bluuebunny/crossref_metadata_2025 huggingface dataset:
Khmers of Cambodia: A comparative genetic study of the populations of Southeast Asia
Authors: Papiha S. S. , Mastana S. S. , Singh N. , Roberts D. F.
Published: June 2005

A sample of the Khmer population from Cambodia has been examined for 30 single‐gene characters (10 blood groups and 20 serum and red cell systems). A locus‐by‐locus comparison suggests that the Khmers differ significantly in several systems from the populations of Eastern India and China. There is remarkable heterogeneity among their geographical neighbors. To elucidate the genetic relationship of the Khmer, genetic data were collected from various published and unpublished sources, and different multivariate analyses were performed. The analyses show that the Khmers definitely show closer affinity for the neighboring populations of Thailand and Malaysia. The Chinese population not only shows a close relationship to the Khmers, but also consistently stays close to the populations of the Southeast Asian peninsula. The present‐day Khmers are genetically distant from the population of Eastern India, but the analyses do not totally exclude gene flow from Eastern India. It is, therefore, concluded that the original gene pool of Khmers may have derived from China, being modified by mixing with the local and Indian migrant populations. © 1994 Wiley‐Liss, Inc.
Anatomical analysis of the developmental effects of aneuploidy in man—the 18‐trisomy syndrome: I. Anomalies of the head and neck
Authors: Bersu Edward T. , Ramirez‐Castro Jose L. , Pettersen James C.
Published: June 2005

This paper describes the anatomical variations observed in the head and neck in eight infants with the 18‐trisomy syndrome that were dissected and studied in detail. Of the usual muscles of facial expression, occipitofrontalis and the auricular and nasal muscles were hypoplastic in all eight bodies and each subject showed extensive fusion of the muscles around the corner of the mouth. In each body there was a supernumerary muscle band that extended from the region near the corner of the mouth to the occipital attachment of trapezius. The otomandibular region in each body showed a variable spectrum of muscular, skeletal, arterial, and salivary gland variations bilaterally. Three of the bodies had infrahyoid muscle variations. The sum of these observations provides a more complete delineation of the variations that occur in the 18‐trisomy syndrome.

Tentative pathogenetic hypotheses for several of the defects are discussed, based on observations from human descriptive embryology. Poswillo's teratological model [1973] implicating hemorrhaging as a causal mechanism in human first and second branchial arch malformations is suggested as a possible mechanism to explain the bilateral otomandibular defects.
The association of Waardenburg syndrome and Hirschsprung megacolon
Authors: Omenn Gilbert S. , McKusick Victor A. , Gorlin Robert J.
Published: June 2005

We describe four patients with Waardenburg syndrome and Hirschsprung aganglionic megacolon. In view of pathophysiologic relationships and animal studies, we conclude that the association of these two uncommon disorders is pathophysiologically significant.
Anatomical abnormalities in mandibulofacial dysostosis
Authors: Herring Susan W. , Rowlatt Ursula F. , Pruzansky Samuel , Optiz John M.
Published: June 2005

A detailed dissection of the head and neck of a 7‐month‐old boy with mandibulofacial dysostosis is described and compared with other reported cases. A general growth retardation was found in the bones of the basicranium and calvaria as well as the face. The base of the skull was kyphotic, and the elements derived from the branchial arches articulated with the basicranium more anteriorly than usual. Certain middle ear structures were found to be extracranial. The facial muscles were generally normal except for the absence of elevators of the upper lip. The laryngeal cartilages were shortened anteroposteriorly, resulting in drastic reduction of the rima glottidis. The attachments of the masticatory muscles to the mandible suggested that the area of the temporomandibular joint had not completed normal differentiation, and that that part of the mandible which functioned as a condyle was actually an ossification around Meckel's cartilage. There was no infraorbital foramen, and the infraorbital neurovascular bundle was distributed instead to the palate. Clinical and functional correlations of the various defects are considered.

Theories of pathogenesis are discussed on the basis of these findings. It is argued that these observations could be accounted for by an altered intercellular matrix with separate effects on skeletal growth and neural crest cell migration.
The Bowen‐Conradi syndrome—a highly lethal autosomal recessive syndrome of microcephaly, micrognathia, low birth weight, and joint deformities
Authors: Hunter Alasdair G. W. , Woerner Sarah J. , Montalvo‐Hicks Lucy D. C. , Fowlow S. Beatrice , Haslam Robert H. A. , Metcalf Peter J. , Lowry R. Brian , Optiz John M.
Published: June 2005

This paper describes six Hutterite children form five families who appear to have been affected by the same syndrome that was described in two brothers by Bowen and Conradi [1]. Our additional cases confirm that the major features of the syndrome include proportionate intrauterine growth retardation, microcephaly, micrognathia, a prominent nose, rocker‐bottom feet, joint limitation, and failure to thrive, with death within the first year of life. Bowen‐Conradi syndrome is an autosomal recessive trait and pedigree records show that all six families now known are related to each other through two couples born in the late 1700s but that there are additional earlier possible sources of the responsible gene. The differential diagnosis of this syndrome is discussed.
A short history of human genetics in the USA
Authors: Reed Sheldon C.
Published: June 2005

The practicing physician discovered human genetics primarily as a result of two events. The use of the atomic bomb generated a vast amount of attention because of the fear of genetic hazards of radiation. Next, the discovery that the Down syndrome resulted from the presence of an extra chromosome finally focused the vision of the medical profession on human genetics as an area of importance in disease. It was also necessary that the erroneous fatalism about the impossibility of treating genetic disease had to diminish before medicine would find human genetics attractive for research in therapeutic techniques.

