bluuebunny/crossref_metadata_2025 huggingface dataset:
Hydrolethalus (Salonen‐Herva‐Norio) syndrome: Further clinicopathological delineation
Authors: Anyane‐Yeboa K. , Collins M. , Kupsky W. , Maidman J. , Malin J. , Yeh M. , Opitz John M. , Reynolds James F.
Published: June 2005

Two brothers with severe CNS abnormalities, cleft lip/palate, polydactyly, and lung hypoplasia are reported as examples of the hydrolethalus syndrome, an autosomal recessive disorder. Death from cardiopulmonary arrest occurred in patient 1 at age 4 months and in patient 2 at age 17 days. Detailed radiological and neuropathological description is provided on patient 2. We recommend realtime ultrasonography and, when indicated, fetpscopy for antenatal detection of the craniofacial and limb malformations associated with this syndrome.
Increased sister chromatid exchange frequency at Xq27 site in affected fragile X males
Authors: Wenger Sharon L. , Hennessey Jill C. , Steele Mark W. , Reynolds James F.
Published: June 2005

Sister chromatid exchange (SCE) was evaluated in peripheral blood lymphocytes cultured from normal subjects, fragile X carrier females, and fragile X affected males and in general did not differ among all subjects whether cells were grown in thymidine‐deficient or complete medium. However, at the Xq27 site, SCE was significantly increased for fragile X affected males, particularly in cells grown in thymidine‐deficient medium.
A 26‐month‐old child with Marden‐Walker syndrome and pyloric stenosis
Authors: Gossage David , Perrin James M. , Butler Merlin G. , Opitz John M. , Reynolds James F.
Published: June 2005

We recently examined a 26‐month‐old boy with abnormal face, blepharophimosis, hypertelorism, apparently low‐set ears, micrognathia, arachnodactyly, talipes equinovarus, and joint contractures. Subsequently he manifested failure to thrive, respiratory infections, and developmental delay. These congenital anomalies and associated findings are consistent with a diagnosis of the Marden‐Walker syn‐drome. He also had mild pyloric stenosis and duodenal bands, not previously reported in this syndrome. This syndrome appears to be an autosomal recessive trait in some families. A summary of findings of the 16 previous published patients is presented.
Trisomy 18 mosaicism in an adult with normal intelligence
Authors: Kohn Gertrude , Shohat Mordechai , Opitz John M. , Reynolds James F.
Published: June 2005

A healthy 30‐year‐old woman was discovered unexpectedly to have trisomy 18/ normal chromosome mosaicism. She was ascertained because of a history of three spontaneous abortions following the birth of a healthy son. Trisomy 18 was present in 18% of her lymphocytes and 2% of her cultured skin fibroblasts. She had several minor malformations associated with trisomy 18 syndrome. She is, to our knowledge, the first person who has clinical stigmata of trisomy 18 but has normal intelligence and leads a normal family life.
Achondroplasia‐hypochondroplasia complex
Authors: Sommer Annemarie , Young‐Wee Theresa , Frye Thomas , Reynolds James F.
Published: June 2005

We report on a 14‐year‐old girl with the achondroplasia‐hypochondroplasia complex. This patient has been reported previously [McKusick et al, 1973], and we offer an update on her condition. The patient has clinical features different from both achondroplasia and hypochondroplasia and is mentally retarded. Radiological changes, which have occurred over 14 years, are included.
Proteus syndrome in Southern Africa: Natural history and clinical manifestations on six individuals
Authors: Viljoen D. L. , Nelson M. M. , de Jong G. , Beighton P. , Opitz John M. , Reynolds James F.
Published: June 2005

Six individuals with Proteus syndrome have been investigated; 2 were adults and the others ranged in age from 2 to 11 years. They had a wide spectrum of manifestations and severity together with the hitherto unreported anomalies of penile hypertrophy, macro‐orchidism, goiter, and failure of breast development. These findings were associated with normal endocrine function. Bizarre digital overgrowth, hemihypertrophy, thickened palms and soles, exostoses of the skull, and multiple hamartomata were common anomalies. Early overgrowth of limbs and digits occurred in several instances but the ultimate stature of 2 adults was normal. Surgical intervention offers cosmetic and orthopedic benefits, but these must be assessed in the light of potential post‐operative complications.
Severe proteus syndrome in an 18‐month‐old boy
Authors: Malamitsi‐Puchner Ariadne , Kitsiou Sophia , Bartsocas Christos S. , Opitz John M. , Reynolds James F.
Published: June 2005

We describe an 18‐month‐old Greek boy with macrocephaly, partial gigantism of hands and feet, hemihypertrophy, pigmented nevi, and other anomalies compatible with the Proteus syndrome. Cerebral involvement in a most severe form and at an early age concurs with the suggestion that encephalocraniocutaneous lipomatosis may represent a more circumscriptive manifestation of Proteus syndrome. Localized triggering of several growth factors is a challenging pathogenetic consideration of the syndrome.
Association of neural tube defects with omphalocele in chromosomally normal fetuses
Authors: Ardinger Holly H. , Williamson Roger A. , Grant Stanley , Opitz John M. , Reynolds James F.
Published: June 2005

