bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment of the embryo and the fetus in the first trimester: Current status and future prospects
Authors: Schulman Joseph D.
Published: June 2005

An effective treatment is now available to prevent the masculinization of female fetuses with congenital adrenal hyperplasia. Some vitamin‐responsive inborn errors of metabolism can be treated prenatally by cofactor administration. Maternal phenylketonuria and maternal diabetes mellitus and the prevention of recurrent neural tube defects are also areas where therapeutic advances are being made. It may be possible to carry out chorionic villi sampling before 8 weeks menstrual age if appropriate catheters and guidance systems (probably transvaginal ultrasound) are used. First trimester diagnosis and treatment of fetal cardiac arrhythmias could prove to be very important, as they are later in pregnancy. Future possibilities for progress include gene microinjection into zygotes, classification and treatment of fresh embryos, biopsy and frozen storage of genetically at‐risk embryos, and therapy of preimplantation embryos by chimera formation or gene introduction by retroviruses.
Micromanipulation of embryos and germ cells: An approach to gene therapy?
Authors: Gordon Jon W.
Published: June 2005

Recent advances in mammalian gamete and embryo micromanipulation have stimulated the scientific and medical communities, and to some degree the public at large, to become aware that treatment of genetic disease by direct alteration of the genetic code may soon be possible. Because these micromanipulation techniques result in modification of the genotype at the earliest stages of development, such “gene therapy” affects not only the conceptus itself but also its germ cells. Thus such genetic modifications are heritable and can be transmitted indefinitely to succeeding generations of progeny. In the presentation, both narrow and broad definitions of gene therapy will be considered with respect to the techniques upon which they are based, their potential for treatment of genetic disease, and their current feasibility.
Spondylocostal dysostosis: Dominant type
Authors: Lorenz Peter , Rupprecht Edgar
Published: June 2005

We report on a father and daughter who have spondylocostal dysostosis. The girl's ribs are more severely abnormal than those of the 2 previously reported cases of dominant spondylocostal dysostosis and are rather suggestive of the autosomal recessive type. The differential diagnosis of both forms is discussed.
Chromosome abnormality in Kallmann syndrome
Authors: Best Lyle G. , Wasdahl Walter A. , Larson Linda M. , Sturlaugson Jean
Published: June 2005

We report on an individual with Kallman syndrome (KS) and a balanced de novo translocation (7;12)(q22,q24). None of 6 full sibs, 3 halfsibs, or parents have KS or this chromosome translocation. This is the only known report of KS with a chromosome abnormality. This may represent a spurious association or genetic heterogeneity vis‐a‐vis the reported linkage of KS to the steroid sulphatase gene on the X chromosome. The pathophysiology and genetics of KS are discussed.
Neural tube defects: Are neurulation and canalization forms causally distinct?
Authors: Seller Mary J.
Published: June 2005

Neural tube defects (NTD) may be separated according to the overall location and probable embryological origin into 2 groups: upper or neurulation defects, and lower or canalization defects. Evidence as to whether these 2 forms are causally related or distinct was sought from 2 sources. Families with more than one NTD individual were studied to examine whether there was concordance within sibships for these 2 types of lesion. Seven of the 38 sibships were discordant (18%). Eight of the 10 cases of NTD that had arisen despite maternal periconceptional vitamin supplementation were neurulation defects and 2 were canalization defects. Both observations suggest that upper and lower types of NTD are causally related, and offer no support for the suggestion that they are distinct.
Acrocallosal syndrome
Authors: Hendriks Han J. E. , Brunner Han G. , Haagen Ton A. M. , Hamel Ben C. J.
Published: June 2005

Acrocallosal syndrome is an autosomal recessive disorder of brain malformation and complex polydactyly. We report on an additional patient with this disorder. It is suggested that increased birth weight and cerebellar hypoplasia occur in acrocallosal syndrome. The finding of an extra bone within the anterior fontanel in our patient suggests similarity to the Xt mouse mutant, which is homologous to Greig syndrome in man. This provides additional support for the hypothesis of allelism of the Greig and acrocallosal syndromes.
Red cell superoxide dismutase, glutathione peroxidase and catalase in down syndrome patients with and without manifestations of Alzheimer disease
Authors: Percy Maire E. , Dalton Arthur J. , Markovic Vjerica D. , McLachlan Donald R. Crapper , Hummel Jocelyn T. , Rusk Ann C. M. , Andrews David F.
Published: June 2005

The activities of red blood cell enzymes that scavenge the superoxide radical and hydrogen peroxide were measured in severely to profoundly retarded adult Down syndrome (DS) patients with and without manifestations of Alzheimer disease (AD), and control individuals matched for sex, age, and time of blood sampling. Cu,Zn superoxide dismutase (SOD‐1) and glutathione peroxidase (GSHPx) activities were significantly elevated (1.39‐fold and 1.24‐fold, respectively) in DS individuals without AD. When an adjustment was made for the SOD gene dosage effect, DS patients with AD manifestations had significantly lower SOD levels than the matched control individuals. In contrast, DS patients with and without AD had a similar elevation in GSHPx (an adaptive phenomenon). The mean catalase (CAT) activity was no different in DS and control individuals; however, in a paired regression analysis, DS patients without AD had marginally lower CAT activity than control individuals, whereas DS patients with AD had slightly but not significantly higher CAT activity. Thus, AD manifestations in this DS population are associated with changes in the red cell oxygen scavenging processes.
New acrofacial dysostosis syndrome in 3 sibs
Authors: Rodríguez José Ignacio , Palacios José , Urioste Miguel
Published: June 2005

