bluuebunny/crossref_metadata_2025 huggingface dataset:
Duplication of 7q31.2→7qter and deficiency of 18qter: Report of two patients and literature review
Authors: Johnson Debra D. , Michels Virginia V. , Aas Martha A. , Dewald Gordon W. , Opitz John M. , Reynolds James F.
Published: June 2005

We describe two male patients with a 46,XY, − 18, +der(18),t(7;18)(q31.2; q23)mat karyotype. Previously, 22 other patients with dup(7q) have been described, but only four of them had duplication of segment 7q31→ 7qter. The two patients in this study were ascertained independently and lived in different states. However, because of the rarity of this translocation, the patients were suspected to be related. The families were investigated extensively, and the patients were found to be third cousins once removed. Both patients had severe hypospadias, large fontanelles, cleft palate, and minor facial anomalies (square and prominent forehead, short, downslanting palpebral fissures, long eyelashes, long philtrum, short nose, thin vermilion border with downcurved upper lip). Their phenotypes were compared with those of previously described patients. One of the two patients described here is alive at 23 months and is the oldest known living patient with this chromosome abnormality. Apneic spells often are present and may be secondary to severe brain abnormalities, such as those identified in our two patients.
Pulmonary hypertension and interstitial fibrosis in von recklinghausen neurofibromatosis
Authors: Porterfield James K. , Pyeritz Reed E. , Traill Thomas A. , Opitz John M. , Reynolds James F.
Published: June 2005

Neurofibromatosis von Recklinghausen (NFvR) has been reported to be associated with diffuse interstitial pulmonary fibrosis. We describe a patient with NFvR presenting in middle age with dyspnea and cyanosis. Chest radiographs showed right ventricular enlargement, dilated proximal pulmonary arteries, and bilaterally increased interstitial markings. Cardiac catheterization showed moderately severe pulmonary hypertension and no evidence of congenital heart defect. The interstitial fibrosis associated with NFvR can result in symptomatic pulmonary hypertension.
Acrocephalopolysyndactyly type II—Carpenter syndrome: Clinical spectrum and an attempt at unification with Goodman and Summit syndromes
Authors: Cohen Donald M. , Green James G. , Miller Janice , Gorlin Robert J. , Reed Jerry A. , Opitz John M. , Reynolds James F.
Published: June 2005

Carpenter syndrorne (ACPS type II) was first described by Carpenter in 1901. The syndrome consists of acrocephaly, soft tissue syndactyly, brachy‐ or agenesis mesophalangy of the hands and feet, preaxial polydactyly, congenital heart disease, mental retardation, hypogenitalism, obesity, and umbilical hernia. Here we review the literature on Carpenter syndrome and add 2 affected sibs with marked intrafamilial variability. This review showed that 2 reported variations of Carpenter syndrome, Goodman and Summitt syndromes, actually fall within the clinical spectrum of this disorder. This confirms earlier suggestions of Gorlin (personal communication 1982) and Hall et al [Am J Med Genet 5:423–34, 1980].
Tibial hemimelia‐cleft lip/palate in a Brazilan child born to consanguineous parents
Authors: Richieri‐Costa A. , Opitz John M. , Reynolds James F.
Published: June 2005

We report on a Brazilian boy with widely cleft lip and palate and bilateral tibial hemimelia. Normal consanguineous parents, unremarkable gestational antecedents, and normal peripheral lymphocytes and chromosomes suggest autosomal recessive inheritance.
Applications of the MEGADATS database system in medical genetics
Authors: Yount Emily A. , Conneally P. Michael , Gersting John M. , Opitz John M. , Reynolds James F.
Published: June 2005

The MEGADATS relational database system has many useful applications in the field of medical genetics. Some of these applications include storage, retrieval, and display of pedigree information; retrieval of sets of individuals, sibships, or families who meet given criteria; storage of necessary information for mailing lists, clinic data, etc; and combination of pedigree information and genotype information into the format needed for linkage analysis packages.
Tetraploidy in a 15‐month‐old girl
Authors: Shiono Hiroshi , Azumi Jun‐ichi , Fujiwara Masataka , Yamazaki Hirobumi , Kikuchi Koukichi , Optiz John M. , Reynolds James F.
Published: June 2005

We present a 15‐month‐old‐girl with tetraploidy and compare the manifestations with those of 3 previously reported liveborn infants with the same type of polyploidy. Common anomalies noted included micro‐turricephaly, a prominent but narrow forehead, microphalmia or anophthalmia, limb anomaly, sacral meningomyelocele, and mental retardation.
Extracellular matrix and cell surface as determinants of connective tissue differentiation
Authors: Solursh Michael
Published: June 2005

This paper reviews in vitro studies, largely from the author's laboratory, concerning the conditions that are permissive for the differentiation, of limb bud mesenchymal cells into chondrocytes. In high‐density cell culture, even in a defined medium, the same normal sequence of events that is found in vivo in developing cartilage is also observed. This system can be used to study heritable disorders in model systems such as in mutant mouse embryos. In addition, single mesenchymal cells can differentiate into hypertrophic chondrocytes in hydrated collagen gel or agarose cultures. A rounded cell shape promotes chondrogenesis, while a flattened cell shape promotes fibroblast differentiation. The actin cytoskeleton is shown to play a central role in regulating connective tissue cell differentiation. By use of such cell culture manipulations, it is now possible to grow large numbers of fibroblastic cells from human biopsy material for storage and to carry out experimental studies after reexpression of chondrogenesis in gel cultures. It is suggested that cytoskeletal‐extracellular matrix interactions play a fundamental role in connective tissue differentiation. Matrix receptors might be developmentally regulated and modify epithelial effects on mesenchymal cells. In this way mesenchymal cells differentiate in a highly organized manner in spatial and temporal terms.
Type I procollagen: The gene‐protein system that harbors most of the mutations causing osteogenesis imperfecta and probably more common heritable disorders of connective tissue
Authors: Prockop Darwin J. , Constantinou Constantinos D. , Dombrowski Kenneth E. , Hojima Yoshio , Kadler Karl E. , Kuivaniemi Helena , Tromp Gerard , Vogel Bruce E.
Published: June 2005