Omphalocele is frequently associated with other congenital malformations or a chromosome abnormality. Previously published series of omphalocele have emphasized the association of congenital heart defects or chromosomal abnormalities. We present five cases of omphalocele with a concurrent neural tube defect from among the 15 cases of omphalocele evaluated between 1981 and 1985. Fourteen of 15 were detected prenatally. A sixth case is presented in which both a neural tube defect and an omphalocele were suspected on a prenatal ultrasound, but only the latter was found on autopsy. We recommend that a systematic evaluation be performed on every fetus with an omphalocele to include amniotic fluid alpha fetoprotein, acetylcholinesterase levels, chromosome study, and careful ultrasonography looking for evidence of other abnormalities, especially neural tube defects, before counseling the parents.
Familial correlations from genes and shared environment for urine, plasma, and intraerythrocytic sodium
Authors: Hunt Steven C. , Dadone Mary M. , Williams Roger R. , Wu Lily L. , Smith Jean B. , Kuida Hiroshi , Ash K. Owen , Opitz John M. , Reynolds James F.
Published: June 2005

Spouse–spouse, sib–sib, and parent–offspring correlations were calculated for urinary, plasma, and intracellular sodium levels on over 1,900 persons aged 3–86 years in 98 Utah kindreds. For 36 hours prior to their clinic visit, 31% of the sample was salt‐loaded with salt tablets, while the rest followed their normal diet. For those on their normal diet, urine creatinine‐, age‐, and sex‐adjusted urinary sodium excretion from a timed 12‐hour overnight sample showed similar and significant correlations between spouses (r = .29), sibs less than 20 years old (r = .38), and parent–offspring pairs for offspring less than 20 years old (r = .29). This contrasted with the lower correlations between sibs 20 years of age and older (r = .10) and parent–offspring pairs for offspring 20 years of age and older (r = .13), presumed to live in different households. Adult plasma sodium sib–sib (r = .13) and parent–offspring (r = .15) correlations were similar to the urinary sodium correlations, while the spouse–spouse (r = .48), the sib–sib (r = .64), and the parent–offspring (r = .63) correlations for those presumed to live in the same household nearly doubled. Intracellular sodium correlations for the adult sibs (r = .32) and offspring (r = .36) were over twice as large as for urinary or plasma sodium, although the spouse–spouse correlation (r = .37) remained large also. Using the salt‐loaded families, only the sib–sib and parent–offspring correlations for those sibs and offspring who were less than 20 years of age for plasma sodium and the spouse–spouse correlation for intracellular sodium changed (decreased). These results indicate that there is a large environmental component not only for urinary sodium excretion but also for plasma sodium concentration, and that plasma sodium may also reflect changes in dietary sodium intake. Intracellular sodium concentration, on the other hand, seems to have a larger genetic component, although because the spouse–spouse correlations were large and decreased upon salt‐loading, there also appears to be an environmental component that can modify the genetically determined sodium handling in an individual.
Isochromosome 12p mosaicism (Pallister mosaic aneuploidy or Pallister‐Killian syndrome): Report of 11 cases
Authors: Reynolds James F. , Daniel Art , Kelly Thaddeus E. , Gollin Susanne M. , Stephan Mark J. , Carey John , Adkins William N. , Webb Mary Jane , Char Florence , Jimenez Jorge F. , Opitz John M. , Neri Giovanni
Published: June 2005

We report on 11 cases of isochromosome 12p mosaicism (or Pallister mosaic aneuploidy syndrome) in which the isochromosome is usually absent in cultured lymphocytes but present in fibroblasts. The patients range in age from a 22‐week‐gestation fetus to a 45‐year‐old man. They have a distinct pattern of anomalies which enables one to make a diagnosis based on clinical manifestations alone. Craniofacial manifestations include “coarse” face with prominent forehead, spars‐ity of scalp hair, hypertelorism, epicanthal folds, flat bridge of nose, and highly arched palate. Affected newborn infants are profoundly hypotonic with sparsity of scalp hair especially bitemporally and a prominent forehead. Most have accessory nipples. Birth weight and growth parameters are usually normal; however, some newborn infants are unusually large. In infancy, the facial appearance becomes “coarse,” hypotonia persists, and seizures may occur. As adults, growth may be normal, scalp hair is thicker and the mandible becomes prominent. Most have a generalized pigmentary dysplasia which may be evident with a Wood's lamp only. All cases have been sporadic and there is no consistent pattern of advanced parental age.
Prenatal ultrasound diagnosis of diastrophic dysplasia at 16 weeks
Authors: Gollop Thomaz Rafael , Eigier Alberto , Opitz John M. , Reynolds James F.
Published: June 2005

We report on the prenatal ultrasound diagnosis of diastrophic dysplasia at 16 wk of gestation. The ultrasound examination showed abnormally short limbs and lateral projection on the thumbs. Radiological and histological studies confirmed the presence of diastrophic dysplasia in the aborted fetus.
ReCAP: The registry of cytogenetic abnormalities and phenylketonuria
Authors: Friedman J. M. , Smith Janet P. , Lerner Barbara N. , Helgeson Jean S. , Howard‐Peebles Patricia N. , Mize Charles E. , Mize Susan G. , Singleton William L. , Smith M. Eileen , Opitz John M. , Reynolds James F.
Published: June 2005

The Registry of Cytogenetic Abnormalities and Phenylketonuria (ReCAP) is a multicenter collaborative registry of information on patients with constitutional cytogenetic abnormalities or hyperphenylalaninemia (HPA). Data are entered by microcomputer at four contributing centers. Records are then electronically trans‐mitted to the coordinating center, where the composite cytogenetic and hyperphen‐ylalaninemia databases are maintained on a mainframe computer. A set of programs, known as the ReCAP ISCN Translator, is used to create additional database records describing in detail the chromosome abnormalities present in each patient. The ReCAP computer system permits rapid and flexible retrieval of cases on the basis of any combination of laboratory, clinical, psychometric, or genetic characteristics contained within the databases. Special procedures protect patient confidentiality and assure that ReCAP data are of consistently high quality. Qualified investigators may use ReCAP as a resource for a variety of scientific studies.
Possible prenatal hydantoin effect in a child born to a nonepileptic mother
Authors: Chodirker Bernard N. , Chudley Albert E. , Reed Martin H. , Persaud T. V. N. , Opitz John M. , Reynolds James F.
Published: June 2005

