bluuebunny/crossref_metadata_2025 huggingface dataset:
Male pseudohermaphroditism in sibs with the α‐thalassemia/mental retardation (ATR‐X) syndrome
Authors: Reardon W. , Gibbons R. J. , Winter R. M. , Baraitser M.
Published: June 2005

Genital abnormalities have been noted in several patients with the X‐linked form of α‐thalassemia and mental retardation syndrome (ATR‐X). The initial clinical report of the condition documented a phenotypic female with 46,XY karyotype. To this we now add 2 further siblings with abnormalities of the external genitalia, manifesting as male pseudohermaphroditism. © 1995 Wiley‐Liss, Inc.
Familial Mediterranean fever: High gene frequency among the non‐Ashkenazic and ashkenazic Jewish populations in Israel
Authors: Daniels M. , Shohat T. , Brenner‐Ullman A. , Shohat M.
Published: June 2005

Familial Mediterranean fever (FMF) is an autosomal recessive recurrent episodic inflammatory disorder that occurs with high frequency in certain populations in the Mediterranean area. Using extended pedigree data of 90 FMF probands, we calculated the FMF gene frequency in various ethnic groups in Israel by analyzing the frequency in a total of 2,312 first cousins. The heterozygote frequencies were as follows: 1:4.9 (0.2 ± 0.06) for the Libyan subgroup, 1:6.4 (0.16 ± 0.03) for the other North African countries subgroup, 1:13.3 (0.07 ± 0.04) for the Iraqi subgroup, 1:11.4 (0.09 ± 0.06) for the Ashkenazic subgroup, and 1:29.4 (0.03 ± 0.03) for the remaining ethnic groups. The observed number of affected parents and offspring of the probands was in agreement with the estimated gene frequency. Thus, the FMF gene frequency is very high in all Jewish ethnic groups in Israel, especially those originating in North African countries. This also explains the parent‐to‐off‐spring transmission of FMF reported in North‐African Jews. © 1995 Wiley‐Liss, Inc.
De novo interstitial deletion q16.2q21 on chromosome 6
Authors: Villa Amelia , Urioste Miguel , Bofarull Josep M. , Martínez‐Frías María‐Luisa
Published: June 2005

A de novo interstitial deletion of 6q16.2q21 was observed in a 23‐month‐old boy with mental and psychomotor delay, obese appearance, minor craniofacial anomalies, and brain anomalies. We compare clinical manifestations of this patient with those observed in previously reported cases with similar 6q interstitial deletions. It is interesting to note the clinical similarities between some patients with interstitial deletions of 6q16 or q21 bands and patients with Prader‐Willi syndrome (PWS) and it may help to keep in mind cytogenetic studies of patients with some PWS findings. © 1995 Wiley‐Liss, Inc.
Germline mosaicism at the fragile X locus
Authors: Prior Thomas W. , Papp Audrey C. , Snyder Pamela J. , Sedra Mary S. , Guida Marco , Enrile Benedicta G.
Published: June 2005

We have identified a fragile X syndrome pedigree where the disorder is associated with a molecular deletion. The deletion was present in the DNA of 2 sons but was absent in the mother's somatic cell (lymphocyte) DNA. The results are consistent with the deletion arising as a postzygotic event in the mother, who therefore is germinally mosaic. This finding has important implications for counseling fragile X families with deletion mutations. © 1995 Wiley‐Liss, Inc.
Localization of a gene for X‐linked nonspecific mental retardation (MRX24) in Xp22.2–p22.3
Authors: Martínez Francisco , Gal Andreas , Palau Francisco , Prieto Félix
Published: June 2005

Nonspecific X‐linked mental retardation (MRX) includes several distinct genetic entities in which mental retardation is not associated with additional distinguishing physical changes. We report linkage data in a Spanish family with MRX, using polymorphic DNA markers distributed over the X chromosome. Two‐point linkage analysis demonstrated close linkage between the MRX locus and DXS85 in Xp22.3 with a peak lod score of 2.28 at a Ø = 0.00. Analysis of multiple informative meioses suggested a localization of the MRX locus (MRX24) between DXS278 and DXS207. Multipoint linkage analysis resulted in a maximum LOD score of 2.45 at 3 cM proximal to DXS85, and allowed us to reject a localization of the MRX24 gene in all other regions from Xp21–Xqter. These findings localize the MRX24 gene in the chromosomal region Xp22.2–p22.3. © 1995 Wiley‐Liss, Inc.
Pelizaeus‐Merzbacher disease in a family of Portuguese origin caused by a point mutation in exon 5 of the proteolipid protein gene
Authors: Pratt Victoria M. , Boyadjiev Simon , Dlouhy Stephen R. , Silver Kenneth , Kaloustian Vazken M. Der , Hodes M. E.
Published: June 2005

Single‐strand conformational polymorphism analysis of an affected male with Pelizaeus‐Merzbacher disease (PMD) showed a slight change in mobility of amplified exon 5 of the proteolipid protein (PLP) gene. The exon was sequenced and a G → A transition at codon 216 was found. This mutation eliminates a BstNI restriction site and creates a MaeI restriction site. In 1989, Gencic et al. reported a mutation that destroyed the same BstNI site, but resulted in a substitution at codon 215 [Am J Hum Genet 45:435–442]. The mutation we report here is also present in the patient's mother and her male fetus as determined by polymerase chain reaction analysis of amniocytes. © 1995 Wiley‐Liss, Inc.
Genetic detection of the silent allele (*Q0) in hereditary deficiencies of the human complement C6, C7, and C9 components
Authors: Alvarez Victoria , Coto Eliecer , Setién Fernando , Spath Peter J. , López‐Larrea Carlos
Published: June 2005

