bluuebunny/crossref_metadata_2025 huggingface dataset:
Nasopharyngeal carcinoma, aplastic anemia, and various malignancies in a family: Possible role of Epstein‐Barr virus
Authors: Schimke R. Neil , Collins Debra , Cross Donald , Opitz John M. , Reynolds James F.
Published: June 2005

We report on a family ascertained because of sibs affected with nasopharyngeal carcinoma. Other relatives had aplastic anemia or other malignancies and most were born of consanguineous parents. Epstein‐Barr virus has been strongly implicated in the pathogenesis of nasopharyngeal carcinoma. It has also been suggested as a cause of aplastic anemia and other neoplasms. We postulate that this extensive German‐Mennonite family has a heritable defect in the immune response to Epstein‐Barr virus making its members at excessive risk for a number of different malignancies. This immunologic predisposition may be HLA associated and appears to be inherited as an autosomal recessive trait.
Trisomy 18 and hepatic neoplasia
Authors: Dasouki Majed , Barr Mason , Reynolds James F.
Published: June 2005

A 2 9/12‐year‐old girl with trisomy 18 presented with a 3‐week history of low grade fever, abdominal distention, and hepatosplenomegaly. Abdominal cytotomography (CT) scan showed hepatic infiltration with a tumor mass presumed to be hepatoblastoma. She deteriorated rapidly and died 3 weeks later. No autopsy and/or biopsy could be done.
Variable expression in ankyloblepharon–ectodermal defects–cleft lip and palate syndrome
Authors: Greene Steven L. , Michels Virginia V. , Doyle John A. , Reynolds James F.
Published: June 2005

The ankyloblepharon‐ectodermal defects‐cleft lip and palate (Hay‐Wells) syndrome is a rare autosomal dominant form of congenital ectodermal dysplasia. It is characterized by coarse, wiry, sparse hair; dystrophic nails; slight hypohidrosis; scalp infections; ankyloblepharon filiforme adnatum; hypodontia; maxillary hypoplasia; and cleft lip and palate. To date, 12 patients have been reported; however, the diagnosis has been questioned in 3 of these patients. We report 2 additional patients, one of whom has nasal speech but not cleft palate, in contrast to all other reported patients. This entity must be distinguished from numerous other forms of ectodermal dysplasia, especially those forms that can be associated with oral clefts and/or ankyloblepharon.
Dyssegmental dysplasias: Clinical, radiographic, and morphologic evidence of heterogeneity
Authors: Aleck Kirk A. , Grix Art , Clericuzio Carol , Kaplan Paige , Adomian Gerald E. , Lachman Ralph , Rimoin David L. , Hall Judith G.
Published: June 2005

The dyssegmental dysplasias are lethal forms of neonatal short‐limbed dwarfism in which vertebral segmentation defects and short, thick, bowed long bones are the prominent radiographic features. Clinically, unusual facies, short neck, narrow thorax, cleft palate, and reduced joint mobility are commonly seen. To date, 18 cases of dyssegmental dysplasia have been reported. Reports of three pairs of affected sibs suggest autosomal recessive inheritance. We have studied eight additional cases of dyssegmental dysplasia, including one pair of affected sibs. Clinical, radiographic, and histologic examination of these new cases and review of the literature demonstrates the presence of at least two distinct forms of dyssegmental dysplasia. The milder form, “dyssegmental dysplasia, type Rolland‐Desbuquois,” is characterized clinically by frequent survival beyond the newborn period and by distinct radiographic changes resembling Kniest dysplasia. The severe form, “dyssegmental dysplasia, type Silverman‐Handmarker,” is charac‐terized by stillbirth or death within the first few days of life and by distinct and more severe radiographic changes. In addition, we have demonstrated chondroos‐seous morphologic differences between the two disorders by light and electron microscopy. We conclude that there are at least two forms of dyssegmental dysplasia, each autosomal recessive, which can be delineated on clinical, radio‐graphic and morphologic grounds.
Radial ray defect and Duane anomaly: Report of a family with autosomal dominant transmission
Authors: MacDermot Kay D. , Winter Robin M. , Reynolds James F.
Published: June 2005

We report on a family in which a mother and her 2 offspring presented with bilateral radial defects and absent thumbs. In addition, Duane anomaly was present in both offspring, one of whom also had anal stenosis. Clinical investigation showed no skeletal, cardiac, or urogenital abnormalities. Autosomal dominant transmission of radial defects is suggested, with Duane anomaly and anal stenosis representing manifestations of the same gene.
Epidemiology of ambiguous genitalia in South America
Authors: Castilla Eduardo E. , Orioli lêda M. , Lugarinho Regina , Dutra Graca , Opitz John M. , Reynolds James F.
Published: June 2005

We present descriptive epidemiologic data on ambiguous genitalia (AG), obtained in the period 1967‐1982 by the Latin American Collaborative Study of Congenital Malformations (ECLAMC) through 70 participating hospitals located in 34 cities of 9 South American countries. The observed prevalence rate for isolated AG was about 1/20,000 births, with at least 1/4 and probably as much as 1/2 due to congenital adrenal hyperplasia. When AG cases associated with other congenital anomalies were also considered, the overall frequency of AG was 1/6,900 total births (1/10,000 for live and 1/350 for stillbirths). The prevalence rates were homogeneously distributed among the different countries, and there was a stable secular trend. AG was more frequent in nontropical than in tropical areas of South America, and there was a significant seasonal variation with its acrophase in August (winter). A case‐control analysis of 14 risk factors showed an association of AG with a prenatal history of acute maternal illnesses. These data do not support an etiological relationship between AG and hypospadias.
Onset in the seventh decade and lack of symptoms in heterozygotes for the TTRMet30 mutation in hereditary amyloid neuropathy—type I (Portuguese, Andrade)
Authors: Sequeiros Jorge , Saraiva Maria João Mascarenhas , Opitz John M. , Reynolds James F.
Published: June 2005

