bluuebunny/crossref_metadata_2025 huggingface dataset:
Partial duplication 8q12→q21.2 in two sibs with maternally derived insertional and reciprocal translocations
Authors: Walker A. P. , Bocian M. , Opitz John M. , Reynolds James F.
Published: June 2005

We report on two sibs with duplication of the segment 8ql2→8q21.2 resulting from malsegregation of a maternal insertional translocation: [inv ins (5;8)(pl3;ql2q2l.2)]. The mother also carries a reciprocal translocation [t (l;6)(q31;q5)], which was transmitted in the balanced state to the propositi and to a phenotypically normal son and daughter. The literature on two translocations occurring in one individual and on insertional rearrangements is reviewed in terms of reproductive risks to balanced carriers. The two affected infants have a previously undescribed partial duplication of an interstitial segment of 8q and a pattern of abnormalities distinct from those seen in other partial duplications of 8. These infants are reviewed with 78 other cases of partial duplication of chromosome 8 with regard to phenotype‐karyotype correlations.
Preliminary evidence for genetic determination of intraerythrocytic sodium concentration in utah pedigrees
Authors: Dadone Mary M. , Smith Jean B. , Wu Lily , Ash K. Owen , Williams Roger R. , Opitz John M. , Reynolds James F.
Published: June 2005

Intraerythrocytic sodium concentration has been reported to be increased in hypertensive individuals and some of their normotensive relatives. We investigated the “familiality” of this trait in 572 nonhypertensive subjects from 34 Utah kindreds. Most of these kindreds were selected because of a high incidence of hypertension, heart attack, or stroke. Intraerythrocytic sodium concentration was correlated with the sex of the subject and suprailiac skinfold thickness. Intraerythrocytic sodium concentration was adjusted by linear regression for these 2 factors. The residual values were positively correlated in parent‐offspring pairs and among sibs, both those presumed to be living together and those presumed to be living apart. The spouse‐spouse correlation was not significant. Pedigree analysis suggested a mixed major‐gene/polygenic model of inheritance, but these data did not allow us to distinguish between dominant and recessive inheritance for the major gene component. Total heritability due to both major‐gene and polygenic components was estimated to be 90–95% the proportion of the total variance due to polygenes was estimated to be 60–75%, These results suggest that further study of the relationship between the inheritance of intraerythrocytic sodium and the pathophysiology of hypertension is warranted.
Cystic hamartomata of lung and kidney: A spectrum of developmental abnormalities
Authors: Graham John M. , Boyle William , Troxell Jeffrey , Cullity Garry J. , Sprague Paul L. , Beckwith J. Bruce , Reynolds James F.
Published: June 2005

We report on a developmental malformation of the lung and kidney which has not been previously described and which we have chosen to call “cystic hamartomata of the lung and kidney” to emphasize the non‐malignant nature of these lesions. We also confirm a previous case report by Weinberg and Zumwalt [1977] as a different distinct disorder that results in a multifocal cystic hamartomata of the lung with associated marked parenchymal overgrowth of the kidney (the Weinberg‐Zumwalt syndrome). These cases represent a spectrum of abnormal morphogenesis affecting both kidney and lung. Patients 1 and 2 presented during infancy with abdominal masses and hypertension due to bilateral multilocular cysts of the kidney with associated hamartomatous pulmonary cysts; patient 2 also had one area of cellular mesoblastic nephroma. Patient 3 demonstrated markedly hyperplastic renomegaly with medullary dysplasia in association with bilateral cystic hamartomata of the lungs. During the fifth week of gestation, the ureteric bud invades the unsegmented mesoderm that becomes the metanephric system, and the lung bud invades the splanchic mesoderm, which provides the stimulus for its growth. We suggest that the predominant pattern of a congenital kidney or lung hamartoma might reflect the timing of a prenatal neoplastic event affecting these developmental processes.
Dominantly inherited dilated cardiomyopathy
Authors: Gardner R. J. M. , Hanson J. W. , Lonasescu V. V. , Ardinger H. H. , Skorton D. J. , Mahoney L. T. , Hart M. N. , Rose E. F. , Smith W. L. , Florentine M. S. , Hinrichs R. L. , Reynolds James F.
Published: June 2005

We describe a family in which there is segregating an autosomal dominant gene determining a cardiomyopathy. The pathodynamics is that of pump failure associated with dilatation of the heart, generally having an overt clinical onset from the fourth through seventh decades. Dysrhythmia is a frequent concomitant feature. There may be an associated skeletal myopathy, either producing a very mild proximal weakness or proving detectable only upon biopsy.

This family is similar to other reported cases of familial dominant “idiopathic” dilated cardiomyopathy, but the nature of the heterogeneity within this category remains to be elucidated. The roles of echocardiography, cardiac biopsy, and skeletal muscle biopsy in the presymptomatic detection of the heterozygote are noted.
Animal model: Skeletal anomalies in mice with cleidocranial dysplasia
Authors: Sillence D. O. , Ritchie H. E. , Selby P. B. , Prieur David J.
Published: June 2005