We describe a child who was born with marked digital hypoplasia of his right hand. Although the mother was not an epileptic, the child was exposed in utero to diphenyIhydantoin.
Phenotypic variation in male‐transmitted fragile X: Genetic inferences
Authors: Loesch Danuta Z. , Hay David A. , Sutherland Grant R. , Halliday J. , Judge C. , Webb G. C. , Opitz John M. , Reynolds James F.
Published: June 2005

Three families with confirmed and one family with suspected male transmission of the fragile X are presented, with psychological and physical assessment of all available members. The psychological tests used were the Peabody Picture Vocabulary test and Block Design which measured verbal and non‐verbal abilities, respectively. Physical status was assessed by recording dysmorphic features and by anthropometric measurements.

This study demonstrated that there are appreciable differences in mental and physical status within sibships of daughters of male carriers, as well as recognizable physical alterations and intellectual impairment in the transmitting males.

These fmdings contradict the concept that there are two distinct categories of fragile X carriers: phenotypically normal as opposed to affected. They suggest instead that the defect may be graded and emphasize the importance of intellectual deficits and physical alterations in defining the fragile X phenotype, both in low‐penetrant males and female heterozygotes.
Herrmann‐Opitz syndrome: Report of an affected fetus
Authors: Anyane‐Yeboa K. , Kasznica J. , Malin J. , Maidman J. , Opitz John M. , Reynolds James F.
Published: June 2005

In 1969, Herrmann and Opitz described a syndrome of acrocephaly, oligosyndactyly, hypertelorism, and mental retardation. We report on a second case, a fetus with cleft palate, urethral astresia, oligohydramnios, and intrauterine death.
Tetrasomy 9p caused by idic (9) (pter→q13→pter)
Authors: Cavalcanti Denise Pontes , Ferrari Iris , de Almeida José Carlos Cabral , de Pina Neto João Monteiro , de Oliveira José A. , Reynolds James F.
Published: June 2005

Cytogenetic investigation on a malformed male infant showed an extra chromosome similar to chromosome 9 in all metaphases studied. GTG, CBG, and G‐11 staining suggested that the extra chromosome was an abnormal 9, permitting the identification of the chromosome constitution as 47,XY, +idic (9) (pter→q13→pter).
Frequency of carriers of chronic (type I) Gaucher disease in Ashkenazi Jews
Authors: Maloth Yehuda , Chazan Sara , Cnaan Avital , Gelernter Ilana , Klibansky Chaya , Reynolds James F.
Published: June 2005

In this study we estimate the frequency of carriers of chronic (type I) Gaucher disease among Ashkenazi Jews by examining the glucocerebrosidase activity in leukocytes in a population of 635 blood donors (441 Ashkenazi) and 57 obligatory heterozygotes. Estimation using the defect in the enzyme glucocerebrosidase (beta‐glucosidase) in leukocytes is complicated by the existence of considerable overlap between enzyme activity in normals and in heterozygotes. The assay was carried out with a natural substrate labeled with 14C. Discriminant analysis was used to establish an optimal cutoff point between the obligatory heterozygotes and normal (non‐Ashkenazi) subjects for the purpose of estimating frequency of carriers. Applied to the Ashkenazi group, the cutoff point identified 3.17% as heterozygotes. Corrected for errors in classification, the carrier rate was estimated as 4.67%. This figure is in good agreement with a carrier rate of 4% estimated from the number of known cases of clinical Gaucher disease ascertained in Israel.
The use of measured genotype information in the analysis of quantitative phenotypes in man. II. The role of the apolipoprotein E polymorphism in determining levels, variability, and covariability of cholesterol, betalipoprotein, and triglycerides in a sample of unrelated individuals
Authors: Boerwinkle Eric , Visvikis Sophia , Welsh Dorothy , Steinmetz Josiane , Hanash Samir M. , Sing Charles F. , Opitz John M. , Reynolds James F.
Published: June 2005

Recent advances in molecular biology provide measures of genotypes at loci involved in lipid metabolism. Genotypes for apolipoprotein E (apo E) and quantitative levels of total plasma cholesterol, betalipoprotein, and triglycerides were measured in a sample of 223 unrelated individuals from Nancy, France. The frequencies of the ε2, ε3, and ε4 alleles are 0.13, 0.74, and 0.13, respectively, in this sample. Significant differences among apo E genotypes were detected for these lipoprotein phenotypes. The average effect of the ε2 allele was to reduce total plasma cholesterol and betalipoprotein levels by 0.52 mmol/L and 0.98, respectively, while the ε4 allele raised these levels by 0.26 mmol/L and 0.61, respectively. Apo E genotype specific correlations suggest that this locus also has an effect on the coordinated metabolism between cholesterol and triglycerides. We infer that approximately 17% of the genetic variability in total plasma cholesterol may be attributable to this apo E polymorphism. No other single locus has been identified with such a large contribution to cardiovascular disease risk factors in the general population.
Microcephaly: Genetic counselling and antenatal diagnosis after the birth of an affected child
Authors: Tolmie J. L. , McNay Margaret , Stephenson J. B. P. , Doyle D. , Connor J. M. , Opitz John M. , Reynolds James F.
Published: June 2005

We describe the clinical and genetic details of a series of microcephalic patients who were referred to the Genetic Counselling Service for the West of Scotland. There were 29 isolated cases of microcephaly and 9 families with recurrent microcephaly. The sib recurrence risk was 19%, which reflects the high incidence of autosomal recessive microcephaly in this series. There was evidence for several varieties of recessive microcephaly. The most frequent, affecting 5 sib pairs, was associated with spastic quadriplegia, seizures, and profound mental handicap.