In a Portuguese‐American family with hereditary amyloid neuropathy (familial amyloidotic polyneuropathy), onset was in the seventh decade in all affected relatives. Another unusual characteristic was their origin from the Portuguese island of Madeira. In spite of this, the mutant transthyretin (TTRMet30) (the same variant prealbumin that is the circulating precursor of AFP protein in the classic Portuguese patients) could be found in the propositus plasma. In addition, three other asymptomatic relatives (ages 90, 73, and 48) were shown to carry the mutation.

Late onset and incomplete penetrance, at a clinical level, raise problems for presymptomatic detection of mutant TTR, as these tend to cluster in families. When counseling asymptomatic heterozygotes, we must consider intra‐familial correlation in age‐of‐onset, and the distribution of age‐of‐onset including age of unaffected heterozygotes.

This family poses interesting questions regarding pathogenesis of this degenerative process and the influence of other genetic factors, such as modifiers, epistasis, and polymorphism of the TTR genes or their regulators. A cis‐effect of a gene linked to the mutant gene, decreasing the synthesis of the mutant TTR and keeping a sufficient amount of the normal one in circulation, or producing some cofactor for TTR, could also explain late onset and apparently incomplete penetrance; the occasional finding of classic forms in these families would be the result of recombinatory events.
Common fragile sites: Their prevalence in subjects with constitutional and acquired chromosomal instability
Authors: Tedeschi Bruna , Porfirio Berardino , Vernole Patrizia , Caporossi Daniela , Dallapiccola Bruno , Nicoletti Benedetto , Neri Giovanni
Published: June 2005

Chromosomal fragile sites that are inducible by methotrexate and aphidicolin are frequent in the human population. To assess the frequency and distribution of these common fragile sites, we performed a cytogenetic survey on lymphocytes from subjects known to be particularly prone to breakage because of constitutional chromosomal instability, the possession of a rare fragile site, or Panconi anemia. Furthermore, a group of cancer patients was included in this study in view of possible acquired chromosomal instability. Lymphocyte chromosomes from several healthy donors were analyzed under identical conditions. We found that methotrexate‐ and aphidicolin‐induced fragile sites are widespread in the general population, showing a similar breakpoint distribution. Ten fragile sites (3pl4, 16q23, 2q32, 6q25, 4pl6, 4q31, 14q24, 1p31, 20pl2, 7q21) were observed in at least 40% of the individuals among the different groups. Our data point out a significantly increased breakage, induced by aphidicolin in lymphocytes from cancer patients and, to a lesser extent, from rare fragile sites carriers. These results suggest that common fragile sites are enhanced in some constitutional and acquired conditions.
Walker‐Warburg syndrome with cleft lip and cleft palate in two sibs
Authors: Burton Barbara K. , Dillard Robert G. , Weaver R. Grey , Opitz John M. , Reynolds James F.
Published: June 2005

Two sibs are reported with Walker‐Warburg syndrome including hydrocephalus, agyria, anterior chamber dysgenesis, and encephalocele. In addition, both had cleft lip and cleft palate and intrauterine growth retardation, findings not previously noted in this condition.
Animal model: Dysmorphogenesis and death in a chicken embryo model
Authors: Fineman Robert M. , Schoenwolf Gary C. , Prieur David J.
Published: June 2005

The chicken embryo is a useful animal model for investigating problems in developmental biology and teratology. Here we report data that further define the causes of 2 different patterns of malformation (one associated with amnion abnormalities, the other with isolated neural tube defects) and death induced by making a window in the shell and subshell membranes during the first day of incubation. The interpretation of these data suggests to us the following hypotheses. An early amnion deficit spectrum or syndrome (EADS) in chicken embryos is caused by a brief (less than 10 sec) perturbation that occurs during the windowing procedure. This perturbation results in an acute increase in mechanical tension to the developing embryo and support structures, dehydration localized to the area of the blastoderm, and/or increased friction between the blastoderm and overlying vitelline and shell membranes. Isolated neural tube defects (NTDs) are caused by a longer perturbation (> 3 hr) consisting of increased mechanical stress across the blastoderm. The mechanical stress is associated with the introduction of a new air space over the animal pole of the yolk during windowing. The new air space causes the shape of the yolk to change (ie, to be deformed), resulting in an increase in mechanical tension across the vitelline membrane and blastoderm. NTDs involving the head are associated with significant early embryonic mortality, whereas those involving the trunk are not. Death may also be caused by cardiovascular anomalies observed in EADS. It is concluded that disturbances in morphogenesis and death in this model are, therefore, the result of extrinsic forces (eg, mechanical stress, localized dehydration, or friction) acting on different tissue types at various critical times in development. Intensity and duration of these forces on the developing blastoderm are important variables.
Apparently new autosomal recessive syndrome of mental retardation, distal limb deficiencies, oral involvement, and possible renal defect
Authors: Buttiens M. , Fryns J. P. , Opitz John M. , Reynolds James F.
Published: June 2005