Recent data from several laboratories have established that most variants of osteogenesis imperfecta (OI) are caused by mutations in the 2 structural genes for type I procollagen. There are 2 general reasons for the large number of mutations in type I procollagen in OI. One reason is that most of the structure of the procollagen monomer is essential for normal biological function of the protein. The second reason is that most of the mutations cause synthesis of structurally altered proα chains of type I procollagen. The deleterious effects of the structurally altered proα chains are then amplified by at least 3 mechanisms. One mechanism is a phenomenon referred to as “procollagen suicide” whereby altered proα chains cause degradation of normal proα chains synthesized by the same cell. Another mechanism involves the fact that many of the structurally altered proα chains prevent normal processing of the N‐propeptides of procollagen and persistence of the N‐propeptide interferes with normal fibril assembly. A third mechanism is a recently discovered phenomenon in which a substitution of a bulkier amino acid for glycine can cause a kink in the triple helix of the molecule. The kinked collagen, in turn, causes formation of abnormally branched fibrils. Because the deleterious effects of abnormal proα chains are amplified by these 3 mechanisms, most of the mutations are dominant and many are dominant lethal.

The conclusion that most variants of OI are caused by mutations in the structural genes for type I procollagen has broad implications for other diseases that affect connective tissue, diseases such as chondrodystrophies, osteoarthritis, and osteoporosis.
Radiologic nosology of bone dysplasias
Authors: Spranger J.
Published: June 2005

The usefulness of radiodiagnostics in the delineation of bone dysplasias is exemplified by an attempt to classify the lethal osteochondrodysplasias. Based on morphologic criteria these disorders are subdivided into 11 major categories. Within these categories pathogenetically related bone dysplasia families can be discerned. Radiology meets its limits when different mutations lead to identical or overlapping phenotypes. In the future radiology will keep its prominent place in the diagnosis and nosology of inborn errors of skeletal development because of its ready availability, speed, non‐invasiveness, and discriminating power. As shown by disorders such as metatropic dysplasia or iduronidase deficiency, radiology is most important to evaluate the prognosis of a given condition.
New X‐linked syndrome of mental retardation, short stature, and hypertelorism
Authors: Stoll Claude , Géraudel André , Chauvin Annick
Published: June 2005

We present a three‐generation family with five retarded, abnormally appearing males and two abnormally appearing females (presumably manifesting carriers). The phenotype of the patients is different from that of all other previously described types of X‐linked mental retardation (XLMR). The patients had prominent forehead, frontal bossing, hypertelorism, broad nasal tip, and anteverted nares. Chromosomes were normal including fragile X analysis. Skeletal roentgenograms were normal.
Inbreeding effect on morbidity: IV. Further data in Brazilian populations
Authors: Kaku Margaret , Freire‐Maia Newton
Published: June 2005

The analysis of the data on 5677 children of 1063 couples from a fourth sample of consanguineous and nonconsanguineous marriages among whites and nonwhites living in the State of Minas Gerais, Brazil led to the following estimates: B (number of abnormal equivalents per gamete) around 0.5; A (morbidity in the non‐inbred subsamples) 2–3 percent; B/A 13, 15, and 27 (this suggests that the morbidity disclosed by inbreeding may predominantly represent a mutational load): RR ( relative risk) about 2 (this means that among the children of consanguineous marriages there is about double the frequency of abnormalities than in those with nonconsanguineous marriages); AR (attributable risk) for the whole sample about 7% (5% for nonwhites and and 15% for whites). These last valuse show the amount that the frequency of abnormalities would decrease in the population in the risk factor (consanguineous marriages) would be eliminated. AR is higher in whites because the frequency of the risk factor is higher among whites.
Hemifacial microsomia: Developmental consequence of perturbation of the auriculofacial cartilage model?
Authors: Cousley R. R. J. , Wilson D. J.
Published: June 2005

The cause of hemifacial microsomia (HFM) is currently the subject of much investigation. Despite a large body of clinical and experimental data, little is certain other than the heterogeneity of this malformation complex. Here we suggest that some of the cases previously designated as being multifactorial in origin may be interpreted instead as resulting from a single‐gene mutation, by applying a stochastic single‐gene model. A variety of models of the pathogenesis of HFM have been described, including the proposal that local embryonic haemorrhage is a causal mechanism. More recently, it has been suggested that an interference in chondrogenesis is primarily responsible for the HFM phenotype. In this paper direct experimental evidence, based on surgical interference of mandibular development in the chick embryo, is applied in favour of the latter concept. In particular, asymmetrical perturbation of Meckel's cartilage has been shown to result in asymmetry of the mandible, and it is proposed that, irrespective of cause, the skeletal pathogenesis of HFM primarily involves the auriculofacial cartilage model.
Marden‐Walker‐like syndrome without psychomotor retardation: Report of a Brazilian girl born to consanguineous parents
Authors: van den Ende Jenny J. , van Bever Yolande , Rodini E. S. O. , Richieri‐Costa A.
Published: June 2005