All of these things have come to pass and human genetics cannot help but enjoy a distinguished and extremely useful future.
Aprosencephaly‐atelencephaly and the aprosencephaly (XK) syndrome
Authors: Lurie Iosif W. , Nedzved Michael K. , Lazjuk Gennady I. , Kirillova Irena A. , Cherstvoy Eugeny D. , Optiz John M.
Published: June 2005

We report on a postnatally dead, postterm male infant with aprosencephaly and the oculofacial manifestations usually seen in the most severe form of alobar holoprosencephaly – namely cyclopia and absence of derivatives of the frontonasal process; in addition the infant had the radius aplasia field defect bilaterally, a high VSD, mobile cecum, and penile hypospadias with cryptorchidism. The same syndrome was reported recently by Garcia and Duncan [2]; however, in that case the brain defect was designated “atelencephaly.” Since atelencephaly is a less severe form of aprosencephaly we chose to designate the condition in these two patients as “the aprosencephaly (XK) syndrome.” Atelencephaly and aprosencephaly may occur also as a single and sporadic malformation. The cause of the aprosencephaly (XK) syndrome is unknown.
Cleft lip±cleft palate: An overview of the literature and an analysis of Danish cases born between 1941 and 1968
Authors: Melnick Michael , Bixler David , Fogh‐Andersen P. , Conneally P. Michael , Elston Robert C.
Published: June 2005

In recent years there has been some controversy over the analytical designs and the meaning of varying results with regard to studies of facial clefting and other common congenital malformations. Regardless, it is still unclear as to the nature of the genetic and environmental components of the etiology as well as the nature of the relevant pathogenetic mechanisms. Despite claims to the contrary, the predictions of a particular multifactorial/threshold inheritance (MF/T) model delineated by Carter [1977d] and others are not well supported by studies worldwide. The present study population consists of 1,895 persons born in Denmark with cleft lip with or without cleft palate (CL ± P) between 1941 and 1968. A test of the MF/T predictions revealed the following: 1) the incidence of CL ± P in siblings was 40 × greater than that in the general population 2) the risk to siblings of CL ± P females was not significantly different from the risk to siblings of CL ± P males; 3) recurrence risk for siblings of CL ± P probands was dependent upon the proband's cleft type; 4) only 0.4% of the variation in risk to the siblings born after the proband could be accounted for by the number of previously affected siblings; 5) the consanguinity rate was 6 times less than the general population rate; 6) heritability estimates from siblings and parents by sex suggest, either the presence of significant dominance effects, or a common sibling environment component in the etiology of the disorder. Further, testing with a multiple‐sex threshold method, designed and provided us by [Kidd and Spence, 1976] revealed that neither the MF/T nor single‐major locus with random environmental variation provided a good fit. In light of recent experimental mouse and human data, an alternative model of monogenic‐dependent susceptibility to a variety of teratogens is discussed. It is suggested that the genetic basis for diverse kinds of common and uncommon congenital malformations may very well be homogeneous while, at the same, the evironmental basis is heterogeneous.
Pathologic findings in the Wolf‐Hirschhorn (4p‐) syndrome
Authors: Gonzalez Claudette H. , Capelozzi Vera L. , Wajntal Anita , Opitz John M.
Published: June 2005

We describe a 1‐month‐old female with the Wolf‐Hirschhorn syndrome. GTG‐banding studies disclosed a 46,XX,del(4)(:p15 → qter) in the child and apparently normal chromosomes in the parents. Autopsy at 4 months showed hypoplasia of most organs.
dup(12p) and hypoplastic left heart
Authors: Qazi Qutub H. , Kanchanapoomi R. , Cooper Rubin , Madahar Cecily , Beller Eva , Francke Uta
Published: June 2005

A six‐week‐old female infant with multiple congenital anomalies including a hypoplastic left‐heart malformation was found to have duplication of 12p. Only two of 17 previously reported cases of dup (12p) had congenital heart disease, and both had hypoplastic left‐heart abnormality.
Recurrence risks for autosomal, epistatic two‐locus systems: The effects of linkage disequilibrium
Authors: Trojak Joseph E. , Murphy Edmond A. , Opitz John M.
Published: June 2005

The properties of the recurrence risk functions for Mendelian models involving two loci with epistatic interaction are examined. The two loci, H (hypostatic) and E (epistatic), are arbitrarily linked and diallelic. The general parameters are the genotypic frequencies and recombination fraction; the particular arguments are the number of affected and unaffected offspring. Limiting properties of the models are first described. Then, the more detailed properties of the models such as the sensitivity of the recurrence risk to the number of affected offspring are examined. If linkage disequilibrium is present, ie, the determinant of the gametic matrix is not zero, the predicted recurrence risk may resemble that empirically found in certain heritable diseases not evidently Mendelian.
A new syndrome of proximal deletion of the long arm of chromosome 1: 1q21–23→1q25
Authors: Taysi Kutay , Sekhon Gurbax S. , Hillman Richard E. , Opitz John M.
Published: June 2005

We present two unrelated children with the de novo interstitial deletion of the proximal segment of the long arm of chromosome 1 (1q21–23→1q25). Comparison of the phenotypic characteristics of these two patients with those of two previously described patients with similar deletion confirms the existence of the proximal 1q deletion syndrome. The characteristics of this newly recognized deletion syndrome include pre‐ and postnatal growth retardation; severe psychomotor retardation; microbrachycephaly; sparse, fine scalp hair and eyebrows; cleft lip and palate; hernias; genitalia defects; small hands and feet; and clinodactyly of the fifth fingers.
The virginia racial integrity act revisited: The Plecker‐Laughlin correspondence: 1928–1930
Authors: Reilly Philip , Shaw Margery
Published: June 2005