Cleidocranial dysplasia in mice, a radiation‐induced skeletal mutation, showed striking homology with cleidocranial dysplasia in humans. Genetic studies indicated that the condition in mice is inherited as an autosomal dominant trait with variable expressivity and almost complete penetrance. The homozygous condition was lethal in utero. Radiographic and alcian blue/alizarin red S‐stained whole‐skeletal preparation studies were used to determine the extent, pattern, incidence, and distribution of skeletal abnormalities in heterozygous mice. Cleidocranial dysplasia in mice was characterized by variable clavicular hypoplasia, delayed closure of cranial fontanelles and sutures, and variable hypoplasia of pelvic bones, in particular ischiopubic rami. The gene symbol Ccd is proposed for the cleidocranial dysplasia mutation in mice and humans.
Trisomy Xq in a male: The isochromosome X Klinefelter syndrome
Authors: Donlan Michael A. , Dolan Cynthia R. , Metcalf Michael J. , Bradley Cynthia M. , Salk Darrell , Reynolds James F.
Published: June 2005

We report on a male with trisomy Xq resulting from an isochromosome Xq which is preferentially inactivated: 47,XY, + i(Xq). Six previous cases have been reported. These patients are similar to patients with classical Klinefelter syndrome (47,XXY) in that they have infertility, decreased masculinization, gynecomastia, and elevated luteinizing hormone (LH) and follide stimulating hormone (FSH) levels. They may differ in having average intelligence and normal to short stature. These findings indicate that extra copies cf the long arm of X have phenotypic expression, even though activated only in early development.
Congenital eventration of the diaphragm: An unusual cause of intractable neonatal respiratory distress with variable etiology
Authors: Moerman Philippe , Fryns Jean‐Pierre , Devlieger Hugo , Van Assche André , Lauweryns Joseph , Opitz John M. , Reynolds James F.
Published: June 2005

We describe two infants dying neonatally of respiratory failure despite all attempts at resuscitation. The most striking finding at autopsy was eventration and reduced muscle content of the diaphragm. Microscopic examination of the skeletal muscles, in combination with retrospective evaluation of the family history, disclosed severe X‐linked centronuclear myopathy in the first patient and congenital myotonic dystrophy in the second. These disorders are probably more frequent than reported before. Their identification is important, not only for genetic counseling of the involved families but also for providing the neonatologist a sufficient explanation for the failure of resuscitation.
Metacarpophalangeal pattern profile analysis in Robinow syndrome
Authors: Butler Merlin G. , Gale David D. , Meaney F. John , Wadlington William B. , Robinow Meinhard , Opitz John M. , Reynolds James F.
Published: June 2005

We analyzed the metacarpophalangeal pattern profile (MCPP) on 15 individuals with Robinow syndrome and calculated a mean Robinow syndrome profile. Correlation studies confirm clinical homogeneity of the hand profile in the Robinow syndrome. Discriminant analysis of individuals with Robinow syndrome compared with a sample of normal individuals produces a function of 6 MCPP variables that may provide a useful tool for diagnosis.
Multiple congenital anomalies associated with apparently normal maternal intake of vitamin A: A phenocopy of the isotretinoin syndrome?
Authors: Lungarotti M. S. , Marinelli D. , Mariani T. , Calabro A. , Opitz John M. , Reynolds James F.
Published: June 2005

The teratogenicity of vitamin A has been repeatedly reported in the literature and confirmed on the basis of several cases of adverse pregnancy outcome associated with maternal isotretinoin exposure.

We report a case which shows a striking similarity with this syndrome, but the child was born to a mother who took a normal supplementation of vitamin A during pregnancy.

The differential diagnosis is discussed.
Mosaic tetrasomy 12p: Four new cases, and confirmation of the chromosomal origin of the supernumerary chromosome in one of the original Pallister‐Mosaic syndrome cases
Authors: Warburton Dorothy , Anyane‐Yeboa Kwame , Francke Uta , Reynolds James F.
Published: June 2005

Four new cases are reported in which mosaicism for a supernumerary chromo‐some interpreted as an isochromosome for 12p [i(12p)] is present. In 2 cases seen in early childhood the mosaicism was present at a low level in peripheral blood and was documented in one case to be present with a higher frequency in fibroblast cultures from skin. These cases have clinical features compatible with those in previously reported cases of the Teschler‐Nicola/Killian syndrome, many of whom have now been found to be mosaic for a similar i(12p) chromosome in fibroblast cultures. One case was diagnosed prenatally from amniotic fluid culture. The fourth case was a neonatal death, in which fibroblast cultures were established from muscle and increased activity of LDH‐B was demonstrated, supporting the theory that the origin of the additional chromosome was from 12p. Loss of the cell line with the supernumerary chromosome occurs after long‐term fibroblast culture. Previously unpublished studies showing increased LDH‐B activity in case 1 of Pallister‐Mosaic syndrome originally reported in 1977 are also reported. It is of interest that our 2 cases which did not survive birth and one previously published case diagnosed prenatally had diaphragmatic herniae.
Skeletal anomalies in a patient with the Pallister/Teschler‐Nicola/ Killian syndrome
Authors: Kawashima H. , Reynolds James F.
Published: June 2005

We report on a 3–8/12‐year‐old boy with the Pallister/Teschler‐Nicola/Killian syndrome and previously unreported bilateral skeletal anomalies consisting of small feet and short but otherwise normal humeri, ulnae, femora, and fibulae. His peripheral blood chromosomes were normal; however, 47,XY,+ i(12p) was found in 100% of fibroblasts.
The effects of storage of blood and isolated DNA on the integrity of DNA
Authors: Madisen Linda , Hoar David I. , Holroyd Catherine D. , Crisp Margaret , Hodes M. E. , Reynolds James F.
Published: June 2005