This paper illustrates a syndrome of distal limb deficiency and oral defects in two sibs, a moderately mentally retarded man and his mildly retarded sister. Both have microretrognathia, microstomia, normal tongue, and symmetric severe limb deficiencies. This seems to be a previously undescribed syndrome. The nosology of the different orofacial syndromes associated with distal limb deficiencies is discussed.
Genetic ascertainment with heterogeneous risk
Authors: Murphy Edmond A. , Meyers Deborah A. , Rohde Charles A. , Opitz John M. , Reynolds James F.
Published: June 2005

Analysis of the bias of ascertainment is reformulated to deal with more general patterns commonly encountered in practice. The goal is to provide a unifying theory that will both replace the traditional, rather piecemeal, treatment of the problem and free it from certain restrictive assumptions. A compact algebraic method is furnished for analyzing the properties of the distributions by means of the probability generating function (PGF). The scope of the generalization is illustrated by applying it to the various classical patterns of bias of ascertainment. It is extended to other patterns in which the conditions of ascertainment, though more plausible, are also logically more complicated. It also accommodates cases hitherto inadequately dealt with, such as where the segregation ratios are heterogeneous (for example because of age‐dependence); and cases where the ascertainment function is of arbitrary form and denies us such valuable, but demanding, assumptions as independence. Not only is the result unifying, but it leads to usable results in specific applications such as diseases that depend on age or birth order. While the commonest applications are in human genetics, there are many other issues (such as the use of batteries of tests) in which it is equally important.
Duplication 7p in a family with t(7;11): Association with anomalies of the anterior cranial base
Authors: Odell J. Michael , Siebert Joseph R. , Bradley Cynthia , Salk Darrell , Reynolds James F.
Published: June 2005

Duplication 7p has been observed in association with several balanced translocations. Of eight previously recorded cases, only one exhibited duplication of the entire short arm of chromosome 7. We report on a newborn infant with multiple congenital anomalies and an abnormal chromosome constitution: 46,XX, −11, +der(11),t(7;11) (p11.1;p15.5)mat. The proposita appeared to possess an isolated duplication of the entire short arm of 7. The patient died at age 4 days because of respiratory complications of meconium aspiration. Clinical and postmortem findings included craniocerebral asymmetry, craniosynostosis of a lambdoid suture, arhinencephaly, hypertelorism, anomalies of the ethmoidal portion of the cranial base, large anterior fontanelle, low set ears, ventricular septal defect (VSD), dysplastic tricuspid and pulmonic valves, hypoplastic genitalia, bilateral dislocated hips, and other minor limb malformations.
Isolation of human Y chromosomal major repetitive sequences from a flow‐sorted Y chromosomal library
Authors: Nishioka Yutaka , Lamothe Estelle , Opitz John M. , Reynolds James F.
Published: June 2005

The human Y chromosome is highly heterochromatic and consists mainly of repetitive sequences, of which 3.4 kb HaeIII or EcoR1 fragments represent the most abundant species. From a flow‐sorted human Y chromosomal library, we isolated 15 clones containing sequences highly homologous to this major repetitive sequence. Although the size of inserts varied from 0.7 to 3.8 kb, their hybridization patterns to human genomic DNA were indistinguishable from each other. These repetitive sequences unambiguously detected the presence of the Y chromosome in a male–female DNA mixture of which 5% was derived from male cells. Thus, these clones would be useful molecular tools to detect contaminating male cells in clinical materials.
Pterygium colli medianum and midline cervical cleft: Midline anomalies in the sense of a developmental field defect
Authors: Godbersen Sönke , Heckel Volker , Wiedemann H.‐R. , Opitz John M.
Published: June 2005

We report on 2 patients (and review a third) with a vertical midline neck web which extends from the lower symphysis of the mandible to a variable extent down to the jugular notch. This uncommon congenital anomaly, previously reported primarily in the (plastic) surgery literature, is interpreted as the mildest form and most dorsal extension of anterior midline cleft defects which include the supraumbilical raphé and cleft sternum with or without congenital hemangiomata. By analogy with the former, and the fact that in a boy with a severe cervical midline web there was a cleft of the upper sternum, we interpret this neck‐web as a developmental field defect. It is a sporadic anomaly but may be associated with other midline malformations including congenital heart defect(s). Thus, finding such a web at birth should prompt a careful search for other anomalies.
The CFC syndrome—report of the first two cases outside the United States
Authors: Neri Giovanni , Sabatino Giuseppe , Bertini Enrico , Genuardi Maurizio , Opitz John M.
Published: June 2005

We report on two additional patients with the cardiofaciocutaneous (CFC) syndrome, the first to be reported outside the United States. They have several of the characteristic manifestations of this new multiple congenital anomalies/mental retardation syndrome, namely, mental retardation, growth retardation, relative macrocephaly, unusual face, abnormal hair, skin involvement, heart defect, hernias, and splenomegaly. Similar to all previously reported cases, these also were sporadic and had normal chromosomes.
Fanconi anemia: Another disease of unusually high prevalence in the Afrikaans population of South africa
Authors: Rosendorff Jennifer , Bernstein Renée , Macdougall Lorna , Jenkins Trefor , Opitz John M. , Reynolds James F.
Published: June 2005

We have investigated the prevalence of homozygous and heterozygous Fanconi anemia (FA) in the Afrikaans community of the southern Transvaal Province. The minimum birth incidence of FA in white, Afrikaans‐speaking South Africans was estimated to be 1 in 22,000, with the calculated heterozygote prevalence being approximately 1 in 77. Alternatively, based on a point prevalence of 1 in 26,000, the carrier rate may be estimated as 1 in 83. It is postulated that this unusually high frequency of the gene for FA is attributable to founder effect.
Neonatal manifestations of Schwartz‐Jampel syndrome
Authors: Farrell S. A. , Davidson R. G. , Thorp P. , Reynolds James F.
Published: June 2005

