bluuebunny/crossref_metadata_2025 huggingface dataset:
Cataract, hypertrichosis, and mental retardation (CAHMR): A new autosomal recessive syndrome
Authors: Temtamy Samia A. , Sinbawy Abdel Hamid H.
Published: June 2005

We have studied 2 Egyptian sibs (the offspring of normal first cousins) with congenital cataract, hypertrichosis, mental retardation, and normal chromosomes. Review showed that the condition of our patients was not similar to any previously reported entity. POSSUM lists 84 syndromes with any of the above 3 main traits. Two disorders with cataract and mental retardation, Martsolf syndrome and Mollica–Pavone–Anterer syndrome, have overlapping manifestations and therefore are particularly differentiated from our cases. We suggest that the association of congenital cataract, hypertrichosis, and mental retardation observed in this report represents a new autosomal recessive syndrome.
Problems in diagnosis and delineation of inherited disorders in highly inbred populations
Authors: Zlotogora Joel
Published: June 2005

Two families were chosen as examples of the problems that may arise in the identification of inherited disorders in populations in which the rate of consanguineous marriages is high. In the first family, mentally retarded children of both sexes were born to 4 sisters married to close relative, and the possibility of an autosomal recessive disease was raised. The diagnosis of an X‐linked disease, Martin Bell Syndrome, was made after the results of the chromosome analysis were at hand. In inbred communities, individuals affected with X‐linked diseases are often born to parents who are related.

In the second family two different autosomal recessive disorders were diagnosed among the children of a couple originating from a very inbred community. One of the children was affected with both disorders. The finding of two sibs with different symptoms may suggest that they have the same syndrome, and the differences in manifestations represent variability. The possibility that there may be more than one common abnormal gene in very inbred communities must be kept in mind, in particular when one is dealing with syndromes in which the diagnosis is based on clinical symptoms only. Another problem is that when the child has a complex unknown syndrome, the possibility that the child is affected simultaneously with 2 different genetic disorders should be raised.
Double vagina, cardiac, pulmonary, and other genital malformations with 46, XY karyotype
Authors: Meacham Lillian R. , Winn Kevin J. , Culler Floyd L. , Parks John S.
Published: June 2005

We have studied two unrelated genetic males with a novel constellation of genital, cardiac, and pulmonary malformations. The genital abnormalities consisted of a true double vagina, retention of Müllerian structures, and undervirilization of the external genitalia. Both infants had complex cyanotic congenital heart defects, hypoplastic right lungs, anomalous pulmonary venous return, and abnormalities of the diaphragm. One patient had rhabdomyomatous dysplasia of the lungs. The cause of this malformation pattern is unknown. There was no family history of similar defects, no consanguinity, no known exposure to teratogens, and no chromsome abnormality.

The retention of Müllerian structures and undervirilization of male genitalia in these cases could be the result of failure in production of adequate amounts of testosterone and Müllerian inhibitory factor at appropriate times in gestation. Because the developing human vagina is at no stage a duplicate structure, a double vagina cannot be the result of arrested genital differentiation. The unusual occurrence of a true double vagina should lead to careful pulmonary and cardiac evaluation.
Congenital cataracts in mother, sister, and son of a patient with Hallermann‐Streiff syndrome: Coincidence or clue?
Authors: Jo Harrod Mary , Friedman Jan M.
Published: June 2005

The son of a patient with Hallermann‐Streiff Syndrome (HSS) was found to have congenital cataracts, but no other findings of the syndrome. Similar findings were reported in the patient's mother and sister. The significance of this observation is uncertain.
Stable ring chromosome 21: Molecular and clinical definition of the lesion
Authors: Falik‐Borenstein T. C. , Pribyl T. M. , Pulst S. M. , Van Dyke D. L. , Weiss L. , Chu M. L. , Kraus J. , Marshak D. , Korenberg J. R.
Published: June 2005

Ring chromosome 21 results in deletions of chromosome 21. We report on a cytogenetic and molecular analysis of a 4‐generation family segregating a stable ring chromosome 21 in 4 relatives. To investigate the molecular structure of the ring chromosome, we have analyzed the DNAs of the transmitted ring in a mother and her daughter. The daughter presented at the age of 2 years with severe growth retardation and microcephaly, whereas her mother had microcephaly but normal intelligence. High resolution chromosome analysis of both cases showed the ring chromosome to be r(21)(p13q22) resulting in deletions of 21p and 21q22. The molecular content of the ring chromosome was determined using quantitative Southern blot analyses of 5 random DNA sequences and 4 expressed genes assigned to chromosome 21 and mapping in the region of q22.3. We have shown that collagen type VI, alpha 2 (COL6A2,) S100 protein, beta polypeptide (neural), (S100B), and D21S44 are present in only one copy in both ring carriers, while CRYA1, CBS, D21S43, D21S42, D21S41, and D21S39 are present in two copies. These data and the breakpoints defining the deletion in these patients show that deletion of COL6A2 and S100B is compatible with normal function and confirm the physical map of 21q22.3 by placing COL6A2, S100B, and D21S44 in very distal 21q22.3. Patients with such small deletions provide unique models for understanding the biological and clinical significance of aneuploidy for specific expressed genes.
De Barsy syndrome: Report of a case, literature review, and elastin gene expression studies of the skin
Authors: Karnes P. S. , Shamban A. T. , Olsen D. R. , Fazio M. J. , Falk R. E.
Published: June 2005