In 15 families with one microcephalic child, prenatal diagnosis by serial ultrasound scans was undertaken in 21 subsequent pregnancies. Four recurrences of microcephaly were detected in the third trimester and one recurrence was missed because no scans were performed after 24 wk gestation when the ultrasound measurements indicated satisfactory head growth. The main reason for late diagnosis of affected fetuses was that head growth did not slow appreciably until the last trimester. The high recurrence risk in this prospective series emphasizes the contribution of autosomal recessive inheritance of microcephaly amongst patients of our Genetic Counselling Service.
Linkage analysis in spinopontine atrophy: Correlation or HLA linkage with phenotypic findings in hereditary ataxia
Authors: Bale Allen E. , Bale Sherri J. , Schlesinger Sandra L. , McFarland Henry F. , Opitz John M. , Reynolds James F.
Published: June 2005

Because linkage has been reported between HLA and the locus for hereditary ataxia in some families, we studied a 3‐generation kindred in which several individuals had dominantly inherited spinopontine atrophy. Affected family members had upper and lower limb ataxia, hypoactive reflexes, loss of proprioception, dysarthria, dysphagia, and pronounced extraocular movement abnormalities. Linkage analysis, based on 25 markers in 28 people, gave strongly negative results with both HLA (z < −2.0 for θ < 0.15) and GLO1 (z < −2.0, θ ⩽ 0.01). The highest LOD score was for linkage to GPT on chromosome 16 (z = 0.42, θ = 0.0), To assess the relationship between HLA linkage and phenotype, 4 published kindreds with adequate clinical and neuropathological descriptions were used for comparison to the present family. Persons in the 3 families showing evidence for HLA linkage had clinical and pathologic changes consistent with olivopontocerebellar atrophy, type 1. The conditions in the 2 “nonlinked” families were phenotypically distinct from the HLA‐linked condition with respect to extraocular movement findings and peripheral sensory nervous system signs. They differed markedly from each other in neuropathologic changes.
Deletion of 2p: A cytogenetic and clinical update
Authors: Neidich Julie , Zackai Elaine , Aronson Margaret , Emanuel Beverly S. , Opitz John M. , Reynolds James F.
Published: June 2005

The locus for acid phosphatase (ACP1) had been alternately assigned to two conflicting regions on the short arm of chromosome 2. We present a clinical and cytogenetic report of one patient who has an interstitial deletion of 2, del(2) (p23p25.1), and a cytogenetic study of another cell line with an interstitial deletion of 2p (p23.1p25.1). Because both patients are heterozygotes for ACP1, the assignment of ACP1 to 2p25.1→‐pter is supported.
The risk of having a second retarded child
Authors: Costeff Hanan , Weller Leonard , Opitz John M. , Reynolds James F.
Published: June 2005

We have studied segregation ratios in 282 Israeli families with normal, nonconsanguineous parents and retarded offspring without specific etiologic diagnosis. Severity of retardation and nature of medical history significantly affected recurrence risk, while sex of propositus and sibs and presence or absence of epilepsy, cerebral palsy, microcephaly, and short stature did not. Segregation rations were 0.095 in cases of severe retardation with normal medical history, 0.216 for mild retardation with normal medical history, 0.230 in cases of all retardation with maternal reproductive inefficiency, and 0.110 for all retardation with other reported prenatal, perinatal, or infantile complications. Estimated recurrence risks in most simplex families dropped sharply with each additional normal child. The recurrence risks are higher than some previously published estimates. Different ascertainment criteria may be responsible for this variation. The criteria used here were compatible with a 3.2% population prevalence of mental retardation with a 0.223 segregation ratio in multiplex sibships. It is recommended that future studies of recurrence risks include similar data permitting evaluation of sensitivity of ascertainment criteria.
Recurrence risk in the Angelman (“happy puppet”) syndrome
Authors: Willems Patrick J. , Dijkstra Irene , Brouwer Oebele F. , Smit G. Peter A. , Reynolds James F.
Published: June 2005

We report on two sibs with Angelman “happy puppet” syndrome. Out of 48 families reported in the literature, this is only the fourth family with affected sibs. A review of the literature shows a low but not negligible recurrence risk. Different explanations for this are discussed.
Interstitial deletion of the long arm of chromosome 3: Case report, review, and definition of a phenotype
Authors: Alvarado Monica , Bocian Maureen , Walker Ann P. , Opitz John M. , Reynolds James F.
Published: June 2005

Interstitial deletions of 3q have, to our knowledge, been reported in only four patients. We present an additional patient with interstitial deletion of 3q, with breakpoints at 3q23 and 3q25. The patient was small for gestational age and had a multiple congenital anomalies (MCA) syndrome including microcephaly; unusual facial appearance with bilateral microphthalmia, blepharophimosis, and ptosis; ventricular septal defect; and bilateral clubfeet. Comparison between the clinical and cytogenetic findings of the present case and those of previously reported cases suggests that a recognizable phenotype may be associated with deletions of 3q2.
Persistent genetic isolation in outport Newfoundland
Authors: Bear J. C. , Nemec T. F. , Kennedy J. C. , Marshall W. H. , Power A. A. , Kolonel V. M. , Burke G. B. , Opitz John M. , Reynolds James F.
Published: June 2005