We report on a Brazilian girl, born to consanguineous parents and presenting a multiple congenital anomaly (MCA) syndrome, mainly characterized by blepharophimosis, cleft palate, and arachnodactyly. The clinical aspects involving this patient suggest an apparently undescribed “new” autosomal recessive syndrome.
Variability in the clinical and pathological findings in the neuronal ceroid lipofuscinoses: Review of data and observations
Authors: Wisniewski K. E. , Kida E. , Patxot O. F. , Connell F.
Published: June 2005

We reviewed the clinical and pathological data on 319 neuronal ceroid lipofuscinosis (NCL) cases to determine the degree of variability within the different forms and among and within families. Thirty‐six cases (11.3%) were the infantile form; 116 cases (36.3%), late infantile, 163 cases (51.1%), juvenile; and four cases (1.3%), the adult form (Kufs disease). Clinical variability was found in all forms studied, but was most striking in the juvenile and late infantile forms of NCL. The expected initial findings of seizures, dementia, blindness, or motor impairment were evident in 255 cases (80%), and rarer, less typical initial neurological symptoms were seen mainly in the 64 cases (20%) of the juvenile form: behavior abnormalities (18/64), psychoses (12/64), neuropathy (2/64), involuntary movements (15/64), ataxia (9/64), Six juvenile and two adult cases had no detectable impairment of vision. All 319 NCL cases had skin or conjunctiva biopsies or buffy that showed the characteristic ultrastructural abnormalities of NCL.

Variability was evident in 16.7% in that a combination of fingerprint, curvilinear, and membranous profile inclusion bodies was observed in storage lysosomes, although one type of inclusion was distinctly predominant for each form. Postmortem examination of brains of 19 NCL cases (three with the infantile form, six with the late infantile form, nine with the juvenile form, and one with the adult form) revealed characteristic changes, Sixteen of the 19 NCL brains (84%) showed pathological variability in that they contained more than one kind of characteristic inclusion body in the neuronal lysosomal storage compartment. In all 19 NCL brains, small amounts of aging lipofuscin were also found. In three late infantile cases, neuronal cytoplasmic inclusion bodies were found mainly in the basal ganglia, midbrain, and cerebellar (BG), At the ultrastructural level, theses inclusions were found to be large lysosomes filled with very densely packed curvilinear profiles. Histological and immunocytochemical staining properties of these basal ganglial, midbrain, and cerebellar neurons were found to be different from those storage neurons of other brain regions in this subform and other NCL forms. Therefore, we conclude that these cases represent a distinct NCL subtype. More confounding was the discovery of several neuritic plaques in the fronto‐temporal lobes of a 53‐year‐old female with the adult form. Our present results reveal theat not all epitopes of amyloid β‐precursor protein (APP) can be detected in the NCL brain, and moreover, their distribution and intensity of immunostaining vary, not only among different NCL forms but in some instances with the same forms. The significance of high levels of epitope expression of certain APP domains in NCL brains is still unknown and needs further biochemical studies.
Neurology of the neuronal ceroid‐lipofuscinoses: Late infantile and juvenile types
Authors: Boustany Rose‐Mary
Published: June 2005

My experience with more than 80 cases of the late infantile and juvenile forms of the neuronal ceroid‐lipofuscinoses over the last 5 years has led to the following realizations. The 2 variants are neurologically distinct entities and probably are the result of different genetic defects. Treatment includes supportive measures and anticonvulsant medication. Therapy for behavioral and psychiatric disturbances in the juvenile type proves to be particularly challenging as neuroleptic medications tend to worsen parkinsonian like symptoms. Neuropathologic and neuro radiologic explanation of clinical symptomatology correlates best with neuronal loss and not neuronal storage. There is a paucity of neuropathologic documentation of these 2 types; additional reports are encouraged.
Protease inhibitors as a model for NCL disease, with special emphasis on the infantile and adult forms
Authors: Ivy Gwen O.
Published: June 2005

An animal model of NCL disease has been developed with the use of protease inhibitors. Young rats received a continuous infusion of various specific protease inhibitors or of physiological saline into the lateral ventricle of the brain using osmotic mini‐pumps. Treatment lasted for 2 weeks, at which time animals were sacrificed and the brains were removed and processed for light or electron microscopic analysis. The thiol protease inhibitors leupeptin and E64C, but not saline or the serine protease inhibitor aprotinin, caused a massive accumulation of ceroid‐lipofuscin (CL) in brain cells that bore a strong morphological resemblance to the CL in the infantile and adult forms of NCL disease, and bore similarity to the CL of the late infantile and juvenile forms. Leupeptin also caused the death of cerebellar Purkinje cells, as is seen in the infantile and adult forms of NCL. Further evidence is presented in support of the hypothesis (Ivy et al.: Science 226:985–987, 1984) that decreased or defective lysosomal thiol proteases or their substrates may underly the pathogenesis of at least the infantile and adult forms of NCL disease. Administration of protease inhibitors to the brains of young rats provides an important model for studying the cellular mechanisms of ceroid‐lipofuscinogenesis.
Ceroid lipofuscinosis in the Border Collie dog: Retinal lesions in an animal model of juvenile Batten disease
Authors: Taylor Rosanne M. , Farrow Brian R. H.
Published: June 2005