Several “progeroid” syndromes have now been identified. The De Barsy syndrome is an autosomal recessive syndrome of dwarfism, mental deficiency, an “aged” appearance at birth, abnormal elastic fibers on skin biopsy, and lax skin, large helices, eye abnormalities, lax joints, hypotonia, and athetoid posturing. We report one case and review 11 cases from the literature. To understand the abnormal appearance of the elastic fibers on biopsy, we performed elastin gene expression studies on fibroblasts cultured from our patient's skin. Molecular hybridization studies revealed reduced elastin mRNA steady‐state levels as compared with age matched control individuals. Assuming normal rates of mRNA translation, reduced elastin synthesis would occur. Diminished dermal elastin content could explain the altered cutaneous elasticity, decreased elastic fibers in the skin, and many clinical manifestations of individuals with this condition.
45,X/46,X, + r(X) can have a distinct phenotype different from Ullrich‐Turner syndrome
Authors: Grompe M. , Rao N. , Elder F. F. B. , Caskey C. T. , Greenberg F.
Published: June 2005

We present a patient with 45,X/46,X, + r(X) mosaicism and lack of inactivation of either the normal or the ring X in the 46,X, + r(X) cells. The patient has mental retardation, syndactyly, minor facial anomalies, and a congenital heart defect. Although most patients with 45,X/46,X, + r(X) have the Ullrich‐Turner syndrome, 2 previously described patients with this karyotype also had a distinct phenotype consisting of severe mental retardation, syndactyly, and abnormal face. The unusually severe phenotype in these patients was thought to be due to lack of X‐inactivation of the ring X chromosome. The findings in our patient support this hypothesis.
Tracheal agenesis with diaphragmatic hernia
Authors: Downing Gregory J.
Published: June 2005

A case is presented of a newborn infant with Type III tracheal agenesis and a right dia‐phragmatic hernia which represents the first report of this occurrence. Associated multi‐organ anomalies and possible embryologic relationships are discussed.
Kenny–Caffey syndrome in two sibs born to consanguineous parents: Evidence for an autosomal recessive variant
Authors: Franceschini P. , Testa A. , Bogetti G. , Girardo E. , Guala A. , Lopez‐Bell G. , Buzio G. , Ferrario E. , Piccato E.
Published: June 2005

We report on 2 sibs with manifestations of the Kenny–Caffey syndrome born to normal, consanguineous parents. Clinical manifestations included dwarfism, internal cortical thickening and medullary stenosis of tubular bones, poorly ossified skull bones, and hypocalcemia. The younger of the two died during a tonic convulsion. The older had neonatal hypoparathyroidism and is now a short intelligent, 1‐year‐old child. This family gives new support to the existence of an autosomal recessive variant of the syndrome.
Use of dystrophin genomic and cDNA probes for solving difficulties in carrier detection and prenatal diagnosis of Duchenne muscular dystrophy
Authors: Shomrat Ruth , Driks Nava , Legum Cyril , Shiloh Yosef
Published: June 2005

Duchenne muscular dystrophy (DMD) results from mutations in the X‐linked gene coding for the muscular protein dystrophin. The isolation of genomic and cDNA probes for this gene has greatly facilitated the detection of DMD carriers, which previously relied mainly on measurements of serum creatine kinase (CK), and has enabled prenatal diagnosis of this disease. However, the relatively large size of the gene and the high frequency of recombination and mutation events within the dystrophin locus continue to pose difficulties in the genetic counselling and prenatal diagnosis of DMD, and render the conclusions of molecular analysis less clear cut. This communication presents examples of two such difficulties: the distinction between sporadic and inherited cases in families with a single patient and normal CK levels in all females, and the distinction between mutant and normal dystrophin alleles in families in which the patients have died. The combined use of genomic and cDNA probes allows one to make these distinctions. An additional complicating factor, gonadal mosaicism, is demonstrated.
Pericardial agenesis and focal aplasia cutis in tetrasomy 12p (Pallister‐Killian syndrome)
Authors: Zakowski Maureen F. , Wright Yvonne , Ricci Andrew
Published: June 2005

We report a stillborn female infant with multiple internal and external anatomic abnormalities and mosaicism for isochromosome 12p. These abnormalities included webbed neck, low‐set ears, lower jaw tooth bud, left simian crease, shield chest, focal aplasia cutis, diaphragmatic hernia, hypoplastic lungs, agenesis of pericardium, and Meckel's diverticulum. Karyotypic analysis on cord blood lymphocytes showed 10% mosaicism of 46, XX/47, XX, + i(12p), and analysis of skin fibroblasts showed 50% mosaicism for the same karyotype. The parental karyotypes were normal. There are many reported cases describing the anomalies seen in isochromosome 12p. None of these cases, however, have displayed pericardial agenesis or aplasia cutis. The clinical and cytogenetic features of Pallister‐Killian syndrome are reviewed.
Distal limb deficiency following chorionic villus sampling?
Authors: Schloo Rüdiger , Miny Peter , Holzgreve Wolfgang , Horst Jürgen , Lenz Widukind
Published: June 2005

We have reviewed the follow‐up of almost 3000 completed preganancies in the Münster CVS Program and identified 4 children with distal limb deficiencies. Two cases involved only minor anomalies of distal digital phalanges. One child had a Hanhart anomaly (hypoglossia hypodactylia).

