Biomedical subjects

J M Graham

Publications and source records attributed to J M Graham.

At least 37 records · Page 2Linked to original sources

PubMed2001

Radiographic findings and Gs-alpha bioactivity studies and mutation screening in acrodysostosis indicate a different etiology from pseudohypoparathyroidism.

Acrodysostosis is an uncommon skeletal dysplasia associated with nasal hypoplasia, midface deficiency, severe brachydactyly, and varying degrees of hearing loss and mental retardation. Previous publications have suggested that it may be difficult to distinguish acrodystostosis from pseudohypoparathyroidism on clinical grounds, but acrodysostosis does appear to have distinct clinical and radiologic findings. Spinal stenosis is an underappreciated risk in acrodysostosis, despite the reported loss of normal caudal widening of the lumbar interpediculate distance on AP spine radiographs in the original report of this disorder by Robinow et al., with confirmation of these radiographic findings by Butler et al. We report two sporadic cases of acrodysostosis, one of which required decompressive laminectomy for symptomatic spinal stenosis, and review 11 cases of acrodysostosis from 9 families that were submitted to the International Skeletal Dysplasia Registry. The objective of this report is to determine the frequency and severity of spinal stenosis in patients with acrodysostosis and to summarize the clinical and radiographic findings of acrodysostosis in an effort to distinguish acrodysostosis clearly from pseudohypoparathyroidism. The pattern of brachydactyly differs between these two conditions, and varying degrees of spinal stenosis are characteristic of acrodysostosis. Both our index patients with acrodysostosis had normal bioactivity of the alpha subunit of the Gs protein, therefore indicating that acrodysostosis has a different pathogenesis from pseudohypoparathyroidism. Furthermore, single-strand confirmational polymorphism (SSCP) analysis failed to demonstrate any confirmational alterations in the coding exons of the Gs alpha gene. These radiographic and laboratory findings substantiate that acrodysostosis is clinically different from pseudohypoparathyroidism and that it is necessary to follow patients with acrodysostosis for signs of spinal stenosis.

Dysostoses↗

PubMed2001

Scanning for telomeric deletions and duplications and uniparental disomy using genetic markers in 120 children with malformations.

We screened 120 children with sporadic multiple congenital anomalies and either growth or mental retardation for uniparental disomy (UPD) or subtelomeric deletions. The screening used short tandem repeat polymorphisms (STRP) from the subtelomeric regions of 41 chromosome arms. Uninformative marker results were reanalyzed by using the next available marker on that chromosome arm. In total, approximately 25,000 genotypes were generated and analyzed for this study. Subtelomeric deletions of 1 Mb in size were excluded for 27 of 40 chromosome arms. Among the 120 subjects none was found to have UPD, but five subjects (4%, 95% confidence interval 1-9%) were found to have a deletion or duplication of one or more chromosome arms. We conclude that UPD is not a frequent cause of undiagnosed multiple congenital anomaly syndrome. In addition, we determined that 9p and 7q harbor chromosome length variations in the normal population. We conclude that subtelomeric marker analysis is effective for the detection of subtelomeric duplications and deletions, although it is labor intensive. Given a detection rate that is similar to prior studies and the large workload imposed by STRPs, we conclude that STRPs are an effective, but impractical, approach to the determination of segmental aneusomy given current technology.

Abnormalities, Multiple↗

PubMed2001

Is there a functioning vestibulocochlear nerve? Cochlear implantation in a child with symmetrical auditory findings but asymmetric imaging.

The finding of an abnormally narrow internal auditory meatus during the assessment of a child for cochlear implantation raises the possibility that the meatus may not contain the normal number of nerves. Even with currently available MRI techniques it may be extremely difficult to decide whether or not to offer cochlear implant in such cases. We present a child of 4 1/2 years, assessed for cochlear implantation. MRI and CT imaging suggested aplasia of one vestibulocochlear nerve and hypoplasia of the other. However, audiological tests showed clear responses to sound in both ears and functional use of sound in her daily life. This child was eventually implanted with encouraging postoperative results.