Schwartz‐Jampel syndrome generally presents in childhood with short stature, limited joint mobility, masklike facies with blepharophimosis, myotonia, and often muscle hypertrophy. Few cases with neonatal manifestations have been described. A newborn with severe manifestations is reported and the literature is reviewed.
Wrinkly skin syndrome: Phenotype and additional manifestations
Authors: Casamassima Anthony C. , Wesson Stanton K. , Conlon Charles J. , Weiss Fred H. , Opitz John M. , Reynolds James F.
Published: June 2005

The wrinkly skin syndrome is an autosomal recessive disorder characterized by wrinkling of the skin of the dorsum of the hands and feet, decreased elastic recoil of the skin, an increased number of palmar and plantar creases, multiple musculoskeletal abnormalities, microcephaly, and mental retardation. Our patient is characteristic of the syndrome as previously described, and confirms the presence of mental retardation and microcephaly as component manifestations, with the additional findings of connective tissue abnormalities evidenced by an atrial septal aneurysm.
Dextrocardia with and without situs viscerum inversus in two sibs
Authors: Distefano Giuseppe , Romeo Mario G. , Grasso Sebastiano , Mazzone Domenico , Sciacca Pietro , Mollica Florindo , Neri Giovanni
Published: June 2005

We describe two sibs born to consanguineous Sicilian parents who died of severe congenital heart malformation. Both had dextrocardia; however, only the girl had situs viscerum inversus. At necropsy she was found to have a right spleen and right pulmonary isomerism (three lobes in each lung, as commonly found in the asplenia syndrome). This observation, together with other literature reports, suggest that isolated dextrocardia, situs viscerum inversus, and the asplenia‐poly‐splenia complex may be different end results of a unique dysmorphogenetic process involving the embryonic midline.
Hydrolethalus syndrome: Report of an apparent mild case, literature review, and differential diagnosis
Authors: Aughton David J. , Cassidy Suzanne B. , Opitz John M. , Reynolds James F.
Published: June 2005

We present an infant with manifestations of the hydrolethalus syndrome who has survived for over 5 months; previously, the longest survival reported in this condition has been 2 days. The literature is reviewed and the clinical and pathological findings of our patient are compared with those of the 50 previously reported cases. The differential diagnosis of the condition is discussed.
Atypical phenotype associated with deletion (15) (pter → q11::q13 → qter)
Authors: Reynolds James F. , Daniel Art , FitzGerald Joan , Opitz John M.
Published: June 2005

We report on a 10‐year‐old boy with an interstitial deletion within the region of bands 15q11 → q13. Authors have associated the manifestation of the Prader‐Willi syndrome (PWS) with variable deletions involving the bands q11 → q13. Our patient had atypical manifestations not usually associated with PWS, ie, normal stature, proportionally sized hands and feet, normal genitalia, and was nonambulatory and severely mentally retarded. This case emphasized the clinical diversity seen in proximal 15q deletions in the region considered to be correlated with the PWS.
Follow‐up on seven adult patients with mild Sanfilippo B‐disease
Authors: Valk H. M. J. Van Schrojenstein‐de , van de Kamp J. J. P. , Reynolds James F.
Published: June 2005

This report describes 7 patients, aged 30 to 43 years, suffering from a mild variant of Sanfilippo B‐disease. Somatic findings in these patients are unremarkable. Dementia and behavioral disturbances occurred late in the course of the disease. All 7 patients were examined 10 years previous to this study and reported in earlier publications [van de Kamp et al, 1976, 1981].
Syndrome of osteopetrosis and muscular degeneration associated with cerebro‐oculo‐facio‐skeletal changes
Authors: Lerman‐Sagie Tally , Levi Yael , Kidron Deborah , Grünebaum Michael , Nitzan Menachem , Opitz John M. , Reynolds James F.
Published: June 2005

We describe an infant with cerebro‐oculo‐facio‐skeletal manifestations, radiologic and pathologic findings of osteopetrosis, and severe myopathic degeneration proven on histopathologic study of muscles. The muscle changes appear to be part of the pathogenetic process in this syndrome and the cause of the flexion contractures present at birth. Real‐time ultrasonography may prove a useful tool in prenatal diagnosis of this syndrome.
A nonpathologic allele (IW) for low α‐L‐iduronidase enzyme activity vis‐a‐vis prenatal diagnosis of Hurler syndrome
Authors: Whitley Chester B. , Gorlin Robert J. , Krivit William , Opitz John M. , Reynolds James F.
Published: June 2005

We identified a phenotypically normal obligate heterozygote for Hurler syndrome with exceedingly low levels of α‐L‐iduronidase enzyme activity. Subsequent investigation determined that low α‐L‐iduronidase activity was systemic, also characteristic of the subject's leukocytes and cultured skin fibroblasts. Residual α‐L‐iduronidase activity of cultured fibroblasts was found to have reduced catalytic activity (Vmax) against the 4‐methylumbelliferone substrate, but normal substrate affinity (KM). Additional studies further characterized the residual enzyme activity in this woman who is an apparent compound heterozygote for Hurler syndrome, and for an allele with low α‐L‐iduronidase activity lacking pathologic manifestation. Such low activity “pseudodeficiency” alleles will complicate attempts at prenatal diagnosis of Hurler syndrome and related disorders in rare families.
Close linkage of the Wieacker‐Wolff syndrome to the DNA segment DXYS1 in proximal Xq
Authors: Wieacker Peter , Wolff Gerhard , Wienker Thomas F. , Opitz John M. , Reynolds James F.
Published: June 2005