We also reviewed 24 cases of limb defects following CVS reported previously. With the exception of a single series, neither the overall incidence of affected children nor cases reported from larger series provide unambiguous evidence of an increased risk of distal limb deficiency caused by CVS.
Growth hormone therapy in achondroplasia
Authors: Horton William A. , Hecht Jacqueline T. , Hood O. Jean , Marshall Robert N. , Moore Wayne V. , Hollowell Joseph G.
Published: June 2005

A pilot study was carried out to examine the safety and efficacy of recombinant human growth hormone for growth‐promoting therapy of achondroplasia. The data suggest that the agent in doses used to treat non‐GH‐deficient forms of short stature (0.3 mg/kg/wk) modestly increases overall height velocity in some children with achondroplasia. The effect was seen mainly in children with the lowest growth velocities prior to treatment. No untoward effects were noted. Several questions were raised that require further study.
Ocular albinism in a male with del (6)(q13–q15): Candidate region for autosomal recessive ocular albinism?
Authors: Rose Nancy C. , Menacker Sheryl J. , Schnur Rhonda E. , Jackson Laird , McDonald‐McGinn Donna M. , Stump Tammy , Emanuel Beverly S. , Zackai Elaine H.
Published: June 2005

We describe a boy with an interstitial deletion of 6(q13–q15) and include “coarse” facial features, upslanting palpebral fissures, thin vermilion border of the upper lip, elongated philtrum, developmental delay, and profound hypotonia. The child's eye findings, pedigree, paucity of maternal ocular changes, and lack of melanin macroglobules in the skin suggest that this individual's phenotype is clinically similar to that of autosomal recessive ocular albinism. Though it is possible that this deletion and his ophthalmic disorder are coincidental, we postulate that the ocular albinism may be due to hemizygosity for a paternally derived ocular albinism gene located on chromosome 6 in the region q13–q15.

This patient's deletion is secondary to a recombination of a maternal intrachromosomal inverted insertion of this region. Of the 7 reported 6q1 deletions, this is the only case that is due to a familial chromosome rearrangement.
Identification of the origin of ring/marker chromosomes in patients with ullrich‐turner syndrome using X and Y specific alpha satellite DNA probes
Authors: Tharapel Sugandhi A. , Wilroy R. Sid , Keath Amber M. , Rivas Marian L. , Tharapel Avirachan T.
Published: June 2005

Fluorescent in situ hybridization (FISH) using X and Y chromosome‐specific α satellite DNA probes hybridizing to loci DXZ1 and DYZ3 was performed to identify the origin of ring/marker chromosomes in 6 patients with Ullrich‐Turner syndrome (UTS). All patients had a mosaic karyotype, 5 with 45, X/46,X,r(?) and one with 45,X/46,X,mar. We demonstrated that the marker/ring chromosome in each of these 6 patients originated from the X. A timely knowledge of the X or Y origin of ring and marker chromosomes can be crucial in genetic counseling and medical management since the presence of Y chromosome material in phenotypic females is known to increase the risk for developing gonadoblastoma.
New case of Bartsocas‐Papas syndrome surviving at 20 months
Authors: Giannotti A. , Digilio M. C. , Standoli L. , Zama M. , Dallapiccola B.
Published: June 2005

We report on patient with Bartsocas‐Papas syndrome surviving at age 20 months. Similar to 7 previously reported families, this patient is of Mediterranean ancestry, pointing to clustering of the responsible mutant gene in Southern Europe. In 3 of the 11 Bartsocas‐Papas syndrome patients described so far, including the present case, the condition has not been neonatally lethal. This suggests that about one‐fourth of these patients could survive. This information is important for genetic counseling.
Heterogeneity in ataxia‐telangiectasia: Classical phenotype associated with intermediate cellular radiosensitivity
Authors: Chessa L. , Petrinelli P. , Antonelli A. , Fiorlli M. , Elli R. , Marcucci L. , Federico A. , Gandini E.
Published: June 2005

We identified a subgroup of ataxia‐telangiectasia (AT) patients (2 sibs and 1 unrelated case) characterized by typical clinical manifestations of the disease and cellular radiosensitivity intermediate between classical AT and normal subjects. Our data and a literature review of the intermediate radiosensitivity AT cases show that radioresistant DNA synthesis, cellular radiosensitivity (measured in terms of survival and chromosome break‐age), and the clinical hallmarks behave independently. This raises a number of interesting questions about the correlation between radiobiological and clinical features, and about the nature of the AT gene(s).
Chromosome analysis in spontaneous pregnancy loss: Use of placental villus mesodermal core cell cultures
Authors: Songster Giuliana S. , Sun Li , Chang Shih‐Chung , Cheung Sau W.
Published: June 2005

Culture of placental villus mesodermal core cells, a method developed for chorionic villus sampling, was used for cytogenetic analysis in 168 spontaneous pregnancy losses. Successful karyotype results were obtained in 72% of cases and 87.5% of cases in which placental tissue was available. Culture of placental villus mesodermal core cells is useful in the evaluation of spontaneous pregnancy loss, particularly when tissues of direct fetal origin are unavailable or unsuitable for culture. Details of culture and specimen handling techniques are provided.
Possible new type of oral‐facial‐digital syndrome with retinal abnormalities: OFDS type (VIII)
Authors: Gurrieri F. , Sammito V. , Ricci B. , Iossa M. , Bellussi A. , Neri G.
Published: June 2005

The most recent classification of the oral‐facial‐digital syndromes (OFDS) includes 7 types distinguishable by different clinical signs. We describe 2 brothers presenting oral, facial, and digital anomalies and an additional manifestation consisting of specific retinal abnormalities, i.e., retinochoroideal lacunae of colobomatous origin. Our patients may be affected with a new type of OFDS, i.e., OFDS type VIII, characterized by eye abnormalities in addition to other manifestations that partially overlap with those of OFDS type II. Given that there are 2 affected brothers, we cannot distinguish between autosomal and X‐linked recessive inheritance.
Partial gonadal dysgenesis in a patient with a marker Y chromosome
Authors: Fechner Patricia Y. , Smith Kirby D. , Jabs Ethylin Wang , Migeon Claude J. , Berkovitz Gary D.
Published: June 2005