DNA polymorphisms (RFLPs) of the human complement component C6, C7, and C9 genes were studied in three C7‐deficient (C7D) families, one C6‐deficient (C6D) family, and one C9‐deficient (C9D) family. The 3 loci are closely linked on human chromosome 5. The haplotypes carrying the “silent” allele (C7*Q0, C6*Q0, and C9*Q0) were defined in each family, allowing for the detection of carriers among asymptomatic relatives. This paper describes familial studies on a type of hereditary trait, characterized by recurrent Neisseria infections in individuals homozygous for “silent” alleles at the C6, C7, or C9 loci. © 1995 Wiley‐Liss, Inc.
Prenatal diagnosis of chromosome 15 abnormalities in the Prader‐Willi/Angelman syndrome region by traditional and molecular cytogenetics
Authors: Toth‐Fejel SuEllen , Magenis R. Ellen , Leff Stuart , Brown Michael G. , Comegys Bonnie , Lawce Helen , Berry Toby , Kesner David , Webb Mary Jane , Olson Susan
Published: June 2005

With improvements in culturing and banding techniques, amniotic fluid studies now achieve a level of resolution at which the Prader‐Willi syndrome (PWS) and Angelman syndrome (AS) region may be questioned. Chromosome 15 heteromorphisms, detected with Q‐ and R‐banding and used in conjunction with PWS/AS region‐specific probes, can confirm a chromosome deletion and establish origin to predict the clinical outcome.

We report four de novo cases of an abnormal‐appearing chromosome 15 in amniotic fluid samples referred for advanced maternal age or a history of a previous chromosomally abnormal child. The chromosomes were characterized using G‐, Q‐, and R‐banding, as well as isotopic and fluorescent in situ hybridization of DNA probes specific for the proximal chromosome 15 long arm.

In two cases, one chromosome 15 homolog showed a consistent deletion of the ONCORPWS/AS region A and B. In the other two cases, one of which involved an inversion with one breakpoint in the PWS/AS region, all of the proximal chromosome 15 long arm DNA probes used in the in situ hybridization were present on both homologs. Clinical follow‐up was not available on these samples, as in all cases the parents chose to terminate the pregnancies.

These cases demonstrate the ability to prenatally diagnose chromosome 15 abnormalities associated with PWS/AS. In addition, they highlight the need for a better understanding of this region for accurate prenatal diagnosis. © 1995 Wiley‐Liss, Inc.
Ectrodactyly and proximal/intermediate interstitial deletion 7q
Authors: McElveen Cathy , Carvajal M. Virginia , Moscatello Deborah , Towner Janet , Lacassie Yves
Published: June 2005

We report on an individual with sever mental retardation, seizures, microcephaly unusual face, scoliosis, and cleft feet and cleft right hand. The chromosomal study showed a proximal interstitial deletion 7c (qll.23q22). From our review of the litera ture, 11 patients have been reported with ectrodactyly (split hand/split foot malforma tion) and proximal/intermediate interstitial deletions or rearrangements of 7q. The critical segment for ectrodactyly seems to be located between 7q21.2 and 7q22.1. This malformation is present in 41% of the patients whose deletion involves the critical segment. © 1995 Wiley‐Liss, Inc.
Cystic kidney disease in Hajdu‐Cheney syndrome
Authors: Kaplan Paige , Ramos Feliciano , Zackai Elaine H. , Bellah Richard D. , Kaplan Bernard S.
Published: June 2005

We report on 2 unrelated patients with Hajdu‐Cheney acroosteolysis syndrome, who had cystic kidneys with ultrasono‐graphic changes similar to those of auto‐somal dominant polycystic kidney disease. Neither had a family history of Hajdu‐Cheney syndrome or polycystic kidneys, nor manifestations of any other syndrome. On the basis of the findings in these 2 patients and a review of published cases, we suggest that cystic kidneys are an important component of Hajdu‐Cheney syndrome. © 1995 Wiley‐Liss, Inc.
Mental retardation/shortness of stature/multiple minor anomalies syndrome associated with insertion of 3q material into 18p
Authors: Al‐Attia Haider M. , Sedaghatian Mohamed R.
Published: June 2005

This is a case report of a 16‐year‐old Arab girl with mental subnormality, shortness of stature and multiple minor phenotypic anomalies. She is obese with normal secondary sexual characteristics, and has a speech deficit. Cytogenetic studies showed a 46,XX,dir ins (18;3)(p11.1;q13.2→q25). The chromosome arrangement appeared balanced. Her condition is not a recognizable specific syndrome; thus, it remained unclear as to whether her condition is attributable to disruption of 3q or 18p or both. Further cytogenetic analysis by molecular biologists is required to solve this problem. © 1995 Wiley‐Liss, Inc.
CD1+ cells in mothers of stillborn infants with neural tube defects
Authors: Seniz Fatma Nur , Müftüoǧlu Ekrem , Batun M. Sabri , Say Burhan
Published: June 2005

In healthy individuals, CD1+ cells are found in thymic tissue, but not in peripheral blood. The thymus, as a key organ of the neuroendocrine system, frequently shows gross abnormalities in infants with neural tube defects. In order to study the immuno‐logic significance of fetal thymic findings, maternal T‐lymphocyte subpopulations were investigated. In 10 mothers of healthy new‐borns, 5 mothers of stillborn infants who had no gross abnormalities, and 5 mothers of stillborn infants with neural tube defects, CD1+, CD3+, CD4+, and CD8+ cells were studied. Only the mothers of the infants with open neural tube defects showed CD1 + cells in their peripheral blood. © 1995 Wiley‐Liss, Inc.
New syndrome of hydrocephalus, endocardial fibroelastosis, and cataracts (HEC syndrome)
Authors: Devi Anne S. , Eisenfeld Leonard , Uphoff Dean , Greenstein Robert
Published: June 2005