Long‐term storage of DNA is required for a number of genetic studies; prior to extraction, blood samples may be subject to elevated temperatures for variable intervals. We have studied the effect of temperatures ranging from −70°C to +65°C on human blood and on DNA extracted from it. DNA in solution stored at ambient temperatures up to 37°C for 6 months was digestible by three different restriction endonucleases, whereas storage at 45°C is deleterious after 6‐7 weeks. DNA can be extracted from blood samples stored at −70°C for at least 2 months or at 23°C for a week or more, but blood stored at these temperatures may yield less high‐molecular‐weight DNA. Cell pellets from which plasma has been removed also can serve as a source of DNA. Isolated DNA stored dry for years (up to 30) is difficult to dissolve and may appear degraded, but a sample stored dry for 13 years and then in solution at −20°C for 7 years appeared to be intact.
Genetic aspects of early chiidhood scoliosis
Authors: Connor J. M. , Conner A. N. , Connor R. A. C. , Tolmie J. L. , Yeung B. , Goudie D. , Reynolds James F.
Published: June 2005

Eighty‐seven families with early onset sccoliosis were evaluated. These were divided into 3 groups: resolving infantile idiopathic scoliosis (15 families), progressive infantile idiopathic scoliosis (21 families), and congenital scoliosis due to vertebral malformations (51 families). The children with congenital scoliosis were subdivided into those who had closed neural arch defect (19 families) and those who did not (32 families).

Resolving infantile idiopathic scoliosis was usually associated with plagiocephaly, and both deformations tended to show spontaneous recovery. These children were otherwise normal. Seven (33%) of the children with progressive infantile idiopathic scoliosis were mnentally retarded, but only 2 had a congenital malformation. In contrast, 18 (33%) of the children with congential scoliosis had other malformations, but only 2 were mentally retarded.

The recurrence risk for scoliosis was low in each group studied. However, there was an incriased risk (4% for sibs) of neural tube defects in the families with congenital scoliosis (with or without neural arch defects). This sib resk was apparent for probands with only a single hemivetebrum in addition to probands with more extensive vertebral defects and would support an etiological relationship between neural tube defects and other vertebral malformations.
Linkage and genetic counselling for the fragile X using DNA probes 52A, F9, DX13, and ST14
Authors: Mulley John C. , Gedeon Agi K. , Thorn Kerry A. , Bates Lyndall J. , Sutherland Grant R. , Opitz John M. , Reynolds James F.
Published: June 2005

Linkage data using the markers DXS51, F9, DXS15, and DXS52 are presented from 14 pedigrees segregating with the fragile X. Cytogenetic and DNA data were combined by two‐ or three‐point linkage analysis for estimation of lod scores and carrier probabilities in potential carriers. Recombination frequencies (\documentclass{article}\pagestyle{empty}\begin{document}$ \hat \theta $\end{document}) corresponding to maximum z scores (ẑ) were obtained for DXS51 (ẑ = 3.45, \documentclass{article}\pagestyle{empty}\begin{document}$ \hat \theta $\end{document} = 0.0), DXS15 (ẑ = 0.40, \documentclass{article}\pagestyle{empty}\begin{document}$ \hat \theta $\end{document} = 0.06), F9 (ẑ = 3.15, \documentclass{article}\pagestyle{empty}\begin{document}$\hat \theta $\end{document} = 0.09), and DX552 (ẑ = 3.60, \documentclass{article}\pagestyle{empty}\begin{document}$\hat \theta $\end{document} = 0.11) with the fragile X. Considerable alterations to carrier probabilities occurred in some cases, especially when flanking markers were informative. The chance of mentally impaired offspring was reduced to 1% for five of eight women with prior carrier probabilities of 32%. Three pedigrees were identified in which mutation had possibly occurred. An alternative explanation for two of these was inheritance of the fragile X from normal males and for the other inheritance from a clinically normal woman. Probabilities were computed for each of these alternatives.
Gonadal function in patients with Down syndrome
Authors: Hsiang Ying‐Hui H. , Berkovitz Gary D. , Bland Gail L. , Migeon Claude J. , Warren Andrew C. , Opitz John M. , Reynolds James F.
Published: June 2005

Gonadal function was evaluated in 100 home‐reared persons with Down syndrome (DS) including 53 boys and men and 47 girls and women. In order to definitively evaluate gondal function in our subjects, all patients with abnormal thyroid function were excluded from endocrine analysis.

Among the men, the frequency of hypospadias and cryptorchidism was similar to that of the general population. In both men and women, the ages for the onset and completion of puberty were also normal. However, among adult men with DS, the mean stretched penile length and the mean testicular volume were singnificantly below the mean value of normal men.

In the 23 men with DS, the mean serum levels of follicle‐stimulating hormone (FSH) and luteinizing hormone (LH) were significantly eleveted above the mean for normal men. By contrast, the mean plasma level of testosterone (T) was normal, suggesting a diagnosis of partial gonadal deficiency. Among the 14 women in the study, 6 had primary gonadal dysfunction. In prepubertal children, serum FSH levels in 3 boys and 5 girls were more than 2 SD above the mean for normal children, while serum levels of LH in 3 boys and 2 girls were abnormally elevated. When gonadal function was evaluated in male infantss, serum levels of FSH were above the normal in 6 of 11 subjects. Serum LH was abnormally elevated in 3 of 8 female infants.

