bluuebunny/crossref_metadata_2025 huggingface dataset:
Lethal multiple pterygium syndrome: Three consecutive cases in one family
Authors: Martin Nicole J. , Hill J. Brian , Cooper David H. , O'Brien Greg D. , Masel John P. , Opitz John M. , Reynolds James F.
Published: June 2005

We report on three sib fetuses with the lethal multiple pterygium syndrome (LMPS), one case occurring in a twin pregnancy. All three fetuses had a cystic hygroma and hydrops was detected by ultrasound. The classification scheme for LMPS proposed by Hall [1984] is examined. With our present state of knowledge of this syndrome, subdivision on bone‐fusion types does not appear to be justified. Antenatal detection by ultrasound is possible in most pregnancies with a second affected fetus because of cystic hygroma and hydrops. In the term or near‐term infant in which ultrasound has not shown cystic hygroma or hydrops, a diagnosis of Pena‐Shokeir type I syndrome should be considered because pterygia are a component of that syndrome but cystic hygroma and hydrops are not.
Another Italian family with mandibuloacral dysplasia: Why does it seem more frequent in Italy?
Authors: Tenconi Romano , Miotti Francesca , Miotti Antonio , Audino Giuliano , Ferro Roberto , Clementi Maurizio , Neri Giovanni
Published: June 2005

We describe three patients (one female and two males in a sibship of 11) with mandibuloacral dysplasia. Only eight families have been reported previously, and of these, four were of Italian origin. The phenotypic spectrum of the condition is delineated and its variability is stressed. The observation of three affected members of both sexes with normal parents supports the hypothesis of autosomal recessive inheritance. The reasons for the high frequency of the condition in Italy are discussed; a local selective advantage for heterozygotes and founder effect might be involved.
Cohabitation, convergence, and environmental covariances
Authors: Lange Kenneth , Reynolds James F.
Published: June 2005

Temporal variation in traits has long been a central theme in epidemiology. However, human geneticists have largely avoided this topic. Recently, several authors have shown how temporal variation in relative‐to‐relative covariances can be accommodated within the framework of variance components analysis. The present paper attempts to clarify the mathematics implicit in their approach. A stochastic mechanism is discussed that causes covariances to converge or diverge exponentially fast as relatives cohabit or lead separate lives.
Updating McKusick: An educational exercise for medical students
Authors: Bodurtha Joann N. , Townsend J. Ives , Proud Virginia K. , Nance Walter E. , Opitz John M. , Reynolds James F.
Published: June 2005

An educational module is described in which first‐year medical students were assigned different entries from the 1983 edition of McKusick's Mendelian Inheritance in Man to revise and update. Following review and discussion in small group sections, the entries were reproduced to provide each student with an updated compendium of the selected genetic disorders. The important principles of Mendelian inheritance could be readily illustrated by the entities assigned to each discussion group. Students learned to use the library and how to understand and integrate clinical and experimental papers. More than half the students reported spending 11–20 h to complete the assignment and reviewed from six to ten articles in detail. The caliber of the entries was found to be significantly correlated with the time students reported they spend on the exercise, but not with the number of papers reviewed, prior knowledge of the disease entity, the frequency of dictionary usage, or undergraduate exposure to genetics.
A computer model for the study of segregation in reciprocal translocation carriers: Application to 20 new cases
Authors: De Arce Miguel A. , Grace Patrick M. , McManus Susan , Neri Giovanni
Published: June 2005

We report on a computer program that, given the breakpoints and the chromosomes involved in a translocation, generates all the possible imbalanced gametes, calculates their corresponding imbalances, and arranges them in order of increasing imbalance. When compared to current, more cumbersome criteria from the literature, both methods agreed on 196 cases of 199 (>98%). When compared to observed data from families with aneuploid offspring, both our program and the other reported methods yield a rate of accurate prediction of 87%. The use of the program is illustrated in 20 new translocations from our laboratory. The possible influence of crossing over in meiosis I in altering the gamete that is most likely to be passed to aneuploid live births is discussed.
Treatment of duchenne muscular dystrophy with growth hormone inhibitors
Authors: Zatz Mayana , Betti Roberto T. B. , Frota‐Pessoa Oswaldo , Opitz John M. , Reynolds James F.
Published: June 2005

A controlled, double‐blind therapeutic trial with the drug mazindol, a growth hormone inhibitor, was performed in a pair of 7 1/2 year‐old monozygotic twins, with Duchenne muscular dystrophy (DMD). The rationable for this trial was based on a patient (reported previously) affected simultaneously with DMD and growth hormone (GH) deficiency, who is showing a benign course of the dystrophic process and is still walking at 18 years.

One of the twins received 2 mg of mazindol daily, while the other received a placebo. The assessment, repeated every 2 months, included weight and height measurements, functional and motor ability tests, ergometry and determinations of serum enzymes and GH levels.