We evaluated a patient with partial gonadal dysgenesis including a right dysgenetic testis and a left streak gonad with rudimentary fallopian tube and uterus. She had ambiguous external genitalia and was raised female. Although her height is normal (25th centile at age 12 years), she has some findings of Ullrich–Turner syndrome. Her karyotype was reported to be 46, X, + marker; subsequent molecular investigations showed the marker to be the short arm of the Y chromosome. Genomic DNA, isolated from leukocytes of the patient and her father, was digested with a variety of restriction endonucleases and subjected to Southern blot analysis. A positive hybridization signal was obtained with probes for the short arm of the Y chromosome (pRsY0.55, SRY, ZFY, 47Z, pY‐190, and YC‐2) in DNA from the patient, indicating the presence of most if not all of the short arm, while long arm probes (HinfA and pY3.4) indicated that at least 75% of the long arm of the Y chromosome was missing. The gene responsible for testicular determination (TDF) is on the distal portion of the short arm of the Y chromosome; Yq has no known influence on sex determination. Hence, the deletion of the long arm of the Y chromosome cannot explain the gonadal dysgenesis in this patient. One explanation for the gonadal dysgenesis and Ullrich–Turner phenotype in the patient could be undetected 45, X/46,X, + marY mosaicism but no such mosaicism was observed in peripheral lymphocytes. Several investigators have suggested the presence of an “anti‐Turner” gene near TDF. Hence it is possible that the clinical phenotype in our patient results from a Y chromosomal defect in sequences flanking TDF, which reduces the function of both TDF and the “anti‐Turner” genes.
Failure of PHA‐stimulated i(12p) lymphocytes to divide in Pallister–Killian syndrome
Authors: Reeser Suzanne L. Thornburg , Wenger Sharon L.
Published: June 2005

The diagnosis of Pallister–Killian syndrome (PKS) is confirmed by tissue‐specific mosaicism of i(12p). The isochromosome is found in skin fibroblasts and bone marrow, but rarely in peripheral lymphocytes. The nature of the isochromosome loss was evaluated using 2 techniques: micronucleus formation for anaphase lag and in situ DNA hybridization for mosaicism in interphase cells. Cells from serial cultured fibroblasts, peripheral blood lymphocytes, and bone marrow from 4 PKS patients were used for the above analysis. Micronucleus formation was similar for PKS and normal diploid cultures, ruling out loss of i(12p) by anaphase lag as the major mechanism of in vitro mosaicism. In situ hybridization using an alpha satellite DNA probe for chromosome 12 was used to examine the presence of the i(12p) in interphase fibroblasts from 1 patient and lymphocytes from 2 patients (age 8 weeks and 1 day). The i(12p) was present in a significantly higher proportion of interphase nuclei in peripheral lymphocytes than in metaphase, suggesting the initial loss of the isochromosome is exaggerated in metaphase by selective division in vitro. In situ hybridization of peripheral lymphocyte interphase cells with chromosome 12 specific probes may be a useful supplemental procedure for the diagnosis of PKS, at least in the newborn infant.
Threshold model in the genetics of age‐dependent disease in twins: I. General principles as applied to Alzheimer disease
Authors: Murphy Edmond A. , Breitner John C. S.
Published: June 2005

In the context of the etiology and pathogenesis of Alzheimer disease (AD), we discuss assumptions under which categorical data on the phenotypes of twin pairs may be used to estimate standardized characteristics (correlation and the critical threshold) for an age‐dependent multinomial process. Important topics include Erlangian, gamma, and Poisson processes, tetrachoric and trichoric functions, and degrees of freedom and how they relate to estimation from both an abstract and a practical standpoint. Under plausible assumptions about the age‐dependence of a heritable trait, it is possible to generate sufficient degrees of freedom to test the genetic model and to explore age‐dependence and the impact of environmental factors that may influence it systematically. Though general in scope, the model is focused on data from twin pairs. The statistical strategy is briefly outlined, but its properties are not examined in detail.
Prenatally detected fragile X females: Long‐term follow‐up studies show high risk of mental impairment
Authors: Brown W. Ted , Jenkins Edmund C. , Goonewardena Ponmani , Miezejeski Charles , Atkin Joan , Devys Didier
Published: June 2005

The prenatal detection of a positive fragile X [fra(X)] female raises difficult counseling issues. In order to address questions regarding the long term outlook, we have conducted follow‐up studies on 4 fra(X) positive females which were carried to term. Three were prenatally detected, and one was a false negative. The subjects were between 3 and 7 years old when follow‐up investigation of mental status was conducted. The first case age, 6 and 9/12 years, had an IQ of 106. On measures of achievement she had some difficulty with arithmetic. The second and third cases were clearly affected. They were judged to be mildly to moderately mentally retarded. The fourth case was borderline normal.

The prenatal amniocentesis cytogenetic frequencies had a mean of 3.74% (range 0 ‐ 8.5%). On postnatal follow‐up testing of blood, the mean cytogenetic frequency increased to 31.75% (range 24 ‐ 47%), an 8.5 fold increase.

Follow‐up DNA samples from 3 of the 4 subjects were analyzed for underlying DNA mutations using probe StB12.3 which detects insertions and methylation status of the FMR‐1 gene. All 3 showed an affected female genotype with a large insert (>500bp) and complete CpG island methylation.