Audiometry↗

PubMed2001

Cross-modal plasticity underpins language recovery after cochlear implantation.

Postlingually deaf subjects learn the meaning of sounds after cochlear implantation by forming new associations between sounds and their sources. Implants generate coarse frequency responses, preventing place-coding fine enough to discriminate sounds with similar temporal characteristics, e.g., buck/duck. This limitation imposes a dependency on visual cues, e.g., lipreading. We hypothesized that cross-modal facilitation results from engagement of the visual cortex by purely auditory tasks. In four functional neuroimaging experiments, we show recruitment of early visual cortex (V1/V2) when cochlear implant users listen to sounds with eyes closed. Activity in visual cortex evolved in a stimulus-specific manner as a function of time from implantation reflecting experience-dependent adaptations in the postimplant phase.

Acoustic Stimulation↗

PubMed2001

Functional plasticity of language-related brain areas after cochlear implantation.

Using PET, the cerebral network engaged by heard language processing in normal hearing subjects was compared with that in patients who received a cochlear implant after a period of profound deafness. The experimental conditions were words, syllables and environmental sounds, each controlled by a noise baseline. Four categories of effect were observed: (i) regions that were recruited by patients and controls under identical task conditions: the left and right superior temporal cortices and the left insula were activated in both groups in all conditions; (ii) new regions, which were recruited by patients only: the left dorsal occipital cortex showed systematic activation in all conditions versus noise baselines; (iii) regions that were recruited by both groups with a different functional specificity; e.g. Wernicke's area responded specifically to speech sounds in controls but was not specialized in patients; and (iv) regions that were activated in one group more than the other: the precuneus and parahippocampal gyrus (patients more than controls) and the left inferior frontal, left posterior inferior temporal and left and right temporoparietal junction regions (controls more than patients). These data provide evidence for altered functional specificity of the superior temporal cortex, flexible recruitment of brain regions located within and outside the classical language areas and automatic contribution of visual regions to sound recognition in implant patients.

Acoustic Stimulation↗

PubMed2001

Klinefelter syndrome and its variants: an update and review for the primary pediatrician.

Klinefelter syndrome is the most common chromosomal abnormality in humans. Recent prospective, unbiased studies have clarified many of the previous misconceptions associated with Klinefelter syndrome, thereby improving our recognition and management of this condition for affected individuals. The primary-care physician has an important role in caring for these individuals and their families by providing anticipatory guidance regarding issues relating to endocrinology, behavior, development, and preventive medical care. Furthermore, the primary-care giver can serve as a valuable source of support and advocacy for the family of a boy with Klinefelter syndrome. We review the current state of knowledge regarding Klinefelter syndrome and its variants, with an emphasis on medical and early developmental interventions.

Diagnosis, Differential↗

PubMed2001

Syndromic ear anomalies and renal ultrasounds.