After one year of trial the code was broken and it was seen that the twin under placebo treatment was strikingly worse than his brother, the progression of whose condition.
Duplication (12q) syndrome in female cousins, resulting from maternal (11;12) (p15.5;q24.2) translocations
Authors: McCorquodale Maureen M. , Rolf Joann , Ruppert Elizabeth S. , Kurczynski Thaddeus W. , Kolacki Paula , Opitz John M. , Reynolds James F.
Published: June 2005

We have studied female cousins with partial duplication of 12q. The cousins' mothers (who are sisters) and the maternal grandmother and great grandmother carried a balanced translocation between chromosomes 11 and 12. We have compared our patients with eight other reported cases of partial duplication of the same chromosome segment (12q24→12qter). Placement of the extra material seems to have little effect on the anomalies present; (only two other cases involved chromosome 11). We propose that our patients provide further evidence that duplication of 12q leads to a clinically identifiable syndrome.
Del(20p) with manifestations of arteriohepatic dysplasia
Authors: Byrne J. L. B. , Harrod M. J. E. , Friedman J. M. , Howard‐Peebles P. N. , Opitz John M. , Reynolds James F.
Published: June 2005

A small‐for‐gestational age white female infant was noted to have multiple minor anomalies and severe jejunal stenosis. Mild peripheral pulmonic stenosis, skeletal anomalies, and cholestasis with paucity of intrahepatic bile ducts were observed, and she was diagnosed as having arteriohepatic dysplasia. Chromosome analysis of peripheral blood leukocytes showed a 46,XX,del(20)(p11.2) chromosome constitution.
Association of amyoplasia with gastroschisis, bowel atresia, and defects of the muscular layer of the trunk
Authors: Reid C. O. M. V. , Hall J. G. , Anderson Carol , Bocian Maureen , Carey John , Costa Theresa , Curry Cynthia , Greenberg Frank , Horton William , Jones Marilyn , Lafer Charlotte , Larson Eunice , Lubinsky Mark , McGillivray Barbara , Pembry Marcus , Popkin James , Seller Mary , Siebert Virginia , Verhagen Arie , Opitz John M. , Reynolds James F.
Published: June 2005

We reviewed 225 cases of amyoplasia, and the association of amyoplasia with gastroschisis and with monozygotic twinning was confirmed. In addition, an apparently increased association of bowel atresia and defects in the muscular layer of the trunk wall with amyoplasia was observed. The association of amyoplasia, monozygotic twinning, and these trunk wall defects strongly suggests that the pathogenesis of amyoplasia is linked to some type of vascular compromise.
Homeostasis VII. A conspectus
Authors: Murphy Edmond A. , Pyeritz Reed E. , Opitz John M. , Reynolds James F.
Published: June 2005

The characteristics and properties of physiological homeostasis are broadly reviewed in terms that should pave the way for definitive genetic analysis. The ideas are illustrated by common physiological and pathophysiological examples with special reference to type II diabetes mellitus.
An apparently new syndrome of microcephalic primordial dwarfism and cataracts
Authors: Toriello Helga V. , Horton William A. , Oostendorp Ann , Waterman Donald F. , Higgins James V. , Opitz John M. , Reynolds James F.
Published: June 2005

We describe two sibs with prenatal‐onset growth deficiency, microcephaly, cataracts, mental retardation, enamel hypoplasia, immune deficiency, and generalized delay of ossification. The combination appears to constitute a previously undescribed autosomal recessive syndrome.
Genetic aspects of immotile cilia syndrome
Authors: Sturgess J. M. , Thompson M. W. , Czegledy‐Nagy E. , Turner J. A. P. , Opitz John M.
Published: June 2005

The genetics of the immotile cilia syndrome has been analyzed in a series of 46 affected individuals from 38 families. Both sexes were equally affected: there were 20 males and 26 females in this series. All patients had upper and lower respiratory disease with chronic sinusitis, otitis, and chronic cough from early childhood. Bronchiectasis was common in older children and adults. Situs inversus occurred randomly, affecting 11 males and 15 females. Biopsies of nasal and bronchial mucosa from these subjects have been investigated by electron microscopy and identified as having specific ultrastructural defects of respiratory tract cilia including deficiencies in outer dynein arms (19), inner dynein arms (3), both inner and outer dynein arms (15), radial spoke defect (5); and microtubular transposition anomaly (4). Segregation analysis of proband sibships was consistent with autosomal recessive inheritance. However, the different ultrastructural defects that underly the immotile cilia syndrome involve presumably different genetic determinants, and the different types have not been analyzed separately. Examination of paternal age and birth order gave no evidence of new autosomal dominant mutation in the series.
Chromosomal mosaicism of trisomy 7 restricted to chorionic villi
Authors: Bartels Iris , Rauskolb Rüdiger , Hansmann Ingo , Neri Giovanni
Published: June 2005

Chromosomal mosaicism confined to the placenta is a serious problem in first‐trimester fetal diagnosis. We report a case of mosaicism of trisomy 7. The aneuploid cell line could not be confirmed in fetal tissue.
Duchenne muscular dystrophy in a girl with an (X;15) translocation
Authors: Ribeiro Maria cecília Menks , Melaragno Maria Isabel , Schmidt Beny , Brunoni Decio , Gabbai Alberto Alain , Hackel Christine , Reynolds James F.
Published: June 2005

This is a report of a girl with Duchenne muscular dystrophy (DMD) associated with an 46,X,t (X;15) (p2l; q 26) chromosome constitution. Although in the eight published cases of girls with DMD and a t(X;aut) different autosomes were involved in the translocation, the breakpoint was always at Xp2l.