We conclude: (1) prenatally detected cytogenetic frequencies of females increase by an average 8.5 fold on follow‐up postnatal studies, (2) genetic counseling should indicate the risks to be affected are approximately 75% when a positive female is prenatally detected, (3) DNA testing can help determine carrier status but may not accurately predict whether a female will be mentally affected.
Premutation for the martin‐bell syndrome analyzed in a large sardinian family: II. Neuropsychological and behavioral data
Authors: Cianchetti Carlo , Filippi Giorgio , Sannio‐Fancello Giuseppina , Fratta Anna‐Lisa , Marrosu Maria‐Giovanna , Dagna‐Bricarell Franca , Siniscalco Marcello
Published: June 2005

We describe the neuropsychological and behavioral profiles of 48 critical members of a previously reported Sardinian pedigree [Filippi et al., 1991], in which the fully manifested Martin‐Bell syndrome (MBS), observed among males of the latest generations, is clearly the result of step‐wise mutational events occurred repeatedly along the X‐chromosome pathway linking all of them to a common ancestress, who must have been heterozygous for a fragile X (FRAX) premutation. We found that the unquestionable presence in the family of normal transmitting males and females could not be determined on the basis of neuropsychological and behavioral data alone. However, we think that the large variation observed in the expression of most diagnostic parameters among the MBS patients and their close female relatives in this family, could by itself be a connotation of the genome instability which characterizes the FRAX region in pedigrees segregating for the FRAX premutation(s) and mutation(s).
Prenatal detection of Fra(X)(q27.3) in female identical twins: Reliability of low level cytogenetic prenatal expression in females
Authors: Jenkins Edmund C. , Brown W. Ted , Schonberg Steven , Krawczun Michael S. , Goldberg James , Golbus Mitchell S.
Published: June 2005

Recently, we detected fra(X)(q27.3) in aminocyte cultures from female identical twins. The pregnant woman did not exhibit fra(X)(q27.3) in whole blood cultures but was the sister of 2 affected brothers. DNA marker analyses showed that she was a carrier of FRAXA. Amniotic fluid cultures (AFCs) from twins A and B exhibited the fragile X [fra(X)] chromosome, but the level of cytogenetic expression was very low in twin A's AFCs. DNA marker studies indicated both twins were carriers of FRAXA. Peripheral umbilical blood sample (PUBS) cultures exhibited fra(X)(q27.3) at a frequency of about 10% for both twins. DNA fingerprinting indicated that the twins were identical, confirming the clinical impression, with a very thin separating amniotic membrane. To our knowledge, this is the only report of prenatal fra(X)(q27.3) detection in female identical twins, and the second report of identical twin detection [Rocchi et al., 1985].

We have diagnosed prenatally fra(X)(q27.3) in 5 female fetuses using AFCs. The average fra(X) frequency was 4% for these positive female fetuses with a range of 0.5% to 8.5%. Follow‐up whole blood studies confirmed our original results at an average fra(X) frequency of 25%. In conclusion: 1. Low frequencies, perhaps 1 or 2%, or a few positive cells in AFCs, are likely to increase in magnitude when confirmed in whole blood cultures either pre‐ or postnatally. 2. It appears likely that the risk is low for false positive results in AFCs when low frequencies of fra(X)(q27.3) are encountered.
Intragenic probe used for diagnostics in fragile X families
Authors: Verkerk Annemieke J. M. H. , De Vries Bert B. A. , Niermeijer Martinus F. , Fu Ying‐Hui , Nelson David L. , Warren Stephen T. , Majoor‐Krakauer Danielle F. , Halley Dicky J. J. , Oostra Ben A.
Published: June 2005

The intragenic (FMR‐1) probe pE5.1 was used for DNA analysis in fragile X families. With this probe fragments of altered size can be detected in female carriers, affected individuals and transmitting males. the length of the altered fragments was found to vary from one generation to another as well as between sibs. This instability of the DNA detected by pE5.1 was also seen in peripheral blood within single individuals. These phenomena are illustrated by 4 exemplary families segregating the fragile X syndrome. We demonstrate the diagnostic contribution of intragenic analysis to carrier detection as well as the identification of normal transmitting males carrying premutations. One of the families illustrates the passage of a premutation to a male through 2 generations.
XLMR genes: Update 1992
Authors: Neri Giovanni , Chiurazzi Pietro , Arena Fernando , Lubs Herbert A. , Glass Ian A.
Published: June 2005

Up to now, we have identified 77 X‐linked conditions in which mental retardation is the primary or a major component manifestation. These conditions were subdivided into 2 categories, designated respectively “X‐linked mental retardation syndromes” and “Non‐specific X‐linked mental retardation”. Forty genes have been regionally mapped onto the X chromosome. However, in several instances the data were derived from a single family and most lod scores were less than 3.0.
Localization of non‐specific X‐linked mental retardation genes
Authors: Kerr Bronwyn , Gedeon Agi , Mulley John , Turner Gillian
Published: June 2005

Gene localization was determined by linkage analysis in 5 families with non‐specific X‐linked mental retardation (MRX) and were MRX1, Xp11.4‐q21.31; MRX10, Xp21.3‐p11.4; MRX11, Xp21.3‐p11.22; MRX12, Xp21.3‐q21.1; and MRX13, Xp22.3‐q21.22. Four of these localizations cross the dystrophin brain promoter, a candidate locus for MRX. None of the affected individuals who were tested showed variation suggestive of a deletion. No consistent clinical features were observed between or within 4 of the 5 families. In MRX12, prematurity or low birth weight, hypotelorism and short stature were seen in several affected males. Heterozygote manifestations occurred in 3 families. There was no evidence to suggest involvement of the same gene in more than one family, nor to clinically separate these families into distinct genetic entities. Non‐overlapping localizations for MRX1 and MRX10 demonstrate the existence of at least 2 separate loci among these 5 families.
Use of linkage data obtained in single families: Prenatal diagnosis of a new X‐linked mental retardation syndrome
Authors: Mulley John C. , Gedeon Agi K. , Wilson Sue , Haan Eric A.
Published: June 2005

Prenatal diagnosis was requested by an obligate carrier of a new syndrome of X‐linked mental retardation. There was close linkage between the disease gene and the hypervariable VNTR marker DXS255 with a lod score of 4.82 at O=0 (90% support interval 0.00–0.12). When the request for prenatal diagnosis was made, additional family members were examined, resulting in an amended lod score of 6.71 at O=0.0 (90% support interval 0.00–0.09). There were no informative flanking markers at the time of the request for prenatal diagnosis; hence it proceeded by 2 point linkage analysis. The fetus was female with a carrier risk in the interval of 91–100%.