OBJECTIVE: Although many pediatricians pursue renal ultrasonography when patients are noted to have external ear malformations, there is much confusion over which specific ear malformations do and do not require imaging. The objective of this study was to delineate characteristics of a child with external ear malformations that suggest a greater risk of renal anomalies. We highlight several multiple congenital anomaly (MCA) syndromes that should be considered in a patient who has both ear and renal anomalies. METHODS: Charts of patients who had ear anomalies and were seen for clinical genetics evaluations between 1981 and 2000 at Cedars-Sinai Medical Center in Los Angeles and Dartmouth-Hitchcock Medical Center in New Hampshire were reviewed retrospectively. Only patients who underwent renal ultrasound were included in the chart review. The literature was reviewed for the epidemiology of renal anomalies in the general population and in MCA syndromes with external ear anomalies. We defined a child as having an external ear anomaly when he or she had any of the following: preauricular pits and tags; microtia; anotia; or cup, lop, and other forms of dysplastic ears. A child was defined as having a renal anomaly if an ultrasound revealed any of the following: unilateral or bilateral renal agenesis; hypoplasia; crossed ectopia; horseshoe, pelvic, cystic kidney; hydronephrosis; duplicated ureters; megaureter; or vesicoureteric reflux. RESULTS: Because clinical genetics assessments were made by the same clinician at both sites (J.M.G.), data were combined. A total of 42 patients with ear anomalies received renal ultrasound; 12 (29%) of them displayed renal anomalies. Of the 12 patients with renal anomalies, 11 (92%) also received a diagnosis of MCA syndrome. Eleven of 33 patients (33%) with MCA syndromes had renal anomalies, whereas 1 of 9 patients (11%) with isolated ear anomalies had renal anomalies. Specific disorders seen were CHARGE association, Townes-Brocks syndrome, branchio-oto-renal syndrome, Nager syndrome, and diabetic embryopathy. CONCLUSIONS: We conclude that ear malformations are associated with an increased frequency of clinically significant structural renal anomalies compared with the general population. This is due to the observation that auricular malformations often are associated with specific MCA syndromes that have high incidences of renal anomalies. These include CHARGE association, Townes-Brocks syndrome, branchio-oto-renal syndrome, Nager syndrome, Miller syndrome, and diabetic embryopathy. Patients with auricular anomalies should be assessed carefully for accompanying dysmorphic features, including facial asymmetry; colobomas of the lid, iris, and retina; choanal atresia; jaw hypoplasia; branchial cysts or sinuses; cardiac murmurs; distal limb anomalies; and imperforate or anteriorly placed anus. If any of these features are present, then a renal ultrasound is useful not only in discovering renal anomalies but also in the diagnosis and management of MCA syndromes themselves. A renal ultrasound should be performed in patients with isolated preauricular pits, cup ears, or any other ear anomaly accompanied by 1 or more of the following: other malformations or dysmorphic features, a family history of deafness, auricular and/or renal malformations, or a maternal history of gestational diabetes. In the absence of these findings, renal ultrasonography is not indicated.

Abnormalities, Multiple↗

PubMed2000

Blaschkolinear skin pigmentary variation due to trisomy 7 mosaicism.

Mosaic trisomy 7 is a rare condition that can be seen in individuals with Blaschkolinear skin pigmentary variation, somatic asymmetry, and variable other clinical anomalies. In any patient presenting with Blaschkolinear skin pigmentary variation, varying degrees of asymmetrical growth disturbance, developmental delay, and a normal lymphocytic karyotype, chromosomal mosaicism may be present. To rule out tissue-specific or occult chromosomal mosaicism, it is recommended to culture and karyotype skin fibroblasts, since lymphocyte cell lines may not demonstrate the abnormal cell line. Early diagnosis is of paramount importance, since early physical, occupational, and speech/language therapy can greatly improve the developmental outcome of these patients. We report on a fourth patient with trisomy 7 mosaicism in whom early diagnosis and developmental therapy contributed to an improved developmental outcome when compared with patients in previous reports. Early intervention can greatly benefit patients with this diagnosis, especially in minimizing the aggressive behavior associated with communication difficulties. Our patient has milder manifestations than the previously reported patients with no seizure activity or asymmetry and fewer cells with trisomy 7.

Adult↗

PubMed2000

Cole-Hughes macrocephaly syndrome and associated autistic manifestations.