The historical development of genetic isolation has been evaluated for three outport Newfoundland study areas. An attempt was made to ascertain all livebirths in each study area, and determine the parentage of each. Data from records of baptism and marriage were used for this, supplemented with other historical and ethnographic information. Parent–offspring migration was used as a measure of genetic exchange between subpopulations within study areas, and gene flow into the study areas. Currently, 1–8% of parents originate outside the study areas; these rates are low compared to earlier periods, and compared to present‐day rates for European isolate populations. Average kinship was estimated, to measure genetic relatedness within and between subpopulations of each area and the potential for random inbreeding; these values, which are minimum estimates, are now at historically high levels. Increased migration into the study areas, which would decrease average kinship, is not likely. Thus, any regionally or locally elevated frequencies of deleterious alleles will persist, and must be taken into account in providing genetic counseling and evaluating the utility of local screening programs.
Y‐derived sequences detected in a 45,X male by in situ hybridization
Authors: Sheehy Robert R. , Brown Michael G. , Warren Richard J. , Schwartzman Mark , Magenis R. Ellen , Opitz John M. , Reynolds James F.
Published: June 2005

A two‐month‐old boy with normal genitalia and descended testes was referred for a suspected hematological disorder. Cytogenetic analysis showed a 45,X chromosome constitution. In situ hybridization with the Y‐derived probe 50f (provided by Professor Marc Fellous) was performed utilizing metaphase chromosomes to determine whether Y material could be detected. A significant amount of label (17 of 150 cells) was found on chromosome 5p suggesting a 5;Y translocation. This translocation was verified by high‐resolution G‐banded and G‐l1‐stained chromosomes.
Lymphedema in Noonan syndrome: Clues to pathogenesis and prenatal diagnosis and review of the literature
Authors: Witt David R. , Hoyme H. Eugene , Zonana Jonathan , Manchester David K. , Fryns Jean Pierre , Stevenson J. Geoffrey , Curry Cynthia J. R. , Hall Judith G. , Opitz John M. , Reynolds James F.
Published: June 2005

The Noonan syndrome (NS) is a true multiple congenital anomalies (MCA) syndrome with numerous manifestations. An association with lymphedema has been noted, but its pathogenesis is not fully understood. Nine new cases and a review of the literature explore the role of lymphedema in NS, including its pathogenesis, presentations, and phenotypic effects. Consideration is given to developmental stage at time of onset, chronicity, resolution, and anatomic site. It appears likely that lymphedema is a much more frequent concomitant in NS than previously realized.

The major source of lymphedema in NS appears to be a presently undefined dysplasia of lymphatic vessels of unknown cause. Further study of lymphedema may provide an understanding of its role in shaping the NS phenotype. Comparison with other MCA syndromes and animal models is made in this regard. Relevance to prenatal diagnosis and treatment is discussed.
Tibial hemimelia: Report on 37 new cases, clinical and genetic considerations
Authors: Richieri‐Costs A. , Ferrareto I. , Masiero D. , da Silva C. R. M.
Published: June 2005

We report on 37 patients belonging to different families, who have the tibial hemimelia‐split hand/foot syndrome. Genetic aspects and phenotypic manifestations are compared with previous reports of tibial hemimelia. An attempt to clinical and genetical approach is suggested.
Gaucher disease: Accurate identification of asymptomatic French‐Canadian carrier using nonlabeled authentic sphingolipid substrate N‐palmitoyl dihydroglucocerebroside
Authors: Choy Francis Y. M. , Bouillon Louis , Laurin Carroll A. , Opitz John M. , Reynolds James F.
Published: June 2005

Gaucher disease is an autosomal recessive sphingolipidosis associated with deficient glucocerebroside β‐glucosidase activity. It is a panethnic metabolic disorder, but the carrier frequency is particularly high among Ashkenazi Jews (estimated between 1:12–1:25). In order to establish a reliable and convenient biochemical assay method for differentiating asymptomatic Gaucher carriers from normal individuals, glucocerebroside β‐glucosidase activity was determined in peripheral blood lymphocytes and cultured skin fibroblasts of 11 Gaucher obligate heterozygotes using the authentic nonlabeled Sphingolipid substrate N‐palmitoyl dihydroglucocerebroside and the artificial fluorogenic substrate 4‐methylumbelliferyl‐β‐D‐glucopyranoside (4MUGP). The level of lymphocyte β‐glucosidase activity on the glucocerebroside substrate was observed to range from 42–65% of that of the control mean, and there was no overlap of enzyme activity between the Gaucher heterozygotes and controls. However, when the artificial fluorogenic substrate 4MUGP was used, the level of β‐glucosidase activity in 2 of the Gaucher obligate heterozygotes was noted to overlap with that of the control individuals. Contrary to findings in the lymphocytes, cultured skin fibroblasts appear to be a reliable enzyme source for Gaucher carrier detection even when the artificial fluorogenic 4MUGP substrate was used, as the level of β‐glucosidase activity in all of the Gaucher obligate heterozygotes tested was intermediate and distinctly separated from that of the control persons. Using the lymphocyte glucocerebroside β‐glucosidase assay and fibroblast 4MUGP β‐glucosidase assay methods, we identified the carrier status in 3 other relatives and ruled it out in 4 others. These data suggest that nonlabeled glucocerebroside is a reliable and highly specific substrate for either lymphocyte or fibroblast β‐glucosidase activity assay in identifying asymptomatic Gauchcr carriers. Use of the 4MUGP substrate for differentiating Gaucher heterozygotes from control persons, on the other hand, should be restricted to the fibroblast enzyme assay method, as considerable overlap of enzyme activity was noted in lymphocytes.
A lethal multiple pterygium syndrome with apparent X‐linked recessive inheritance
Authors: Tolmie J. L. , Patrick A. , Yates J. R. W. , Opitz John M. , Reynolds James F.
Published: June 2005