Our data argue that primary gonadal deficiency is common in DS, that it is progressive from birht to adolescence, and that it is clearly manifest in adult patients.
Congenital anomalies: Mortality and morbidity, burden and classification
Authors: Chung Chin S. , Myrianthopoulos Ntinos C. , Opitz John M. , Reynolds James F.
Published: June 2005

This study has attempted to assess the burden imposed by congenital anomalies in terms of postnatal mortality and morbidity, which were in turn used to classify anomalies as severe and mild types. Factors studied were postnatal mortality through age 7 years and morbidity, as measured by neurologic and psychologic abnormalities, histories of major surgery, prolonged hospitalization, and chronic infections. The study was based on a prospective study of 52,332 liveborn singletons of the Collaborative Perinatal Project of the National Institute of Neurological and Communicative Disorders and Stroke. In general, the highest degree of burden was observed in syndromes and sequences, followed by multiple and single major anomalies. The burden due to major abnormalities as measured by attributable risk ranged from 0.436 for prolonged hospitalization up to one year, to 0.010 for chronic infections in subjects 1–7 years of age. In terms of mortality, the total attributable risk was 0.164, and the mean potential years of life lost was 5,020 per 10,000 population, which is considerably greater than that reported in other studies. An index constructed from mortality, neurologic, psychologic, and surgical variables provides a reasonable and objective means for classifying anomalies into severe and mild types.
The relationship between fetal hemoglobin and disease severity in children with sickle cell anemia
Authors: Odenheimer Daniel J. , Sarnaik Sharada A. , Whitten Charles F. , Rucknagel Donald L. , Sing Charles F. , Opitz John M. , Reynolds James F.
Published: June 2005

A study was conducted in a sample of 140 children with sickle cell anemia to evaluate the relationship between hematological variables (%HbF, %HbA2, %Hb, and mean cell volume) and disease severity. A patient's severity status was determined by whether he/she was hospitalized, had a transfusion, and/or had a pain crisis at 2 evaluation periods; the first was based on a patient's history taken at the initial assessment visit to the Wayne State Comprehensive Sickle Cell Center, and the second was based on a 1–3 year follow‐up at the center. Fetal hemoglobin was a strong predictor of a patient's hospitalization and transfusion status. A decrease in %HbF of 4.76% (one SD of %HbF) was associated with a 3.58 fold (95% confidence interval, 1.18–7.28) greater odds of being hospitalized both prior to initial assessment and on follow‐up, compared to not being hospitalized at either evaluation. Similarly, a decrease in %HbF of 4.76% was associated with a 5.56 fold (95% confidence interval, 1.67–18.96) greater odds of having a transfusion both prior to initial assessment and on follow‐up compared to not having a transfusion at either evaluation. Patients who were both hospitalized and transfused at initial assessment and on follow‐up (n = 12) had a mean %HbF of 7.59%, while patients who were not hospitalized or transfused at either evaluation (n = 19) had a mean %HbF of 13.61%. Fetal hemoglobin was not a significant predictor of pain crises in this sample of patients. None of the other hematological variables were significant predictors of disease severity in this study. The strong relationship between %HbF and disease severity identified in this study suggests that a single %HbF measurement may be useful in predicting important aspects of the clinical course of children with sickle cell anemia.
De novo X;Y translocation associated with imperforate anus and retinal pigmentary abnormalities
Authors: Johnston Kathreen , Schonberg Steven , Littman Victoria , Gregory Teresa , Gelbart Samuel , O'Donnell James , Cox David R. , Opitz John M. , Reynolds James F.
Published: June 2005

Cytogenetically detectable translocations of Y chromosome material onto the distal short arm of an X chromosome are rare and result in a variable and poorly defined phenotype of short stature and short limbs occasionally associated with mental retardation. We report on a patient with a de novo 46,X,t (X;Y) (p22;q11) chromosome constitution who has additional features not previously described with this chromosome abnormality, including abnormal retinal pigmentation, imperforate anus, and hydronephorosis. Our patient extends the phenotype associated with X;Y translocations, raising new considerations for the clinical management and genetic counseling of such patients and their families.
Segregation and linkage analyses of dopamine‐β‐hydroxylase activity in a six‐generation pedigree
Authors: Asamoah Alexander , Wilson Alexander F. , Elston Robert C. , Dalferes Edward , Berenson Gerald S. , Opitz John M. , Reynolds James F.
Published: June 2005

Serum dopamine‐β‐hydroxylase (DBH) levels and 30 polymorphic markers were determined on 178 individuals of the HGAR 29 family, ascertained through six probands who had clinical and electrocardiographic evidence of myocardial infarction. Individuals in this pedigree with a history of heart attack had significantly lower levels of DBH, but this difference was partly confounded with age differences. Pedigree segregation analysis showed evidence of a codominant gene for DBH segregating in the family. Linkage analysis between the putative DBH locus and 30 polymorphic marker loci, assuming a codominant model, yielded a largest lod score of 0.53, with ABO at 20% recombination. Adding this to the lod scores obtained by Elston et al [1979] and Goldin et al [1982], we obtain combined lod scores of 2.49 and 2.50 at 0.0 and 10% recombination respectively.
Delineation of the male phenotype in craniofrontonasal syndrome
Authors: Morris Colleen A. , Palumbos Janice C. , Carey John C. , Opitz John M. , Reynolds James F.
Published: June 2005