We performed clinical and autopsy studies on 3 sibs with an acrofacial dysostosis (AFD) syndrome. All 3 died neonatally from respiratory complications derived from their severe mandibular hypoplasia. They presented a malformation syndrome characterized by mandibulofacial dysostosis, predominantly preaxial limb deficiencies, rare postaxial limb anomalies, shoulder/pelvis girdle hypoplasia, and cardiac and CNS malformations. This syndromal form of AFD could represent a distinct entity with autosomal‐recessive inheritance. Its delineation from other AFD syndromes is discussed.
Factors influencing the reproductive decision after genetic counseling
Authors: Frets Petra G. , Duivenvoorden Hugo J. , Verhage Frans , Niermeijer Martinus F. , van de Berge Sophie M. M. , Galjaard Hans
Published: June 2005

Here we report a follow‐up study involving interviews with 164 couples 2–3 years after genetic counseling to assess the influence of various factors on their reproductive planning. The results show that the desire to have children and the absence of personal experience with the disorder (no close relative being affected) are important single factors for the decision to opt for having children after genetic counseling.

The magnitude of the genetic risk is of relative importance in reproductive planning. Seventy percent of the couples with a high genetic risk (>15%) opted for having children. When the disorder was perceived as severe and the risk was interpreted as high, 72% opted for having children. The availability of prenatal diagnosis became important only in combination with a high genetic risk (>15%). Forty‐seven percent of the couples with a high genetic risk refrained from having children when prenatal diagnosis was not available. In the absence of prenatal diagnosis, couples who had an affected child were more cautious about trying again than those who did not—50% versus 14% decided to abstain.

This study has provided some insight into the complexity of reproductive decision‐making after genetic counseling. The findings may help genetic counseleors and clinical geneticists understand and support counselees in their decision‐making process, which is “multi‐factorial”.
Attitudes of at‐risk and affected individuals regarding presymptomatic testing for autosomal dominant polycystic kidney disease
Authors: Sujansky Eva , Kreutzer Susan Beeler , Johnson Ann M. , Lezotte Dennis C. , Schrier Robert W. , Gabow Patricia A.
Published: June 2005

One hundred forty‐one individuals with autosomal dominant polycystic kidney disease (ADPKD) and 137 at‐risk individuals from 107 kindreds answered a questionnaire to determine knowledge and attitudes about ADPKD and the use of gene linkage analysis for prenatal and postnatal presymptomatic diagnosis. Both groups of individuals displayed a high level of knowledge about the disease. Although 87% of affected individuals considered the recurrence risk of ADPKD high, only 11% of ADPKD did not have children for this reason after diagnosis. Ninety‐seven percent of at‐risk individuals would utilize gene testing for themselves. Eight‐eight percent of ADPKD and 89% of at‐risk individuals would test offspring (not significant, NS) and 65% of ADPKD and 50% of at‐risk individuals between the ages of 18 and 40 would use prenatal testing (NS). Only 4% of ADPKD and 8% of at‐risk individuals between the ages of 18 and 40 would terminate a pregnancy for ADPKD. A greater percentage would terminate a pregnancy for a serious medical problem. The factors influencing presymptomatic testing were analyzed. The data suggest that presymptomatic testing will not substantially modify incidence of ADPKD since it may only occasionally alter reproductive plans.
Pyridoxine‐unresponsive homocystinuria with an unusual clinical course
Authors: Cochran Frederick B. , Sweetman Lawrence , Schmidt Kathleen , Barsh Greg , Kraus Jan , Packman Seymour
Published: June 2005

Progressive premature atherosclerosis and associated thromboembolic complications are the main causes of morbidity and mortality in patients with homocystinuria. However, thrombosis is rarely the predominant or presenting manifestation leading to the diagnosis of homocystinuria. We report on an otherwise asymptomatic teenage boy of normal intelligence who had a superior sagittal sinus thrombosis documented by CT and MRI scans. He presented with pneumothoraces, papilledema, and transient right hemiparesis. He subsequently developed empyema and necrotizing pneumonia as well as deep venous thromboses. The diagnosis of pyridoxine‐unresponsive homocystinuria was made on the basis of clinical chemistry analyses, enzyme assay, and clinical trial. He has remained symptom‐free under treatment with betaine and methionine restriction. We suggest that there exists a subset of patients with pyridoxine‐unresponsive homocystinuria who are at risk for thromboembolism, but who may remain undiagnosed because of an otherwise mild clinical course.
Prenatal diagnosis of Pallister‐Killian syndrome
Authors: Soukup S. , Neidich K.
Published: June 2005

We describe a case of Pallister‐Killian syndrome ascertained by routine amniocentesis as i(12p). The i(12p) was also found in 4 tissues of the aborted fetus, where various degrees of mosaicism 46/47 + i(12p) were seen. Although autopsy showed no major malformations, some of the minor anomalies of Pallister‐Killian syndrome were found.
Double chromosome anomaly: Interstitial deletion 5q and reciprocal translocation (1;11) (p22;q21)
Authors: de Michelena María I. , Villacorta Jorge , Chávez Julio
Published: June 2005

We describe a girl with multiple congenital abnormalities and developmental delay; her karyotype showed an apparently balanced translocation between the short arm of chromosome 1 and the long arm of chromosome 11, and an interstitial deletion of the long arm of chromosome 5 (q15q31). The clinical findings are compared with those described in other cases of 5q deletion, and the origin of the chromosome rearrangements is briefly discussed.
Detection of heterozygotes for recessive alleles. Homocyst(e)inemia: Paradigm of Pitfalls in phenotypes
Authors: McGill James J. , Mettler Gabrielle , Rosenblatt David S. , Scriver Charles R.
Published: June 2005