Based on cases that had been excluded from a previous clinical study of Sotos syndrome, Cole and Hughes [1991: Am J Med Genet 41:115-124] reported a new syndrome associated with marked obesity, occasional delayed bone age, distinctive facial anomalies, mental retardation, and progressive postnatal macrocephaly in the context of autosomal dominant familial macrocephaly. Subsequently, Stevenson et al. [1997: Lancet 349:1744-1745] emphasized the association of progressive postnatal macrocephaly with autism, and they suggested that this might comprise a recognizable autism syndrome. We report two additional patients with Cole-Hughes syndrome and associated autistic characteristics with attention deficit hyperactivity disorder. These patients seem to manifest a distinctive behavioral phenotype associated with Cole-Hughes syndrome and they manifest a distinct subgroup of persons with autism that may ultimately shed light on the pathogenesis of this disorder.

Attention Deficit Disorder with Hyperactivity↗

PubMed2000

Manitoba aboriginal kindred with original cerebro-oculo- facio-skeletal syndrome has a mutation in the Cockayne syndrome group B (CSB) gene.

Cerebro-oculo-facio-skeletal (COFS) syndrome is a rapidly progressive neurological disorder leading to brain atrophy with calcification, cataracts, microcornea, optic atrophy, progressive joint contractures, and growth failure. Cockayne syndrome (CS) is a recessively inherited neurodegenerative disorder characterized by low-to-normal birth weight; growth failure; brain dysmyelination with calcium deposits; cutaneous photosensitivity; pigmentary retinopathy, cataracts, or both; and sensorineural hearing loss. CS cells are hypersensitive to UV radiation because of impaired nucleotide excision repair of UV radiation-induced damage in actively transcribed DNA. The abnormalities in CS are associated with mutations in the CSA or CSB genes. In this report, we present evidence that two probands related to the Manitoba Aboriginal population group within which COFS syndrome was originally reported have cellular phenotypes indistinguishable from those in CS cells. The identical mutation was detected in the CSB gene from both children with COFS syndrome and in both parents of one of the patients. This mutation was also detected in three other patients with COFS syndrome from the Manitoba Aboriginal population group. These results suggest that CS and COFS syndrome share a common pathogenesis.

Abnormalities, Multiple↗

PubMed2000

Brain iron deposition in Parkinson's disease imaged using the PRIME magnetic resonance sequence.

Iron content of the basal ganglia was investigated in 25 patients with idiopathic Parkinson's disease and 14 matched healthy control subjects using a partially refocused interleaved multiple echo sequence on a 1.5 Tesla MRI system. R(2)* (1/T(2)*) and R(2)' (1/T(2)') relaxation rates were higher in the substantia nigra of patients with Parkinson's disease, which indicates that iron content is elevated in this region. R(2)' was lower in the putamen, indicating reduced iron levels; reduction in this region was positively correlated with disease duration. Iron-related oxidative stress may contribute to the neurodegeneration of Parkinson's disease, which may lead to alterations in the iron levels of the striatum. We describe a simple, non-invasive technique for measuring iron content.

Adult↗

PubMed2000

Association study of dopamine receptor gene polymorphisms with drug-induced hallucinations in patients with idiopathic Parkinson's disease.

Some patients with idiopathic Parkinson's disease experience hallucinations as a result of treatment with levodopa and dopamine agonists. There is evidence for some heterogeneity in these hallucinating patients based on duration of Parkinson's disease at onset of hallucinations. We compared the frequency of polymorphisms in the dopamine D2 and D3 receptor genes between patients with drug-induced hallucinations and non-hallucinating patients. Two polymorphisms close to DRD2 and one in DRD3 were studied. No association was found with the whole group of hallucinating patients and their controls. However, an association was found with late-onset hallucinations and the C allele of the TaqIA polymorphism, 10.5 kb 3' to DRD2. This polymorphism may be in linkage disequilibrium with a mutation in DRD2 or a nearby gene that predisposes to drug-induced hallucinations which occur later in the course of idiopathic Parkinson's disease.

Alleles↗

PubMed2000

Congenital malformations of the ear and cochlear implantation in children: review and temporal bone report of common cavity.