We are reporting on a 4‐generation family in which 6 individuals had frontonasal dysplasia with variable extracranial abnormalities. All affected persons had hypertelorism, bifid or broad nose, and highly arched palate. Associated abnormalities included cleft lip and palate (1/6), webbed neck (2/6), Sprengel anomaly (2/6), pseudoarthrosis of the clavicle (2/6), pectus excavatum (3/6), narrow, sloping shoulders (3/6), diaphragmatic hernia (2/6), broad first toe (4/6), brachydactyly (3/6), fifth finger clinodactyly (5/6), longitudinal grooves of nails (5/6), shawl scrotum (2/3 males), first degree hypospadias (1/3), and mild mental retardation (1/6). Only one affected female had brachycephaly and right coronal synostosis. Four other affected relatives had varying degrees of facial asymmetry, but normal skull contour. No male to male transmission is observed, and both daughters of an affected male were affected. Based on the phenotype of the 3 affected females, craniofrontonasal syndrome (CFNS) is the likely diagnosis. However, there are 3 affected males in this kindred, and 2 of the 3 had significant anomalies. Affected males also had genital abnormalities and pectus deformity of the chest, not previously reported in this condition. Two of the 3 males have posterolateral diaphragmatic hernia. This family expands the phenotype of affected males.
Intrafamilial variability in lysosomal storage diseases
Authors: Zlotogora Joël , Opitz John M. , Reynolds James F.
Published: June 2005

In most lysosomal storage diseases clinical variability is found and affects age‐of‐onset, severity, and the degree of neurological involvement. Very often the variability is due to the existence of different mutations leading to the same enzyme deficiency. In most of the families with more than one person affected, the clinical picture is very similar. Intrafamilial variation has been reported in the lysosomal storage diseases related or not related to genetic heterogeneity. In families in which different affected persons have the same genotype, as in X‐linked disorders, or autosomal recessive diseases in which both parents of the affected sibs are carriers and healthy, the variability must be due to factors not related to the genotype. On the other hand, when different mutations are present in the same family, the variability may be related to the differences in the genotype of the affected persons. Knowledge of the possibility of intrafamilial variability and its genetic basis is essential in clinical and prenatal diagnosis of the lysosomal storage diseases.
Do some patients with seckel syndrome have hematological problems and/or chromosome breakage?
Authors: Butler Merlin G. , Hall Bryan D. , Maclean Ronald N. , Lozzio Carmen B. , Opitz John M. , Reynolds James F.
Published: June 2005

We report on a 12‐yr‐old female and a 14‐yr‐old male with Seckel syndrome. The 12‐yr‐old female had pancytopenia, which is seen occasionally in patients with Seckel syndrome and is also a feature of Fanconi anemia, a well‐recognized autosomal recessive dwarfism syndrome with chromosome instability. Chromosome breakage analysis of both of our patients also indicated chromosome instability. We suggest that there may be a subgroup of Seckel syndrome patients with chromosome instability and/or hematological problems.
Waardenburg syndrome, Hirschsprung megacolon, and Marcus Gunn ptosis
Authors: Meire F. , Standaert L. , De Laey J. J. , Zeng L. H. , Neri Giovanni
Published: June 2005

A patient with Waardenburg syndrome type II associated with Hirschsprung megacolon and Marcus Gunn ptosis is presented. It is suggested that these different anomalies are manifestations of the same neurocrestopathy.
Chromosome 20 deletion in multiple endocrine neoplasia type 2: Expanded double‐blind studies
Authors: Babu V. Ramesh , Van Dyke Daniel L. , Flejter Wendy L. , Jackson Charles E. , Opitz John M. , Reynolds James F. , Opitz John M. , Reynolds James F.
Published: June 2005

Multiple endocrine neoplasia (MEN) type 2A and 2B are autosomal dominant syndromes in which medullary thyroid cancers are associated with adrenal pheochromocytomas. We have expanded our double‐blind studies of high‐resolution G‐banded chromosomes from lymphocytes to a total of 12 MEN‐2A families, 7 MEN‐2B (mucosal neuroma phenotype) families and 23 non‐MEN control subjects. Eighteen of 23 different control subjects were scored as having normal chromosomes 20, and 15 of 21 MEN‐2A and 4 of 8 MEN‐2B patients were scored as having an interstitial deletion: del(20) (p12.2p12.2). These findings suggest that the dominant mutation in many MEN‐2A and MEN‐2B families is a visible deletion within band 20p12.2. Combining the results of these double‐blind studies with those of the only other comparable reported double‐blind series provides a statistical probability of less than 1/1000 that the association between MEN‐2A and the deletion was observed by chance alone. However, the occasional discrepancies in classification using presently available techniques preclude the use of high resolution chromosome studies for the diagnosis of MEN‐2.
A major gene model for the familial aggregation of plasma IgA concentration
Authors: Asamoah Alexander , Wyatt Robert J. , Julian Bruce A. , Quiggins Patricia A. , Wilson Alexander F. , Elston Robert C. , Reynolds James F.
Published: June 2005

Plasma IgA concentration was determined on 94 individuals of an eastern Kentucky family (IGAN1) with some members having clinical and biopsy‐proven IgA nephropathy, and on 197 individuals of a large Louisiana family (HGAR29) with no clinical history of IgA nephropathy but on whom 30 polymorphic markers had previously been typed. Pedigree segregation analysis was used to fit a major gene model, and a moderately large lod score for linkage to the ABO locus (1.50 at 0% recombination) suggested the existence of a recessive allele for high plasma IgA concentration. This allele is only slightly more prevalent in pedigree IGAN1 than in pedigree HGAR29, indicating that it is a minor, rather than a major, etiologic factor in IgA nephropathy.
Osteogenesis imperfects type III: An ancient mutation in Africa?
Authors: Viljoen Denis , Beighton Peter , Opitz John M. , Reynolds James F.
Published: June 2005