Correspondence between Walter Ashby Plecker, Virginia State Registrar of Vital Statistics between 1912 and 1938, and Harry Hamilton Laughlin, Superintendent of the Eugenics Record Office at Cold Spring Harbor between 1910 and 1939, provides evidence of efforts to enforce the Virginia Racial Integrity Act of 1924. After antimiscegenation policy is placed in a historical context, excerpts from the letters are offered to demonstrate the zeal with which one state official pursued this “eugenic” policy.
Multiple skeletal familial abnormalities associated with balanced reciprocal translocation 2;8(q32;p13)
Authors: Ventruto V. , Pisciotta R. , Renda S. , Festa B. , Rinaldi Maria Michela , Stabile M. , Cavaliere Maria Luigia , Esposito M. , Opitz John M.
Published: June 2005

A father and three of his offspring had skeletal abnormalities consisting of a short forearm, cubitus valgus, fusion of first and second cervical vertebrae, and cleft of L5 and SI. All four had a reciprocal, apparently balanced, translocation 2;8(q32;p13). Normal sibs had normal chromosomes. We conclude that this may be a rare instance of an autosomal dominant condition associated with a balanced chromosome translocation.
Tracheal agenesis and associated malformations: A comparison with tracheoesophageal fistula and the VACTERL association
Authors: Evans J. A. , Reggin J. , Greenberg C. , Opitz John M. , Reynolds James F.
Published: June 2005

Tracheal agenesis is a rare malformation of the lower respiratory tract. Investigation of a patient with multiple congenital anomalies and tracheal agenesis prompted a review of the literature which uncovered 42 previously published cases, most of whom had other defects. The presence in our patient of a tracheal abnormality in association with radial hypoplasia, single umbilical artery, tetralogy of Fallot, and left hydroureter initially suggested presence of the VACTERL association. However, numerical classification of malformation patterns in the reported patients with tracheal agenesis and in a series of patients with tracheoesophageal fistula and other components of the VACTERL association suggests that tracheal agenesis does not occur in the VACTERL association and may be part of another pattern of malformations which includes laryngeal atresia, complex congenital heart anomalies, radial ray defects, and duodenal atresia.
Congenital absence of left pericardium in a family
Authors: Taysi Kutay , Hartmann Alexis F. , Shackelford Gary D. , Sundaram Vasantha , Opitz John M. , Reynolds James F.
Published: June 2005

Characteristic radiographic findings of absence of the left pericardium were observed in two relatives who were related to two other individuals with different types of congenital heart defects. Familial occurrence of congenital absence of pericardium has not been reported previously. The strong male sex predilection in the previously reported patients, the segregation pattern of affected individuals in the pedigree presented here, and the presence of two other individuals with multifactorially determined congenital heart defects in the same pedigree suggest multifactorial determination of congenital absence of the left pericardium.
Familial occurrence of a developmental defect of the medial nasal processes
Authors: Toriello Helga V. , Higgins James V. , Walen Annette , Waterman Donald F. , Opitz John M. , Reynolds James F.
Published: June 2005

We report on a family in which the propositus and two distant relatives have a wide nose, broad philtrum, and short columella, a fusion defect of the medial nasal processes. This anomaly resembles potato nose [Benjamins and Stibbe, Acta Otolaryngol 11:274–284, 1927] and bifid nose [Anyane‐Yeboa et al, Am J Med Genet 17:561–563, 1984], which are also fusion anomalies of the medial nasal processes. Potato nose is an autosomal dominant trait, whereas bifid nose is likely heterogeneous. In this family autosomal recessive inheritance is likely, therefore suggesting that anomalies of the medial nasal processes are causally heterogeneous and represent a developmental field defect.
X‐linked syndrome of branchial arch and other defects
Authors: Toriello Helga V. , Higgins James V. , Abrahamson Jon , Waterman Donald F. , Moore W. David , Opitz John M. , Reynolds James F.
Published: June 2005

We report on two brothers and their maternal first cousin who have branchial arch defects and other anomalies. Similar physical findings in all three include microcephaly, downslanting palpebral fissures, highly arched palate, apparently lowset, protruding ears, bilateral hearing loss, slightly webbed neck, and mild short stature. In addition, two boys had cryptorchidism, and one had subvalvar pulmonic stenosis and body asymmetry. We suggest that these cousins have an X‐linked syndrome of which branchial arch defects are a component. Other pleiotropic manifestations of the mutant gene include microcephaly and cryptorchidism; body asymmetry and relatively short stature may be components as well.
Bilateral renal agenesis in twins
Authors: Wilson R. Douglas , Hayden Michael R. , Opitz John M. , Reynolds James F.
Published: June 2005

We present the second report of like‐sex twins concordantly affected with bilateral renal agenesis (BRA). Mode of inheritance is proposed to be autosomal dominant. Screening of first‐degree relatives of the BRA proband by ultrasound of the GU system is recommended. Prenatal diagnosis with second‐trimester ultrasound screening is recommended when a previous fetus has been affected by bilateral renal agenesis.
Renal agenesis in British Columbia
Authors: Wilson R. D. , Baird P. A. , Opitz John M. , Reynolds James F.
Published: June 2005