We describe three male fetuses with a lethal multiple pterygium syndrome (LMPS). The family was ascertained when the first pregnancy of healthy, unrelated Scottish parents ended with a miscarriage at 23 weeks gestation. The macerated male fetus had a cystic hygroma, cleft palate, and webbing of the neck, elbows, and thighs. Radiographs showed lack of modeling of long bones, with broad ribs and clavicles, hypoplastic radii and ulnae, abnormal jaw angle, and dislocated femoral heads. Two other fetuses with similar anomalies were born to a first cousin of the propositus. These three male fetuses with a similar lethal multiple pterygium syndrome born to mothers who are second‐degree relatives through the female line suggest X‐linked recessive inheritance of LMPS in this family.
X‐linked hydrocephalus
Authors: Willems Patrick J. , Brouwer Oebele F. , Dijkstra Irene , Wilmink Jan , Opitz John M. , Reynolds James F.
Published: June 2005

We report on a family with X‐linked hydrocephalus: progressive increase in head circumference (OFC) led to the diagnosis in 3 patients; however, in 5 with normal OFC, the initial diagnosis had been “nonspecific” mental retardation, until identification of relatedness between 3 macrocephalic boys suggested segregation of a major Mendelian gene. Moderate to severe hydrocephaly was present in all macrocephalic patients and in 3 of the 5 with normal OFC, but CT‐scan of the brain did not show aqueductal stenosis in any of them.

We stress the importance of a brain CT‐scan in every male with “nonspecific” mental retardation, especially in cases with X‐linked inheritance, because confirmation of X‐linkage has important genetic counseling consequences.
Transient cysts of the fetal choroid plexus: Morphology and histogenesis
Authors: Farhood Anwar I. , Morris James H. , Bieber Frederick R. , Opitz John M. , Reynolds James F.
Published: June 2005

In this report, we correlate the clinical and morphologic features of bilateral choroid plexus cysts in three fetuses. These cysts were detected as incidental findings during sonography at 18 to 20 weeks gestation before elective abortion. Two fetuses were normal; the third had trisomy 18. All cysts were present bilaterally in the posterior horns of the lateral ventricles and ranged from 0.5 cm to 1.0 cm in diameter. The walls were translucent, and the cavities were filled with clear serous fluid, except for the left cyst in the third fetus, which was hemorrhagic. The cysts were surrounded by the loose stroma of the choroid plexus. We believe that the formation of these cysts is related to the histogenesis of the choroid plexus. Although such cysts have now been described by sonographers in several fetuses with chromosomal anomalies, this association may reflect ascertainment bias. At this time, we therefore advise caution in interpreting sonographic evidence of isolated choroid plexus cysts as anomalous.
Audiometric evidence for two forms of X‐linked hypophosphatemia in humans, apparent counterparts of Hyp and Gy mutations in mouse
Authors: Boneh Avihu , Reade Theresa M. , Scriver Charles R. , Rishikof Ellen , Opitz John M. , Reynolds James F.
Published: June 2005

Two forms of X‐linked hypophosphatemia occur in the mouse. One form, caused by the Hyp gene, is a counterpart of human X‐linked hypophosphatemic “vitamin D‐resistant rickets”. The other, recently characterized, is caused by a different gene (Gy) closely linked to Hyp on the mouse X‐chromosome. The Gy mutation also impairs cochlear function in the mouse. We measured hearing in 22 patients with X‐linked hypophosphatemia; five, including 2 mother‐son pairs, had sensorineural hearing deficits due to cochlear dysfunction. We suggest the disease in these persons may be the human counterpart of the Gy phenotype in the mouse, which implies there are 2 forms of X‐linked hypophosphatemia in humans.
Familial Prader‐Willi syndrome with apparently normal chromosomes
Authors: Lubinsky Mark , Zellweger Hans , Greenswag Louise , Larson Gary , Hansmann Irving , Ledbetter David , Opitz John M. , Reynolds James F.
Published: June 2005

We report on 4 sibs (2F, 2M) with Prader‐Willi syndrome (PWS). Diagnosis was made clinically on the basis of history, behavior, and physical findings in 3 of the sibs. The other child had died at age 10 months with a history and clinical findings typical of first phase of PWS. Results of chromosome studies on the parents and surviving sibs were normal. The implications of this unusual familial occurrence for our understanding of PWS are discussed.
Clinical heterogeneity associated with deletions in the long arm of chromosome 15: Report of 3 new cases and their possible genetic significance
Authors: Kaplan Lawrence C. , Wharton Robert , Elias Ellen , Mandell Frederick , Donlon Timothy , Latt Samuel A. , Opitz John M. , Reynolds James F.
Published: June 2005