In a survey of institutions for crippled persons in Zimbabwe, 58 patients with osteogenesis imperfecta (OI) were identified; 42 had the rare OI Type III. The Shona and Ndebele people, who comprise the major tribal groups in Zimbabwe, both had a similar and relatively high gene frequency for this disorder. Both tribes were derived from common progenitors, but until 150 years ago had been geographically separated for 2 millenia. Subsequently, they have remained culturally and socially distinct. The implications are that the mutation for OI III in Africa occurred at least 2,000 years ago.
New autosomal dominant branchio‐oculo‐facial syndrome
Authors: Fujimoto Atsuko , Lipson Mark , Lacro Ronald V. , Shinno Nancy W. , Boelter William D. , Jones Kenneth L. , Wilson Miriam G. , Opitz John M. , Reynolds James F.
Published: June 2005

We observed an autosomal dominant disorder of abnormal upper lip, which resembles a poorly repaired cleft lip, malformed nose with broad bridge and flattened tip, lacrimal duct obstruction, malformed ears, and branchial cleft sinuses and/or linear skin lesions behind the ears in several persons in 3 families. In each of the 3 families, an affected parent had at least one affected child. Father‐to‐son transmission in one of these families ruled out X‐linked inheritance. Other anomalies include coloboma, microphthalmia, auricular pits, lip pits, highly arched plate, dental anomalies, and subcutaneous cysts of the scalp. Premature graying of hair occurred in the affected adults. Growth retardation, developmental delay, and hand anomalies are variable components of the syndrome.
The Nager syndrome
Authors: Hecht Jacqueline T. , Immken LaDonna L. , Harris Lileah F. , Malini Srini , Scott Charles I. , Opitz John M. , Reynolds James F.
Published: June 2005

The Nager syndrome was identified in a newborn infant and in a subsequent sib by prenatal ultrasonography. This report documents an autosomal recessive pattern of inheritance for this disorder.
Neu‐Laxova syndrome: Report of a case and comments
Authors: Karimi‐Nejad Mohammad Hassan , Khajavi Hooshang , Gharavi Mohammad Jafar , Karimi‐Nejad Roxana , Opitz John M. , Reynolds James F.
Published: June 2005

We report on an infant with Neu‐Laxova syndrome [Neu et al, 1971; Laxova et al, 1972; Povysilova et al, 1976; Lazjuk et al, 1979; Scott et al, 1981; Fitch et al, 1982; Mueller et al, 1983; Turkel et al, 1983; Paes et al, 1985], and emphasize the ichthyotic skin lesions as a prominent characteristic change in this syndrome and as the probable cause of some of the other findings. Also, we call attention to the increased fatty tissue beneath the epidermis and the atrophic muscles there embedded. These findings should be considered in the diagnosis of this syndrome.
Twinning, nonrighthandedness, and fusion malformations: Evidence for heritable causal elements held in common
Authors: Boklage Charles E. , Opitz John M. , Reynolds James F.
Published: June 2005

Certain relatively common congenital malformations that are reported to be excessive in frequency among twins are also found in excess among first‐degree relatives of twins. They are familially associated with each other. Like twinning, they are familially associated with nonrighthandedness (NRH). They also share the fact that they affect structures that are built by the fusion of bilateral embryonic halves and then remodeled under the influence of neural crest mesenchyme. This conjunction of associations suggests that twinning, NRH, and the fusion malformations share causal elements, some of which may be heritable. Determination of spatial relationships in embryogenesis (“embryonic body symmetry determination”) and the functions of neural crest mesenchyme may be mechanisms unifying these effects.
Goldenhar complex in discordant monozygotic twins: A case report and review of the literature
Authors: Boles Debra J. , Bodurtha Joann , Nance Walter E. , Reynolds James F.
Published: June 2005

In 1952, Goldenhar described a pair of monozygotic twins who were discordant for epibulbar dermoids, auricular appendages, malformations of the auricle, and hemifacial microsomia. Eighteen twin pairs have subsequently been described in which at least one member exhibited these manifestations. We report on an additional pair of discordant dichorionic monozygotic male twins. All of the 5 monozygotic twin pairs for which placental information is available have been discordant and 2 of these had dichorionic membranes. The failure of discordant monozygotic twins to be limited to monochorionic pairs argues against the hypothesis that developmental abnormalities arising from the placental vascular anastomoses that are commonly found in monozygotic twins is the probable explanation for the discordant expression of these traits in twins.
Gonadal mosaicism in pseudoachondroplasia
Authors: Hall Judith G. , Dorst John P. , Rotta Julie , McKusick Victor A. , Opitz John M. , Reynolds James F.
Published: June 2005

We report on a family in which a brother and sister have pseudoachondroplasia and normal parents. The brother married a normal woman, and they have 2 daughters; one of them has typical changes of pseudoachondroplasia, the other is normal. The most likely explanation in this family is gonadal (germinal cell) mosaicism in one of the grandparents. Other reports of possible autosomal recessive pseudoachondroplasia are reviewed. It is likely that gonadal mosaicism is responsible for a small percentage of cases with what appears to be a new mutation for pseudoachondroplasia.
Recurrence risks in the presence of single gene susceptibility to environmental agents
Authors: Khoury Muin J. , Beaty Terri H. , Opitz John M. , Reynolds James F.
Published: June 2005