The present case supports the hypothesis that the DMD gene must be located at Xp21. In this study, involvement of the father's chromosomes in the translocation was detected.
Duchenne muscular dystrophy in a girl with a 45, X/46, XX/47, XXX chromosome constitution
Authors: Bortolini Eliete Rabbi , da Silva Déa Martins , Chequer Rosemary Santos , Vianna‐Morgante Angela M. , Zatz Mayana , Opitz John M. , Reynolds James F.
Published: June 2005

We report on a 4‐year‐old girl with Duchenne muscular dystrophy (DMD). One of her sisters had grossly elevated serum creatine‐kinase and pyruvate‐kinase levels, and one of her maternal great uncles was presumptively affected by DMD. Cytogenetic analysis showed a 45,X/46,XX/47,XXX chromosome constitution. The maternally inherited DMD gene is presumed to be present on the single X of the 45,X cell line.
Aniridia, congenital glaucoma, and hydrocephalus in a male infant with ring chromosome 6
Authors: Levin Henry , Ritch Robert , Barathur Raj , Dunn Michael W. , Teekhasaenee Chaiwat , Margolis Sheila , Opitz John M. , Reynolds James F.
Published: June 2005

A premature infant with unilateral aniridia and congenital ectropion uveae, contralateral Rieger anomaly, bilateral congenital glaucoma, and hydrocephalus was found to have ring chromosome 6. The findings are consistent with multiple manifestations of a neural crest–derived maldevelopment of the anterior segment and central nervous system. Comparison with the 14 previously reported cases of ring chromosome 6 illustrates the phenotypic variability of this syndrome.
Trisomy 21: Rate in second‐degree relatives
Authors: Eunpu Deborah L. , McDonald Donna M. , Zackal Elaine H. , Reynolds James F.
Published: June 2005

The risk of recurrence for trisomy 21 offspring in couples with one affected child is accepted to be 1%. The rate of trisomy 21 in second‐ and third‐degree relatives is not established. Tamaren et al [Am J Med Genet 15:393–403, 1983] reported a Down syndrome rate of 0.67% among aunts and uncles (second‐degree relatives) of a Down syndrome proband. This eightfold rate increase over that for a control group can also be applied to nieces and nephews who are also second‐degree relatives. One routinely discusses amniocentesis for lower risk levels; thus, should one offer amniocentesis to every sib of a trisomy 21 proband?

We obtained extensive family histories on 141 trisomy 21 kinships to ascertain the rate of trisomy 21 in second‐degree relatives. The rate for sibs agreed with the accepted 1% rate. Among aunts and uncles we found no trisomy 21 individuals. We conclude that the rate of trisomy 21 in second‐degree relatives does not appear to be sufficiently increased to warrant routine discussion of amniocentesis with sibs of trisomy 21 individuals.
Interstitial deletion of the long arm of chromosome 2 in a malformed infant with karyotype 46, XX, del(2) (q31q33)
Authors: Benson Kaaron , Gordon Margaret , Wassman E. Robert , Tsi Chung , Opitz John M. , Reynolds James F.
Published: June 2005

We describe a malformed newborn girl with an interstitial deletion of the long arm of chromosome 2 (karyotype: 46, XX, del (2) (q31q33)). This is the first report of this particular chromosome abnormality that includes autopsy findings. Comparison with previous cases in the literature suggests that this particular deletion uniformly results in developmental delays, craniofacial changes, and occasionally results in microcephaly, low‐set ears, and hand and foot abnormalities.
Animal Model: Causes of windowing‐induced dysmorphogenesis (neural tube defects and early amnion deficit spectrum) in chicken embryos
Authors: Fineman Robert M. , Schoenwolf Gary C. , Huff Monte , Davis Peter L. , Prieur David J.
Published: June 2005

Previous reports suggest that windowing the shells of chicken eggs during the first day of incubation frequently results in dysmorphogenesis of the central nervous system. We report here data that further delineate the neural tube defects associated with this animal model. In addition, we describe another birth defect syndrome associated with windowing: the early amnion deficit spectrum (EADS). Several components of the egg are altered structurally by windowing: the shell, outer and inner shell membranes, yolk, and air space at the blunt end of the egg. A new air space is formed over the embryo as the original one at the blunt end is obliterated. A series of studies (pH, oxygen and carbon dioxide tensions, relative humidity, temperature, and deformation of the yolk documented with magnetic resonance imaging) examining individual steps of the windowing procedure and additional techniques that simulate windowing suggest that mechanical stress causes isolated neural tube defects and dehydration causes amnion defects. These amnion defects are associated with other embryonic abnormalities suggestive of deformations consistent with EADS.
Risks to sibs of probands with neural tube defects: Data for clinic populations in British Columbia
Authors: Keena B. , Sadovnick A. D. , Baird P. A. , Hall J. G. , Opitz John M. , Reynolds James F.
Published: June 2005

The purpose of this study is to determine whether couples receiving genetic counselling because of a child with a neural tube defect (NTD) are a selected group and therefore not representative of the general population with respect to sib risks for NTDs.

British Columbia (B.C.) provides an excellent opportunity to look at this for several reasons. Firstly, genetic counselling services are centralized. Secondly, there is virtually complete ascertainment of all infants with NTDs in the province. Thirdly, sib risks for NTDs in the general population have been derived previously [McBride, 1979] and, therefore, are available for comparison with the risks for sibships in the clinic populations.