Excess homocysteine in body fluids has been implicated as a factor in the pathogenesis of occlusive vascular disease (peripheral and cerebrovascular arterial disease, and perhaps coronary artery disease). Heterozygotes for inborn errors of homocysteine metabolism (transsulfuration or remethylation pathways) are much more frequent than are homozygotes/compounds. If heterozygotes are at increased risk (a question not addressed here), it is of interest to know whether they can be identified consistently by a “screening” measurement of blood homocyst(e)ine. We used hyperhomocyst(e)inemia (cystathioninemia β‐synthase deficiency) as a test case. From reviews of metabolite values in blood samples either fasting (11 articles) or after a methionine load (8 articles), and of measures of enzyme activity (12 articles), it is apparent that (1) The heterozygous phenotype cannot be identified consistently by any single measure (there is overlap with normal values); and (2) the exaggerated gene dosage effect (negative allelic complementation) present in most heterozygotes does not assist their classification. The failure of enzyme assay to distinguish heterozygotes consistently (relative to normal values) may reflect allelic heterogeneity. The failure of metabolic values to identify heterozygotes consistently reflects the local and global properties of the homeostatic system controlling the homocysteine pool size. The problem described here is a particular example of a general one in physiological and medical genetics, namely detection of heterozygotes for recessive alleles, affecting metabolic homeostasis, for purposes of medical intervention and for genetic counselling.
Fetal disruptions: Assessment of frequency, heterogeneity, and embryologic mechanisms in a population referred to a community‐based stillbirth assessment program
Authors: Luebke Heidi J. , Reiser Catherine A. , Pauli Richard M.
Published: June 2005

The Wisconsin Stillbirth Service Project (WiSSP) is a community‐based program for the investigation of the cause of fetal death. From its inception in 1983 through July 1988, 629 referrals were made to WiSSP. All referrals were assessed for the presence of disruptional characteristics, and 23 were found to have major or primary disruptive effects. Most of these were either early amnion disruption/limb‐body wall disruption (treated as a single group, since analysis suggests a continuum of clinical characteristics) and twin–twin disruptions. Therefore, disruptions accounted for 3.6% of all referrals (including liveborn and miscarriage referrals) to WiSSP. When only stillborn fetuses are considered, approximately 2.4% appear to have died because of disruptions. This makes disruptions one of the most frequent, identifiable causes of late intrauterine death. We estimate that 0.6‐1.4% of all stillborn fetuses die because of early amnion disruption/limb–body wall disruption which, when taken with previous estimates of the frequency of such problems in early miscarriages and liveborn in fants, suggests that these disruptions result in a 95% prenatal mortality rate.

We suggest a unified model of likely pathogenetic mechanisms which may help explain the continuum of multisystem involvement seen in those with early amnion disruption/limb body wall disruption. In addition, 3 patients with atypical disruptions are reviewed who exemplify the difficulty and importance of differentiating disruptional and malformational processes.
Angular homeostasis: VI. Threshold processes with bivariate liabilities
Authors: Murphy E. A. , Berger K. R. , Pyeritz R. E. , Sagawa Y.
Published: June 2005

The general structure of the threshold model of multifactorial determination is discussed. It is supposed that in place of a single liability (in Falconer's sense) there are two separate liabilities; and wheter or not the pathological trait is present depends on a non‐additive interaction between the liabilities, so that the region has curved boundaries. The genetics of ontogeny of a process involving spatial orientation (e.g., cardiac ontogeny) is used as a substantive illustration. Genetic analysis of the trait (as contrasted with the liabilities) yields results that on the one hand may seem quite counterintuitive, yet on the other hand they correspond to the kind of bizarre patterns encountered in quasi‐empirical genetic counseling for cleft palate or neural tube defect. The impact of refinement of phenotype made possible by non‐invasive methods is sketched. This model can be generalized to any number of liabilities, independent or not.
Atelosteogenesis type III: A distinct skeletal dysplasia with features overlapping atelosteogenesis and oto‐palato‐digital syndrome type II
Authors: Stern Harvey J. , Graham John M. , Lachman Ralph S. , Horton William , Bernini Philip M. , Spiegel Peter K. , Bodurtha Joann , Ives Elizabeth J. , Bocian Maureen , Rimoin David L.
Published: June 2005

We present 5 cases of a short‐limb dwarfism syndrome whose manifestations overlap those of atelosteogenesis and oto‐palato‐digital syndrome Type II. Clinical, radiographic, genetic, and histologic data are presented which demonstrate differences between our patients and previously reported cases of these other conditions. We conclude that the disorder seen in these children represents a distinct chondrodysplasia for which we propose the name atelosteogenesis Type III.
Craniosynostosis in an infant with an interstitial deletion of 15q [46, XY,del(15)(q15q22.1)]
Authors: Fukushima Yoshimitsu , Wakui Keiko , Nishida Toshiro , Nishimoto Hiroshi
Published: June 2005

An interstitial deletion of 15q [46, XY, del(15)(q15q22.1)] was found in a malformed infant with craniosynostosis. Although the parents had normal chromosomes, the study of heteromorphic markers of chromosome 15 showed that the deleted chromosome 15 was of paternal origin. The 2 previously reported cases with an interstitial deletion of the middle portion of 15q were not complicated with craniosynostosis, and their deleted region did not include 15q15 band. The deletion of chromosome band 15q15 might be responsible for craniosynostosis.
Deletions in chromosome 2 and fragile sites
Authors: Palmer C. G. , Heerema N. , Bull M.
Published: June 2005