Linkage studies with RFLPs were performed in a large family in which the Wieacker‐Wolff syndrome is segregating. In this new syndrome (McKusick, 1986, No.31458) patients have congenital contractures, progressive neuropathic muscle atrophy, involving also some cranial nerves with oculomotor apraxia and dyspraxia of the face and tongue muscles, and mental retardation. This is an X‐linked recessive syndrome. We found close linkage between the syndrome locus and the DNA segment DXYS1 (ẑ=3.225 at \documentclass{article}\pagestyle{empty}\begin{document}$ \mathord{\buildrel{\lower3pt\hbox{$\scriptscriptstyle\frown$}} \over \Theta } = 0.0 $\end{document} =0.0) in proximal Xq.
A patient with partial duplication 2q and partial deficiency 11q
Authors: Ho Chen‐Kung , Henderson Kenneth C. , Bowyer Frank P. , Eilers Kathryn B. , Andrews Lucy G.
Published: June 2005

A patient with partial duplication 2q and partial deficiency 11q is reported. The propositus was delivered at 30 weeks gestation, with a birth weight of 1,390 g. He had severe hyaline membrane disease, intraventricular hemorrhage, bronchopulmonary dysplasia, hypotonia, psychomotor retardation, hearing loss, and other anomalies including a short bitemporal diameter, prominent occiput, low‐set ears, exophthalmos, short nose with depressed nasal root, downturned mouth corners, narrow high‐arched palate, micrognathia, a deep longitudinal groove over the sacrococcygeal region, clinodactyly, and abnormal dermatoglyphics. Chromosome analysis showed the following karyotype: 46,XY,der 11,t(2:11)(q32.2;q25)pat.
High degree of satellite association and decreased nucleolar organizer activity in cystic fibrosis subjects
Authors: Ravia Yehoshua , Lieberman Llana , Ravé Abraham , Kremer Moshe , Avivi Lydia , Opitz John M. , Reynolds James F.
Published: June 2005

The effect of colchicine at concentrations of 0.25 × 10−6 M, 1.0 × 10−6 M, and 2.0 × 10−6 M on the degree of satellite association (SA) was estimated in phytohemagglutinin‐stimulated lymphocytes of individuals in the following groups: cystic fibrosis (CF) children, obligatory CF heterozygotes, control children, and control adults. In all four groups increasing colchicine concentration caused a higher degree of SA. The degree of SA differed between the two control age groups (children vs adults) only at the lowest concentration. CF patients had a significantly higher degree of SA than CF heterozy gotes and than control individuals at all colchicine concentrations; CF heterozygotes had a significantly higher degree of SA than control adults at the low and intermediate concentrations. There was a strong interaction between genotype and colchicine concentration: the differences between the CF patients and the control individuals were most distinct at the intermediate concentratio n and between the carriers and the control individuals at the low colchicine concentration. Colchicine had no effect on the activity of the nucleolar Organizer regions (NORs), as measured by the frequency of the silver‐stained NORs (AgNORs), while the frequency of AgNORs in CF patients was significantly lower as compared to control individuals. Yet, the increase in the degree of SA caused by the CF mutant allele involved specifically the satellited chromosomes carrying active NORs.
Predicting recurrence risks under epistatic models
Authors: Beaty T. H. , Maestri N. E. , Meyers D. A. , Murphy E. A. , Opitz John M. , Reynolds James F.
Published: June 2005

We present the expected recurrence risks to a sib of an affected proband under 4 simple 2‐locus epistatic models for various allele frequencies at both the disease locus and the epistatic locus. Four obvious epistatic models are considered: an autosomal recessive disease with both 1) dominant and 2) recessive masking by the epistatic locus, and an autosomal dominant disease again with both 3) dominant and 4) recessive masking. Expected recurrence risks to a sib of an affected proband and to a sib of an affected proband with another normal sib are presented in the absence of information on parental status. Similar risks are presented for the case where both parents are known to be phenotypically normal. These recurrence risks were calculated using a convenient matrix notation which allows sequential calculation of genotypic probabilities. In general, 2‐locus epistatic models can give surprisingly low recurrence risks, and often these risks, especially for models of recessive diseases, fall into the range associated with a more general multifactorial model for liability.
Deletion (13) (q14.1q14.3) in two generations: Variability of ocular manifestations and definition of the phenotype
Authors: Wilson William G. , Campochiaro Peter A. , Conway Brian P. , Carter Bruce T. , Sudduth Kathy W. , Watson B. Allen , Sparkes Robert S. , Opitz John M. , Reynolds James F.
Published: June 2005

A 5‐yr‐old girl with unilateral retinoblastoma was found to have del(l3)(q14.lql4.3). Her 16‐month‐old sister and 35‐year‐old mother, with retinal colobomata but without retinoblastoma, have the same deletion. Esterase D studies indicate reduced gene dose at this locus in the 3 females, consistent with a deletion of band 13ql4. These patients are of apparently normal intelligence but have a mildly “coarse” facial appearance, a broad nasal bridge, upturned nares, and a long upper lip with thin upper lip vermillion similar to the phenotype suggested by Motegi et al [1983a] for patients with this deletion. Review of the literature documents 2 other patients with deletions of band 13ql4 but without retinoblastoma, indicating that retinoblastoma is not a necessary consequence of this deletion. Of the 12 reported patients with deletions limited to band 13ql4, seven had normal intelligence and five were macrocephalic. Insufficient clinical information is provided to draw conclusions about phenotype. The family which we describe and those reviewed by Motegi et al suggest that there may be a characteristic appearance in patients with this deletion.
Female external genitalia and müllerian duct derivatives in a 46,XY infant with the Smith‐Lemli‐Opitz syndrome
Authors: Bialer Martin G. , Penchaszadeh Victor B. , Kahn Ellen , Libes Richard , Krigsman Gary , Lesser Martin L. , Opitz John M. , Reynolds James F.
Published: June 2005

We report on a 46,XY newborn infant with Smith‐Lemli‐Opitz (SLO) syndrome with female external genitalia, intraabdominal testes with epididymides and deferent ducts and a normally shaped uterus and vagina. Polydactyly, cleft palate, and several internal organ malformations were also present, and the patient died shortly after birth.