In the present study, data were available on 398 sibships in which the index case had anencephaly and/or spina bifida. In all instances, sib risks for the clinic populations did not differ significantly from those for the general population. In addition, congenital malformations other than NTDs did not occur among sibs of index cases more often than expected, based on provincial incidence data.
The statistics of quantifiable homeostasis I. Simple linear homeostasis
Authors: Murphy Edmond A. , Opitz John M.
Published: June 2005

The statistical properties are explored of the least‐squares estimators of the parameters of a deterministic linear model for homeostasis with random, normally distributed technical errors. The parameters are: the amplitude of perturbation (A), the homing value (H), the restoration constant (B), and the lag time (L). The former two, although important in their own right, tell us nothing about the processes of biologic restitution and are thus considered “nuisance” parameters; the latter two are the “business” parameters, which tell us about the processes of biologic adjustment. The properties studied include bias and precision and their relationships to the number of data points and to the size of the technical error. Efforts have been concentrated on data points equally spaced over six lag times (which corresponds roughly to the period of observation used in loading studies, such as glucose tolerance tests). The distributions of these four estimators are studied in sets of 100 Monte Carlo simulations, each with 15, 30, and 100 data points, respectively. The estimators are virtually unbiased and all statisfactorily close to Gaussian. The residual mean‐square errors (the divisor being four less than the number of data points, since four parameters are estimated) seem to be unbiased estimators of the variances of the errors. Moreover, when suitably scaled, the residual sums of squares have distributions close to the chi‐square distribution for the appropriate degrees of freedom and with the corresponding means and variances. The correlations among the estimators are modest and, except where A is involved, small.
Metabolic myopathies
Authors: DiMauro Salvatore , Miranda Armand F. , Sakoda Saburo , Schon Eric A. , Servidei Serenella , Shanske Sara , Zeviani Massimo , Opitz John M. , Reynolds James F.
Published: June 2005

Six glycogen storage diseases (resulting from deficiencies of acid maltase, phosphorylase, phosphofructokinase, phosphoglycerate kinase, phosphoglycerate mutase, and lactate dehydrogenase) and one mitochondrial myopathy (cytochrome c oxidase deficiency) are reviewed to illustrate: 1) clinical heterogeneity, 2) biochemical heterogeneity, 3) evidence for tissue‐specific and developmentally controlled isozymes, and 4) molecular genetic studies.
Small‐caliber skeletal muscle fibers do not suffer deleterious consequences of dystrophic gene expression
Authors: Karpati George , Carpenter Stirling , Opitz John M.
Published: June 2005

In Duchenne dystrophy and in the genetic dystrophies of CHF‐147 hamsters and MDX mice, the fundamental deleterious consequence of dystrophic gene expression is segmental necrosis of skeletal muscle fibers. The nature of the gene defects and the pathogenesis of muscle fiber damage are not known. However, clinical and experimental evidence indicates that muscle fibers whose girth is below a certain level (estimated at approximately 20–25 μm in diameter in dystrophic hamsters and MDX mice) are not susceptible to necrosis. This apparent “immunity” has been observed in muscle fibers that are naturally of small girth (such as those in extraocular muscles), and in fibers that were prevented from growing normally by experimental procedures (hamsters and mice) or by pathological processes (Duchenne patients). The cellular or molecular basis by which small‐caliber muscle fibers are resistant to the necrotizing effect of the dystrophic gene expression remains unknown. In small‐caliber muscle fibers, the normal contraction‐related mechanical strains per unit surface area are relatively less than in larger fibers; this could explain their relative resistance to necrosis in some dystrophies.
A severe form of congenital contractural arachnodactyly in two newborn infants
Authors: Currarino Guido , Friedman J. M. , Opitz John M. , Reynolds James F.
Published: June 2005

Congenital contractural arachnodactyly (CCA) is an uncommon condition characterized by arachnodactyly, dolichostenomelia, kyphoscoliosis, “crumpled” auricles, and flexion contractures at knees, elbows, fingers, and sometimes other joints. The long‐term prognosis for affected individuals is usually relatively good. We report on two newborn infants with severe CCA, both of whom died in the first year of life. One child also had other anomalies not generally associated with this disorder. These observations are consistent with the possibility that CCA is an etiologically and clinically heterogeneous disorder.
Campomelia, cervical lymphocele, polycystic dysplasia, short gut, polysplenia
Authors: Cumming William A. , Ohlsson Arne , Ali Ashraf , Opitz John M. , Reynolds James F.
Published: June 2005

An aborted fetus, the offspring of consanguineous parents, had the unusual combination of campomelia, cervical lymphocele, polycystic kidneys, pancreas, and liver, short gut, and polysplenia. Births of earlier similarly affected fetuses suggest an autosomal recessive inheritance. Skeletal, lymphatic, and renal lesions were seen at 26 weeks' gestation by ultrasonography, but not at 16 weeks.
X‐linked mental retardation with marfanoid habitus
Authors: Fryns Jean‐Pierre , Buttiens Marc , Opitz John M. , Reynolds James F.
Published: June 2005

Here we report on two pairs of mildly to moderately mentally retarded brothers with marfanoid habitus and similar craniofacial changes. They had a long and narrow face, small mandible, high‐arched palate, and hypernasal voice, as previously reported by Lujan et al (Am J Med Genet 17:311–322, 1984) in four mentally retarded males of a large kindred. The present data suggest the existence of a specific type of X‐linked mental retardation with marfanoid habitus.
A girl with G syndrome and agenesis of the corpus callosum
Authors: Neri G. , Genuardi M. , Natoli G. , Costa P. , Maggioni G. , Reynolds James F.
Published: June 2005

We report on a female patient with G syndrome. The clinical expression is relatively severe and includes 2 manifestations not previously reported, ie, agenesis of the corpus callosum and umbilical hernia. These new findings support the notion that there is a developmental defect of the midline as the basis of the G syndrome.
Apparent G syndrome presenting as neck and upper limb dystonia and severe gastroesophageal reflux
Authors: Williams Charles A. , Frias Jaime L. , Opitz John M. , Reynolds James F.
Published: June 2005