We report on 2 patients with de novo deletions of 2q and chromosome constitutions of 46, XY,del(2)(q32.3q33.3) and 46,XX,del(2) (q21q23.2), respectively. Comparisons of breakpoints of interstitial deletions show frequent correspondence to common fragile sites.
X‐linked recessive torsion dystonia in the Philippines
Authors: Kupke Kenneth G. , Lee Lillian V. , Viterbo George H. , Arancillo Jose , Donlon Timothy , Müller Ulrich
Published: June 2005

The occurrence of an X‐linked form of torsion dystonia in the Philippines was demonstrated by the genetic and biochemical analysis of affected males and their relatives. Thirty‐six affected males were ascertained in 21 families by clinical neurologic evaluation. The mean age‐of‐onset of dystonia was 37.9 years with a range from 12 to 52 years. Neurologic symptoms began focally and progressed to either segmental or generalized involvement in all cases. Generalized dystonia developed in 78% of the patients after a mean duration of 6.8 years from the onset of symptoms. A family history of dystonia was elicited in 17 of the 21 kindreds, accounting for a total of 64 males and one possibly affected female, distributed among 224 individuals in 33 sibships. In 18 of the 33 sibships, 2 or more brothers reportedly had dystonia. There were 12 kindreds with a history of multigenerational dystonia. In those, only males of maternal ancestry were affected, and in 7 of these families, maternal grandfathers reportedly had dystonia. There were no instances of male‐to‐male transmission. Cytogenetic analysis did not show any X chromosome abnormalities in 4 affected propositi. Several secondary causes of torsion dystonia were excluded, including Wilson disease, aminoacidopathies, organic acidurias, oligosaccharidoses, and chronic hexosam‐inidase A and B deficiency. These findings substantiate the existence of an X‐linked recessive form of primary torsion dystonia.
Novel isodicentric chromosome 18 in an abnormal infant with a mosaic karyotype [46, XY/46,XY, –18,+ dic(18)(q12.2)]
Authors: Bryke Christine R. , Lindgren Valerie , Fryburg Julie S. , Yang‐Feng Teresa L.
Published: June 2005

A previously unreported isodicentric chromosome 18 was discovered in an abnormal infant boy whose mosaic karyotype was 46, XY/46,XY,–18, + idic(18)(q12.2). His constellation of congenital anomalies was typical of the 18q‐syndrome. The clinical and cytogentic characteristics of this patient are reported, and the literature concerning isochromosomes of 18 is reviewed.
Hypogonadotropic hypogonadism in mentally retarded adults with microphthalmia and clinical anophthalmia
Authors: Keppen Laura Davis , Brodsky Michael C. , Michael Judith M. , Poindexter Ann R.
Published: June 2005

Five of 13 patients with microphthalmia or clinical anophthalmia studied in an institution of 650 mentally retarded adults had hypogonadotropic hypogonadism. Four males had low testosterone levels and sexual infantilism, manifesting as micropenis with small testes or cryptorchidism. One female had primary amenorrhea. All 5 patients had low gonadotropin levels, confirming a hypothalamic or pituitary basis for their hypogonadism. Thyroxin, thyroid stimulating hormone, prolactin, and A.M. cortisol were also measured and were normal. All patients with hypogonadotropic hypogonadism were chromosomally normal and had variable central nervous system defects, suggesting that they comprise a heterogeneous group of disorders. Microphthalmia or anophthalmia in a mentally retarded patient is associated with hypogonadotropic hypogonadism.
Trisomy 20q caused by der (X)t(X;20)(q28;q11.2)
Authors: Waters Jonathan J. , Gourley David S. , Aitken David A. , Davison B. C. Clare
Published: June 2005

A first case of “pure” trisomy 20q (q11.2‐qter) is described in a female child with minor anomalies and developmental delay. This resulted from the inheritance, from a carrier mother, of an abnormal X chromosome: der (X)t(X;20)(q28;q11.2). Involvement of other autosomes has complicated the interpretation of the phenotypic effect of trisomy 20q in previously published case reports.

Red cell gene dosage studies using adenosine deaminase (ADA) have confirmed that the proposita is trisomic for 20q. Taken together with RBG staining studies, these results suggest that there is incomplete inactivation, if any, of the autosomal portion of the consistently late‐replicating abnormal X. Unexpectedly, ADA gene dosage results in the carrier mother showed a level of gene expression about half that of normal controls.
Frequency of congenital heart defects in patients with hemophilia
Authors: Jedele Kerry B. , Michels Virginia V. , Gordon Hymie , Gilchrist Gerald S.
Published: June 2005

Most structural congenital heart defects (CHD) are thought to be multifactorially determined, but the precise causal factors usually are unknown. One may postulate that vascular events, such as hemorrhage in the developing embryo, could influence morphogenesis of the heart. One method of studying this hypothesis is to determine the frequency of CHD in persons with heritable bleeding diatheses and their families. We reviewed retrospectively medical and family histories of 120 hemophilia A and 14 hemophilia B patients seen in our Genetics Department. The family histories included 1, 126 maternal relatives of hemophiliac patients. We also reviewed the family histories of 138 patients with X‐linked disorders who did not have bleeding diatheses or syndromes associated with CHD; these histories included 960 maternal relatives. There was one confirmed case of a CHD in 134 hemophilia patients, giving a frequency of 0.75% compared to 0.8% in the general population at birth. There was no apparent difference in the frequency of CHD in hemophilia A and B patients compared to the general population or in the relatives of hemophilia patients as compared to control individuals.
Temperament in Williams syndrome
Authors: Tomc Susan A. , Williamson Nancy K. , Pauli Richard M.
Published: June 2005