We report on two unrelated male infants with similar findings of communicating hy‐drocephalus, endocardial fibroelastosis (EFE) and congenital cataracts, who died at 4 months of age. Both mothers reported an upper respiratory infection during the first trimester of pregnancy which was further complicated by polyhydramnios in the third trimester. The infants were diagnosed with bilateral congenital nuclear cataracts at birth. Serologic tests for toxoplasmosis, rubella, cytomegalovitrus, herpes simplex virus, syphilis, and galactosemia screens were negative. Chromosome analyses were, normal. Both children developed communicating hydrocephalus between one and three months after birth. Patient 1 died suddenly at 4 months following an upper respiratory infection. Patient 2 developed congestive heart failure and also died at 4 months. At autopsy, both infants had enlarged hearts with endocardial fibroelastosis. No identifiable organism could be isolated. We discuss the association of birth defects in widely separated organ systems in these patients and suggest that this may represent a genetic syndrome; however, a viral etiology cannot entirely be excluded. We believe this is a distinct disorder and propose the acronym HEC for hydrocephalus, EFE and cataracts. © 1995 Wiley‐Liss, Inc.
Novel spinal dysplasia in two generations
Authors: Anhalt Henry , Parker Bruce , Paranjpe D. V. , Neely E. Kirk , Silverman Frederic N. , Rosenfeld Ron G.
Published: June 2005

We report on a father and son with a previously undescribed skeletal abnormality and severe short stature. Antenatal sonographic evaluation of the propositus (son), obtained due to maternal pre‐eclampsia, suggested an abnormal spine. At birth, no congenital anomalies were noted and transition to extra‐uterine life was smooth. Radiographs performed five days after birth showed spina bifida, hemivertebrae in the mid‐thoracic region, and widened lumbar in‐terpedicular distances. MRI of the lower thoracic and lumbar vertebrae documented crescent‐shaped appearance of the affected vertebrae and abnormally narrow A‐P diameter of the vertebral bodies. Intervertebral discs were small, and the posterior elements, as well as the spinous processes of the affected vertebrae, were markedly hypoplas‐tic. However, there was no narrowness of the spinal canal, and the limbs were unaffected. CT scan with three‐dimensional reformatting of the thoracic and lumbar vertebrae documented unusual sagittal clefting of all of the vertebral bodies, which has previously been undescribed.

The father had severe kyphoscoliosis and a height of 131.6 cm (−7.5 S.D.). Radiograph‐ically, he was found to have multiple segmentation anomalies and diminished A‐P diameter of his affected vertebral bodies. The multiple vertebral anomalies are the probable cause for the father's severe kyphoscoliosis. The pattern of inheritance suggests that an autosomal dominant gene is responsible for this condition and that father represennts a de novo mutationn. These radiographic abnormalities have not been described previously and represent a new form o vertebral spinal dysplasia. © 1995 Wiley‐Liss, Inc.
Tumors in Rubinstein‐Taybi syndrome
Authors: Miller Robert W. , Rubinstein Jack H.
Published: June 2005

The 14 tumors reported in Rubinstein‐Taybi syndrome since 1989, when added to the 22 previously reported, are beginning to show a pattern of neural and developmental tumors, especially of the head, which is malformed in the syndrome. Among the neoplasms were 12 of the nervous system: 2 each of oligodendroglioma, medulloblastoma, neuroblastoma, and benign meningioma, a pheochromocytoma, and 3 other benign tumors; 2 of nasopharyngeal rhabdomyo‐sarcoma; and 1 each of leiomyosarcoma, seminoma, and embryonal carcinoma. Among the other benign tumors were an odontoma, a choristoma, a dermoid cyst, and 2 pilomatrixomas. © 1995 Wiley‐Liss, Inc.
Bilateral ulna hypoplasia, club feet, and mental retardation: A new mesomelic syndrome
Authors: Kohn G. , Malinger G. , El Shawwa R. , Scheinfeld A. , Tepper R. , Ornoy A. , Lachman R. , Rimoin D. L.
Published: June 2005

We report on 2 sibs with a previously unreported type of mesomelia of the upper limbs due to ulnar hypoplasia. Prenatal diagnosis was made by ultrasound during one pregnancy and an affected fetus was confirmed. This family documents a previously unreported autosomal recessive syndrome. © 1995 Wiley‐Liss, Inc.
Agenesis of the corpus callosum and Dandy‐Walker malformation associated with hemimegalencephaly in the sebaceous nevus syndrome
Authors: Dodge Nancy N. , Dobyns William B.
Published: June 2005

The sebaceous nevus syndrome is sometimes associated with hemimegalencephaly and a group of related abnormalities including ipsilateral gyral malformation, mental retardation, seizures, especially infantile spasms, and facial hemihypertrophy. This combination has been described as the “neurological variant of epidermal nevus syndrome.” Other brain malformations have been reported only rarely. We report on a child with a subtle sebaceous nevus associated with hemimegalencephaly who also had agenesis of the corpus callosum and Dandy‐Walker malformation. © 1995 Wiley‐Liss, Inc.
Severe case of al Awadi/Raas‐Rothschild syndrome or new, possibly autosomal recessive facio‐skeleto‐genital syndrome
Authors: Mollica Florindo , Mazzone Domenico , Cimino Gabriella , Opitz John M.
Published: June 2005

A Sicilian girl whose parents were first cousins had a severe tetramelic limb deficiency (amelia of lower limbs, peromelia of upper limbs) and other defects including cleft lip and palate, facial anomalies, athelia, low umbilicus, bladder exstrophy, no external genitalia, and anteriorly displaced anus. This probably represents a particularly severe case of Al Awadi/Raas‐Rothschild syndrome (limb/pelvis‐hypoplasia/aplasia syndrome, LPHAS), but the possibility of a new autosomal recessive facio‐skeleto‐genital syndrome cannot be excluded. © 1995 Wiley‐Liss, Inc.
Familial inverted duplication 7p
Authors: Schaefer G. Bradley , Novak Kelli , Steele David , Buehler Bruce , Smith Shelley , Zaleski Dianna , Pickering Diane , Nelson Marilu , Sanger Warren
Published: June 2005