We have studied a 3‐month‐old boy with severe gastroesophageal reflux, feeding difficulties, neck and upper limb dystonia, abnormal ears, normal genitalia, and anatomically apparently normal larynx and trachea. Initially diagnosed as suffering from Sandifer “syndrome,” he was treated with a gastrostomy and Nissen fundoplication. However, his characteristic facial appearance subsequently led to the diagnosis of G syndrome.
Reproductive plans of genetic counseling clients not eligible for prenatal diagnosis
Authors: Sorenson James R. , Scotch Norman A. , Swazey Judith P. , Wertz Dorothy C. , Heeren Timothy C. , Opitz John M. , Reynolds James F.
Published: June 2005

A prospective study of the reproductive plans of 185 genetic counseling clients at risk for birth defects not diagnosable prenatally found, 6 months after counseling, 1) a small increase in the number of pregnancies initiated and planned, compared to pregnancies planned before counseling; 2) an increase in initiated and planned pregnancies among clients at both high as well as low risk; and 3) reproductive plans after counseling more closely correlated with clients' perceptions of the social, familial, and economic burdens of an affected child than with medically defined risk and specific clinical characteristics of the birth defects. In discussing the burden of a birth defect with clients, counselors are encouraged to discuss not only the medical burden, but the social, familial, and financial burdens as well.
Y‐specific DNA sequences in male patients with 46,XX and 47,XXX karyotypes
Authors: Müller Ulrich , Latt Samuel A. , Donlon Timothy , Opitz John M.
Published: June 2005

Y chromosomal DNA sequences were detected in three of four 46,XX males and in one 47.XXX male. One reiterated Y chromosomal sequence, Y‐190, was localized by in situ hybridization to the distal short arm of an X chromosome of the 47,XXX male. This result is compatible with the hypothesis that an aberrant X/Y interchange has occurred, most likely during paternal meiosis, and that this interchange accounts for Y chromosomal material and sex reversal in this 47,XXX individual.
Chorea‐acanthocytosis: A report of three new families and implications for genetic counselling
Authors: Vance Jeffery M. , Pericak‐Vance Margaret A. , Bowman Michael H. , Payne Cynthia S. , Fredane Louis , Siddique Teepu , Roses Allen D. , Massey E. Wayne , Opitz John M. , Reynolds James F.
Published: June 2005

Chorea‐acanthocytosis (CHA) is a rare inherited neurologic disorder with peripheral red cell acanthocytes and normal serum lipoprotein levels. To date, 8 families with the disorder have been reported outside of Japan. We describe 4 patients in 3 families with CHA and review the clinical presentations in previous reports. In addition, we report magnetic resonance imaging scans in these patients. The pattern of inheritance in these families is most likely autosomal recessive. Obligate heterozygotes do not have acanthocytes on wet preparation under phase microscope.

Two of 3 propositi were initially diagnosed as having Huntington chorea. Chorea‐acanthocytosis is an important differential in the diagnosis of Huntington chorea and should be considered in families without a family history. The paucity of families with CHA reported to date may represent lack of recognition.
A comparative study of the lesions in cultured fibroblasts of humans and four species of animals with Chediak‐Higashi syndrome
Authors: Penner Jocelyn D. , Prieur David J. , Opitz John M. , Reynolds James F.
Published: June 2005

The Chediak‐Higashi syndrome (CHS) is an autosomal recessive genetic disease of humans, and clinically similar diseases occur in cats, mink, cattle, mice, killer whales, blue foxes, and silver foxes. It is characterized by incomplete albinism, increased susceptibility to infection, and the most distinctive hallmark, the presence of enlarged cytoplasmic granules in many cell types. The acid phosphatase‐positive granules, lysosomes, of fibroblasts from control and CHS humans, cats, mink, cattle, and mice were examined, These studies represent the initial characterization of the lesions in fibroblasts of CHS cats, mink, and cattle. Fibroblasts from each species and genotype were stained histochemically for acid phosphatase, and morphometric analysis of the distribution of acid phosphatase‐positive granules was performed. The lysosomes in the CHS fibroblasts tended to be restricted to the perinuclear area of the cytoplasm, whereas the lysosomes in the normal fibroblasts were generally more widely distributed in the cytoplasm. The lysosomes in the CHS fibroblasts of all species examined were also more enlarged and heterogeneous than those in the control fibroblasts.
Further evidence for genetic heterogeneity of whistling face or Freeman‐Sheldon syndrome in a Chinese family
Authors: Wang Tso‐Ren , Lin Shio‐Jean , Opitz John M. , Reynolds James F.
Published: June 2005

We report on 2 brothers with severe manifestations of the whistling‐face/windmill‐vane‐hand syndrome (also called “craniocarpotarsal dystrophy”; Freeman‐Sheldon syndrome); they were born to normal, nonconsanguineous parents. Our observations support the theory of causal heterogeneity of this syndrome and suggest existence of an autosomal or X‐linked recessive form of this syndrome.
Clinical, pathological, and biochemical studies on an infantile case of sulfatide/GM1 activator protein deficiency
Authors: Wenger David A. , DeGala Gregory , Williams Carolyn , Taylor Harold A. , Stevenson Roger E. , Pruitt James R. , Miller John , Garen Paul D. , Balentine J. Douglas
Published: June 2005