Data on six reported male infants with SLO syndrome and female external genitalia suggest a correlation between degree of genital involvement and overall degree of severity. Scoring systems to quantify overall degree of severity (SLO score) and degree of genital involvement in males (genital score) were devised and applied to 122 reported cases from the literature. Statistical analyses showed a unimodal distribution of the SLO severity scores, and positive correlations between the SLO score and the genital score in males, the presence of polydactyly, and the presence of cleft palate. In 19 multiplex families the affected sibs were generally similar in their SLO scores.

The above analyses suggest that the wide phenotypic variability in the SLO syndrome is determined by variable expressivity of the same entity as opposed to genetic heterogeneity. The observed phenotypic correlations naturally determine that males with complete feminization are among the more severe patients and tend to have polydactyly and cleft palate.
Deletions of proximal 15q without Prader‐Willi syndrome
Authors: Greenberg Frank , Ledbetter David H. , Opitz John M. , Reynolds James F.
Published: June 2005

Fifteen patients with deletion of proximal 15q without typical Prader‐Willi syndrome (PWS) have been reported previously [Schwartz et al, 1985]. We report on 2 additional patients without typical PWS found to have deletions of 15qll‐13 on chromosome analysis done for evaluation of developmental delay. Their manifestations include broad nasal bridge with telecanthus, full nasal tip with flare of nasal alae, long upper lip, posteriorly angulated ears, highly arched palate, hypotonia, seizures and marked developmental delay. It was suggested that there may be a specific phenotype associated with this deletion which differs from PWS. Whether this deletion differs from the deletion associated with PWS awaits delineation on a molecular level.
Linear growth response to exogenous growth hormone in Prader‐Willi syndrome
Authors: Lee Phillip D. K. , Wilson Darrell M. , Rountree Lois , Hintz Raymond L. , Rosenfeld Ron G. , Reynolds James F. , Ledbetter David H.
Published: June 2005

Linear growth retardation and adult short stature are usual characteristics of Prader‐Willi syndrome. Several lines of evidence suggest that a deficiency in growth hormone (GH) secretion may contribute to this abnormal growth pattern. We have recently reported observations in 4 children with Prader‐Willi syndrome treated with GH. This report extends our observations in 2 of these cases. Both cases had abnormally low growth rate, normal stimulated GH levels, and low somatomedin‐C levels prior to therapy. GH treatment led to significant increases in linear growth rate and somatomedin‐C levels. An additive effect of oxandrolone therapy on linear growth rate was demonstrated in one case. Our resu1ts support the possibility of a neurosecretory GH deficiency in Prader‐Willi syndrome and suggest a need for further investigations.
Clinical comparison of 59 Prader‐Willi patients with and without the 15(Q12) deletion
Authors: Wenger Sharon L. , Hanchett Jeanne M. , Steele Mark W. , Maier Beate V. , Golden Wendy L.
Published: June 2005

Fifty‐nine patients with Prader‐Willi syndrome (PWS) (including three blacks) were enrolled in a behavior modification program including dietary restriction, nutritional education for self‐management of food intake, and exercise. Caloric intake for most patients was 700–800 calories per day. The average stay per patient was 5 weeks with a mean weight loss of 6.6 kg. Thirty‐one patients (53%) had apparently normal chromosomes compared to 25 patients (42%) with apparent 15(ql2) deletion. Three patients had other chromosome abnormalities including two with mosaicism for idic(15)(qll) and one with a de novo apparently balanced translocation t(8q;18q).

There were no differences in manifestations or the effects of the behavior modification program between chromosomally normal and abnormal patients. However, the mean weight loss in the 59 PWS patients was less than would have been expected based on their calculated daily caloric requirements suggesting that PWS patients have reduced caloric needs per unit of body weight compared to normal individuals. Supporting this also was that weight maintenance could be accomplished with only 1000 calories per day on the average. In general, behavioral response to the modification program was successful in that tantrum responses, while not eliminated, were reduced in frequency and severity.
Choanal atresia and athelia: Methimazole teratogenicity or a new syndrome?
Authors: Greenberg Frank , Opitz John M. , Reynolds James F.
Published: June 2005

An infant girl with choanal atresia, athelia, minor anomalies, and mild to moderate mental retardation was born to a woman treated for hyperthyroidism throughout pregnancy with methimazole and propranolol. The patient's defects may be due to methimazole teratogenicity or could represent a previously undescribed syndrome affecting ectodermal structures.
Pathological confirmation of cystic fibrosis in the fetus following prenatal diagnosis
Authors: Ornoy A. , Arnon J. , Katznelson D. , Granat M. , Caspi B. , Chemke J. , Opitz John M. , Reynolds James F.
Published: June 2005