The objective of this review is to analyze aspects of congenital malformation of the ear in relation to cochlear implantation in children. Having briefly described the in utero development of the ear and the classification of types of external, middle and inner ear malformation, five practical aspects of these malformations are discussed. It seems likely that the combination of bilateral profound sensorineural deafness with bilateral microtia severe enough to make a surgical approach to the cochlea difficult will be extremely uncommon. No such cases have been reported, although Klippel-Feil deformity seems the syndrome most likely to produce this set of circumstances. Abnormalities in the intratympanic course of the facial nerve have been associated with cochlear malformation, emphasizing the benefit of intra-operative facial nerve monitoring, and a technique suggested for safely avoiding an abnormally placed nerve. Fistulae of cerebrospinal fluid (CSF) and perilymph can complicate surgery and are relatively common in common cavity and Mondini malformations. Strategies for facilitating surgery in the presence of 'gushers', for measuring the pressure of a gusher and for placement of the cochlear implant electrode array are reviewed, with reports of fluctuating levels of electric current when implants lie in dysplastic cochleas. The relationship of implant performance to VIIIth nerve tissue in malformed cochleas is discussed, with a description of the histological findings in a common cavity cochlea. Techniques for identifying the absence of the cochlear nerve are reviewed. Stimulation of the facial nerve by cochlear implants has been described in cases of congenital malformation of the labyrinth but is relatively uncommon. Case reports of the benefit received by implanted children with congenital cochlear malformation have appeared since 1988. Most cases reported have not yet been followed for long enough to establish a clear picture of the outcome following cochlear implantation in such children; no centre has yet built up a large series of cases, but there have been two multicentre postal surveys. It seems likely that in cochlear malformation the range of potential outcomes in terms of hearing threshold and the development of speech perception and production will be similar to the range found in implanted children without cochlear dysplasia. However there is, as yet, no clear picture of the mean level of performance within this range.

Adolescent↗

PubMed1999

Familial lissencephaly with cleft palate and severe cerebellar hypoplasia.

Lissencephaly is a brain malformation characterized by absence of gyral formation, resulting in a smooth brain surface. Histologic study shows severe anomalies of cerebral cortical development. Several lissencephaly syndromes have been described. Here we report a familial syndrome of lissencephaly, cleft palate, diffuse agyria, and severe cerebellar hypoplasia. Microscopic examination of the abnormally thick cerebral cortex showed absence of cortical layering, with preservation of the pia-glial barrier. This is the first report of recurrent lissencephaly with cleft palate and severe cerebellar hypoplasia in which these unique neuropathology findings are described. Autosomal recessive inheritance is suggested by recurrence in sibs within the same family, but germ cell mosaicism for a dominant mutation is not excluded.

Abnormalities, Multiple↗

PubMed1999

Separation of the intracellular secretory compartment of rat liver and isolated rat hepatocytes in a single step using self-generating gradients of iodixanol.

A novel method is described for the separation on a single gradient of the major intracellular organelles of the secretory pathway, the Golgi, the smooth endoplasmic reticulum, and the rough endoplasmic reticulum. Total microsomes were prepared from rat liver by differential centrifugation and resuspended in 20% iodixanol. The microsomal suspension was then layered between a 30% iodixanol cushion and a layer of 15% iodixanol and centrifuged in a vertical rotor for 2 h. The microsomes distributed in four visible bands. The gradients were collected by upward displacement and were characterized (i) by determination of UDP galactose-galactosyltransferase (Golgi marker) NADPH-cytochrome c reductase (endoplasmic reticulum marker) and RNA (rough endoplasmic reticulum marker); (ii) by immunoblotting for TGN38 (trans-Golgi marker) and GS28 (cis-Golgi marker) and for protein disulfide isomerase (endoplasmic reticulum lumenal marker); (iii) by determination of the lipid composition; and (iv) by electron microscopy. The results suggest that the top band (density 1.045-1. 090 g/ml), which contains 68% of the galactosyltransferase activity, consists of vesicles derived from the Golgi. The second broad band in the middle of the tube (density 1.130-1.160 g/ml), which contains 54% of the NADPH-cytochrome c reductase activity, consists mainly of vesicles derived from the smooth endoplasmic reticulum, overlapped at the top by a small band of Golgi-derived lamellae. The two bands at the bottom of the tube (density 1.130-1.160 and density 1.180-1. 220 g/ml) appear to contain two subfractions of vesicles derived from the rough endoplasmic reticulum.