A 28‐month‐old black male died with severe complications of mental and motor deterioration, seizures, and aspiration. Autopsy demonstrated moderate liver enlargement, normal spleen and kidneys, small testes, and a grossly normal brain. Further examination showed irregular macrogyrae with evidence of a storage or sclerotic process. Thin layer chromatography of the lipids in formalin‐fixed tissue demonstrated elevated levels of ceramide trihexoside and possibly sulfatides in liver and a decrease in the ratio of galactosylceramide to sulfatide in brain. Examination of the gangliosides in formalin‐fixed brain indicated a slight increase in the percentage of GM1 ganglioside and a clear elevation in GM2 and GM3 gangliosides. Cultured skin fibroblasts had a normal activity for a large number of lysosmal enzymes including arysulfatase A and galactocerebrosidase. When the cells were loaded with [14C]sulfatide only about 12% of sulfatide was metabolized after 3 days. Extracts of the cells were subjected to SDS‐PAGE and immunoblotting with antisphingolipid activator protein‐1 (SPA)rabbit antiserum, and no cross‐reacting material was detected confirming the diagnosis of metachromatic leukodystrophy caused by SAP‐1deficiency. This patient was clinically more severe than the other patuent described previsously with this deficiency. Further studies are underway to define the nature of the mutation in this patient.
Growth factors, their receptors and development
Authors: Hollenberg M. D.
Published: June 2005

The hypothesis is put forward that the localized production of growth factors and the regulation both of their receptors and their receptor‐triggered transmembrane signaling reactions played an important role in organ development. The developing palate is used as an example to support this hypothesis. Data are summarized to demonstrate that during palatogenesis, there are variations in the amount of fetal epidermal growth factor‐urogastrone (EGF‐URO), in the amount of EGFURO receptor, and that there is a developmentally regulated variation in cellular responsiveness to EGF‐URO. Further, it is demonstrated that the growth factor EGF‐URO itself can regulate the production by palate tissue of a second growth factor, insulin‐like growth factor (IGF). The multiple actions of the many so‐called growth factors, quite apart from their ability to regulate cell growth are pointed out; and the implications of the many distinct actions of a single growth factor on a single cell type are discussed in the context of a developmental process like palate formation. A model is developed to illustrate the kinds of interactive processes that may occur in a tissue microenvironment during a developmental process, involving cell‐cell communication and an influence of the extracellular matrix.
Associations of the skeletal and immune systems
Authors: Hong Richard
Published: June 2005

Certain disorders of the immune system seem to be associated with skeletal defects. The association was first recorded by McKusick et al. (Bulletin of the Johns Hopkins Hospital 116:285–326, 1964). A number of relationships between lymphocytes and osteocytes can be proposed. These include a common environment for development, common metabolic needs and effects upon osteocytes by products (cytokines) elaborated from lymphocytes or monocytes during immune responses. Thus, bony defects of varying degrees of severity are seen in short‐limb dwarfs, cartilage‐hair hypoplasia, and adenosine deaminase (ADA) deficiency. Cytokine activation of osteoclasts accounts for the lytic lesions seen in malignancies and the excessive bone resorption which accompanies autoimmune disorders such as rheumatoid arthritis.

Correction of primary immune deficiency is accomplished by bone marrow transplantation. If the bony abnormality is subtle (as in some cases of ADA deficiency) the skeletal problem is resolved; if the bone defect is major as in short‐limb dwarfism, no improvement is seen.
Inherited disorders of collagen gene structure and expression
Authors: Byers Peter H.
Published: June 2005

As a result of investigations completed during the last 15 years, the molecular bases of most form of osteogenesis imperfecta (OI) and of some forms of the Ehlers‐Danlos syndrome (EDS) are now known. Most forms of OI result from point mutations in the genes (COL1A1 and COL1A2) that encode the chains of type I procollagen or mutations that affect the expression of these genes. Less frequently, mutations that affect the size of the chain can also result in these phenotypes. The phenotypic presentation appears to be determined by the nature of the mutation, the chain in which it occurs, and, for point mutations, the position of the substitution and the nature of the substituting amino acid in the protein product. Similar mutations in the gene (COL3A1) that encodes the chains of type III procollagen result in the EDS type IV phenotype. Mutations which result in deletion of the cleavage site for the aminoterminal procollagen protease result in the EDS type VII phenotype and other mutations which affect the structure of the triple‐helical domain by deletions and alter the conformation of the substrate at the site of proteolytic conversion can produce mixed phenotypes. Alterations in post‐translational processing of collagenous proteins can result in the EDS type VI and EDS type IX phenotypes. Linkage analysis and study of type II collagen proteins from individuals with a variety of skeletal dysplasias suggest that similar mutations in these genes also result in clinically apparent phenotypes. Mutations in the majority of the 20 known collagen genes have not yet been identified.
Statistical approaches for the detection of heterozygotes for biotinidase deficiency
Authors: Weissbecker Karen A. , Nance Walter E. , Eaves Lindon J. , Piussan Charles , Wolf Barry
Published: June 2005

We applied and evaluated 3 statistical approaches for the detection of heterozygotes for biotinidase deficiency in a randomly selected population of French adults. The first method, which used a cutoff value to dichotomize the population, lacked sensitivity. The second approach calculated the probability of heterozygosity for a given enzyme activity through the application of Bayes theorem to the normal density functions of the enzyme distributions of the obligate heterozygote and the test populations. A priori values of the means and standard deviations (SDs) of the genotypic distributions were used. This method was sufficiently sensitive for both population screening and genetic counseling, but requires prior knowledge of the frequency of the deficient gene (q). The third approach was similar to the second, however, maximum likelihood estimates of the means and SDs of the genotypic distributions were calculated and used to determine the probability of heterozygosity for a given enzyme activity. This method was as sensitive as the second method and is appropriate for screening populations for which there is little prior information about the gene frequency and the genotypic distributions. This method can also be used to estimate the gene frequency of the disorder within a given ethnic or racial population. Using this method, we estimated the frequency of heterozygotes (2pq) in the French population to be 0.012, which was similar to that estimated from the results of neonatal screening for biotinidase deficiency. These methods can be used to detect heterozygotes and to estimate the gene frequency of other inherited enzyme deficiencies.
Complementation by two non‐homologous recombinant chromosomes 3
Authors: Allderdice P. W. , Ali M. , McAlpine P. J.
Published: June 2005