Prenatal diagnosis of cystic fibrosis is presently based on the determination of microvillar enzyme activities in the amniotic fluid. However, there seems to be no accurate means for confirming the diagnosis of the aborted fetus. During the past year we performed pathological and histopathological examinations on 7 fetuses diagnosed in the second trimester of pregnancy to be affected by cystic fibrosis and compared them with 4 control age‐matched fetuses. Glycol‐methacrylate‐embedded 2–3‐μ thick sections of the pancreas, lungs, bronchial tree, and GI tract were stained with toluidine blue, H&E, PAS, and AB‐PAS, and examined microscopically. In the controls, PAS‐positive granules were dispersed throughout the cytoplasm of most pancreatic acinar and tracheal submucosal glandular cells. In the affected fetuses 2 distinct groups were identified. In one group of 4 fetuses, the pancreatic and tracheal submucosal glands were dilated and contained a weak PAS‐positive material. The glandular epithelial cells had very little PAS‐positive granules. In this group, the tracheal epithelium was either atrophic or metaplastic and devoid of microvilli. In the second group of 3 fetuses there was less dilation of the glands, and both pancreatic acinar cells and tracheal submucosal glandular epithelial cells contained few PAS‐positive granules, which were confined mainly to a perinuclear location. The tracheal epithelial cells contained few microvilli which, when present, appeared thicker and shorter as compared to controls. We feel that histochemical evaluation of pancreatic abd vribcguak tussye nat ve if geko ub tge oatgikigucak cibfurnatuib if cstuc fuvrisus ub gynab fetyses wgere tge results of the biochemical studies are suggestive of the disease.
Genetic counselling in unexpected familial recurrence of achondroplasia
Authors: Dodinval P. , Le Marec B. , Opitz John M. , Reynolds James F.
Published: June 2005

Two additional pedigrees with familial recurrence of achondroplasia are described. Genetic risk for children of sibs of affected individuals or premutation carriers seems to be low, but it is advisable to monitor at risk pregnancies by midtrimester ultrasonogra‐phy to diagnose fetal achondroplasia.
X chromosome aneuploidy in lymphocyte cultures from women with recurrent spontaneous abortions
Authors: Horsman D. E. , Dill F. J. , McGillivray B. C. , Kalousek D. K. , Opitz John M. , Reynolds James F.
Published: June 2005

Occasional metaphases with X chromosome aneuploidy can be detected in short‐term lymphocyte cultures from women with recurrent abortions. The significance of this finding is unknown. It has been suggested that it may reflect a genetic tendency to nondisjunction that predisposes these women to an increased risk of producing aneuploid offspring.

We have investigated prospectively the frequency of X chromosome aneuploidy in lymphocyte cultures from 104 women with a normal chromosome constitution and a history of recurrent pregnancy loss defined as 2 or more spontaneous abortions. Seventeen women (16%) had a significant number (2–10%) of X aneuploid cells in cultured lymphocytes but no evidence of constitutional chromosome mosaicism, based on analysis of fibroblast cultures. A control group of age‐matched fertile women without a history of recurrent abortions showed a similar level of X chromosome aneuploidy in lymphocyte cultures. No increased risk for production of liveborn children with aneuploidy was found on retrospective analysis of the reproductive histories of these women. A significant effect of culture conditions on X chromosome gain or loss has been demonstrated by comparison of medium 199 with Dulbecco's modified Eagle medium.
An integrated microcomputer system to maintain a genetic register for Huntington disease
Authors: Sarfarazi Mansoor , Quarrell Oliver W. J. , Wolak Geoffrey , Harper Peter S. , Opitz John M. , Reynolds James F.
Published: June 2005

A microcomputer program has been designed to maintain a large data base for Huntington disease. This program facilitates such data manipulation as adding, altering, retrieving, deleting, and printing pedigrees. The program is self‐contained and has a risk‐calculating routine built in which automatically provides both the Mendelian and age‐modified risks. This package is capable of printing the pedigrees on a simple printer or, alternatively, creates an output‐file which can be used with a dedicated plotting program for drawing the pedigrees and their data on a plotter. The program has a routine which can provide a series of statistical data from the register including age‐of‐onset, diagnosis, death, and other useful information.
Hirschsprung disease in the offspring of mothers exposed to hyperthermia during pregnancy
Authors: Lipson Anthony , Optiz John M. , Reynolds James F.
Published: June 2005

Interview data for events of pregnancy on 40 infants with Hirschsprung disease showed a significant relationship to a history of hyperthermia in the mother in the first trimester, during the time of embryonic development and migration of ganglion cells along the intestine. In order to eliminate maternal recall bias, a control group consisted of 41 malformed infants with congenital limb deficiency. Hyperthermia may be one factor contributing to the cause of some cases of Hirschsprung disease.
Skeletal anomalies in trisomy 21 as an example of amplified developmental instability in chromosome disorders: Histological study of the feet of 21 mid‐trimester fetuses with trisomy 21
Authors: Blum‐Hoffmann Ellen , Rehder Helga , Langenbeck Ulrich , Optiz John M. , Reynolds James F.
Published: June 2005

In a previous radiographic study on the feet of 71 adults with trisomy 12 we found, in comparisn to control individuals, an increased prevalence of biphalangeal toes and metatarsophalangeal sesamoid bones. The present histological study on the feet of 21 mid‐trimester fetuses with prenatally diagonosed trisomy 21 confirms results of the earlier study. At both stages of development these minor bone anomalies have about the same frequency, thus suggesting 1) that they are selectively neutral, and 2) that they reflect a basic (innate) failure of ordered morphogenesis. Our observation that the normal spatial pattern skeletal variants is reproduced in trisomy 21 simply on a quantitavely higher level lends sound support to the hopothesis of amplified developmental instability in chromosome trisomies.
Duplication 11q and deletion 5p syndromes due to a reciprocal translocation segregating in four generations
Authors: Mutchinick Osvaldo , Ramos Zarina , Sánchez Francisco , Ruz Lizbeth , Lisker Rubén , Ovseyevitz Jacobo , Optiz John M. , Reynolds James F.
Published: June 2005