We review the incidence of bilateral and unilateral renal agenesis occurring in more than 625,000 consecutive births in British Columbia from 1952 to 1982. In total, 92 cases of bilateral renal agenesis and 117 cases of unilateral renal agenesis were identified. Congenital anomalies occurring in association with these conditions were also analyzed. The findings of the study support a mechanism in at least a proportion of cases of a primary developmental defect involving multiple systems within the fetus, with oligohydramnios being the result of the syndrome not the cause. Oligohydramnios no doubt contributes to the anomalies of the face, musculoskeletal system, and genitalia. No trends in changing incidence over time were identified.
The Gardner‐Silengo‐Wachtel or genito‐palato‐cardiac syndrome: Male pseudohermaphroditism with micrognathia, cleft palate, and conotruncal cardiac defect
Authors: Greenberg Frank , Gresik Mary V. , Carpenter Robert J. , Law Samuel W. , Hoffman Lynn P. , Ledbetter David H. , Opitz John M. , Reynolds James F.
Published: June 2005

We report on two sib fetuses with similar abnormalities detected prenatally by ultrasound. The first fetus had micrognathia, was without cleft palate, and had low‐set ears, double outlet right ventricle with a ventricular septal defect, and 46,XY gonadal dysgenesis. The second sib fetus was born with cleft lip and palate, micrognathia, transposition of the great vessels, ventricular seplal defect, a right‐sided aorta arch, and bilateral cystic kidneys with hypospadias. We were able to identify 11 additional cases in the literature with similar findings. We think this set of defects is a recognizable syndrome that appears to be inherited either as an autosomal recessive or as an X‐linked recessive and may overlap with the Smith‐Lemli‐Opitz syndrome.
Progressive form of multiple pterygium syndrome in association with nemalin‐myopathy: Report of a female followed for twelve years
Authors: Papadia Francesco , Longo Nicola , Serlenga Luigi , Porzio Gemma , Reynolds James F.
Published: June 2005

We report on a girl with progressive multiple pterygium syndrome in association with gluteal muscle fibrosis and nemalin‐myopathy. This girl has been followed for 12 years. Clinical findings, natural history, and the presence of nemalin myopathy suggest the possibility of a distinct form of multiple pterygium syndrome in this patient.
Prenatal diagnosis policy without routine amniocentesis in pregnancies with a positive family history for neural tube defects
Authors: Papp Zoltán , Tóth Zoltán , Török Olga , Szabó Mária , Reynolds James F.
Published: June 2005

The recurrence risk for neural tube detects in pregnancies of women with a family history of neural tube defects greatly exceeds the general population risk. In these high risk pregnancies, we used a prenatal diagnostic method differing from thai usually employed, relying mainly on the results of maternal serum alpha‐fetopro‐tcin (MSAFP) and ultrasound examination, without routine aminocentcsis. During the b years reviewed in this study, this method was applied in 539 pregnancies Of a total of 20 neural tube defects, 19 were detected using this combination oi MSAFP, ultrasound, and selective amnioccntcsis, and the authors estimate tha about 8–10 spontaneous abortions were avoided because only 28 amnioccntese; were carried out instead of 539. The risk of recurrence was found to be lowei than that experienced earlier.
Animal model: Renal lesions in cats with Chediak‐Higashi‐Steinbrinck syndrome
Authors: Hargis Ann M. , Prieur David J. , Opitz John M. , Reynolds James F.
Published: June 2005

In this study designed to characterize the renal lesions in cats with the autosomal recessive Chediak‐Higashi‐Steinbrinck syndrome (CHS), the renal tubular epithelial cells of CHS cats were examined by light microscopy. Numerous cells of proximal convoluted and straight tubules, thin loop of Henle, distal convoluted and straight tubules, and collecting tubules contained enlarged cytoplasmic granules morphologically consistent with lysosomes. In general, the enlarged lysosomes were larger and more numerous in proximal convoluted and straight tubular cells and were generally more massive in older cats. The lesions observed were similar to those in the renal epithelial cells of other species with CHS and were consistent with those reported previously in other tissues of CHS cats. It is concluded that CHS cats are an appropriate model in which to study the effects of the CHS renal lesions on renal function in this syndrome.
Intended use of predictive testing by those at risk for Huntington disease
Authors: Meissen Gregory J. , Berchek Roxanna L. , Opitz John M. , Reynolds James F.
Published: June 2005

Huntington disease (HD) is a late‐onset genetic disorder that is incurable and undetectable until the onset of symptoms. A marker for the gene that causes HD was recently discovered that will lead to a predictive test. The purpose of this research was to assess the attitudes, beliefs, and behavioral intentions concerning the impending predictive test by those at risk for HD. Results from a sample of 56 at‐risk individuals indicated that a majority (65%) favored using the presymp‐tomatic test and would encourage their adult children to use it as well. Fewer but still a substantial percentage of respondents would use the prenatal test (42%) and would test at‐risk minors (35%). Surprisingly, knowledge about predictive testing was quite low and a majority of those least knowledgeable about predictive testing intended to use the test. These findings emphasized the need for outreach and prevention efforts to prepare the at risk and specialized programs of genetic counseling and follow up to accompany predictive testing.
A new syndrome with features of the Smith‐Lemli‐Opitz and Meckel‐Gruber syndromes in a sibship with cerebellar defects
Authors: Casamassima Anthony C. , Mamunes Peter , Gladstone Igor M. , Solomon Stuart , Moncure Charles , Opitz John M. , Reynolds James F.
Published: June 2005