A 10‐month‐old female with developmental delay and failure to thrive was referred for genetic evaluation as part of an adoption assessment. Physical exam showed a mildly beaked nose and clinodactyly, but otherwise nothing remarkable. Chromosome analysis showed an inverted duplication of the p12.2→p13 portion of chromosome 7[46, XX, dup(7)(p13p12.2)]. The proposita's older brother, mother, and grandmother were cognitively delayed and had the same chromosome 7 duplication. A review of the literature showed no other cases involving this exact duplication. © 1995 Wiley‐Liss, Inc.
Submicroscopic deletions at 22q11.2: Variability of the clinical picture and delineation of a commonly deleted region
Authors: Lindsay Elizabeth A. , Greenberg Frank , Shaffer Lisa G. , Shapira Stuart K. , Scambler Peter J. , Baldini Antonio
Published: June 2005

DiGeorge anomaly (DGA) and velo‐cardiofacial syndrome (VCFS) are frequently associated with monosomy of chromosome region 22q11. Most patients have a submicroscopic deletion, recently estimated to be at least 1–2 Mb. It is not clear whether individuals who present with only some of the features of these conditions have the deletion, and if so, whether the size of the deletion varies from those with more classic phenotypes. We have used fluorescence in situ hybridization (FISH) to assess the deletion status of 85 individuals referred to us for molecular analysis, with a wide range of DGA‐like or VCFS‐like clinical features. The test probe used was the cosmid sc11.1, which detects two loci about 2 Mb apart in 22q11.2. Twenty‐four patients carried the deletion. Of the deleted patients, most had classic DGA or VCFS phenotypes, but 6 deleted patients had mild phenotypes, including 2 with minor facial anomalies and velopharyngeal incompetence as the only presenting signs. Despite the great phenotypic variability among the deleted patients, none had a deletion smaller than the 2‐Mb region defined by sc11.1 Smaller deletions were not detected in patients with particularly suggestive phenotypes who were not deleted for sc11.1, even when tested with two other probes from the DGA/VCFS region. © 1995 Wiley‐Liss, Inc.
Chromosome instability in ICF syndrome: Formation of micronuclei from multibranched chromosomes 1 demonstrated by fluorescence in situ hybridization
Authors: Sawyer Jeffrey R. , Swanson Charles M. , Wheeler Gary , Cunniff Christopher
Published: June 2005

We report on a new patient with immunodeficiency, centromeric heterochromatin instability, and facial anomalies (the ICF syndrome). Studies with traditional cytogenetic methods demonstrate that aberrations in this syndrome primarily involve the centromeric regions of chromosomes 1 and 16. We applied fluorescence in situ hybridization (FISH) using “painting” probes for chromosomes 1 and 16 to document the progression of centromeric instability from simple decondensation aberrations to the subsequent formation of complex multi‐branched chromosomes 1, and finally to the interphase aberrations of nuclear projections and micronuclei involving both chromosomes 1 and 16. The loss of the large multibranched chromosome 1 configurations from the cells as micronuclei suggests that the centromeric aberrations subsequently interfere with normal chromosome movement at anaphase in ICF syndrome. Circular areas of counterstained chromatin were observed by FISH in the micronuclei corresponding to the intertwined segments of centromeric heterochromatin seen involving multibranched chromosomes 1 in the patient's Gbanded chromosome study. The current hypothesis of recessive inheritance for this disorder suggests that the chromosomal aberrations are not a causative event in this syndrome; however, the chromosome aberrations are clearly an important basic diagnostic criterion. © 1995 Wiley‐Liss, Inc.
Trisomy 9: Review and report of two new cases
Authors: Arnold Georgianne L. , Kirby Russell S. , Stern Thomas P. , Sawyer Jeffrey R.
Published: June 2005

Trisomy 9 is a relatively uncommon chromosome abnormality that may sometimes be seen in the nonmosaic state. We reviewed 23 mosaic and 15 nonmosaic cases of trisomy 9, including 2 new cases, in order to better define the prognosis and phenotype of this disorder. A recognizable trisomy 9 phenotype was identified and included a “bulbous” nose, microphthalmia, and dislocated limbs. Other nonspecific anomalies involving various organ systems were also common. With one exception, all survivors had severe mental impairment. Mosaicism for trisomy 9 predicted longer survival, but the degree of mosaicism in lymphocytes or fibroblasts did not predict survival or degree of impairment. Parental chromosome variations were not uncommon. In contrast to prior reports, no specific prognostic finding was identified. A meiotic origin with loss of a trisomic cell line in mosaic cases is suggested. © Wiley‐Liss, Inc.
Multiple congenital malformations in two sibs reminiscent of hydrolethalus and pseudotrisomy 13 syndromes
Authors: Dincsoy Mehmet Y. , Salih Mustafa A. M. , Al‐Jurayyan Nasir , Al Saadi Muslim , Patel Pravinchandra J.
Published: June 2005

We report on two sibs, born to consanguineous parents, with defects of the midline including cleft lip and palate, flat nose, hypotelorism, and dysgenesis of corpus callosum, in addition to short limbs, radiolucent tibial notch, digital anomalies, ambiguous genitalia, and hypopituitarism. In spite of the similarities between this condition and the hydrolethalus and pseudotrisomy 13 syndromes, our patients had neither preaxial nor postaxial polydactyly, but had previously undescribed bilateral radiolucent tibial notch, which is not known to be part of those two syndromes. The cases presented here may very well represent a new autosomal recessive syndrome. © Wiley‐Liss, Inc.
46,XY/47,XYY/48,XYYY karyotype in a 3‐year‐old boy ascertained because of radioulnar synostosis
Authors: James Con , Robson Lisa , Jackson Julianne , Smith Arabella
Published: June 2005