Ceroid lipofuscinosis, an inherited disorder of lipopigment accumulation, was identified in a group of Border Collie dogs. The dogs developed mental, motor, and visual signs between age 15 and 22 months and progressed rapidly to severe neurological disease. The principal signs were blindness and gait and behavioural abnormalities with progressive dementia. Lipopigment accumulation was severe in neurones and glial cells of the central nervous system and was present in some visceral cells. Inclusions with variable ultra‐structure were common in all cells of the retina, but the pigment accumulation did not damage the retinal architecture. The cytoplasmic inclusions were granular, sud‐anophilic, eosinophilic, and autofluorescent. Ultrastructural morphology varied, but fingerprint and curvilinear patterns predominated. The retinal lesions in the Border Collies were similar to those in English Setters with ceroid lipofuscinosis, but were much less severe than in juvenile human ceroid li‐pofuscinosis. This disorder bears a close resemblance to ceroid lipofuscinosis in English Setters and is another useful model for Batten's disease.
Report of another family with Simpson‐Golabi‐Behmel syndrome and a review of the literature
Authors: Garganta Cheryl L. , Bodurtha Joann N.
Published: June 2005

Simpson‐Golabi‐Behmel Syndrome (SGBS), an X‐linked encephalo‐tropho‐schisis syndrome described in fewer than a dozen families, is characterized by pre‐ and postnatal overgrowth, “coarse” face, minor facial anomalies and, in more severe cases, multiple congenital anomalies and mental retardation. We report on 2 brothers with overgrowth, macrocephaly, polydactyly, supernumerary nipples, and characteristic facial appearance. In addition, the propositus also had pulmonic stenosis and a cleft palate. The findings present in our patients are compared to those in the original patients and to those in patients described more recently. Despite the fact that our patients have most of the minor and several of the more severe malformations, they are not mentally retarded. © 1992 Wiley‐Liss, Inc.
Proximal 7q interstitial deletion in a severely mentally retarded and mildly abnormal infant
Authors: Gillar Patty J. , Kaye Celia I. , Ryan Stephen G. , Moore Charleen M.
Published: June 2005

We describe a boy with an interstitial deletion of 7q [46,XY,del(7)(pter→q11.21::q11.23→qter)] and severe mental retardation, bilateral inguinal hernias, plagiocephaly, and mildly abnormal facial appearance. This is the 21st case report involving a proximal 7q deletion, but the first report of this specific deletion in the absence of Zellweger syndrome. Specific genotype‐phenotype correlations are still not possible for this region of chromosome 7. © 1992 Wiley‐Liss, Inc.
Deletion (14) (q24.3q32.1): Evidence for a distinct clinical phenotype
Authors: Karnitis Sue A. , Burns Kathy , Sudduth Kathy W. , Golden Wendy L. , Wilson William G.
Published: June 2005

We report on a 4‐year‐old girl with distinctive facial features (redundant skin, bushy eyebrows, narrow palpebral fissures, short, upturned nose, epicanthal folds, and a long upper lip with well‐defined philtrum) who has an interstitial deletion of chromosome 14 including band 14q31, designated as 46,XX,del(14) (pter→q24.3::q32.1→qter). Comparison with previously reported patients with deletions of 14q involving band 14q31 suggests that there is a distinctive clinical phenotype associated with this deletion. Our patient had dental abnormalities (3 maxillary and 3 mandibular incisors) not described in the other patients. © 1992 Wiley‐Liss, Inc.
Experimental fetal alcohol syndrome: Proposed pathogenic basis for a variety of associated facial and brain anomalies
Authors: Kotch Lori E. , Sulik Kathleen K.
Published: June 2005

Acute teratogenic exposure of C57Bl/6J mouse embryos to ethanol in vivo results, within 12 hours of initial insult, in excessive cell death in selected cell populations. The patterns of excessive cell death observed following exposure of gestational day 8 embryos (late presomite—approximately 5 somite pair stages) vary somewhat temporospatially, but primarily involve the cell populations at the rim of the anterior neural plate. The cell death patterns appear to be pathogenically correlated with subsequently observed malformations including exencephaly (anencephaly), arhinencephaly, pituitary dysplasia, bilateral or unilateral cleft lip, maxillary hypoplasia, and median facial deficiencies and clefts. The association of these brain and facial malformations in this model, and perhaps in humans, may be accounted for by early insult to the selected cell populations identified in the current investigation. © 1992 Wiley‐Liss, Inc.
Esophageal atresia and tracheoesophageal fistula in two infants born to hyperthyroid women receiving methimazole (tapazol®) during pregnancy
Authors: Ramírez Aurora , de los Monteros Antonio Espinosa , Parra Adalberto , de León Beatriz
Published: June 2005

We report on 2 newborn infants with esophageal atresia and tracheoesophageal fistula (EA + TEF) born to hyperthyroid mothers receiving methimazole (Tapazol ®) before and during their entire pregnancies. Both mothers were euthyroid during gestation and developed hydramnios diagnosed during weeks 34 and 33 of gestation. Premature delivery (36.2 weeks of gestation) occurred in one case, and both newborn infants were small for date with palpable goiter; one of them had other associated malformations. Hypo‐thyroidism was diagnosed by laboratory tests in both cases. Corrective surgery was undertaken, but both newborn infants developed septicemia and renal insufficiency and died in the first week of life. The EA + TEF and a normally placed enlarged thyroid gland were confirmed at necropsy. These cases represent a previously unreported example of the association of maternal ingestion of methimazole during pregnancy and EA + TEF. © 1992 Wiley‐Liss, Inc.
Tentative assignment of a locus for Rubinstein‐Taybi syndrome to 16p13.3 by a de novo reciprocal translocation, t(7;16)(q34;p13.3)
Authors: Tommerup Niels , Van Der Hagen Carl B. , Heiberg Arvid
Published: June 2005