Given the limitations of the mapping data available for this disorder at the time of the request, the options of accepting or rejecting this as a case for prenatal diagnosis were carefully considered. Whilst prenatal diagnosis based on fetal sexing would be sufficient to prevent the birth of an affected child, the magnitude of the known two‐point lod score between DXS255 and the disease gene provided a means for diagnosis with an accuracy between 91 and 100%.
Aarskog syndrome: The changing phenotype with age
Authors: Fryns J. P.
Published: June 2005

We describe the Leuven experience with 52 males with Aarskog syndrome particularly with respect to clinical variability, changing phenotype with age, and previously unreported signs.

At least 30% of affected males were mentally retarded, two thirds of them at the level of slight mental handicap. Hyperactive behavior and symptoms of attention deficit disorders were frequently observed (61% of the mentally normal and 84% of the mentally subnormal), but regressed completely after the age of 12 to 14 years. The social integration and functioning as adults is satisfactory. Postpubertal males with Aarskog syndrome have only minor remnant manifestations of the prepubertal phenotype, making clinical diagnosis in adults extremely difficult.
Congenital X‐linked ataxia, progressive myoclonic encephalopathy, macular degeneration and recurrent infections
Authors: Bertini Enrico , Cusmai Raffaella , de Saint Basile Genevieve , Le Deist Françoise , Di Capua Matteo , Gaggero Di Roberto , Dionisi‐Vici Carlo , Santillo Clemente , Caniglia Maurizio
Published: June 2005

We report on 2 boys (maternal cousins), with severe congenital ataxia with generalized hypotonia, psychomotor retardation and recurrent bronchopulmunary infections. Later, they developed myoclonic encephalopathy and macular degeneration. Serial brain imaging investigations showed a cyst of the septum pellucidum, persistence of the cavum vergae, corpus callosum and cerebellar vermis hypoplasia without cortical atrophy. In the maternal pedigree, 5 males had recurrent bronchopneumonia associated with severe congenital hypotonia and died during the first years of life. Neurophysiological studies, including nerve conduction velocities, brainstem auditory evoked responses, somatosensory evoked potentials were normal. Electroretinogram showed normal wave morphology. Visual evoked potentials were mildly impaired. Extensive screening for metabolic disease gave normal results. Immunologic investigations showed normal T and B cell number, T cell function and immunoglobulin levels in both patients with a reduced level of IgG2 subclass in one.
X‐linked mental retardation and characteristic physical features in two brothers with duplication Xp22‐Xpter
Authors: Cianchetti Carlo , Muntoni Francesco , Falchi Angela‐Maria , Nucaro Annalisa , Sannio‐Fancello Giuseppina , Cao Antonio , Marrosu Maria‐Giovanna
Published: June 2005

Two brothers are reported who share mental retardation, conjuntival teleangectasias (mainly equatorial) and characteristic flat face with small mouth and thin prolabia. At the neuropsychological examination, the older brother at 14 years showed a full scale IQ of 40 (WISC), with verbal IQ 45 and performance IQ 44. The younger brother at 7 years showed a full scale IQ of 58 (WPPSI), with verbal IQ 67 and performance IQ 55. Chromosome studies showed a duplication Xp22‐Xpter in both brothers and in the inactivated X of their mother. The anomaly was not present in a 3rd healthy brother and in other healthy relatives. The mother has normal intelligence and did not present any of the physical features of her affected sons.
Molecular and cytogenetic investigation of complex tissue‐specific duplication and loss of chromosome 21 in a child with a monosomy 21 phenotype
Authors: Krasikov Natalie , Takaesu Norma , Hassold Terry , Knops Judith F. , Finley Wayne H. , Scarbrough Paula
Published: June 2005

Several recent molecular studies have suggested that the clinical phenotype of Down syndrome may be due to triplication of 21q22 [McCormick et al., 1989] as initially suggested by Niebuhr [1974], and perhaps just 21q22.2 [Korenberg et al., 1989, 1990; Rahmani et al., 1989]. Recently, we studied a patient with a phenotype inconsistent with Down syndrome, whose lymphocyte karyotype on several occasions detected only 46,XX,−21,+dic(21)(qter→p11::p11→qter). Combined karyotype and molecular studies on both lymphocytes and fibroblasts allowed correct identification of the abnormality as a complex monosomy/trisomy 21 mosaicism involving a marker derived from idic (21) (p11), and probable assignment of a maternal origin for the error(s). The patient's phenotype was found to be most consistent with monosomy 21. Detailed study of our patient underscores (1) the need for confirmation that there is phenotype/karyotype correlation and (2) the usefulness of molecular analyses to complement the cytogenetic interpretation of marker chromosomes. © 1992 Wiley‐Liss, Inc.
Vascular abnormalities at the site of limb deficiency
Authors: Hall Bryan D.
Published: June 2005

A case is presented of a child born with a left forearm deficiency and a cavernous hemangioma covering the tip of the forearm and left elbow. Points relative to the potential associations of vascular abnormalities and limb deficiencies are discussed. © 1992 Wiley‐Liss, Inc. © 1992 Wiley‐Liss, Inc.
Nail‐Patella syndrome in a spontaneously aborted 18‐week fetus: Ultrastructural and immunofluorescent study of the kidneys
Authors: Drut Rosa Monica , Chandra Sunita , Latorraca Rocco , Gilbert‐Barness Enid
Published: June 2005

Nail‐patella syndrome (NPS), hereditary onycho‐osteodysplasia, is an autosomal dominant disorder of nail dystrophy, patellar absence or hypoplasia, incomplete elbow extension, conical posterior iliac horns, and nephropathy.