Chromosome analysis was performed on a 3‐year‐old boy because of bilateral radioulnar synostosis and demonstrated a mosaic karyotype 46,XY/47,XYY/48,XYYY. He had minor facial anomalies and mild intellectual delay. He appears to be the youngest patient reported with this rare chromosome complement. His father, mother, and brother had normal chromosomes. Fluorescence in situ hybridization (FISH) was performed on the propositus and his father with the Y chromosome heterochromatic probe (pHY3.4) to add to the evaluation of mosaicism. © 1995 Wiley‐Liss, Inc.
Uniparental isodisomy 13 in a normal female due to transmission of a maternal t(13q13q)
Authors: Stallard R. , Kruegor S. , James R. S. , Schwartz S.
Published: June 2005

Chromosomes from a normal 23‐year‐old, primigravid woman were examined at 10 weeks of gestation because of her mother's history: 8 miscarriages and two liveborn infants (the proposita and a brother who died at 3 days with multiple anomalies). Karyotypes of the proposita and her normal mother were 45,XX, t(13q13q). No evidence of mosaicism was encountered. When the proposita inherited the t(13q13q), she received two copies of 13q from her mother. Moreover, she and her mother shared the same homozygous pattern of alleles from 7 highly polymorphic microsatellite repeats localized along 13q. No evidence of paternal markers from 13 was detected, although biparental inheritance was demonstrated with DNA markers from chromosomes 2 and 17. Cytogenetic and molecular findings indicated that the proposita's chromosomal complement included mUPD 13q. The proposita's normal phenotype suggested that no maternally imprinted genes map to 13q. © 1995 Wiley‐Liss, Inc.
Outcome of Sturge‐Weber syndrome in 52 adults
Authors: Sujansky Eva , Conradi Susan
Published: June 2005

Sturge‐Weber syndrome (SWS) is a neuro‐cutaneous disorder characterized by cutaneous facial angioma, leptomeningeal angioma associated with seizures and other neurologic complications including mental retardation, and glaucoma. Only limited information about long‐term outcome, including the societal integration of adult patients, is available in the literature.

Data on 52 adults with SWS, ages 18‐63 years, ascertained through the Sturge‐Weber Foundation, were obtained via written questionnaires, telephone interviews, and reviews of medical records. The distribution of port‐wine stains (cranial 98%, extracranial 52%) and the prevalences of glaucoma (60%), seizures (83%), neurologic deficit (65%), and other complications were established. The age of onset of glaucoma (0‐41 years), the age of onset of seizures (0‐23 years), and the correlation between the distribution of port‐wine stains and the prevalence of seizures was identified. The relationship between the age of onset of seizures and seizure control was established. In those with and without seizures, the prevalences of developmental delay (43% vs. 0%), emotional and behavior problems (85% vs. 58%), special education requirements (71% vs. 0%), and employability (46% vs. 78%) were analyzed. Overall, 39% were financially self‐sufficient, and 55% were or could be married. Ten participants produced 20 liveborn offspring; 17 were healthy, and tuberous sclerosis, a café‐au‐lait spot, and a “birthmark” were found in 1 child each. The results of this study can be used for genetic counseling in Sturge‐Weber syndrome. Adults, emotional problems, behavior problems, offspring, education, employment, genetic counseling © 1995 Wiley‐Liss, Inc.
Monosomy 9p24→pter and trisomy 5q31→qter: Case report and review of two cases
Authors: Schimmenti Lisa A. , Higgins Rodney R. , Mendelsohn Nancy J. , Casey Timothy M. , Steinberger Julia , Mammel Mark C. , Wiesner Georgia L.
Published: June 2005

Partial deletion of the short arm of chromosome 9 (p24→pter) and partial duplication of the long arm of chromosome 5 (q32→qter) were observed in an abnormal boy who died at age 8 weeks of a complex cyanotic cardiac defect. He also had minor anomalies, sagittal craniosynostosis, triphalangeal thumbs, hypospadias, and a bifid scrotum. Two other infants with similar cytogenetic abnormalities were described previously. These patients had severe congenital heart defect, genitourinary anomalies, broad nasal bridge, low hairline, apparently low‐set ears, short neck, and triphalangeal thumbs, in common with our patient. We suggest that combined monosomy 9p23,24→pter and trisomy 5q31,32→qter may constitute a clinically recognizable syndrome. © 1995 Wiley‐Liss, Inc.
Autosomal dominant inheritance in setleis syndrome
Authors: Masuno Mitsuo , Imaizumi Kiyoshi , Makita Yoshio , Nakamura Mihoko , Kuroki Yoshikazu
Published: June 2005

Setleis syndrome is characterized by bitemporal skin depressions resembling forceps marks, abnormalities of the eyelashes, and “leonine” facial appearance. The cause is unknown, although autosomal recessive inheritance has been proposed. Recently, two families were reported in which one of the parents of a patient with Setleis syndrome showed mild manifestations, suggesting autosomal dominant inheritance. We describe a 9‐month‐old Japanese boy with typical Setleis syndrome. His father, who has normal intelligence, has bitemporal focal dermal dysplasia but a normal face. His paternal second cousin also has Setleis syndrome. This family shows autosomal dominant inheritance including father‐to‐son transmission of Setleis syndrome with variable expressivity and reduced penetrance. Careful examination of the relatives of patients with Setleis syndrome is recommended. © 1995 Wiley‐Liss, Inc.
Neoplasms in proteus syndrome
Authors: Gordon Patricia L. , Wilroy R. Sid , Lasater Olga E. , Michael M. Cohen
Published: June 2005