During a systematic chromosomal survey of 7 unrelated patients with Rubinstein‐Taybisyndrome, an apparently balanced de novo reciprocal translocation, t(7;16)(q34;p13.3), was detected in an affected boy. The involvement of the region 16p13.3 coincides with the position of one of the breakpoints in another de novo reciprocal translocation associated with Rubinstein‐Taybi syndrome, suggesting that a locus for this syndrome maps to 16p13.3. © 1992 Wiley‐Liss, Inc.
Tracheoesophageal fistula, gastrointestinal abnormalities, hypospadias, and prenatal growth deficiency
Authors: Martínez‐Frías María‐Luisa , Frías Jaime L. , Galán Enrique , Domingo Rosario , Paisán Luis , Blanco Manuel
Published: June 2005

We studied 2 sibs, born to consanguineous parents, who presented with an MCA pattern which includes low birthweight, tracheo‐esophageal fistula, duodenal atresia, extrahepatic biliary atresia, hypoplastic pancreas, and hypospadias. This constellation of congenital anomalies appears to be a previously unreported autosomal recessive syndrome. A computerized search of the data files of the Spanish Collaborative Study of Congenital Malformations (ECEMC) identified 3 other unrelated infants with intestinal atresias, hypospadias, and low birth weight. These cases may represent a milder expression of the same syndrome. © Wiley‐Liss, Inc.
Clinical phenotype and molecular analysis of a three‐generation family with an interstitial deletion of the short arm of chromosome 5
Authors: Keppen L. D. , Gollin S. M. , Edwards D. , Sawyer J. , Wilson W. , Overhauser J.
Published: June 2005

We report on a 3‐generation family with an interstitial deletion of the short arm of chromosome 5. Varied manifestations were found among the affected individuals including microcephaly, hypertonia, and micrognathia; mental retardation was common to all affected individuals. High resolution chromosome analysis was interpreted as del(5) (pter‐>p14.3::p13.3‐>qter). Molecular comparison of the deletion in this family with individuals with other 5p deletions suggests that the clinical findings are due specifically to the chromosomal material deleted from 5p13. © Wiley‐Liss, Inc.
Golgi‐Kopsch silver study of the brain of a patient with untreated phenylketonuria, seizures, and cortical blindness
Authors: Kornguth Steven , Gilbert‐Barness Enid , Langer Elaine , Hegstrand Linda
Published: June 2005

This report describes the morphological changes observed in the brain of an untreated 27‐year‐old man with phenylketonuria, cortical blindness, and seizures. Golgi–Kopsch silver, cresyl violet, and hematoxylin and eosin stains were used to study cell structure and organization of the cerebellum, the lateral geniculate nuclei, the visual cortex, frontal cortex, and hippocampus. Extensive neuronal losses occurred in the right lateral geniculate nucleus (LGN), the visual cortex, and hippocampus. The left LGN, cerebellum, and frontal cortex retained neuronal components; there was a reduction in the number of dendritic processes on the Purkinje cells of the PKU subject. The loss of neurons in the LGN and occipital cortex is related to the blindness and the neuronal loss in the hippocampus is related to seizure activity. © Wiley‐Liss, Inc.
Charcot‐Marie‐Tooth neuropathy type 1A mutation: Apparent crossovers with D17S122 are due to a duplication
Authors: Nicholson Garth A. , Kennerson Marina L. , Keats Bronya J. B. , Mesterovic Nikola , Churcher Wayne , Barker David , Ross David A.
Published: June 2005

A locus for the slow conducting form of Charcot‐Marie‐Tooth neuropathy (CMT1A) was localised to the proximal short arm of chromosome 17, in band p11.2, distal to D17S58. Linkage studies of CMT1A in 3 large Australian families with the marker loci D17S58, D17S71, and D17S57 suggested the order, pter–CMT1A–D17S71–D17S58–centromere–D17S57. However, the estimate of the recombination fraction between CMT1A and D17S122, also assigned to p11.2, was incompatible with known map distances. The impasse was resolved when the D17S122 genotypes were revised to take into account a dosage effect due to a duplication. After correction of the genotypes, the maximum lod score between CMT1A and D17S122 increased from 0.53 at a recombination fraction of 0.3 to 34.28 at zero recombination. This result emphasizes that genotypes for markers in the p12–p11.2 region should be examined very carefully as ignoring the duplication changes the linkage results dramatically. The fact that no crossovers were found between CMT1A and D17S122 suggests that the duplication may cause the disease phenotype. © Wiley‐Liss, Inc.
Phenotypic evidence for a common pathogenesis in X‐linked deafness pedigrees and in Xq13–q21 deletion related deafness
Authors: Reardon W. , Roberts S. , Phelps P. D. , Thomas N. S. , Beck L. , Issac R. , Hughes H. E.
Published: June 2005

A structural cochlear abnormality has been observed by high resolution CT scanning in some families where X‐linked deafness is segregating. We now present evidence that the same abnormality is present in a deaf patient who has a deletion within Xq21. This observation provides phenotypic evidence that the genotypic basis of deafness is the same in both patient groups. It is also likely that the peri‐lymphatic fluid “gusher” abnormality may be common to both. © Wiley‐Liss, Inc.
Elevated sulfatide excretion in heterozygotes of metachromatic leukodystrophy: Dependence on reduction of arylsulfatase a activity
Authors: Molzer Brunhilde , Sundt‐Heller Regine , Kainz‐Korschinsky Marina , Zobel Marta
Published: June 2005