Anecdotal reports suggest that children with Williams syndrome are loquacious, affectionate, charming, open, and gentle. The temperament, or behavioral style, of individuals with Williams syndrome was assessed using standard temperament scales of parental response. Children with Williams syndrome appear, on average, to display higher activity, lower rhythmicity, greater approach, lower adaptability, greater intensity, more negative mood, less persistence, greater distractibility, and lower threshold to arousal than will average children. Older children with Williams syndrome will likely be viewed as “difficult”. Despite this overrepresentation in the “difficult” cluster, on average, this population differs from the usual population of “difficult” children in being approaching, rather than displaying a tendency to withdraw. Parents of a child with Williams syndrome should be apprised of potentially negative temperament characteristics, relieved of the burden of responsibility for having a difficult child who “should” be easy, and counselled, when appropriate, regarding the efficacy of modification of parent‐child interactions with children having the difficult temperament.
Nager anomaly with severe facial involvement, microcephaly, and mental retardation
Authors: Palomeque A. , Pastor X. , Ballesta F.
Published: June 2005

A girl is reported who has severe facial abnormalities with preaxial anomalies of upper and lower limbs indicative of Nager syndrome. Additional findings include marked microcephaly, mental retardation, and normal hearing.
A sibship with Roberts/SC phocomelia syndrome
Authors: Holmes‐Siedle Monica , Seres‐Santamaria Agustin , Crocker Mark , Hall Judith G. , Crouchman Marion
Published: June 2005

We report on a family in which 3 sibs have Roberts/SC phocomelia syndrome. One child has survived to age 9 years. The clinical manifestations and the natural history of this syndrome are reviewed.
Familial tetralogy of fallot and glaucoma
Authors: Chen Su‐chiung , D'souza Noreen
Published: June 2005

All 3 daughters of a mother with glaucoma had a conotruncal abnormality of the heart and glaucoma. The presence of heart and eye anomaly may be coincidental; however, both may be related to abnormal development of neural crest. The pedigree suggests autosomal dominant inheritance in this family.
Unilateral VATER association
Authors: Syed Shamsuddin A. , Onizuka Keiko , Yamanobe Yuji , Fuji Tohru , Namba Katsuya
Published: June 2005

We describe a case of unilateral “VATER association.” In addition to the VATER manifestations, the patient had hemihypoplasia, unilateral congenital paralysis of a leg, and delayed ossification of the femoral head and carpal bones. All of the manifestations involved the left side of the body. The only drug exposure identified was a Chinese herbal medicine taken by the mother during early pregnancy.
Syndrome of mental retardation, facial anomalies, hypopituitarism, and distal arthrogryposis in sibs
Authors: Chitayat David , Hall Judith G. , Couch Robert M. , Phang Min S. , Baldwin Virginia J.
Published: June 2005

A brother and a sister presented with a malformation syndrome consisting of facial anomalies, distal arthrogryposis with camp‐todactyly of fingers and “hammer toes,” severe mental retardation, and hypopituitar‐ism. The girl is now 6½ years old and exhibits severe mental retardation. She has abnormal secretion of growth hormone and responded to growth hormone therapy. Her brother was born with the same facial manifestations, distal contractures, and hypopituitarism. He died unexpectedly at age 3 months of no apparent cause. The occurrence of the syndrome in 2 sibs of different sex suggests auto‐somal recessive inheritance.
Adjacent‐2 disjunction of a maternal t(9;22) leading to duplication 9pter→q22 and deficiency of 22pter→q11.2
Authors: Pivnick Enikö K. , Wilroy R. Sid , Summitt John B. , Tucker Barbara , Herrod Henry G. , Tharapel Avirachan T.
Published: June 2005

The proposita presented at birth with multiple congenital anomalies including craniofacial anomalies, bilateral cleft lip and palate, abnormalities of the urogenital system, talipes equinovarus, and the DiGeorge sequence. Cytogenetic investigation showed a 46,XX,‐ 22,+der(9)t(9;22)(q22;q11.2) karyotype. The mother, maternal uncle, and maternal grandmother of the infant are carriers of a reciprocal balanced translocation involving chromosomes 9 and 22 at regions q22 and q11.2, respectively. The unbalanced karyotype seen in the proposita arose due to an adjacent‐2 disjunction of the quadrivalent in the mother. Prenatal diagnosis of the second pregnancy of this woman showed a similar karyotype. Review of the literature shows that adjacent‐2 disjunction may occur preferentially when certain chromosomes are involved in translocations.
Rokitansky sequence in association with the facio‐auriculo‐vertebral sequence: Part of a mesodermal malformation spectrum?
Authors: Wulfsberg Eric A. , Grigbsy Tamara M.
Published: June 2005

We report on a 4‐year‐old first‐born mono‐zygotic twin girl with a hypoplastic left face, mandible and zygoma, left microtia without an external auditory canal, a U‐shaped cleft palate, right ectopic‐fused kidneys, a blindly ending vaginal pouch, and absent uterus. We review 3 other cases with the manifestations of the Rokitansky and the facio‐auriculo‐vertebral sequence. The anomalies in these disorders can be thought of as deriving from an early defect or disruption in fetal mesoderm or its progenitor tissue at the time of primitive streak formation. They are frequently associated with other mesodermally derived defects or sequences and may together represent an extended polytopic field defect. While such speculation on how these spatially separated anomalies develop is probably simplistic, the concept of a mesodermal “malformation” spectrum is helpful in reminding the clinician to look for other mesodermal defects when one mesodermally derived defect or sequence is detected.
The syndrome of hirschsprung disease, microcephaly, unusual face, and mental retardation
Authors: Halal Fahed , Morel Johanne
Published: June 2005

