by sex and age (45 yr ⩽ vs ≥ 46 yr). Demographic data included age, occupation, marital status, religion, education, ethnic background, and family size. We recorded (1) attitudes toward reproduction, (2) nature of contact with affected family member(s), (3) effects of HD on family planning, (4) attitudes toward AID, and (5) concern about donor selection criteria. Results suggest that (1) men and women differ in several ways with regard to their views about AID, and (2) that more vigorous educational programs might increase utilization of AID for the prevention of not only HD, but other human genetic diseases as well.
Deletion mapping of polymorphic loci by apparent parental exclusion
Authors: Daiger Stephen P. , Chakravarti Aravinda , Opitz John M.
Published: June 2005

Deletion of a chromosome region containing a polymorphic marker may result in apparent parental exclusion at that locus. We present a general method for calculating the probability that deletion at a specific locus would have such an effect. For many autosomal loci this probability is substantial, justifying attempts at deletion mapping in most cases. This method may be especially valuable in assigning DNA restriction fragment polymorphisms to chromosome regions.
Inheritance of immunoglobulin E: Genetic model fitting
Authors: Hasstedt Sandra J. , Meyers Deborah A. , Marsh David G. , Opitz John M.
Published: June 2005

Total serum immunoglobulin E (IgE) concentration was measured on 316 members of five pedigrees selected through breast cancer probands. Sex‐ and age‐adjusted natural logarithm‐transformed IgE level was not found to differ between individuals with breast cancer or with cancer of any site and other relatives. Likelihoods of the polygenic and of one‐locus, two‐allele major gene and mixed models were computed. The analysis provided evidence for the presence of a polygenic component in the determination of IgE; it did not show evidence of a major gene effect.
Duplication (17p) in a child with an isodicentric (17p) chromosome
Authors: Mascarello J. T. , Jones M. C. , Hoyme H. E. , Freebury M. M. , Opitz John M.
Published: June 2005

We present a child with multiple structural defects due to duplication of the short arm and a small portion of the long arm of chromosome 17. Three children with similar cytogenetic abnormalities have been reported previously. The karyotype contained an isodicentric chromosome derived from chromosome 17. A clue to the mechanism that produced the isochromosome was retained in the genome in the form of a part of the chromosome 17 long arm which was attached to the short arm of a chromosome 10.
Deficiency of lysosomal hydrolases in apparently healthy individuals
Authors: Zlotogora Joel , Bach Gideon
Published: June 2005

The deficiency of a lysosomal hydrolase usually results in the storage of its substrate(s) leading to various clinical abnormalities, typical for each deficiency. However, in certain lysosomal hydrolases, an apparent deficiency was noted which does not result in the classical clinical picture. This condition was described for aryl sulfatase A, β‐hexosaminidase, α‐galactosidase, and galactocerebrosi‐dase, where apparently healthy individuals showed in vitro very low hydrolase activity, usually indistinguishable from the affected patients. The deficiency was usually observed with both the synthetic and natural substrates. In the case of aryl sulfatase A deficiency, no clinical abnormalities were noted in these individuals, and cultured cells obtained from them were able to catabolize normally the natural substrate. Such cases are therefore referred as pseudodeficient. In other cases, such as in β‐hexosaminidase‐A deficiency, mild manifestations of the corresponding disorder were reported with subsequent intralysosomal storage of GM2 gan‐glioside. Our analysis indicates that most of these cases represent a compound heterozygote for the deficient allele and another allele coding for an in vitro low enzyme activity (pseudodeficiency). A complete biochemical explanation for this phenomena is not yet established. The importance of understanding this condition(s) for proper genetic counseling is discussed.