Sulfatide excretion in urine and arylsulfatase A (ASA) activity in leukocytes were determined in 10 homozygotes of metachromatic leukodystrophy (MLD), 7 obligate and 5 facultative MLD heterozygotes, 6 low ASA subjects (not related to MLD homozygotes), and in 9 controls. As compared to controls (sulfatides: 0–2 nmol/mg lipid; ASA: 101–287 nmol p‐nitro‐catechol/mg protein/hr), MLD homozygotes displayed highly increased sulfatide excretions (27–280 nmol) and low residual ASA activities (0–13 nmol). Of 12 MLD heterozygotes (ASA: 18–87 nmol) 10 showed increased sulfatides (3–24 nmol). All heterozygotes with ASA activity <60 nmol (n = 8) had elevated sulfatide excretions (4–24 nmol). Thus, reduction of ASA activity below 40% of the mean value of controls seems to be the critical threshold for elevated sulfatide excretion in MLD heterozygotes. The low ASA subjects (ASA in the heterozygote range) excreted sulfatides in the control range, even those with ASA activities <60 nmoles (n = 3; including a definite homozygote for ASA‐pseudodeficiency; ASA: 25 nmol). Statistical evaluation of sulfatide excretion and ASA activity in all subjects (n = 37) revealed a significant inverse relation (Spearman rank correlation; R = 0.8278, P< 0.001). The finding of elevated sulfatide excretion in certain MLD heterozygotes might point to increase of sulfatides also in the nervous system. © Wiley‐Liss, Inc.
Prader‐Willi syndrome in a brother and sister without cytogenetic or detectable molecular genetic abnormality at chromosome 15q11q13
Authors: Heleneörstavik Karen , Tangsrud Svein Erik , Kiil Ragnhild , Hansteen Inger‐Lise , Steen‐Johnsen Jon , Cassidy Suzanne B. , Martony Anna , Anvret Maria , Tommerup Niels , Bröndum‐Nielsen Karen
Published: June 2005

We report on a 12‐year‐old boy and his 7‐year‐old sister with the Prader‐Willi syndrome. They both had severe initial hypotonia with feeding problems and later developed an increasing appetite. Both sibs have almond‐shaped eyes, triangular mouth, hypogonadism, retarded growth, and mental retardation. An older brother suffered from severe hypotonia and died at 7 days of age. The children have normal chromosomes by high‐resolution technique and have inherited the same chromosomes 15 short arm polymorphisms from their parents. The family was informative for one of four DNA markers specific for the 15q11q13 region. No deletion was found using this marker. The parents were healthy and unrelated. Autosomal recessive inheritance or a paternally inherited submicroscopic deletion are possible explanations for the sib occurrence in this family. © Wiley‐Liss, Inc.
Histidinuria: Defective transport of histidine
Authors: Nyhan William L. , Hilton Saskia
Published: June 2005

A‐7‐year‐old boy was found to have histidinuria without histidinemia. Low concentrations of histidine in plasma were consistent with impaired intestinal and renal tubular absorption of histidine. The patient was developmentally delayed and had some minor anomalies. Only 4 other patients in 3 families have been reported. Each had abnormality of the central nervous system. All were male. © 1992 Wiley‐Liss, Inc.
Infant with del(3) (p25‐pter): Karyotype‐phenotype correlation and review of previously reported cases
Authors: Nienhaus H. , Mau U. , Zang K. D.
Published: June 2005

We describe a boy with monosomy for the distal part of the short arm of chromosome 3. He had a congenital heart defect, tetramelic hexadactyly, and typical craniofacial anomalies. Comparison with previously reported cases confirms that the phenotype consists of an identifiable pattern of malformation.
Twin studies of alzheimer disease: II. Some predictions under a genetic model
Authors: Breitner John C. S. , Murphy Edmond A.
Published: June 2005

The twin method for investigating genetic and environmental causes of disease has been applied mostly in early‐onset illnesses. Analysis of late‐onset disorders requires reexamination of common assumptions about the relation between genetic causes and the degree of concordance expected. This paper considers Alzheimer disease (AD) as an example of a late‐onset disorder with putative genetic factors. For argument it employs the strong hypothesis that AD is an autosomal dominant trait with age‐dependent expression, as described by a previously published parametric model. That model encompasses 2 principal variants of disease: a rare form with onset in middle life, and a more common late‐onset type which is nonetheless eventually fully penetrant. The present work then specifies the probability that, when a given member of a twin pair (the proband) is affected, an identical or fraternal cotwin also shows the disease. Such probability is expressed as a function of the age at onset of the proband and the current age of the pair. Even under strong working assumptions regarding genetic influence, the expected proportion of identical cotwins actually affected with AD will not exceed 40% until the subjects are about 80 years old. Therefore, except in very old subjects, modest twin concordance is a feeble argument against genetic causes, or in favor of exclusively environmental ones. In this sense the interpretation of results of twin studies in AD and other late‐onset disorders differs substantially from studies of diseases with early onset. © 1992 Wiley‐Liss, Inc.
Dietary folate and nonneural midline birth defects: No evidence of an association from a case‐control study in western australia
Authors: Bower Carol , Stanley Fiona J.
Published: June 2005

In a population‐based case‐control study of dietary folate and neural tube defects, information was collected by interview and self‐administered questionnaires from the mothers of cases with only neural tube defects, from the mothers of matched control infants with defects other than neural tube defects, and from the mothers of matched liveborn infants with no birth defects. The association of midline birth defects (excluding neural tube defects) with dietary folate intake in the first 6 weeks of pregnancy was assessed by restricting the analysis to the 59 mothers of infants with midline defects in the first control group and comparing them with their matched control infants in the second control group. The crude and adjusted odds ratios for dietary folate and for folic acid supplementation were close to one, and all confidence intervals embraced unity. These data do not provide evidence of an association between midline birth defects (excluding neural tube defects) and either dietary folate or folic acid supplementation. © 1992 Wiley‐Liss, Inc.
Robin sequence and a deficiency of the left forearm in a girl with a deletion of chromosome 4q33‐qter
Authors: Menko F. H. , Madan K. , Baart J. A. , Beukenhorst H. L.
Published: June 2005