The Smith‐Lemli‐Opitz syndrome (SLOS) and the Meckel syndrome (MS) have been regarded as separate autosomal recessive entities. Recently, overlap of these two syndromes has been discussed. A sibship cóntaining a probable new syndrome with features reminiscent of the SLOS and the MS is presented. The literature is reviewed with regard to the frequency of various malformations in these syndromes. Clinical manifestations and cerebellar abnormalities in these sibs are similar to those described in the Joubert syndrome (JS). These three cases may represent a new syndrome with features in common with SLOS, MS, and JS resulting from the same mutant gene, which exhibits considerable pleiotropy.
A clinico‐genetic investigation of Leydig cell hypoplasia
Authors: Saldanha P. H. , Arnhold I. J. P. , Mendonça B. B. , Bloise W. , Toledo S. P. A. , Opitz John M. , Reynolds James F.
Published: June 2005

We report on a kindred including a patient (46,XY) with typical manifestations of Leydig cell hypoplasia who was born to parents who were first cousins. A sister had secondary amenorrhea possibly due to primary ovarian dysfunction. Analysis of six pedigrees fits to a male‐limited autosomal recessive pattern of inheritance; its implication for the mutational dynamics in the populations is evaluated.
Renal‐hepatic‐pancreatic dysplasia: A syndrome reconsidered
Authors: Bernstein Jay , Chandra Manju , Creswell Jim , Kahn Ellen , Malouf Nadia N. , McVicar Melinda , Weinberg Arthur G. , Wybel Robert E. , Opitz John M. , Reynolds James F.
Published: June 2005

Five infants, three dying neonatally and two later in the first year of life, had renal, hepatic, and pancreatic dysplasia, a combination of abnormalities first described by Ivemark et al [1959]. The renal malformation consisted of cystic dysplasia, with abnormally differentiated ducts, deficient nephron differentiation, and glomerular cysts. The hepatic abnormality consisted of enlarged portal areas containing numerous elongated biliary “profiles,” with a tendency to perilobular fibrosis. Serial liver biopsies in one child with cholestasis from birth showed a progression from bile duct paucity at 11/2 wk to typical biliary “dysgenesis” at 7 mo. Four of the five children had intrahepatic ductal dilatation, diagnosed ante mortem in the two older children as Caroli disease. The pancreatic abnormality consisted of fibrosis and cysts, with a diminution of parenchymal tissue. The clinical and functional reflection of these abnormalities in the two children surviving the newborn period included renal insufficiency, chronic jaundice, and insulin‐dependent diabetes mellitus. Similar renal, hepatic, and pancreatic abnormalities occur in other syndromes, including trisomy 9, Meckel syndrome, Jeune, Saldino‐Noonan, and Elejalde types of chondrodysplasia, and glutaric aciduria II. After exclusion of identifiable syndromes, the remaining cases of renal‐hepatic‐pancreatic dysplasia do not necessarily constitute a homogeneous group.
Megalocornea and mental retardation syndrome: Two new cases
Authors: Del Giudice Ennio , Sartorio Renata , Romano Alfonso , Carrozzo Romeo , Andria Generoso , Neri Giovanni
Published: June 2005

We report on 2 patients with the Neuhäuser megalocornea‐mental retardation syndrome, a recessively inherited clinical entity of relatively recent description (McKusick 24931). A review of the few previous reported patients and our 2 patients shows that megalocornea and mental retardation are the 2 minimal diagnostic criteria. Short stature, seizures, neurological symptoms, microcephaly or macrocephaly, and minor anomalies are all additional nonobligatory manifestations. The small number of published cases may be due to the fact that the association of these two signs has often escaped attention until now.
A case of the Neu‐Laxova syndrome: Prenatal ultrasonographic monitoring in the third trimester and the histopathological findings
Authors: Muller Linnie M. , de Jong Greetje , Mouton S. C. E. , Greeff M. J. , Kirby P. , Hewlett R. , Jordaan H. F. , Reynolds James F.
Published: June 2005

A diagnosis of the NeuLaxova syndrome was made by ultrasonography in the third trimester of pregnancy.

Initial Ultrasonographic examination, at approximately 28 wk gestation, showed intrauterine growth retardation (IUGR), hypoechoic skeletal structures, kyphosis, feeble fetal activity, and restricted limb movement. Subsequent sonograms showed microcephaly with a receding forehead and prominent eyes, generalised edema and flexion deformities of limbs. Late third trimester findings included polyhydramnios, swelling and webbing of the knee and elbow joints, and severe edema of the hands and feet, giving the impression of absent digits.

The clinical features of this case are consistent with group II of Curry's classification of the Neu‐Laxova syndrome [Curry, 1982]. The histopathological findings, a triad of dermatological features, poor cortex formation of the long bones, and central nervous system (CNS) dysgenesis, are discussed.

In view of the 25% recurrence rate, at risk pregnancies should be carefully monitored by ultrasonography: at 6–8 wk for accurate dating, at 12–16 weeks for active fetal limb movement, and at 16–24 wk for facial and skeletal anomalies, the detection of IUGR, and polyhydramnios.
Agenesis of succedaneous teeth: An expression of the homozygous state of the gene for the pegged or missing maxillary lateral incisor trait
Authors: Witkop Carl J. , Reynolds James F.
Published: June 2005

Agenesis of the permanent teeth that replace the primary teeth, the succedaneous teeth, was found in children from two kindreds wherein both parents had pegged maxillary lateral incisor teeth. The trait small‐pegged‐missing maxillary lateral incisor teeth is inherited in an autosomal dominant manner, as demonstrated in the literature and in these families. Agenesis of succedaneous teeth is most likely an autosomal recessive trait due to the homozygous state of the gene for small‐pegged‐rnissing maxillary incisor teeth.
Estimating frequency of Kallmann syndrome among hypogonadic and among anosmic patients
Authors: Pawlowitzki I. Harry , Diekstall Peter , Schadel Alex , Miny Peter , Reynolds James F.
Published: June 2005