We studied the kidneys of an 18‐week spontaneously aborted fetus of a mother with the NPS. Ultrastructural examination of the kidney showed thickening of the capillary walls of the glomeruli and mesangium. There was irregular thickening of basement membranes with subendothelial fibrillar electron‐dense deposits. Immunofluorescence showed fibrinogen deposition in glomerular basement membranes. Fibrinogen deposition in utero may ultimately lead to glomerular fibrosis and intrabasement membrane collagen deposition as seen in the adult renal lesion of this syndrome.

This is the first report of the NPS in which the renal abnormalities have been studied in a fetus. These findings provide support for possible prenatal diagnosis of NPS by intrauterine kidney biopsy. © 1992 Wiley‐Liss, Inc.
Reciprocal translocation t(1;15)(p36.2;p11.2): Confirmation of a suggestive cytogenetic diagnosis by in situ hybridization and clinical case report on resulting monosomy (1p)
Authors: Barbi Gotthold , Kennerknecht Ingo , Klett Christine
Published: June 2005

A newborn girl with generalized muscular hypotonia and minor anomalies was referred for chromosome analysis. Cytogenetic investigation showed a satellite and an Ag‐positive NOR on the distal short arm of one chromosome 1, thus indicating an unbalanced translocation involving the short arm of an acrocentric chromosome. The phenotypically normal mother had the same satellited chromosome 1 with Ag‐positive NOR. One chromosome 15 was the only acrocentric chromosome in her karyotype lacking recognizable satellites and an Ag‐positive NOR. Thus a balanced reciprocal translocation between the short arms of chromosomes 1 and 15 in the mother was suggested. The cytogenetic diagnosis was confirmed by nonradioactive in situ hybridization with the most distal DNA probe on chromosome 1, the probe p1‐79, localized at chromosome band 1p36.3. The probe was biotinylated by nick‐translation, and detection was done by FITC labelled avidin binding. Hybridization signals were observed on both the mother's normal chromosome 1 and the derivative chromosome 15 but not on her derivative chromosome 1. Consequently, the index patient has an unbalanced karyotype with monosomy (1p36.3). Comparing their clinical reports shows that patients with similar terminal deletions of 1p share several manifestations. © 1992 Wiley‐Liss, Inc.
Familial aplasia cutis congenita and coarctation of the aorta
Authors: Dallapiccola B. , Giannotti A. , Marino B. , Digilio C. , Obregon G.
Published: June 2005

We report on the association of aplasia cutis congenita (ACC) in the midline of the scalp vertex and coarctation of the aorta (CA) in mother and son. The acronym of ACCCA syndrome is proposed for this condition. Autosomal dominant inheritance is most commonly implicated in the familial cases of ACC. The familial aggregation of CA is attributed, in general, to a multi‐factorial causation, with a few reported families suggesting autosomal dominant inheritance. The ACCCA syndrome could be due to a Mendelian mutation. © 1992 Wiley‐Liss, Inc.
TAR‐like syndrome in a consanguineous Mayan girl
Authors: Ceballos‐Quintal Jose M. , Pinto‐Escalante Doris , Gongora‐Biachi Renan A.
Published: June 2005

We report on a 3‐month‐old girl with a TAR‐like syndrome. Her older brother died with a similar disorder at 3 months of unknown causes. The parents are second cousins of Mayan ancestry. The infant also had, in addition to the usual abnormalities of TAR syndrome, depressed nasal bridge, cataracts, glaucoma, megalocorneae, and blue sclerae. © 1992 Wiley‐Liss, Inc.
Genetic evidence that Turcot syndrome is not allelic to familial adenomatous polyposis
Authors: Tops Carli M. J. , Vasen Hans F. A. , Henegouwen Gerard van Berge , Simoons Peter P. , van de Klift Heleen M. , van Leeuwen Inge S. J. , Breukel Cor , Fodde Riccardo , den Hartog Jager Frieda C. A. , Nagengast Fokko M. , Griffioen Gerrit , Khan P. Meera
Published: June 2005

Turcot syndrome (TS) is a rare genetic disease in which brain tumors occur in association with colonic polyposis. Since Turcot's original description in 1959, there have been disagreements about the mode of inheritance as well as the clinical expression of this condition. Some investigators maintain that TS is a phenotypic variant of the autosomal dominant familial adenomatous polyposis (FAP), while others observe that there are clinical differences between TS and FAP, and that the pattern of inheritance of TS is autosomal recessive.

The distribution of persons with colonic lesions in a family with a patient of colonic polyposis and a brain tumor, described in this report, favored the recessive hypothesis. In this family, the involvement of the FAP gene on chromosome 5q21–q22 could be excluded by a linkage study using a panel of FAP‐linked DNA markers.