The first example known to us of complementation by two non‐homologous chromosomes 3 is present in the karyotype of a phenotypically normal brother of an inv(3)(p25q21) carrier. The normal chromosomes 3 are replaced by two complementary recombinant chromosomes 3. The longer recombinant duplicates 3q21‐qter and is deficient for 3p25pter. It is identical to the recombinant inherited by infants born with multiple congenital anomalies to inv(3)(p25q21) carriers. The shorter recombinant duplicates 3p25‐pter and is deficient for 3q21‐qter. This recombinant has previously been observed only in prometaphase spreads from sperm of an inv(3) carrier from the same kindred. Theoretically it is possible for the carrier of these complementary recombinant chromosomes 3 to produce sperm carrying either a normal 3, or the inversion 3, which could then fertilize an egg carrying a normal 3 followed by normal fetal development. However, the spouse of our propositus reported one first trimester spontaneous abortion, followed by no recognized pregnancy over the next 12 years of marriage.
Ullrich‐Turner syndrome in mother and daughter: Prenatal diagnosis of a 46, X, del(X)(p21) offspring from a 45, X mother with low‐level mosaicism for the del(X)(p21) in one ovary
Authors: Varela M. , Shapira E. , Hyman D. B.
Published: June 2005

A woman with Ullrich‐Turner syndrome but with normal secondary sex characteristics became pregnant on two occasions (ages 23 and 24). She had a 45, X karyotype in 100/100 lymphocytes and 50/50 skin fibroblasts. The first pregnancy ended in a miscarriage at 2 months of gestation. In the second pregnancy cultured amniocytes showed a 46, X, del(X)(p21) karyotype. This pregnancy resulted in an apparently normal girl. Biopsies of the mother's ovaries were obtained at the time of cesarean section. Grossly the ovaries appeared normal, and histologically the number of primordial follicles appeared normal. In the right ovary, 5/100 cells were 46, X, del(X)(p21), while all 100 cells in the left ovary were 45, X.
Difference in early development of presumed monozygotic twins with Rett syndrome
Authors: Bruck Isac , Philippart Michel , Giraldi Dinarte , Antoniuk Sergio
Published: June 2005

Normal early development has generally been insisted on as an essential criterion for the diagnosis of Rett syndrome. A new set of monozygotic female twins is reported. Twin 1 was considered to be abnormal from birth while delay was not suspected in twin 2 until she was about one year old. Some regression occurred during the second year in both twins, who are now clinically indistinguishable from each other at age 4 years. Other than a slight difference in head circumference at birth, no environmental factor which could account for the clinical difference has been identified.
Interstitial tandem direct duplication of the long arm of chromosome 4 (q23‐q27) and possible assignment of the structural gene encoding human aspartylglucosaminidase to this segment
Authors: Halal Fahed , Vekemans Michel , Chitayat David
Published: June 2005

We report on a girl with a previously undescribed de novo direct tandem duplication 4q involving the segment q23→q27. Clinical manifestations included postnatal growth and psychomotor retardation, microcephaly, hirsute forehead, epicanthic folds, strabismus, depressed nasal bridge, long philtrum, small mouth, tetralogy of Fallot, and sacral dimple. Her phenotype is compared with that of previously reported cases of duplication 4q. An increased activity of the enzyme aspartylglucosaminidase (AGA) in cultured fibroblasts was demonstrated. This suggests possible assignment of the AGA gene to the chromosomal segment 4q23→4q27.
Mouse major histocompatibility complex and lung development: Haplotype variation, H‐2 immunolocalization, and progressive maturation
Authors: Jaskoll Tina , Hu Ching‐Chung , Melnick Michael
Published: June 2005

The association of the mouse major histocom‐patibility complex (H‐2), lung maturation, and corticosteroid responsiveness has recently been demonstrated in congenic B10 (H‐2b) and B10.A (H‐2a) mice (Hu et al.:American Journal of Medical Genetics 35:126–131, 1990). We have investigated additional haplotypes [B10.BR (H‐2k) and B10.D2 (H‐2d] to confirm that there is a strong association between H‐2 haplotype variation and the degree of pulmonary maturation. Lungs of B10.D2, B10.BR, B10, and B10.A congenic mice achieve haplotypic specific maturation:B10.D2 lungs > B10 lungs = B10.BR lung > B10.A lungs. It appears that the expression of these developmental potentials is under corticosteroid regulation. Further, to test the hypothesis that H‐2 antigens would be expressed earlier in embryonic lungs with the H‐2b (BIO) or H‐2k (B10.BR) haplotype than with the H‐2a (B10.A) haplotype, we investigated the spatiotemporal patterns of H‐2 antigen localization in B10, B10.BR, and B10.A congenic mouse strains with and without corticostroid treatment. The spatial patterns of H‐2 antigen localization was similar in the B10, B10.BR, and B10.A mouse lungs; however, these patterns appeared earlier in both untreated and treated B10 and B10.BR mice as compared with untreated B10.A mice, suggesting an H‐2 haplotype associated rate of pulmonary maturation. Following corticosteroid treatment, all congenic strains had a temporally comparable spatial distribution of H‐2 antigens. Our results provide preliminary evidence suggesting that both a lung “developmental gene(s)” and a “glucocorticoid responsiveness gene(s)” are most likely outside the K‐D subregions of the H‐2 complex. A model of the H‐2 regulation of lung maturation and corticosteroid responsiveness is discussed.
Biochemical and clinical characterization of prealbumin CHICAGO: An apparently benign variant of serum prealbumin (transthyretin) discovered with high‐resolution two‐dimensional electrophoresis
Authors: Harrison Harold H. , Gordon Edys D. , Nichols William C. , Benson Merrill D.
Published: June 2005