The frequency of Kallmann syndrome (hypogonadotropic hypogonadism and anosmia, HHA) was estimated in patients presenting with hypogonadism and patients with anosmia. Of 791 hypogonadal males 19 had HHA. The frequency of IIHA was about 1:25 (n = 8/189) in outpatients questioned about their sense of smell, about 1:50 (n = 11/579) in patients whose blood samples were sent to us for chromosome analysis, and about 1:30 (n = 19/605) in males with hypogonadism and 46,XY chromosomes. The relation of patients with HHA to those with Klinefelter syndrome was 1:10 (n = 19/186). From 24 patients presenting with anosmia we found 1 hitherto undiagnosed case of HHA. The mean age at diagnosis was 24.8 and 24.9 years in our cases and cases from literature, respectively. These data provide evidence that Kallmann syndrome is not infrequent and that most patients remain undiagnosed until the third decade of life. Earlier diagnosis is emphasized by questioning each hypogonadal patient about his sense of smell because therapeutic success seems to be age dependent.
Dandy‐Walker (like) malformation, atrio‐ventricular septal defect and a similar pattern of minor anomalies in 2 sisters: A new syndrome?
Authors: Ritscher Daniel , Schinzel Albert , Boltshauser Eugen , Briner Jakob , Arbenz Urs , Sigg Peter
Published: June 2005

We report on sisters with similar craniofacial anomalies, a brain malformation in the area of the posterior fossa, and a congenital heart defect. The craniofacial findings include macrocephaly, a prominent forehead and occiput, foramina pari‐etalia, hypertelorism, downslanting palpebral fissures, a depressed nasal bridge, narrow palate, and apparently low‐set ears. Patient 1 had a Dandy‐Walker malformation with communicating hydrocephalus, aplasia of the posterior portion of the cerebellar vermis, and high insertion of the confluent sinus, while in patient 2, a Dandy‐Walker variant was found with aplasia of the cerebellar vermis and hypo‐plasia of the hemispheres, large cisterna magna, high insertion of the confluent sinus, but no hydrocephalus. Both sibs were moderately mentally retarded. The older sister had a complete atrio‐ventricular canal and died after unsuccessful heart operation at 31/2 years. The younger had a successful operation on a cleft mitral valve and septum primum defect. Chromosomes were normal. The occur‐rence of a distinct and similar pattern of congenital anomalies in sisters born to healthy parents points toward a “new” syndrome caused by the homozygous state of an autosomal recessive gene.
Genetic analysis of serum lipid levels and blood pressure in a large kindred
Authors: Marazita Mary L. , Elston Robert C. , Namboodiri Kadambari K. , Hames Curtis G. , Opitz John M. , Reynolds James F.
Published: June 2005

A 267‐member Caucasian kindred with a high incidence of cardiovascular disease, originally from Evans County, Georgia, was chosen for genetic analysis of serum lipid levels and blood pressure. Total serum cholesterol, triglycerides, high density lipoprotein cholesterol (HDL), and systolic and diastolic blood pressures were natural logarithm transformed and then adjusted for significant age, sex, and behavioral trait effects. Major gene pedigree analysis was used to estimate genetic parameters and to test hypotheses about the mode of transmission of each trait. Multivariate methods were also used to estimate linear combinations of the variables that best fit genetic models.

The data were consistent with a major gene segregating for high levels of triglycerides in this kindred. However, dominant and recessive hypotheses could not be distinguished. Although diastolic blood pressure fit a mixture of two distributions significantly better than a single normal, major gene hypotheses could be rejected while the no‐transmission hypothesis could not. There was no evidence of a major gene effect on cholesterol, HDL, systolic blood pressure, or any of the hypothetical traits represented by linear functions of the physical‐lipid traits.
Maternal serum alpha‐fetoprotein and fetal trisomy‐21 in women 35 years and older: Implications for alpha‐fetoprotein screening programs
Authors: Ashwood Edward R. , Cheng Edith , Luthy David A. , Opitz John M. , Reynolds James F.
Published: June 2005

A retrospective study of 3,411 women who underwent midtrimester amniocentesis for fetal chromosome analysis between June 1979 and August 1984 was performed to evaluate an association between low maternal serum alpha‐fetoprotein (AFP) concentrations and Down syndrome (DS) pregnancies. A total of 71 pregnancies was found with abnormal fetal chromosomes; of these, 26 cases were trisomy‐21 and 10 cases were trisomy‐18. The maternal serum AFP in women with DS fetuses was relatively lower than levels in women with fetuses that had normal chromosomes. In addition, the AFP concentrations in amniotic fluid were decreased in cases involving DS fetuses. We have estimated the risks for DS pregnancy at all maternal ages and most serum AFP concentrations. Using these calculations, genetic counselors will be able to provide more accurate risk estimates for trisomy‐21 following maternal serum AFP testing.
Trisomy 14 mosaicism syndrome
Authors: Lipson Mark H. , Opitz John M. , Reynolds James F.
Published: June 2005

A girl with multiple anomalies was found to have trisomy 14 mosaicism. The physical findings in reported cases indicate the condition is a recognizable syndrome.
Dysgenetic male pseudohermaphroditism in a 45,X/46,X,del(Y)(q11.1) mosaic infant
Authors: Gaba Arthur R. , Van Dyke Daniel L. , Weiss Laster , Opitz John M. , Reynolds James F.
Published: June 2005