This finding, which indicates the occurrence of another polyposis gene elsewhere in the genome, will have consequences for the presymptomatic diagnosis of FAP by linked DNA markers. We conclude that TS is a distinct clinical‐genetical entity with the triad of atypical polyposis coli, CNS tumors, and a recessive mode of inheritance. © 1992 Wiley‐Liss, Inc.
Oculoauriculovertebral anomaly: Segregation analysis
Authors: Kaye Celia I. , Martin Alice O. , Rollnick Beverly R. , Rollnick R. , Nagatoshi Konrad , Israel Jeannette , Hermanoff Mark , Tropea Brad , Richtsmeier Joan T. , Morton Newton E.
Published: June 2005

Seventy‐four families of probands with oculoauriculovertebral anomaly were evaluated, including 116 parents and 195 off‐spring. Relatives were examined to identify ear malformations, mandibular anomalies, and other craniofacial abnormalities. For segregation analysis using POINTER, selection of the sample was consistent with single as‐certainment. Different population liabilities were used for probands and relatives, because affection was narrowly defined for probands and broadly defined for relatives. The hypothesis of no genetic transmission was rejected. The evidence favored autosomal dominant inheritance; recessive and polygenic models were not distinguishable. © 1992 Wiley‐Liss, Inc.
Ophthalmological, skeletal, and cardiac abnormalities in sibs born to consanguineous parents: A new syndrome?
Authors: dos Santos Rita de Cassia Stocco , Castro Nelson H. C. , Ferraz Oilita Pereira , Walter‐Moura Janete , Mustachi Zan , Pagnan Nina A. B. , Gollop Thomaz R.
Published: June 2005

We report on a sibship from a consanguineous couple consisting of one boy with anophthalmia, one boy with buphthalmos and multiple congenital skeletal, muscle, and cardiac abnormalities, and a stillborn girl with anophthalmia and cardiac and skeletal abnormalities. A possible new syndrome of autosomal recessive inheritance and variable expressivity is discussed, comparing this report with others. © 1992 Wiley‐Liss, Inc.
Clinical variability and genetic heterogeneity within the Acadian Usher population
Authors: Smith Richard J. H. , Pelias Mary Z. , Daiger Stephen P. , Keats Bronya , Kimberling William , Hejtmancik J. Fielding
Published: June 2005

A number of Usher syndrome (USH) families are found among the French‐Acadians living in southwestern Louisiana. These families are descended from a few common ancestors, suggesting that USH may be homogeneous within this ethnic group. However, we report distinct phenotypic variability. Based on differences in psychomotor development and tests of auditory and vestibular function, Acadian individuals with both USH Type 1 and Type 2 can be identified. One additional family, with unusual findings, represents a third clinical phenotype. Linkage data strongly support these clinical observations. © 1992 Wiley‐Liss, Inc.
Diagnosis of arylsulfatase A deficiency
Authors: Li Z. G. , Waye J. S. , Chang P. L.
Published: June 2005

Metachromatic leukodystrophy (MLD) is a neurologically devastating autosomal recessive disorder in humans associated with deficient arylsulfatase A activity. However, clinically normal individuals described as being pseudo‐arylsulfatase‐A deficient also demonstrate the same deficiency. Genotypically, they may be homozygous for the pseudodeficiency mutation (associated with 2 A→G transitions in the cDNA of arylsulfatase A) or heterozygous with one pseudodeficiency and one MLD allele. Using as examples 2 families in which the pseudo deficiency condition occurs either independently or together with MLD, we demonstrate the utility of a proposed diagnostic protocol to provide complete genotype identification of individuals suffering from arylsulfatase A deficiency. Patient fibroblasts are extracted for DNA and a cytoplasmic fraction, which is used for arylsulfatase A enzyme assay. This will identify an arylsulfatase A‐deficient group, which is further analyzed electrophoretically. Cells from the clinically affected patients with MLD are completely deficient in arylsulfatase A activity, whereas those from the pseudodeficient individuals demonstrate a characteristic residual arylsulfatase A activity detectable only after electrophoresis. Within this pseudodeficient group, gene amplification of DNA specific for the A→G mutations will distinguish between those who are homozygous for the pseudodeficiency allele and those who are compound heterozygous for the pseudodeficiency and MLD alleles. This protocol of complete genotype identification requires only about 106 fibrobalsts (1 × 100 mm dish) and 2 days to complete. Such variant‐specific genotype identification increases accuracy and prognostic value of the diagnosis. It will likely become the preferred choice for diagnosis of genetic disease in the future as more variant‐specific mutations are identified at the molecular level. © 1992 Wiley‐Liss, Inc.
Weissenbacher‐Zweymüller syndrome: A distinct autosomal recessive skeletal dysplasia
Authors: Chemke Juan , Carmi Rivka , Galil Aharon , Bar‐Ziv Yaakov , Ben‐Ytzhak Ilan , Zurkowski Loretta
Published: June 2005

The Weissenbacher‐Zweymüller syndrome (WZS) is defined as congenital neonatal rhizomelic dwarfism with metaphyseal widening of the long bones and vertebral coronal clefts. Catch‐up growth after 2–3 years is one of the striking manifestations. It is generally thought that WZS is a neonatal expression of the Stickler syndrome, even though in the latter, myopia, retinal detachment and a progressive metaphyscal dysplasia are characteristics that are not found in WZS. A critical analysis of all published patients with WZS in addition to 5 patients in 3 new families, shows that the WZS is a distinct syndrome of delayed skeletal maturation, different from the Stickler syndrome, and inherited as an autosomal recessive trait. The recognition of its unique characteristics has important implications in genetic counseling. © 1992 Wiley‐Liss, Inc.
VACTERL or MURCS association in a girl with neurenteric cyst and identical thoracic malformations in the father: A case of gonosomal mosaicism?
Authors: Örstavik Karen Helene , Steen‐Johnsen Jon , Foerster Arnold , Fjeld Tore , Skullerud Kari , Lie Sverre O.
Published: June 2005

We report on a female infant with lethal congenital amalformations including extreme hydrocephalus due to aqueductal stenosis, vertebral segmentation anomalies, fused costae, anal atresia, renal dysplasia, and bicornuate uterus with a double blind vagina. The VAC‐TERL and the MURCS associations are possible diagnoses. Her father had a neurenteric cyst in infancy. He has identical vertebral and costal malformations as his daughter but is otherwise healthy. The possibility of dominant inheritance with gonosomal mosaicism in the father is discussed. © 1992 Wiley‐Liss, Inc.