Here we report on a boy with Hirschsprung megacolon associated with microcephaly, narrow palpebral fissures, broad nasal bridge, congenital heart defect, cryptorchidism, wide‐base gait, short stature, developmental delay and abnormal computed tomography (CT) brain scan. The findings are compared with those of previously described patients with the same syndrome.
The Cohen syndrome: Does mottled retina separate a finnish and a jewish type?
Authors: Kondo Ikuko , Nagataki Shigetoshi , Miyagi Nobuo
Published: June 2005

A new familial cases of the Cohen syndrome in two brothers of one‐half second‐cousin parents is reported. Typical clinical manifestations of the syndrome; i.e., mental deficiency, hypotonia, characteristic facial appearance, long, narrow hands and feet with elongated fingers, and mottled retinae were present in both patients. Both patients also had leukopenia. Clinical manifestations of the Cohen syndrome in patients are highly variable, and mottled retina has been observed in 22 of 87 patients (25%). However, an association of mottled retina in patients with the Cohen syndrome is likely to be related to the families and ethnic groups. Among 19 familial cases, mottled retina was observed in all affected sibs from five families, but in 13 families none of the affected sibs had the mottled retina. All Finnish patients had the mottled retina, but this was noted in only one of 39 Jewish patients. Based on these data, we hypothesize that two alleles at the gene locus for the Cohen syndrome exhibit different clinical manifestations: one is a Finnish type with mottled retina, and the other is a Jewish type without retinal anomalies.
Second trimester maternal serum pregnancy specific beta‐1 glycoprotein (SP‐1) levels in normal and down syndrome pregnancies
Authors: Petrocik Elizabeth , Wassman E. Robert , Lee J. Jack , Kelly JoAnn C.
Published: June 2005

Maternal serum pregnancy specific beta‐1 glycoprotein (SP‐1) levels in the second trimester may be predictive of Down syndrome (DS). An enzyme immunoassay was used to measure SP‐1 sera from 46 DS pregnancies and 117 normal control women matched for maternal age, gestational age, and length of storage. In the normal control samples, there were slight correlations between the SP‐1 concentration and maternal age. The maternal serum SP‐1 levels increased with each week of gestation from 15 to 20 weeks. All but one of the DS sera had SP‐1 levels greater than the normal median. Using a cutoff of 2.8 multiples of the median (MoM), 15.2% of the DS pregnancies were detected with a false‐positive rate of 4.3%. A combinational logistic regression analysis of maternal age and pregnancy related serum proteins will detect additional DS pregnancies and decrease the false‐positive rate. The combination of maternal age and SP‐1 detected 33 (71.7%) of Down syndrome pregnancies. The addition of maternal serumα‐fetoprotein (AFP) and human chorionic gonadotropin (hCG) levels allowed for the detection of 36 (78.3%) of the DS pregnancies with a decrease in the false‐positive rate to 3.4%. The measurement of other serum constituents in conjunction with AFP appears to be a valuable addition to current screening programs, as this can increase the proportion of DS cases detected prenatally.
Severe combined immunodeficiency syndrome associated with autosomal recessive familial multiple gastrointestinal atresias: Study of a family
Authors: Moreno Luis A. , Gottrand Frédéric , Turck Dominique , Manouvrier‐Hanu Sylvie , Mazingue Françoise , Morisot Cyril , Le Deist Françoise , Ricour Claude , Nihoul‐Feketé Claire , Debeugny Pierre , Griscelli Claude , Farriaux Jean‐Pierre
Published: June 2005

Hereditary multiple atresias involving the gastrointestinal tract from pylorus to rectum are the most unusual form of intestinal atresia; the type of inheritance was suggested to be autosomal recessive. The inheritance of the severe combined immunodeficiency syndrome can be autosomal recessive or X‐linked.

We report on 3 sibs with multiple‐level intestinal atresias. One sib had severe combined immunodeficiency syndrome and clinical histories of the other 2 sibs strongly suggested a congenital immunodeficiency syndrome. The parents of those children were healthy and nonconsanguineous.

To our knowledge, this is the first report of the association of multiple gastrointestinal atresias and immunodeficiency which appears to have an autosomal recessive pattern of transmission. Our family report suggests that, in the presence of multiple gastrointestinal atresias, attention should be given to possible associated immunological disorders.
Clinical anophthalmia, dextrocardia, and skeletal anomalies in an infant born to consanguineous parents
Authors: Aughton David J.
Published: June 2005

Clinical anophthalmia; unusual facies (sloping forehead, prominent nasal root and bridge, large pinnae, mild micrognathia); dextrocardia; vertebral fusion defects; supernumerary ribs; and normal growth and development in infancy.
On the measurement and interpretation of birth defect associations in epidemiologic studies
Authors: Khoury Muin J. , James Levy M. , Erickson J. David
Published: June 2005