We have investigated a patient with the Robin sequence and a unilateral deficiency of the left forearm. She was found to have a terminal deletion of the long arm of chromosome 4, del(4)(q33). The clinical manifestations of this patient differ from those of 7 previously described patients with a deletion of the same segment. © 1992 Wiley‐Liss, Inc.
Late diagnosis of phenylketonuria in a bedouin mother
Authors: Usha R. , Uma R. , Farag T. I. , Girish Y. , Al‐Ghanim M. M. A. , Al‐Najdi K. , Al‐Awadi S. A. , El‐Badramany M. H.
Published: June 2005

We report on the first case of phenylketonuria in a Bedouin woman with 3 children having the phenylketonuria embryofetopathy. Herein, we discuss briefly hazards of late diagnosis of maternal phenylketonuria. © 1992 Wiley‐Liss, Inc.
Choanal atresia: Evidence for autosomal recessive inheritance
Authors: Gershoni‐Baruch Ruth
Published: June 2005

Three individuals with choanal atresia were born in an inbred kindred. This report shows that nonsyndromal choanal atresia can be transmitted as an autosomal recessive trait. © 1992 Wiley‐Liss, Inc.
Acro‐fronto‐facio‐nasal dysostosis: Report of a new brazilian family
Authors: Richieri‐Costa A. , Guion‐Almeida M. L. , Pagnan Nina A. B.
Published: June 2005

We report on a Brazilian woman with severe mental retardation, facial and skeletal anomalies characterized by hypertelorism, eye anomalies, broad notched nasal tip, cleft lip, highly arched palate, camptobrachysyndactyly of fingers and toes, and anomalies of the feet. A similarly affected brother died at age one year. The clinical picture strongly suggest the diagnosis of the autosomal recessive acro‐fronto‐facio‐nasal dysostosis syndrome (AFFND). Clinical and genetic aspects are discussed. © 1992 Wiley‐Liss, Inc.
Congenital diaphragmatic hernia associated with ipsilateral upper limb reduction defects: Report of a case with thumb hypoplasia
Authors: Lerone M. , Soliani M. , Corea D. , Romeo G. , Martucciello G. , Silengo M. C.
Published: June 2005

Four unrelated cases of congenital diaphragmatic hernia associated with ipsilateral upper limb reduction defects were reported by McCredie and Reid in 1978 (J Pediatr 92:762–765). As contiguous segments of the cervical neural crest are involved in the development of diaphragm and arms, the authors suggested that an early injury to the cervical neural crest might be the common underlying pathogenesis. We describe here a further example of this malformation complex: a newborn with a left posterolateral diaphragmatic hernia associated with ipsilateral thumb hypoplasia. © 1992 Wiley‐Liss, Inc.
Quantitation of craniofacial anomalies in utero: Fetal Alcohol and Crouzon Syndromes and Thanatophoric Dysplasia
Authors: Escobar Luis F. , Bixler David , Padilla Lillie M.
Published: June 2005

The study of fetal growth and development by ultrasound has been greatly facilitated in the past few years by the availability of anthropometric standards for the fetal body. Thus, the obstetrician is able to discern between normal and grossly abnormal, and even to quantitate certain fine fetal structures such as the face. This paper presents results obtained from a group of 5 patients referred to the Medical Center from private practices in Indianapolis, Indiana. Prenatal cephalometric analyses by ultrasound suggested the presence of craniofacial anomalies in all 5 cases. However, such defects were not detectable by routine ultrasonographic examination. A clinical examination after birth of each of these 5 patients suggested the following diagnoses: Fetal Alcohol Syndrome (FAS) in 2 individuals, Fetal Alcohol Effects (FAE) in one individual, Crouzon Syndrome (CS) in one patient, and Thanatophoric Dyslpasia (TD) in one patient. In order to compare the craniofacial measurement values for each patient to normal standards, we developed Z‐Score profiles and Pattern Variability Indexes (PVI) as described by Garn et al. [1984, 1985]. The values presented here support the idea that even mildly abnormal fetal craniofacial patterns are detectable by this relatively new application of ultrasound. At the present time, no conclusions can be made regarding the diagnostic accuracy of these patterns and profiles. However, the potential value of fetal cephalometry for documenting craniofacial dysmorphology is clearly indicated. © 1993 Wiley‐Liss, Inc.
Absent chondrodysplasia punctata in a male with an Xp terminal deletion involving the putative region for CDPX1 locus
Authors: Ogata Tsutomu , Goodfellow Peter , Petit Christine , Maroteaux Pierre , Matsuo Nobutake
Published: June 2005

This is a follow‐up report on a male patient with a 46, Y, r(X) karyotype. Although he had no clinico‐radiological features of X‐linked recessive chondrodysplasia punctata (CDPX1), molecular studies revealed an Xp terminal deletion involving the putative region for the CDPX1 locus (PABX‐DXS31). We suspect that the absence of CDPX1 may be attributable to the nature of the disease and the extreme short stature of the patient (mean – 5.6 S.D.). © 1993 Wiley‐Liss, Inc.
Regulation of expression of the type I collagen genes
Authors: Slack James L. , Liska Deann J. , Bornstein Paul
Published: June 2005