Investigators often attribute the 2‐5% sibling recurrence risks of common congenital malformations to a multifactional/threshold model (MFT) mechanism. However, most studies fail to address adequately the role of specific environmental factors and their interaction with genetic factors in recurrence risks. We consider the effects of a hypothetical environmental agent on recurrence risks in the presence of a single gene‐mediated differential susceptibility. It can be shown that recurrence risks increase with increasing population exposure frequency to the agent and the strength of gene‐environment interaction (relative risk among susceptible genotypes). However, they are usually much lower than expected on the basis of simple Meridelian segregation. Moreover, recurrence risks decline considerably between 1st, 2nd, and 3rd degree relatives, especially for recessive traits. Because single gene‐mediated differen‐tial susceptibility can mimic the MFT model in many instances, family studies of malformations (and other common diseases) could be more rewarding if they incorporate in their design and analyses specific environmental exposures affecting disease risk.
Decreased cell viability of fibroblasts from two patients with a ring chromosome: An in vitro reflection of growth failure?
Authors: Kosztolányi György , Opitz John M. , Reynolds James F.
Published: June 2005

We found decreased cell viability in fibroblast cultures from two patients, one with ring chromosome 4, the other with ring chromosome 15, who had severe somatic retardation. Cell viability was studied with the trypan blue exclusion assay, and in comparison with matched control cells was found to be 72.0 vs. 93.1%, and 79.8 vs. 90.2%, respectively. Cloning efficiency of fibroblasts from the patient with ring chromosome 15 was also decreased (12.3 vs. 25.7%). It is suggested that the decreased cell viability is due to a continuous production of hypomodal cells, a process related to the ring structure per se, and perhaps responsible for the severe somatic retardation frequently observed in patients with a ring chromosome.
Further delineation of the 3‐M syndrome with review of the literature
Authors: Hennekam Raoul C. M. , Bijlsma Jan B. , Spranger Jürgen , Neri Giovanni
Published: June 2005

The 3‐M syndrome is a clinically recognizable disorder characterized by prenatal and postnatal growth retardation and a spectrum of consistent minor anomalies. Intelligence seems normal. Inheritance is probably autosomal recessive, with possible expression of the mutant gene in the heterozygote. Three sibs with the 3‐M syndrome are reported, together with an extensive review of the pertinent literature.
Limb‐body wall complex: II. Limb and spine defects
Authors: Van Allen M. I. , Curry C. , Walden C. E. , Gallagher L. , Patten R. M. , Opitz John M. , Reynolds James F.
Published: June 2005

Limb defects from 25 fetuses with limb‐body wall (LBW) complex were evaluated to determine the mechanism of limb damage. The limb defects could be divided into 3 pathogenetic groups: (1) secondary to disruption of embryonic vessels and surrounding tissue (84%), (2) secondary to amniotic bands or adhesions (16%), and (3) deformation versus hemorrhage (44% with club feet), with some fetuses having more than one pathogenetic mechanism causing limb defects. The hypothesis that the majority of limb defects resulted from disruption of embryonic vessels was supported by the following findings: 96% of the LBW complex fetuses had limb defects; the lower limbs were at greater risk of damage than the upper limbs (28% rt arm, 52% 1t arm, 60% rt leg, 72% lt leg); there was a distal to proximal progression of limb damage in 92% of the fetuses; statistical analysis of comparing the location of the most severe limb defect and the body wall defect did not find concordance between the side (p = l.0) and the region (p = 0.18) of the body wall defect; and limb defects found in the human specimens were similar to those produced in experimental animals following disruption of embryonic vessels at a corresponding gestation. In the specimens with amniotic band related limb defects (16%), the most likely pathogenesis is mechanical rupture through the amnion in the presence of a persistent extraembryonic coelom or from adhesion of the amnion to necrotic embryonic tissue after the initial disruptive event. Club feet were present in 44% and may be due either to disruption of embryonic vessels or to deformation. Further studies are needed to resolve this question.
New autosomal dominant syndrome resembling craniofrontonasal dysplasia
Authors: Teebi Ahmad S. , Reynolds James F.
Published: June 2005

Craniofrontonasal dysplasia, a distinct malformation syndrome, is characterized by varying degrees of frontonasal dysplasia, craniosynostosis, and variable extracranial abnormalities—in particular, brittle nails with prominent longitudinal grooves or Splitting. There is marked female preponderance and variable expressivity not only between males and females but also between females. However, mode of inheritance is still unclear. We describe a large Arab kindred with 16 individuals (9 males, 7 females) in 4 generations having an apparently new autosomal dominant syndrome with features of Craniofrontonasal dysplasia but with normal or slightly broad nasal tip and without evidence of craniosynostosis or nail abnormalities. These cases were segregating in 5 sibships and include male to male transmission with full expression in males and females. Chromosomes of the proposita and her father were normal. Aarskog syndrome has been also considered in the differential diagnosis and was excluded.
Prenatal diagnosis of retinal detachment in Walker‐Warburg syndrome
Authors: Farrell S. A. , Toi A. , Leadman M. L. , Davidson R. G. , Caco C. , Opitz John M. , Reynolds James F.
Published: June 2005

Lissencephaly, hydrocephalus, and eye abnormalities characterize patients with the Walker‐Warburg syndrome, an uncommon autosomal recessive condition. Encephaloceles occur in about 50% of patients. We describe the prenatal diagnosis of this condition based on the ultrasonographic findings of retinal detachment, hydrocephalus, and an encephalocele in a fetus not known to be at risk.
Unique skeletal dysplasia with absence of the distal ulnae
Authors: Goldblatt J. , Behari D. , Opitz John M. , Reynolds James F.
Published: June 2005

We report on an Indian woman with a severe shortness of stature, absence of the distal ulnae, and a predominantly spondylometaphyseal skeletal dysplasia. The clinicoradiographic changes in this patient appear to represent a unique skeletal disorder.
Familial ossicular malformations: Case report and review of literature
Authors: Higashi Koichiro , Yamakawa Koji , Itani Osamu , Togawa Kiyoshi , Opitz John M. , Reynolds James F.
Published: June 2005

Familial middle ear ossicular anomalies are rare. We report on a daughter and her mother with congenital conductive hearing loss. Tympanotomy disclosed hypoplasia of long crus of incus whose tip had been replaced with a fibrous strand.