The extent of clustering of 2 or more defects in the same infant can be expressed as the ratio of the observed number of infants with the defects (O) over the expected number of such infants (E). The expected is usually derived from the product of population rates of individual defects. Because large O/E ratios are obtained for many defect combinations, it has been suggested that clustering of defects is generalized and nonspecific. To control for the tendency of nonspecific clustering of defects, an alternative method is to perform the same calculations among multimalformed infants only. A main limitation of this method is that it adjusts for the clustering tendency of all defects rather than the ones of interest, often resulting in spuriously low O/E ratios. We present a new method to adjust for the tendency for nonspecific clustering between defects that overcomes this limitation. With this method, adjusted O/E ratios are inversely related to the proportion of infants who are multimalformed and have one or more of the defects being examined. Using data from the Metropolitan Atlanta Congenital Defects Program, we apply this method to the previously described associations among VACTERL defects and midline or “schisis” defects. We show that adjusted O/E ratios obtained are greater than those obtained by using multimalformed infants. For midline defects, many of the adjusted ratios were close to one, indicating nonspecific clustering of these defects. Finally, using the example of isotretinoin embryopathy, we show that O/E ratios depend highly on the frequency of exposure in the population, and thus, they should be interpreted with caution.
New findings in a patient with dubowitz syndrome: Velopharyngeal insufficiency and hypoparathyroidism
Authors: Lerman‐Sagie Tally , Merlob Paul , Shuper Avinoam , Kauli Rivka , Kozokaro Zilli , Grunebaum Michael , Mimouni Marc
Published: June 2005

We report on a boy with Dubowitz syndrome and hypoparathyroidism from which he recovered, only to redevelop it at 6 years. He also had a submucous cleft palate and cineradiographic studies showed velopharyngeal insufficiency. Although a submucous cleft palate is a well‐known manifestation of Dubowitz syndrome, velopharyngeal insufficiency has not been previously described.
Ulnar agenesis and endocardial fibroelastosis
Authors: Marles Sandra L. , Chudley Albert E.
Published: June 2005

We report on an infant with bilateral ulnar agenesis, radial hypoplasia, oligodactyly, hydrops fetalis, and endocardial fibroelastosis (EFE). The presence of the 2 major malformations and parental consanguinity suggests the possibility of a new autosomal recessive MCA syndrome.
Maternal serum hCG and SP1 in pregnancies with fetal aneuploidy
Authors: Bartels Iris , Thiele Marion , Bogart Mark H.
Published: June 2005

In a retrospective study, maternal serum levels of chorionic gonadotropin (hCG) and pregnancy specific β1‐glycoprotein (SP1) from 63 pregnancies with aneuploid fetuses were compared to the levels observed in pregnancies with a chromosomally normal fetus. Thirty‐eight percent of the abnormal pregnancies had elevated levels (>2.0 multiples of the normal median [MoM]) of hCG and 14% had depressed levels (<0.25 MoM). With a false‐positive rate of 5%, 44% of the 42 fetuses with trisomy 21 would have been detected by elevated hCG levels. With the same false‐positive rate, only 21% had elevated SP1 levels. hCG was significantly depressed in 12 pregnancies affected by fetal trisomy 18.
Spondyloepiphyseal dysplasia, mild autosomal dominant type is not due to primary defects of type II collagen
Authors: Anderson Ilse J. , Tsipouras Petros , Scher Carron , Ramesar Raj S. , Martell Robert W. , Beighton Peter
Published: June 2005

A mild autosomal dominant form of spondylo‐epiphyseal dysplasia (SED) is present in several generations of a South African family of English stock. This phenotype differs from that of any other previously described. Although type II collagen defects have been found in some families with SED congenita, the phenotype in our family showed discordant segregation with COL2A1 gene associated restriction fragment length polymorphisms (RFLPs), the markers for the structural locus of type II collagen. It is evident that the SED group of disorders is heterogeneous.
Clinical manifestation of prenatal exposure to valproic acid using case reports and epidemiologic information
Authors: Martínez‐Frías Maria Luisa
Published: June 2005

The present study includes 28 patients prenatally exposed to valproic acid (VPA) monitored by the Spanish Collaborative Study of Congenital Malformations (ECEMC), from April 1976 to December 1988. Among the 28 cases, 15 (53.6%) were exposed only to VPA and 13 (46.4%) to VPA plus other anticonvulsant drugs. The clinical manifestations observed in those prenatally exposed only to VPA, are compared with the abnormalities observed in those with prenatal exposure to VPA plus other anticonvulsant drugs. To better define the spectrum of clinical manifestation of the prenatal exposure to VPA we used, besides our clinical observations and those from the literature, all available epidemiological data.

We consider that a “valproate embryofetopathy (VPEF)” could exist, because different anomalies have been observed in children prenatally exposed to VPA in monotherapy. A facial phenotype of VPA exposure has been reported, and epidemiologic studies have shown an increased risk for congenital defects. However, from a review of published cases as well as those in the present study, it appears that the spectrum of VAE in monotherapy may not include oral clefts.
Mental retardation, short stature, almond‐shaped eyes, small downturned mouth and coned epiphyses: A new case of Hunter‐fraser syndrome
Authors: Van Maldergem L. , Gillerot Y. , Perlmutter N. , Wetzburger C. , Koulischer L.
Published: June 2005

A 21‐year‐old male with mental retardation, short stature, almond‐shaped eyes, small downturned mouth, and coned epiphyses is presented. The clinical presentation, as well as the metacarpal phalangeal pattern profile, was similar to the affected members of a family reported by Hunter et al.: (Hunter et al.: J Med Genet 14:430–437, 1977). In addition, many features of our patient resembled Ruvalcaba syndrome. However, skeletal abnormalities were different. A reciprocal translocation was also observed in 3 members of our patient's family.
Agnathia, holoprosencephaly, and situs inversus: A third report
Authors: Meinecke Peter , Padberg Barbara , Laas Rudolf
Published: June 2005