Deletions, duplications, and rearrangements of the long arm of chromosome 15 are frequently associated with the clinical diagnosis of the Prader‐Willi syndrome. However, a number of other clinical entities have also been associated with similar, if not identical, cytogenetic defects, arguing for clinical heterogeneity associated with abnormalities in this region of chromosome 15. We present 3 patients who all appear to have deletions in 15q11–15q12, such as described for many patients with Prader‐Willi syndrome; however, none of these patients has classical clinical features of the Prader‐Willi syndrome. The first patient is a child with Williams syndrome, the second, Angelman (Happy Puppet) syndrome, and the third is a child with hypotonia of infancy, obesity, and developmental delay, but who does not meet specific diagnostic criteria for the Prader‐Willi syndrome. It is proposed that different molecular abnormalities involving specific points or segments along the long arm of chromosome 15 might account for the clinical diversity seen among these and other patients.
Cyclopia and congenital cytomegalovirus infection
Authors: Byrne Paul J. , Silver Meredith M. , Gilbert Joseph M. , Cadera Werner , Tanswell A. Keith , Reynolds James F.
Published: June 2005

We describe the first documented association of congenital cytomegalovirus (CMV) infection and cyclopia. A previous report has suggested that any infant with congenital ocular defects should be investigated for CMV infection [Frenkel et al, 1980]. Our case underlines this suggestion and questions a teratogenic role for CMV in cyclopia‐holoprosencephaly. More documented cases may help clarify the relationship of transplacental CMV infection to the holoprosencephaly developmental field defect, including cyclopia.
X‐linked laterality sequence: Situs inversus, complex cardiac defects, splenic defects
Authors: Mathias Robert S. , Lacro Ronald V. , Jones Kenneth Lyons , Opitz John M. , Reynolds James F.
Published: June 2005

The association of abdominal situs inversus, complex cardiac defects, and alterations in development of the spleen represents a developmental field complex with variable expression of altered laterality. Familial and inherited cases documenting respectively autosomal recessive and dominant inheritance have been reported. We report on the first family in which X‐linked recessive inheritance of this defect has been documented.
Thrombocytopenia with absent radius in a boy and his uncle
Authors: Schnur Rhonda E. , Eunpu Deborah L. , Zackai Elaine H. , Opitz John M. , Reynolds James F.
Published: June 2005

We report a boy and his maternal uncle who have Thrombocytopenia‐Absent Radius (TAR) syndrome. The mother of the propositus is normal. A maternal aunt has mild radial hypoplasia, possibly representing partial expression of the syndrome. A review of the literature shows several pedigrees in which relatives other than sibs were affected with TAR. Thus, autosomal recessive inheritance may not account for all cases and alternate modes of transmission should be considered.
Renal insufficiency in Williams syndrome
Authors: Biesecker Leslie G. , Laxova Renata , Friedman Aaron , Reynolds James F.
Published: June 2005

A 19‐year‐old patient with Williams syndrome and renal cystic dysplasia is presented. This young man has had gradual deterioration of renal function and recurrent, acute episodes of dehydration secondary to a concentrating defect. A review revealed several reports of renal dysfunction in patients with Williams syndrome, but this complication has not been sufficiently emphasized. We recommend that all patients with Williams syndrome undergo periodic ultrasound examination and renal function evaluation.
Apparent Apert syndrome with polydactyly: Rare pleiotropic manifestation or new syndrome?
Authors: Maroteaux Pierre , Fonfria Marie Christine , Opitz John M. , Reynolds James F.
Published: June 2005

Two patients are described with a syndrome which resembles Apert syndrome with polydactyly of hands and feet. This association is apparently rare and we think that this may represent a distinct syndrome separate from Apert syndrome.
45X/46X,r(X) with syndactyly and severe mental retardation
Authors: Kushnick Theodore , Irons Thomas G. , Wiley John E. , Gettig Elizabeth A. , Rao Kathleen W. , Bowyer Susan , Opitz John M. , Reynolds James F.
Published: June 2005

Two white females, age 2 1/2 and 33 years, respectively, were investigated because of severe mental retardation associated with neurologic abnormalities, coarse face, and soft tissue syndactyly involving upper and lower limbs. Each had cytogenetic findings of a mosaic variant of Ullrich‐Turner syndrome with X ring chromosome in peripheral lymphocyte and skin fibroblasts. Early X replication occurred in one‐third of the X ring chromosomes; there was no evidence for X‐autosome translocation involving either X and an autosomal duplication; results of studies for fragility of the X chromosomes were unremarkable. In situ hybridization with an X centromere probe was positive for the ring. To our knowledge, the unusual constellation of cytogenetic, physical, and mental findings seen in these 2 individuals has not been reported previously.
Elevated glucocorticoid receptor levels in lymphocytes of children with the fetal hydantoin syndrome (FHS)
Authors: Goldman Allen S. , Van Dyke Don C. , Gupta Chhanda , Katsumata Masuyuki , Opitz John M. , Reynolds James F.
Published: June 2005

Our recent studies of the teratogenic mechanisms of phenytoin (DPH) and glucocorticoid in mice have indicated that DPH utilizes the anti‐inflammatory pathway of glucocorticoids in producing congenital defects, such as cleft palate. This pathway is influenced by H‐2 and H‐3 histocompatibility‐linked genes in the mouse, such that congenic strains have H‐2 or H‐3 alleles that confer susceptibility to DPH‐induced‐induced congenital defects, and susceptible H‐2 congenic strains have high glucocorticoid receptor levels. However, other H‐2 or H‐3 alleles confer resistance to these defects in their otherwise genetically identical congenic partner strains, and “resistant” H‐2 alleles are associated with low levels of these receptors.

To determine whether this animal work is applicable to the human, we have sought to investigate whether the level of glucocorticoid receptors in circulating lymphocytes of children with the fetal hydantion syndrome (FHS) is as it is in the animals.