Animals↗

PubMed1999

Clinical and behavioral characteristics in FG syndrome.

FG syndrome is a rare X-linked recessive form of mental retardation, first described by Opitz and Kaveggia in 1974. Based on over 50 reported cases, FG syndrome is associated with agenesis of the corpus callosum, minor facial anomalies (high, broad forehead with frontal cowlick, ocular hypertelorism, down-slanted palpebral fissures, and small cupped auricles), relative macrocephaly, broad thumbs and halluces, and prominent fetal fingertip pads. Affected individuals manifest neonatal hypotonia and severe constipation, which usually resolves during mid-childhood. The hypotonia with joint hyperlaxity evolves into spasticity with joint contractures in later life. Affability, hyperactivity, and excessive talkativeness are noted frequently in patients with FG syndrome. Recently, we described three additional families (six additional patients) with FG syndrome who support the localization of a gene for the FG syndrome in chromosome region Xq12-q21 [Graham JM Jr, Tackels D, Dibbern K, Superneau D, Rodgers C, Corning K, Schwartz CE. 1998. Am J Med Genet 80:145-156.]. Using these same families and one additional sporadic case of FG syndrome, we compared behavioral and personality characteristics of 6 FG boys with other boys with syndromic and nonsyndromic mental retardation: eight with Down syndrome, seven with Prader-Willi syndrome, eight with nonspecific mental retardation, and 13 with Williams syndrome. Using the Vineland Adaptive Behavior Scales, the Reiss Personality Profiles, and the Achenbach Child Behavior Checklist, parents were asked to characterize the behavior and personality of their boys from ages 4 to 10 years. When compared with Williams syndrome, the FG boys had fewer internalizing behaviors and were significantly less anxious and withdrawn but had similar socially oriented, attention-seeking behaviors. On the Reiss Profile, FG boys were also quite similar to Williams syndrome boys. On the Vineland Scales, FG boys demonstrated significant relative strengths in their socialization skills, consistent with their personality, tending to confirm previous descriptions of their personalities.

Abnormalities, Multiple↗

PubMed1999

Proteus syndrome: diagnostic criteria, differential diagnosis, and patient evaluation.

Proteus syndrome is a complex disorder comprising malformations and overgrowth of multiple tissues. The disorder is highly variable and appears to affect patients in a mosaic manner. This intrinsic variability has led to diagnostic confusion associated with a dearth of longitudinal data on the natural history of Proteus syndrome. To clarify some of these issues, a workshop on Proteus syndrome was held in March 1998 at the National Institutes of Health, and participants developed recommendations for diagnostic criteria, differential diagnosis, and guidelines for the evaluation of patients. This is a review of those recommendations.

Diagnosis, Differential↗

PubMed1999

Contribution of clinical teratologists and geneticists to the evaluation of the etiology of congenital malformations alleged to be caused by environmental agents: ionizing radiation, electromagnetic fields, microwaves, radionuclides, and ultrasound.

Analysis of these six clinical problems demonstrates the value of a complete clinical evaluation of a child with congenital malformations by an experienced and well-trained physician who is familiar with the fields of developmental biology, teratology , epidemiology, and genetics. Too often, the entire emphasis is placed on epidemiological data that may be meager or insufficient for a rational conclusion when clinical findings that are readily available can provide definitive answers with regard to the etiology of a child's malformations or the merits of an environmental etiology.

Abnormalities, Radiation-Induced↗