We report identification, biochemical, clinical, and genetic studies of an apparently benign, electrophoretic variant of serum prealbumin (PALB, transthyretin, TTR) in a North American kindred of Swedish ancestry. The variant polypeptide stems from a C to T point mutation in exon 4 which results in methionine instead of threonine at position 119 of the mature molecule. It was discovered incidentally in a girl with classic alpha‐1‐antitrypsin (A1AT) deficiency and her father during diagnostic A1AT phenotyping by ISO‐DALT high‐resolution two‐dimensional electrophoresis (2DE). Twelve relatives in the four‐generation paternal kindred, including five individuals who were heterozygous for the variant prealbumin, were studied. In each of these five heterozygotes, the variant allele product was equimolar and isoelectric with the normal protein, yet migrated with an apparently lower mass in the SDS‐PAGE dimension. The inheritance pattern was consistent with autosomal dominant transmission. Histories and physical examinations showed no evidence of amyloidosis, as has been observed with other variants of prealbumin. Mean values of serum prealbumin and retinol binding protein levels were higher in the carriers as compared to the normal relatives in the family, but the difference was not statistically significant. Thyroid hormone levels and distribution of thyroxine and triiodothyronine among binding proteins in serum were within reference limits. Four members of the lineage had dominant, scalp‐restricted keratinaceous cysts, yet only three of these four individuals had the variant. We counseled the family that this is likely a benign variant with regard to amyloidosis‐related morbidity or shortened life span, although senile effects cannot be entirely ruled out. The provisional designation assigned to this allele is PALBCHICAGO. The substitution of methionine at position 119, as predicted by the DNA sequence, was confirmed by amino acid sequencing of CNBr and tryptic peptides. This substitution occurs at a CpG dinucleotide that may be a point mutational “hot spot,” as has been postulated for the methionine‐30 and isoleucine‐122 PALB variants. The apparently lower mass of the variant probably results from a more compact conformation in SDS. With the exception of histidine‐58, a charge substitution, all other amyloidosis‐related prealbumin variant polypeptides had normal mobility in the ISODALT 2DE system.
Prenatal sonographic documentation of cystic hygroma regression in Noonan syndrome
Authors: Donnenfeld Alan E. , Nazir Munir A. , Sindoni Frank , Librizzi Ronald J.
Published: June 2005

Prenatal diagnosis of a posterior nuchal cystic hygroma was made at 13 weeks of gestation in a fetus diagnosed at birth with Noonan syndrome. Through serial sonographic evaluation during pregnancy, the embryologic evolution of cystic hygroma into nuchal skin thickening was appreciated and later correlated with postnatal findings of nuchal skin fold redundancy and pterygium colli in a patient with Noonan syndrome. These observations support the concept of the jugular lymphatic disruption sequence as pathogenesis of the nuchal findings in severely affected Noonan syndrome patients.
Fat distribution in overweight patients with Ullrich‐Turner syndrome
Authors: Hanaki Keiichi , Ohzeki Takehiko , Ishitani Nobuo , Motozumi Hiroko , Matsuda‐Ohtahara Hiroko , Shiraki Kazuo
Published: June 2005

Overweight patients with Ullrich‐Turner syndrome (UTS) and control children with similar weight/height and indices of overweight were studied to clarify the unique fat distribution in the syndrome. Triceps and ulnar skinfold thickness (SFT) in UTS patients was significantly less than that of obese children without the syndrome. The means of SFT at the subscapular and paraumbilical regions were also less in the patients than control girls, though significance was not documented. Thus, increased body weight in UTS children seems mainly to be due to excess of adipose tissue, not in the limbs but on the trunk, and/or due to the increment of lean body mass.
Dextrocardia, microphthalmia, cleft palate, choreoathetosis, and mental retardation in an infant born to consanguineous parents
Authors: Nachlieli Tal , Gershoni‐Baruch Ruth
Published: June 2005

We report on an infant (born to consanguineous parents) with an unusual face, microphthalmia, cleft palate, dextrocardia, choreoathetosis, and mental retardation. This child has many traits in common with an infant recently described by Aughton [1990] as a probable new syndrome.
Ventricular extrasystoles with syncopal episodes, perodactyly, and Robin sequence in three generations: A new inherited MCA syndrome?
Authors: Stoll Claude , Kieny Jean‐René , Dott Béatrice , Alembik Yves , Finck Sonya
Published: June 2005

We observed the combination of the Robin sequence with perodactyly (hypoplasia and/ or agenesis of the distal phalanx of the toes) and cardiac arrhythmia (ventricular extra‐systoles occurring as bigemini or multifocal tachycardia with syncopal episodes) in 6 relatives in 3 generations. This familial association has not been reported before and probably represents a previously unrecognized heritable malformation syndrome.