We report on 2 relatives with duplication 11q and deletion 5p, resulting from an adjacent‐1 segregation of a balanced reciprocal translocation 5pl5;11q23, segregating in 4 generations of this family. Twelve out of 16 at‐risk relatives of inheriting the translocation were shown to be carriers, giving a significant (p <.05) 3:1 ratio of carriers/noncarriers. The breakpoint on chromosome 11 at q23 is a folate sensitive fragile site into where the proto‐oncogene c‐ets has been mapped.
Noonan Syndrome: Partial factor XI deficiency
Authors: de Haan M. , Kamp J. J. P. v. d. , Briët E. , Dubbeldam J. , Optiz John M. , Reynolds James F.
Published: June 2005

Among the multiple extracardiac abnormalities seen in the Noonan syndrome, several authors have mentioned an unexplained bleeding tendency. In 1983 Kitchens and Alexander reported on a partial deficiency of coagulation factor XI in four patients with Noonan syndrome. We examined 9 patients with Noonan syndrome and 9 of their 18 parents (3 of them also had Noonan syndrome). Four Noonan patients were found to have a partial deficiency of factor XI (30–65%). The Noonan patients had a mean factor XI level of 67%, significantly lower than the normal parents (mean level of 109%). Our study suggests a relationship between Noonan syndrome and a partial deficiency of factor XI.
Heterochrony and human malformation
Authors: Wilson Golder N. , Optiz John M. , Reynolds James F.
Published: June 2005

The role of altered developmental timing or heterochrony in morphologic evolution has intrigued classical and modern biologists. Analogous manifestations of developmental asynchrony occur in human dysmorphogenesis where they illustrate the residue and repertoire of phylogenetic change. Certain single malformations such as holoprosencephaly immediately suggest heterochrony by their resemblance to antecedent phylogenetic or embryologic structures. Multiple malformation syndromes of genetic, chromosomal, or teratogenic etiology may have altered developmental timing as an underlying theme. The persisting alpha‐fetoprotein synthesis in ataxia‐telangiectasia, the morphologic atavisms in Down or trisomy 13 syndromes, and the delayed growth or fetal to adult hemoglobin switch in diabetic embryopathy all exemplify developmental asynchrony. The perspective of heterochrony stresses the molecular history and hierarchy which is recapitulated with each pregnancy, and reconciles apparent discrepancies between the rates of molecular and morphologic evolution. Recognition of heterochrony places isolated anomalies in the context of pattern and suggests monitoring of teratogenesis through altered expression of ontogenetically regulated, phylogenetically relevant molecules.
Pressure, biochemical, and culture characteristics of CSF associated with the in utero drainage of various fetal CNS defects
Authors: Simpson Gary F. , Edwards Michael S. B. , Callen Peter , Filly Roy F. , Anderson Robert L. , Golbus Mitchell S. , Optiz John M. , Reynolds James F.
Published: June 2005

An attempt has been made to begin delineation of the in utero dynamics of fetal intracranial fluid in the presence of brain malformations. In a series of patients with fetal CNS defects, cephalocentesis was performed at the time of therapeutic abortion or to facilitate vaginal delivery. Intracranial CSF pressures and volumes were quite variable. There did not appear to be any discernible correlation between the type of lesion and the intracranial pressure. Fetal CSF glucose levels were moderately depressed and protein concentrations were very high. Neither virus nor bacteria were cultured from fetal CSF or amniotic fluid of any patients in this series.
Rett syndrome: Abnormal membrane‐bound lamellated inclusions in neurons and oligodendroglia
Authors: Papadimitriou John M. , Hockey Athel , Tan Noel , Masters Colin L. , Optiz John M. , Reynolds James F.
Published: June 2005

The brain biopsy of a patient with Rett syndrome showed light microscopic evidence of white matter disease. Ultrastructurally, many neurons and oligodendroglia contained membrane‐bound electron‐dense inclusions with a distinct lamellar and granular substructure. This substructure suggests that part of these inclusions are derived from phospholipid. If confirmed in other cases of Rett syndrome, the neurochemical study of these inclusions may contribute to an understanding of this disorder.
Congenital optic atrophy and brachytelephalangy: The Berk‐Tabatznik syndrome
Authors: Hartwell Elizabeth A. , Robinson Luther K. , Robinson Lawrence H. , Aceves Javier , Reynolds James F.
Published: June 2005

Here we report on a prepubertal boy with the Berk‐Tabatznik syndrome. Manifestations included short stature, congenital optic atrophy, and hypoplasia of the cervical vertebral bodies and distal phalanges. Prognosis was adversely affected by visual and auditory difficulties. The cause of this condition remains unknown.
Hydrocephalus in asphyxiating thoracic dystrophy
Authors: Singh Meharban , Ray D. , Paul V. K. , Kumar Arun , Optiz John M. , Reynolds James F.
Published: June 2005

We document four patients, including two sibs, with asphyxiating thoracic dystrophy and mild congenital hydrocephalus. All infants were males; three had postaxial polydactyly. The CT scan of brain showed moderate dilatation of the lateral ventricles in all cases. This appears to be the first documentation of apparent hydrocephalus in this condition.