We describe an infant with dysgenetie male pseudohermaphroditism and the karyotype 45, X/46, X,del (Y)(q11.1). Histologic examination of the resected gonads showed cortical dysplasia indicative of incipient gonadoblastoma.
Cat‐eye syndrome with different marker chromosomes in a mother and daughter
Authors: Ing Paul S. , Lubinsky Mark S. , Smith Shelley D. , Golden Ellen , Sanger Warren G. , Duncan Alessandra M. V. , Opitz John M. , Reynolds James F.
Published: June 2005

Except for atypical eye findings in the daugher, a mother and daughter with bisatellited marker chromosomes had abnormalities consistent with cat‐eye syndrome. The mother's marker chromosome (mar number 1) is derived from one 22 and another acrocentric, possibly also a 22; the daughter's marker (mar number 2) may be an iso‐dicentric, inv‐dup (22) derivative of mar number 1. The mother has a tertiary trisomy translocation chromosome composed of at least one and perhaps two copies of 22pter → qll.2, whereas the daughter clearly has a second‐ary trisomy 22pter → qll.2 isochromosomc, confirming this region as a cause of cat‐eye syndrome. Results of hybridization using a unique sequence probe local‐ized to 22qll are consistent with the interpretation that both ends of both marker chromosomes are derived from 22.
Familial achalasia associated with adrenocortical insufficiency, alacrima, and neurological abnormalities
Authors: Ehrich Elliot , Aranoff Gaya , Johnson William G. , Reynolds James F.
Published: June 2005

We report on two brothers with achalasia, adrenocortical insufficiency, alacrima, short stature, microcephaly, ataxia, optic atrophy, and developmental delay. The parents and three sibs are unaffected. Achalasia, adrenocortical insufficiency, and alacrima comprise a recently characterized familial multisystem disorder of unknown cause. Achalasia has also been described in association with microcephaly and mental retardation in one family and ataxia, optic atrophy, and mental retardation in another. The above reports and these sibs may represent variants of a single pleiotropic recessive gene. We suggest that abnormalities of the central nervous system arc a manifestation of the achalasia, adrenocortical insufficiency, alacrima syndrome.
Recombination between the factor VIII gene and the DXS52 locus gives the most probable genetic order as centromere‐FRA(X)‐DXS15‐DXS52‐F8C‐telomere
Authors: Mulligan Lois M. , Grover Hilary J. , Blanchette Victor S. , Giles Alan R. , Lillicrap David P. , Phillips Ann , Holden Jeanette J. A. , White Bradley N. , Opitz John M. , Reynolds James F.
Published: June 2005

The linkage relationship between the factor VIII gene (F8C) and the DXS52 locus was examined in 8 families. Two recombinations were identified in 35 informative meioses (Zmax= 5.67; θ = 0.05), one in a family with hemophilia A, the other in a family with the fra(X) syndrome. Based on the latter recombination, the most probable order of loci was determined to be centromere‐fra(X)‐DXSl5‐DXS52‐F8C‐telomere. When these data are added to those reported previously the most probable genetic distance between F8C and DXS52 is 3 cM (Z = 14.62). Identification of these and other recombinations suggests that the use of DXS52 as a genetic marker for carrier detection and prenatal diagnosis of hemophilia A has an error rate between 3–5%.
Complex chromosome rearrangements and congenital anomalies
Authors: Kousseff Boris G. , Nichols Pat , Essig Yau‐Ping , Miller Karen , Weiss Avery , Tedesco Thomas A. , Opitz John M. , Reynolds James F.
Published: June 2005

Congenital complex chromosome rearrangements (CCR) compatible with life are rare in man. Thus patients with CCR usually present considerable diagnostic difficulties both clinically and cytogenetically. We studied a 12‐year‐old mentally retarded male with minor congenital anomalies as described below and his first‐degree relatives. The propositus had an unbalanced karyotype with eight break points and seven derivative chromosomes; two deletions, del(6) (q25 → qter) and del(14) (q31 → qter), and four translocations, t(2;11), t(5;15), t(6;11), t(6;20) were present. Parental chromosomes were normal; however, the mother had a few metaphases with abnormal chromosomes suggestive of chromosome instability; These findings and a review of reported patients with CCR are presented with regard to speculations about etiology, pathogenesis, phenotypic expression, and prognosis. Physicians should be aware of CCR and broader indications for cyto‐genetic studies appear warranted in view of these data.
Use of genetic counselling services for neural tube defects
Authors: Sadovnick A. D. , Baird P. A. , Hall J. G. , Keena B. , Opitz John M. , Reynolds James F.
Published: June 2005

Genetic counselling is recommended for parents of children with neural tube defects (NTDs) to inform them of the recurrence risks and the option of prenatal diagnosis. British Columbia provides an excellent site to examine the use by parents of genetic counselling services for NTDs. Genetic services for the entire province are centralized, and there is virtually complete ascertainment of all NTD births. The resulis from this study indicate that use of genetic counselling services is influenced by the type of NTD present and whether the index case was live or stillborn. Genetic counselling is most often sought after the birth of a liveborn infant with spina bifida.
Making the most of multiple measurements in estimating carrier probability in Duchenne muscular dystrophy: The Bayesian incorporation of repeated measurements using logistic discrimination
Authors: Percy Maire E. , Andrews David F. , Brasher Penelope M. A. , Rusk Ann C. M. , Reynolds James F.
Published: June 2005

In carrier detection studies, females‐at‐risk are usually tested several times if the results are ambiguous, whereas subjects in the control and obligate carrier refer‐ence groups may not be tested as often. The question is how to incorporate the multiple measurements most effectively with information in the family pedigree into combined carrier risks.