A review suggests that middle ear ossicular anomalies may be inherited as autosomal dominant traits. Most individuals were bilaterally affected. Most isolated cases were affected unilaterally.
Cases of neurofibromatosis with rearrangements of chromosome 17 involving band 17q11.2
Authors: Schmidt Michael A. , Michels Virginia V. , Dewald Gordon W. , Opitz John M. , Reynolds James F.
Published: June 2005

We report on a family in which a mother and her 2 children each had von Recklinghausen neurofibromatosis and a balanced chromosome rearrangement t(1;17)(p34.3;qll.2). In addition, we describe another unrelated patient with neurofibromatosis and a presumed secondary myelodysplastic syndrome in which the bone marrow contained an abnormal clone with an unbalanced rearrangement involving a breakpoint in band 17qll.2. These findings may suggest that the neurofibromatosis gene is located in or near band 17qll.2. This information supports the studies which assign the neurofibromatosis gene to a region of chromosome 17 between the proximal p arm and band q22 on the long arm.
Sister chromatid exchange analysis in the Prader‐Labhart‐Willi syndrome
Authors: Butler Merlin G. , Jenkins Bonnie B. , Opitz John M. , Reynolds James F. , Ledbetter David H.
Published: June 2005

The number of sister chromatid exchanges (SCE) and cell kinetics in lymphocytes were investigated from 16 Prader‐Lab‐hart‐Willi syndrome (PLWS) patients [8 with 15ql2 deletion (4 females, 4 males; x age = 12.9y with age range of 0.3 to 24y), and 8 non‐deletion (2 females, 6 males; x age = 16.8y with age range of 5 to 26y)], 18 parents of PLWS patients and age‐matched control individuals. The average SCE frequency and standard deviation in PLWS patients with and without the chromosome 15 deletion was 6.6 ± 1.3 and 6.2 ± 0.8, respectively. Therefore no significant difference in SCE frequency or replicative index was found between the two PLWS subgroups. There was also no significant difference in SCE frequency or replicative index between the 16 PLWS patients and age‐matched control subjects. The average SCE frequency and standard deviation in 8 fathers who were previously identified to have donated the chromosome 15 with the deletion in the child was 7.5 ± 1.2, which was not significantly different from 8.5 ± 2.0 seen in age‐matched control subjects. There was also no significant difference in the SCE frequency or replicative index of 18 parents of PLWS patients with and without the chromosome 15 deletion when compared with age‐matched control subjects.
Is angelman syndrome an alternate result of del(15)(qllql3)?
Authors: Magenis R. Ellen , Brown Michael G. , Lacy Deborah A. , Budden Sarojini , LaFranchi Stephen , Opitz John M. , Reynolds James F. , Ledbetter David H.
Published: June 2005

Two unrelated females, age 15 and 5 years respectively, were studied cytogenetically because of severe mental retardation, seizures and ataxia‐like incoordination. A similar deletion of the proximal long arm of chromosome 15 was found in both patients.

Re‐evaluation showed no voracious appetite or obesity; normal size of hands and feet, minimal to no hypotonia by history or examination and facial features not typical of the Prader‐Willi syndrome. However, the facial appearance of the girls was similar to each other with mild hypertelorism.

The similarity of these girls and dissimilarity to Prader‐Willi syndrome suggest a different syndrome, perhaps the result of deletion of a different segment of 15q. The findings of ataxic‐like movements, frequent, unprovoked and prolonged bouts of laughter and facial appearance are more compatible with the diagnosis of Angelman syndrome.
Steroid metabolic disturbances in Prader‐Willi syndrome
Authors: Chasalow Fred I. , Blethen Sandra L. , Tobash Judith G. , Myles Darlene , Butler Merlin G. , Opitz John M. , Reynolds James F. , Ledbetter David H.
Published: June 2005

We have studied steroid sulfate conjugates in serum samples from 17 children with Prader‐Willi syndrome (PWS) by extraction, enzymatic hydrolysis and chromatography of the hydrolysed, free steroids. The chromatograms in patients with PWS can be divided into 2 classes. Ten (A with the deletion on chromosome 15 and 6 without) of 17 had a normal pattern with dehydroepiandrosterone (DHEA) as the only steroid detected. However, 7 out of 17 (3 with the deletion and 4 without) had a very different pattern. The chromatogram derived from these hydrolysates had 5 major peaks. One of these was DHEA; a second peak was tentatively identified as 16α‐hydroxy‐DHEA on the basis of column retention time and immunoreactivity. The remaining 3, more polar, compounds have not yet been identified. The presence of unusual steroid sulfo‐conjugates in serum may correlate with other features of PWS and may be the basis for dividing PWS into two separate disease states: a) PWS‐1 associated with DHEA‐S as the only sulfo‐conjugate and b) PWS‐2 associated with unusual sulfo‐conjugates. One interesting possiblitiy is that these sulfo‐conjugates may have a hormonal function, even though no function has yet been recognized for DHEA‐S. Then, PWS may be the common clinical manifestation of a variety of different defects in the sulfo‐conjugate metabolic pathway.