We found that children with FHS had glucocorticoid receptor levels significantly elevated above those of unaffected children was also significantly levels significantly elevated above those of unaffected children with similar DPH exposure in control families. The receptor level of affected children was also significantly elevated above that of fathers of children with the FHS and of fathers and mothers of control children. These findings are consistent with those documented in the animal models and suggest that an elevated level of glucocorticoid receptors in lymphocytes may be a marker for susceptibility to the FHS syndrome.
New autosomal dominant radial ray hypoplasia syndrome
Authors: Goldblatt J. , Viljoen D. , Opitz John M. , Reynolds James F.
Published: June 2005

We report on an autosomal dominant syndrome of radial ray hypoplasia, esotropia, and choanal atresia with variable manifestations in a father and his 2 daughters.
Amniotic band sequence and its neurocutaneous manifestations
Authors: Chen Harold , Gonzalez Enrique , Opitz John M. , Reynolds James F.
Published: June 2005

Six new cases of the amniotic band sequence with a wide spectrum of defects were studied with respect to neurocutaneous manifestations, including histopathologic characteristics. Fetuses 1 and 2 were stillborn. Despite severe craniofacial involvement, infants 3 and 4 survived 1 yr and 22 months, respectively. Patients 5 arid 6 had only limb defects. Craniofacial and neurologic manifestations of our longer‐survival patients with severe craniofacial anomalies were microcephaly, encephalocele, micro‐ or anophthalmia, mental retardation, hydrocephaly, seizures, EEG abnormalities, impaired body temperature control, impaired vision, hypertonia, and other psychomotor deficits. Characteristic cutaneous manifestations seen in our patients were clefting, schisis, fibrous strings, ring constriction, lymphedema, pseudosyndactyly, and intrauterine amputation. Histologic examination of the amniotic bands attaching to the skin showed autolyzed amnion in patient 2, erosion of the band into upper dermis in patient 1, and fibrosis underlying the constricted areas in patient 5. Prenatal diagnosis by ultrasonography is possible in patients with severe craniofacial defects (patient 2). A brief review of the literature is offered.
Metacarpophalangeal pattern profile analysis in diastrophic dysplasia
Authors: Butler Merlin G. , Gale David D. , Meaney F. John , Opitz John M. , Reynolds James F.
Published: June 2005

We analyzed the metacarpophalangeal pattern profile (MCPP) on 16 individuals with diastrophic dysplasia and calculated a mean syndrome profile. Correlation studies confirm clinical homogeneity of the hand profile in diastrophic dysplasia. Discriminant analysis of individuals with diastrophic dysplasia compared with a sample of normal individuals produced a function of 3 MCPP variables plus age that appears to be a useful diagnostic tool.
Duplication of proximal 15q as a cause of Prader‐Willi syndrome
Authors: Pettigrew Anjana L. , Gollin Susanne M. , Greenberg Frank , Riccardi Vincent M. , Ledbetter David H. , Opitz John M. , Reynolds James F.
Published: June 2005

We describe an apparent duplication of proximal 15q, i.e., 15qllql2 or 15ql2ql3 in two patients. Prometaphase chromosome analysis, C‐banding and distamycin A/DAPI staining were used to exclude a translocation between the abnormal 15 homolog and another chromosome. The 2 patients have many manifestations of the Prader‐Wil1i syndrome (PWS) including at least 5 of the following: obesity, compulsive eating, mental retardation, short stature, central hypotonia, hypogonadism, small hands and feet, hypopigmentation, and feeding problems in infancy. Results of high resolution chromosome analysis of the parents of both patients were normal. A comparison between these patients and 2 subjects from previous reports demonstrates phenotypic heterogeneity among the duplication 15q PWS patients. Two patients have the hypopigmentation seen in chromosomally normal and deletion PWS patients. These cases add to the variety of chromosome 15 aberrations which are associated with PWS.
Neonatal diagnosis of Prader‐Willi syndrome and its implications
Authors: Greenberg Frank , Elder Fred F. B. , Opitz John M. , Reynolds James F. , Ledbetter David H.
Published: June 2005

Although Prader‐Willi syndrome (PWS) patients usually first present with neonatal hypotonia and feeding difficulty, they later show hyperphagia, obesity and men tal retardation. Since deletions of chromosomes 15qll‐ql3 are noted in most PWS patients cytogenetic analysis allows one to diagnose infants suspected of PWS with a greater certainty. We report on 5 hypotonic infants clinically suspected of PWS in the first 3 months of life, whose diagnosis was confirmed by cytogenetic studies showing monosomy of 15qll‐ql3. Early diagnosis of PWS can lead to prevention of obesity, but counseling of parents has been difficult. Although there are significant benefits to the early diagnosis of PWS, the cost‐effectiveness and practi cality of screening all hypotonic infants using high resolution cytogenetic analysis has not been addressed systematically.
Premature coronary artery atherosolerosis in a patient with Prader‐Willi syndrome
Authors: Lamb Andrew S. , Johnson William M. , Opitz John M. , Reynolds James F. , Ledbetter David H.
Published: June 2005

A 26‐year old white male with Prader‐Willi syndrome (PWS) and non‐insulin‐dependent diabetes mellitus Presented with asymptomatic bilateral lower limb swelling. An electrocardiogram was consistent with an inferior wall myocardial infarction of unknown age and a graded exercise test using the Bruce protocol was consistent with inferolateral ischemia. Subsequent cardiac catheterization showed severe, inoperable, three‐vessel coronary artery disease. Atherosclerotic coronary artery disease in PWS has been documented only once in the literature, and then only postmortem. This case provides further (and for the first time, premortem) ducumentation that premature atherosclerotic coronary artery disease may play an important but presently unrecognized role in the morbidity and mortality in PWS.