We report on 2 children with Proteus syndrome who developed neoplasms. Patient 1 had a probable mesothelioma, although papillary carcinoma of the thyroid could not be completely ruled out. Patient 2 had bilateral ovarian serous cystadenomas with nuclear atypia. Other unusual neoplasms in Proteus syndrome are discussed, together with their etiologic and pathogenetic possibilities. © 1995 Wiley‐Liss, Inc.
Translocation 10;18 in a patient with juvenile neuronal ceroid‐lipofuscinosis (Batten disease)
Authors: Tuck‐Muller Cathy M. , Dyken Paul R. , Li Shibo , Chen Harold , Labbé Elise , Wertelecki Wladimir
Published: June 2005

We report the first observation of a chromosome abnormality in a patient with typical juvenile ceroid‐lipofuscinosis (NCL), who was found to have an apparently balanced translocation between chromosomes 10 and 18 [t(10;18)(q22.1;q21.1)]. Since juvenile NCL was previously mapped to 16p12, this report raises the possibility of heterogeneity in this form of NCL. © 1995 Wiley‐Liss, Inc.
Pathogenesis of brain dysfunction in Batten disease
Authors: Walkley Steven U. , March Philip A. , Schroeder Charles E. , Wurzelmann Sarah , Jolly Robert D.
Published: June 2005

Animal models of Batten disease and other neuronal storage disorders offer important opportunities to study the pathogenesis of brain dysfunction in this family of diseases. Although all of these conditions exhibit progressive intraneuronal storage, we have found that other aspects of the cellular pathology of Batten disease differ markedly from those of storage disorders caused by lysosomal hydrolase deficiencies. Likewise, atrophy of cerebral cortex and other select brain regions, a prominent characteristic of Batten disease, does not occur in most other storage disorders. Our studies indicate that Batten disease has findings in common with human neurodegenerative diseases and that neuron death may be caused by excitotoxicity occurring secondary to the combined effects of suboptimal mitochondrial function and GABAergic (inhibitory) cell loss. © 1995 Wiley‐Liss, Inc.
Morphological alterations in neocortical and cerebellar GABAergic neurons in a canine model of juvenile Batten disease
Authors: March Philip A. , Wurzelmann Sarah , Walkley Steven U.
Published: June 2005

The pathogenesis of brain dysfunction in a canine model of juvenile Batten disease was studied with techniques designed to determine sequential changes in mitochondrial morphology and cytochrome oxidase (CO) activity, and in neurons and synapses using gamma‐aminobutyric acid (GABA) as a neurotransmitter. Histochemical and immunocytochemical methods were employed. Mitochondrial alterations were found in a select population of nonpyramidal neurons in neocortex and claustrum, and in cerebellar basket cells. Proportions of affected neurons at any one time remained constant over the disease course, with morphologically‐abnormal mitochondria first being recognized at age 6 months. Enlarged mitochondria were readily identifiable at the light microscope (LM) level as large CO‐positive or mitochondrial antibody‐positive granular structures. Colabelling with antibodies to GABA or to parvalbumin (PV) indicated that most of these cells were GABAergic. Ultrastructurally, atypical mitochondria were characterized by globular enlargement, intramitochondrial membranous inclusions, and disorganized internal structure. CO activity in all other cell somata and in neuropil was diminished compared with normal, age‐matched tissue. Glutamic acid decarboxylase (GAD), PV, and GABA studies demonstrated loss of GABAergic neurons and synapses in cortex and cerebellum of affected dogs. These results indicate that abnormal mitochondria are present in neurons in Batten disease, and suggest that suboptimal mitochondrial function may play a role in the pathogenic mechanisms of brain dysfunction in this disorder. © 1995 Wiley‐Liss, Inc.
Free radicals, anticonvulsants, and the neuronal ceroid‐lipofuscinoses
Authors: Maertens Paul , Dyken Paul , Graf William , Pippenger Charles , Chronister Robert , Shah Arvind
Published: June 2005

The relationship between free radicals and scavenger enzymes, and the disorders called the neuronal ceroid‐lipofuscinoses, has long been an argumentative one. Recent evidence would seem to support the fact that such a relationship might exist but that it is indirect. The relationship does not seem due to an inborn error of free radical scavenger enzyme metabolism. Anticonvulsants play a role, as they influence free radical generating systems. At this juncture, no one has studied the relationship of anticonvulsant therapy, neuronal ceroid‐lipofuscinosis, and the free radical‐scavenging enzyme system, and their interplay.

We have studied a large number of patients with epilepsy who are on either monotherapeutic or polytherapeutic regimens of most of the common anticonvulsants. We have found excessive free radical production in many of these patients, ranging from minor effects in the simpler anticonvulsants when used monotherapeutically, to more complex changes in polytherapeutic combinations. Likewise, we have found subtle and inconsistent findings in the free radical‐scavenging enzyme system in a variety of examples of neuronal ceroid‐lipofuscinosis.

When refractory seizure disorders stimulate the vigorous use of polytherapy with a variety of free radical‐facilitating anticonvulsants, free radical production becomes deleterious. Likewise, in certain types of neuronal ceroid‐lipofuscinosis, polypharmacy with anticonvulsants, by enhancing the production of free radicals or suppressing scavenging enzymes, tends to be deleterious and induces a worsening in the disease process. © 1995 Wiley‐Liss, Inc.
Biosynthesis and metabolism of 4‐hydroxynonenal in canine ceroid‐lipofuscinosis
Authors: Siakotos Aristotle N. , Schnippel Kathryn , Lin Renee C. , Van Kuijk Frederick J. G. M.
Published: June 2005