We report on a male infant with cyclopia, agnathia, and situs inversus. In addition, anal atresia and horseshoe‐kidneys were present. To our knowledge, this is the third published case of the “agnathia‐holoprosencephaly‐further midline defects association”.
Cleft lip and palate in Aicardi syndrome
Authors: McPherson Elizabeth , Jones Susan M.
Published: June 2005

Cleft lip and palate were described previously in two patients with Aicardi syndrome; this report presents a third similarly affected child. Thus, facial clefts may be an occasional manifestation of Aicardi syndrome.
LEOPARD syndrome: Death because of chronic respiratory insufficiency
Authors: Peter John R. , Kemp James S.
Published: June 2005

Most patients with LEOPARD syndrome (L—lentigines, E—electrocardiographic conduction defects, O—ocular hypertelorism, P—pulmonary stenosis, A—abnormalities of genitalia, R—retardation of growth, D–deafness) seem to lead a relatively normal life, cardiomyopathy being the cause of death in a few. We describe a 19‐year‐old woman with an extreme form of the syndrome requiring correction of her thoracic deformities and cardiac defects, succumbing ultimately to respiratory insufficiency. The respiratory insufficiency was secondary to her deformed thorax, with the congenital heart defect contributing to the development of pulmonary hypertension. The ventilatory status of LEOPARD syndrome patients may require careful assessment.
Iron storage disease in parents and sibs of infants with neonatal hemochromatosis: 30‐ year follow‐up
Authors: Dalhøj Jørgen , Kiaer Henrik , Wiggers Preben , Grady Robert W. , Jones Robert L. , Knisely A. S.
Published: June 2005

Neonatal hemochromatosis (NH), an uncommon and generally fatal disorder of infancy, is defined by hepatic disease of antenatal onset, generally manifest at birth, and by stainable iron in a tissue distribution like that seen in heritable adult‐onset hemochromatosis (HH). It is not known if parents and sibs of infants with NH are at risk of iron storage disease in later life. We provide 30‐year follow‐up for iron overload of a family in which 6 of 9 children died in utero or early in the neonatal period. Four of the 6 came to autopsy, where severe liver disease was found; in 3 of the 4, autopsy material could be reviewed. These 3 children had NH. Studies 30 years later did not identify HH or other iron storage disease in the parents or surviving sibs. These findings suggest that first‐degree relatives of persons with NH are not necessarily at increased risk of iron storage disease in later life.
Pre‐ and postnatal diagnosis of trisomy 4 mosaicism
Authors: Marion Janet P. , Fernhoff Paul M. , Korotkin Jeffrey , Priest Jean H.
Published: June 2005

A liveborn girl with 46,XX/47,XX + 4 mosaicism is reported for the first time. The diagnosis of true mosaicism was established initially in the assay of cultured amniotic fluid cells, although fetal blood obtained by percutaneous umbilical blood sampling showed a 46,XX chromosome constitution. The liveborn infant had manifestations previously reported in dup(4p) and dup(4q) syndromes. Cells in cord and arterial blood samples also were 46,XX, but cultures of placenta and bilateral forearm skin biopsies showed 46,XX/47,XX, +4 mosaicism. This case illustrates the disadvantage of chromosome analysis from blood alone when tissue‐specific mosaicism is present.
Malformations and minor anomalies in children whose mothers had prenatal diagnosis: Comparison between CVS and amniocentesis
Authors: Kaplan Paige , Normandin Jean , Wilson Golder N. , Plauchu Henri , Lippman Abby , Vekemans Michel
Published: June 2005

The frequency of abortion following chorionic villus sampling (CVS) is similar to that following amniocentesis. However, there is no information on long‐term effects, such as malformations in liveborn children exposed to CVS. We evaluated 189 infants whose mothers had either CVS or amniocentesis as participants in the Canadian Collaborative Randomized Trial, a prospective assessment of the safety of CVS compared with amniocentesis. The participation rate of children who could be contacted was 95%. Ninety‐five of the 189 infants (50.2%) had been exposed to CVS, 87 (46%) to amniocentesis, and 7 (3.8%) to both. (The latter group was excluded from calculations.) One hundred twenty‐eight (128) children had ⩾ one minor anomalies but no major abnormalities: 58 of 95 (60%) in the CVS and 70 of 87 (80%) in the amniocentesis group. Twenty‐six children had malformations: 17 (17.8%) in the CVS and 9 (10.3%) in the amniocentesis group. Only one anomaly, Sturge‐Weber dysplasia (amniocentesis group), was potentially severe and none were life‐threatening. Superficial cavernous hemangiomas (strawberry nevi) were noted more frequently in children in the CVS group (12.6%) than in the amniocentesis group (3.4%), but only slightly higher than in the general public.

We conclude that exposure to CVS is not associated with an increased frequency of malformations or minor anomalies in infants compared with amniocentesis although we observed a higher frequency of superficial cavernous (strawberry) hemangiomas in the children in the CVS group.
Nonrandom chromosome changes in multiple sclerosis
Authors: D'Alessandro Elvira , Cola Mario Di , Lo Re Maria Luisa , Ligas Claudio , Vaccarella Corinna , D'Andrea Francesco , Marini Carmine , Prencipe Massimiliano
Published: June 2005

In order to study the role of genetic factors in multiple sclerosis, cytogenetic analysis was performed on 48 patients with the clinically defined disease.

We found a high incidence of subjects (50%) with abnormal chromosomes, showing premature centromere division of the X chromosome and structural aberrations, translocations, or deletions that could suggest preferential breakpoints.

Correlation between clinical and cytogenetic data showed that cytogenetic abnormalities were more common in patients with high frequency of relapse or with a progressive form of the disease.