The identification and functional analysis of DNA‐protein interactions in the intronic and 5′ flanking regions of the type I collagen genes has begun to define a series of cis‐elements and trans‐acting factors which regulate transcription of these genes. Studies such as these will eventually be expected to elucidate the mechanisms responsible for coordinate transcription of the α1 and α2 genes, a question which remains central to the field of collagen research. Although it is relatively straightforward to define sites of DNA‐protein binding, interpretation of the functional importance of such interactions can be extremely complex. Furthermore, while mutation or deletion of a particular binding site may alter the functional activity of a construct transfected into cultured cells, there is no guarantee that a similar change will have the same effect in vivo, where the entire gene locus is present in its native chromosomal context. Nevertheless, these kinds of in vitro studies offer the best current approach to defining and isolating transcription factors that control expression of the α1 and α2 genes. Ultimately, it will be necessary to test the activity of such factors (and their respective cis‐elements) in defined systems in vivo.
Heritable dentin defects: Nosology, pathology, and treatment
Authors: Ranta Helena , Lukinmaa Pirjo‐Liisa , Waltimo Janna
Published: June 2005

Heritable dentin defects have been divided into 2 main categories: dentinogenesis imperfecta (DI) and dentin dysplasia (DD). Recent studies have shown that they share many features in common. Of the connective tissue diseases, only osteogenesis imperfecta (OI) has been linked to these disorders. So far, no definitive relation between the type of OI and the dental involvement can be established. Familial occurrence of DI with OI cannot be comprehensively explained by mutations in type I collagen genes. No information about the gene defects in DD is available. At the ultrastructural level, the organization of the normally cross‐striated collagen fibers in the dentin matrix varies markedly in patients affected by DI.
Psychosocial aspects of osteogenesis imperfecta: An update
Authors: Cole David E. C.
Published: June 2005

Osteogenesis imperfecta (OI) is an inherited disorder in which affected individuals are stigmatized by virtue of physical differences from their peers. The extent to which these differences alter life style depend on the severity of the disorder, its natural history, the extent to which it affects social integration, the effect on physical appearance, and the presence of other affected family members. Some of these factors may adversely influence the ability of affected individuals to effectively adjust to their social and work environment and recognition of these factors may aid individuals and helpers in easing the path to a constructive life.
Haplotype analysis of collagen type I genes in the general population and in osteogenesis imperfecta families
Authors: Mottes Monica , Sangalli Antonella , Pignatti Pier Franco
Published: June 2005

The allele frequencies of 2 new polymorphic markers of collagen type I proalpha 1 (COL1A1) and proalpha 2 (COL1A2) genes were determined in a random sample of chromosomes by polymerase chain reaction. The minor allele frequencies were 0.27 for COL1A1/+88Mn1I, and 0.39 for COL1A2/1446 PvuII RFLPs, respectively. These 2 polymorphisms increased the combined (PIC) values we previously determined in the Italian population with Southern blotting procedures, from 0.71 at the COL1A1 locus to 0.81, and from 0.71 at the COL1A2 locus to 0.88, respectively. With a combination of these markers, we have carried out the segregation analysis of 4 new families in which osteogenesis imperfecta (OI) segregated as a dominant trait. The disease segregated with COL1A1 in 2 OI type I families, and with COL1A2 in one OI type IV family. In one OI type I family the concordant locus was uncertain. This analysis was extended to the 7 dominant OI families we previously reported: in 3 out of 11 pedigrees either locus still could not be excluded, indicating the need for more genetic markers.

COL1A1 and COL1A2 haplotype frequencies were compared in normal and OI chromosomes: no preferential association of the disease with a given haplotype was detected. The correlation between affected locus and clinical aspects is discussed.
Collagen fibrils of osteoid in osteogenesis imperfecta: Morphometrical analysis of the fibril diameter
Authors: Stöss H. , Freisinger P.
Published: June 2005

Comprehensive electron‐microscopic studies showed that the structure of the collagen fibrils in the osteoid is not uniform. In 82 cases of osteogenesis imperfecta (OI), the diameter of the collagen fibrils was determined mor‐phometrically under standardized magnification. The morphometric investigations of collagen fibrils of the osteoid in OI show clear differences in the four subtypes and in comparison with the control group.
Spondylo‐meta‐epiphyseal dysplasia (SMED), short limb‐hand type: A congenital familial skeletal dysplasia with distinctive features and histopathology
Authors: Borochowitz Zvi , Langer Leonard O. , Gruber Helen E. , Lachman Ralph , Katznelson Mariassa Bat‐Miriam , Rimoin David L.
Published: June 2005

We report on a “new” severe short‐limb bone dysplasia which can be labeled descriptively a spondylo‐meta‐epiphyseal dysplasia. The 3 patients were born to 2 unrelated Sepharadic Jewish families and a Puerto Rican family.

Clinical abnormalities include small stature with short limbs including short hands, a short nose with wide nasal bridge and wide nostrils, a long philtrum, ocular hypertelorism, retro/micrognathia, and a narrow chest. Radiological abnormalities include platyspondyly, short tubular bones with very abnormal metaphyses and epiphyses beyond early infancy, short ribs, and a typical evolution of bony changes over time. Chondroosseous morphology and ultrastructure document sparse matrix and degenerating chondrocytes surrounded by dense amorphous material in the 1 patient studied.

Consanguinity is present in 1 family. In addition to the described patient, 2 other short‐limb sibs, who did not survive infancy, were born into this family. Even in the absence of any photographic or radiologic documentation of these other 2 infants, autosomal recessive mode of inheritance seems probable. © 1993 Wiley‐Liss, Inc.