Canine ceroid‐lipofuscinosis (CCL) is a model of the juvenile type of Batten disease in human patients. Abnormalities have been reported previously in 4‐hydroxynonenal (HNE) levels in English setters with CCL. The purpose of this study was to examine the sources of HNE in neutrophil membranes and plasma of CCL dogs. The fatty acid composition of neutrophil phospholipids, i.e., phosphatidyl ethanolamine and phosphatidyl serine, was determined by gasliquid‐chromatography (GLC) since some polyunsaturated fatty acids (PUFA) are precursors of HNE. The copper catalyzed peroxidation of low density lipoprotein (LDL) was examined to determine the susceptibility of LDL from CCL dogs to peroxidation. The results indicated that a number of PUFA precursors of HNE decreased in affected and carrier neutrophil phospholipids, indicating that this source of HNE may be disease specific. The Cu++ catalyzed formation of HNE from LDL demonstrated that carrier and normal LDL produced large amounts of HNE, while LDL from affected dogs required much higher concentrations of Cu++ for maximal HNE production. These results provide additional support for the role of HNE in the pathogenetic events in NCL and support the view that lipid peroxidation may be an important contributor to the complex pathogenesis of the NCL. © 1995 Wiley‐Liss, Inc.
Palmitate oxidation in muscle mitochondria of patients with the juvenile form of neuronal ceroid‐lipofuscinosis
Authors: Majander Anna , Pihko Helena , Santavuori Pirkko
Published: June 2005

The finding that the intracellular storage material in juvenile neuronal ceroid lipofuscinosis (JNCL) consists of the subunit c of ATP synthase prompted us to study energy conservation in JNCL patients. The activities of respiratory chain enzymes in isolated muscle mitochondria from 8 JNCL cases were normal, but oxidation of palmitate was reduced in 6 patients. The degree of reduction was related to the age of the patients. None of the patients had clinical symptoms or laboratory findings of impaired energy conservation, which suggest that the reduced palmitate oxidation was not associated with a major defect in fatty acid oxidation. © 1995 Wiley‐Liss, Inc.
Comparative biology of the neuronal ceroid‐lipofuscinoses (NCL): An overview
Authors: Jolly R. D.
Published: June 2005

Multiple forms of ceroid‐lipofuscinosis occur in human beings and animals. They are characterized by brain and retinal atrophy associated with selective necrosis of neurons. This neurodegenerative disease appears associated with the disease process rather than storage of fluorescent lipopigment per se, and there is now growing evidence that pathogenesis may involve mitochondria rather than a primary defect of lysosomal catabolism. Of the forms of ceroid‐lipofuscinosis studied, most but not all reflect accumulation of subunit c of mitochondrial ATP synthase. If there is a common denominator between all forms other than the presence of fluorescent lipopigment, then it may be the accumulation of hydrophobic protein. Analogous diseases in animals can be expected to reflect the same spectrum of biochemical changes, and they warrant in‐deptb study to help understand the pathogenesis and heterogeneity of the group. © 1995 Wiley‐Liss, Inc.
Isolation of genes from the Batten candidate region using exon amplification
Authors: Lerner T. J. , D'Arigo K. L. , Haines J. L. , Doggett N. A. , Taschner P. E. M. , de Vos N. , Buckler A. J.
Published: June 2005

In order to identify genes originating from the Batten disease candidate region, we have used the technique of exon amplification to identify transcribed sequences. This procedure produces trapped exon clones, which can represent single exons or multiple exons spliced together and is an efficient method for obtaining probes for physical mapping and for screening cDNA libraries. The source of DNA for these experiments was a collection of chromosome 16 cosmid contigs isolated by the direct subcloning of region‐specific yeast artificial chromosomes (YACs) and hybridization of inter‐alu PCR products from these YACs to the flow‐sorted Los Alamos chromosome 16 cosmid library. We are now using the resulting exon probes to screen retina and brain cDNA libraries for candidate JNCL genes. © 1995 Wiley‐Liss, Inc.
Role of subunit‐9 of mitochondrial ATP synthase in Batten disease
Authors: Johnson David W. , Speier Susanne , Qian Wei‐Hua , Lane Steven , Cook Alyson , Suzuki Kinuko , Daniel Peter , Boustany Rose‐Mary
Published: June 2005

The role of subunit‐9 of mitochondrial ATP synthase in Batten disease was defined by characterizing the expression of genes encoding this protein in human tissues. Two genetically distinct neuronal ceroid‐lipofuscinoses (NCL) comprise Batten disease: the late‐infantile (LINCL) and juvenile (JNCL) types. We tested cell lines and tissues from both types of patients, along with normal controls. Differences in expression between diseased and normal samples were found for both mRNA and protein. Antibody staining of subunit‐9 protein was detected in LINCL and JNCL tissues, and in 6 LINCL and 4 of 5 JNCL fibroblast lines. No immunoreactivity was seen in fibroblasts from obligate carriers, normal controls, and 6 other storage disease controls, with the exception of faint staining in Niemann‐Pick, type C cells. There was an appreciable difference in staining pattern in both tissue sections and fibroblasts between LINCL and JNCL. Three subunit‐9 transcripts (Hum1, Hum2, and Hum3) were specifically detected in NCL and normal human tissue from heart, liver, brain, muscle, and pancreas. Transcriptional regulation of subunit‐9 genes was found to be altered in Batten disease. Pseudogenes related to each of the subunit‐9 genes were isolated. Sequence analysis of cDNAs spanning the protein‐coding regions of the Hum1, Hum2, and Hum3 genes showed conclusively that the primary defect(s) causing NCL are not mutations in the protein‐coding regions of the 3 known subunit‐9 genes. © 1995 Wiley‐Liss, Inc.
Genetics of primary and timing effects in the mnd mouse
Authors: Messer A. , Plummer J. , MacMillen M. C. , Frankel W. N.
Published: June 2005

The mnd mouse shows a spontaneous adultonset hereditary neurological disease, with motor abnormality by 6 months of age, progressing to severe spastic paralysis and premature death. The disease is autosomal recessive, with heterozygote effects seen under stress. It maps to mouse chromosome (chr) 8. Histopathology with Nissl stains documents substantial abnormalities of upper and lower motor neurons, and there is retinal degeneration beginning in the first month, even without light exposure. Increasing levels of autofluorescent lipopigment are found in both neuronal and non‐neuronal tissues as the mnd mice age. Recently, NCL‐like inclusions and accumulating subunit c have also been described.