Sets of measurements on individuals are not independent, but are related with the correlation coefficient 0 < ρ < 1. We have developed a procedure for incor‐porating repeated measurements on individuals and their a priori chance of having the disease into logistic models. This procedure utilizes the set of measurements and an estimate of ρ. We describe application of this procedure to carrier detection in Duchenne muscular dystrophy (DMD) using serum creatine kinase (CK) mea‐surements as the biochemical indicator of carrier status.

Estimates of ρ for controls and obligate DMD carriers did not differ signifi‐cantly from 0.5. Repeated testing with use of ρ = 0.5 significantly decreased the median logistic carrier probability for controls and increased it for carriers. In some cases four to six rather than the three CK tests conventionally used in genetic counseling were necessary to obtain a stable logistic carrier probability for a subject.
Median cleft of the upper lip associated with lipomas of the central nervous system and cutaneous polyps
Authors: Pai G. S. , Levkoff Abner H. , Leithiser Richard E. , Reynolds James F.
Published: June 2005

An unusual combination of three rare developmental anomalies, ie, complete median cleft lip, cutaneous polyps, and midline lipomas of the central nervous system, was discovered in a male newborn. Inguinal hernia, cryptorchidism, and clinodactyly of the fifth fingers were other features. His mother was found to have clinodactyly, antimongoloid slant to her palpebral fissures, and computed tomog‐raphy (CT) scan evidence of asymptomatic hydrocephaly. Family history and clinical investigations did not reveal any clues to etiology. This combination of findings may represent a new syndrome or another expression of frontonasal dysplasia.
Isolation of the right subclavian artery with subclavian steal in a child with Klippel–Feil anomaly: An example of the subclavian artery supply disruption sequence
Authors: Brill Charles B. , Peyster Robert G. , Keller Marc S. , Galtman Lawrence , Opitz John M. , Reynolds James F.
Published: June 2005

We studied a patient with Klippel–Feil anomaly and subclavian steal due to isolation of the right subclavian artery. Other anomalies included hypoplasia of the right clavicle and right vertebral artery, low bifurcation of the left common carotid artery and left choanal atresia. The patient was mentally retarded with corticospinal, cerebellar, and brain stem signs. The entire brain and cervical spinal cord were small; there was no central nervous system malformation, hydroceph‐alus, or bony impingement on neural structures.

Embryologic vascular disorders have been found to be responsible for various congenital systemic and neurologic anomalies such as intestinal atresia and hydra‐nencephaly. Subclavian artery supply disruption sequence has been hypothesized to result in Klippel‐Feil, Poland, and Möbius anomalies. In this case the vertebral and facial abnormalities may well be related to anomalous subclavian and carotid supply.

An embryonic vascular “steal” has been thought to cause the sirenomelia anomaly. We postulate that the subclavian steal, during the embryonic period, may have been responsible for the small size of this patient's cerebral hemi‐spheres, brain stem, cerebellum, and cervical spinal cord.
Familial rhizomelic dysplasia: Phenotypic variation or heterogeneity?
Authors: Viljoen Denis , Goldblatt Jack , Wallis Colin , Beighton Peter , Opitz John M. , Reynolds James F.
Published: June 2005

In a consanguineous kindred of mixed ancestry in Cape Town we observed a boy with severe shortness of stature and an unusual skeletal dysplasia with marked shortness of the humeri. A male one‐half second cousin had gross abnormalities of the lower limbs, which were worst in the femora, but his skeleton was otherwise virtually normal. A brother and sister of this latter individual had been similarly affected and their parents were consanguineous. The question arises as to whether two similar but separate disorders are present in this family or whether the condition in these two persons represents extreme phenotypic variability of the same autosomal recessive entity.
Psychiatric manifestations of homocystinuria due to cystathionine β‐synthase deficiency: Prevalence, natural history, and relationship to neurologic impairment and vitamin B6‐responsiveness
Authors: Abbott Margaret H. , Folstein Susan E. , Abbey Helen , Pyeritz Reed E. , Opitz John M.
Published: June 2005

Homocystinuria commonly affects the central nervous system (CNS), primarily as mental retardation, seizures, and stroke. Case reports have long suggested a predisposition to schizophrenia, but no careful study of predisposition to psychiatric illness has been performed. Accordingly, we evaluated 63 persons with homocystinuria due to cystathionine β‐synthase deficiency for psychiatric disturbance, intelligence, evidence of other CNS problems, and responsiveness to vitamin B6. The overall rate of clinically significant psychiatric disorders was 51%, predominated by four diagnostic categories: episodic depression (10%), chronic disorders of behavior (17%), chronic obsessive‐compulsive disorder (5%), and personality disorders (19%). The average IQ was 80 ± 27 (1 SD); and an IQ of ≤ 79 was two‐thirds more commom among vitamin B6‐nonresponsive patients compared to vitamin B6‐responsive patients. Aggressive behavior and other disorders of conduct were particularly common among patients with mental retardation and among vitamin B6‐nonresponsive patients.
Low maternal serum alpha‐fetoprotein levels and congenital diaphragmatic defects
Authors: Resta Robert G. , Luthy David A. , Karp Laurence E. , Hickok Durlin E. , Opitz John M. , Reynolds James F.
Published: June 2005

We report on 2 cases of fetal congenital diaphragmatic defects with normal chromosomes among 105 patients referred for evaluation for low maternal serum alpha‐fetoprotein (MSAFP) levels. The mechanism for this striking association is not clear. The association of low MSAFP levels and congenital diaphragmatic defects may have importance for MSAFP screening programs.