When mnd is outcrossed to the AKR/J genetic background, ca. 40% of the mnd/mnd F2 progeny show early onset (onset by 4.5‐5 months and death by 7 months.) This accelerated timing effect seems to be strainspecific, and unlinked to the mnd gene itself. Our current working hypothesis is that the timing effect is due to 2 or 3 unlinked dominant genes with incomplete penetrance at any single locus. In a combined RFLP/PCR fragment genetic analysis, the strongest deviation from the expected ratio of AKR vs B6 alleles occurs with markers on proximal half of chr 1. Additional loci on chrs 5 and 10 may also be involved. The mechanism of interaction of these modifying genes with the primary mnd gene may offer new therapeutic avenues. © 1995 Wiley‐Liss, Inc.
Hematopoietic cell transplantation in fetal lambs with ceroid‐lipofuscinosis
Authors: Westlake Valerie J. , Jolly Robert D. , Jones Boyd R. , Mellor David J. , Machon Roslyn , Zanjani Esmail D. , Krivit William
Published: June 2005

Hematopoietic cells from the liver of normal 45‐48‐day‐old fetal lambs (Hb type AA) were transplanted intraperitoneally into 58‐60‐day‐old recipient fetuses (Hb type BB). The recipient fetuses resulted from mating homozygous ceroid‐lipofuscinosis affected males with heterozygous, phenotypically normal, females. The sex of the donor fetus was also recorded. At age 21/2 months the recipient lambs with ceroid‐lipofuscinosis were diagnosed by histopathology of brain biopsies. Monitoring of blood and bone marrow cells showed that an average of 9% of blood cells in ceroid‐lipofuscinosis affected recipients were of donor origin. No differences were evident in the clinical course of disease, brain weight, or histopathology of organs between transplanted and non‐trans‐planted lambs with ceroid‐lipofuscinosis. Under the conditions of this experiment, transplantation of fetal hematopoietic cells was not beneficial. © 1995 Wiley‐Liss, Inc.
Femoral‐facial syndrome–prenatal diagnosis–autosomal dominant inheritance
Authors: Robinow Meinhard , Sonek Jiri , Buttino Louis , Veghte Anne
Published: June 2005

Fetal micrognathia and short, bowed femora were found on a routine prenatal ultrasonogram. At birth, a cleft palate and the characteristic facial appearance confirmed the diagnosis of the femoral‐facial syndrome. (The femoral‐facial syndrome [McKusick 137840] was first delineated by Daentl et al. [1975: J Pediatr 86:197–211 ] and called the “femoral hypoplasia‐unusual fa‐cies syndrome.” We prefer the “femoral‐facial syndrome” because it is shorter, more easily translated, and because the McKusick catalog is the most widely recognized standard of nomenclature.) A paternal great uncle, deceased at age 4 years, seems to have had the same condition. © 1995 Wiley‐Liss, Inc.
Two sisters with Escobar syndrome
Authors: Spranger Stephanie , Spranger Matthias , Meinck Hans‐Michael , Tariverdian Gholamali
Published: June 2005

We report on 2 sisters with an autosomal‐recessive multiple pterygium syndrome, type Escobar, consisting of multiple pterygia with severe contractures, short stature, and minor facial and external genital anomalies. The striking finding was severe muscular atrophy. We speculate that a neu‐romuscular disorder is the underlying pathogenesis of Escobar syndrome. © 1995 Wiley‐Liss, Inc.
Heritability and heteromorphic distributions of AluI chromosome banding variants in twins
Authors: Huang Bing , Meyer Joanne M. , Jackson‐Cook Colleen K.
Published: June 2005

The heritability and heteromorphic appearance of chromosomal banding patterns induced through in situ digestion with the restriction enzyme Alul were studied by analyzing the chromosomes of 25 monozygotic and 25 dizygotic twin pairs selected at random from a juvenile twin registry. A total of 19 Alul banding variants were found to be heteromorphic, with the pericentromeric region of chromosome 3 and the satellites of chromosome 22 being most and least heteromorphic, respectively. As expected, the correlations of the semi‐quantitative scores for each of the chromosomal variants were significantly higher between MZ twin pairs (ranging from 0.48 to 0.95) than DZ twin pairs (ranging from ‐ 0.02 to 0.69), suggesting that genetic factors play an important role in their appearance. This finding was confirmed in a model fitting analysis in which the heritabilities of the Alul‐induced chromosome variants were found to range from 70 to 96% for 12/13 heteromorphisms studied. These consistent findings are significant in that these variants may be useful for family studies in clinical genetics. © 1995 Wiley‐Liss, Inc.
L206W mutation of the cystic fibrosis gene, relatively frequent in French Canadians, is associated with atypical presentations of cystic fibrosis
Authors: Rozen Rima , Ferreira‐Rajabi Leonor , Robb Laura , Colman Neil
Published: June 2005

Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Over 400 mutations have been reported at this locus. Although severe forms of cystic fibrosis are usually associated with pancreatic insufficiency, pulmonary dysfunction, and elevated sweat chloride, there is a wide range of phenotypes, including congenital absence of the vas def‐erens, observed with some of the milder mutations. The L206W mutation, which was first identified in patients from South France, is relatively frequent in French Canadians from Quebec. In this report, we document the atypical form of cystic fibrosis associated with this mutation, in a cohort of 7 French Canadian probands. © 1995 Wiley‐Liss, Inc.