Thanatophoric dysplasia in monozygotic twins discordant for cloverleaf skull: Prenatal diagnosis,clinical and pathological findings

We present male monozygotic twins with thanatophoric dysplasia (TD) type I concordant for long bone abnormalities and discordant for cloverleaf skull. The twins were the product of the second pregnancy of unrelated parents, with advanced paternal age. Prenatal diagnosis and postmortem examination showed severe rhizomelic shortness of limbs, bowing of the long bones with “telephone-receiver” femora in both twins, and cloverleaf skull and hydrocephalus in one of them. It is now accepted that most of cases of TD, such as in the present report, represent an autosomal dominant mutation with a high new mutations rate.     

Thanatophoric dysplasia: Fetal manifestations and prenatal diagnosis

One of a pair of female monozygotic twins showed skin atrophy with linear alternation of depressed scarlike areas and intervening ridges of normal or nearly normal skin. She was born with friable skin and a vesicular-bullous eruption which was followed by gradual scabbing. Hypohidrosis in the affected areas, heat intolerance, and febrile convulsions were noted in infancy and childhood. No new skin lesions developed, and the existing ones, the sweating disturbance, and the heat intolerance gradually improved with time. Scarring alopecia, congenital absence of three toenails, and a scarlike lesion of the tongue were also present. Their absence in the other twin supports the view that 1) these manifestations all are part of the same syndrome, and 2) this syndrome is nongenetic. Histologically, there were no diagnostic or consistent findings, but the number of skin appendages was diminished, and the elastic fibers were reduced in number and size in one biopsy. The calculated probability for the twins being monozygotic was 0.9998. This family was also remarkable for the presence of alopecia areata in three successive generations with only one instance of apparent nonpenetrance. We conclude that this may represent a previously undescribed syndrome of congenital fragility of connective tissue which predisposed to damage of the elastica, possibly caused by an early inflammatory phase.     

Thanatophoric dysplasia: fetal manifestations and prenatal diagnosis

This paper describes two fetuses with thanatophoric dysplasia (TD) diagnosed in utero by ultrasonography. The fetuses were found to have severely short (less than 3rd centile), mildly bowed bones in one of them at 20 weeks and straight bones in the other at 34 weeks; bell-shaped chest; abnormal ribs (broadened and flattened at their ends); severe lung hypoplasia; hypoplastic, round-shaped vertebral bodies with hypoplastic arches; abnormally small pelvic bones, phalanges, metacarpals, and metatarsals. There was also an incipient "cloverleaf" skull deformity produced by fused posterior sagittal and lambdoidal sutures in the 20-week fetus and a definitive cloverleaf skull with communicating hydrocephaly in the 34-week fetus. The autopsies did not show any other abnormality. By xeroradiography after delivery, marked abnormalities of the endochondral and perichondral bone structures could be demonstrated in the 20-week fetus but not in the 34-week fetus. They appear to constitute two different conditions. These cases are good examples of the possibilities brought by ultrasound to the analysis of the fetal phenotype in utero.     

Thanatophoric dysplasia in identical twins.

Female twins concordant for thanatophoric dysplasia are presented. Monozygosity was confirmed using minisatellite DNA genetic fingerprinting. The evidence supporting new dominant mutations as the likely cause of thanatophoric dysplasia is reviewed.     

Mosaic trisomy 11p in monozygotic twins with discordant clinical phenotypes

We report on monozygotic (MZ) twins with a de novo mos 46,XX,der(15)t(11;15)(p12;p11.2)/46,XX karyotype varying in different tissues. The clinical presentation and findings at the cytogenetic level are described. One of the infants had definite minor anomalies at birth, also found in other cases of trisomy of 11p resembling the Beckwith-Wiedemann syndrome. Theoretical backgrounds regarding the string of events leading to the cytogenetic findings in these twins and the various factors that might have contributed to the dissimilarities in phenotype between these twins are discussed.     

Trisomy 13 in monozygotic twins discordant for major congenital anomalies.

The occurrence of trisomy 13 in twins is very rare. We report a pair of genotypically identical twins with trisomy 13 discordant for major anomalies. This case contributes to the already published data on the contribution of non-genetic factors to the aetiology of congenital malformations in monozygotic twins.     

EEG differences in monozygotic twins discordant and concordant for schizophrenia

In an electroencephalographic (EEG) study of 27 pairs of monozygotic (MZ) twins discordant for schizophrenia, 13 pairs of MZ twins concordant for schizophrenia, 40 pairs of healthy MZ twins, and 91 healthy, unrelated subjects with repeated assessments, we investigated (a) the trait quality of brainwave patterns with respect to interindividual differences, intraindividual stability over time, and within-pair MZ concordance; (b) the EEG characteristics that enable discrimination between affected and unaffected individuals; and (c) the EEG characteristics that reflect the severity of illness. In comparison with healthy control subjects, the MZ twins who were discordant and concordant for schizophrenia exhibited a much lower within-pair EEG concordance, so that EEG abnormalities associated with schizophrenia and manifested differently in the co-twins concordant for schizophrenia seemed to reflect nongenetic, pathological developments of genetically identical brains.     

Bronchial reactivity and allergy-promoting factors in monozygotic twins discordant for allergic rhinitis.

Bronchial reactivity was studied twice in eight monozygotic twin pairs discordant for allergic rhinitis with pollen hypersensitivity, during the winter season (all eight pairs) and during the pollen season (seven pairs). On both occasions, the allergic twins showed significantly higher reactivity than their nonallergic siblings. The results indicate that moderate allergic rhinitis is associated with increased bronchial reactivity. This increased reactivity is an acquired trait; however, bronchial reactivity is not constantly increased in pollen rhinitis and may be normal even during the pollen season. The symptoms of allergic rhinitis usually started in childhood before the separation of the siblings. We could not demonstrate any major differences in exposure to allergens or airway irritants between the siblings. The allergic twins tended to have lower birth weight and insufficient weight increase just after birth.     

An fMRI study in monozygotic twins discordant for obsessive-compulsive symptoms

To examine neurobiological changes underlying obsessive-compulsive symptoms (OCS) we examined intrapair differences in behavior and fMRI brain activation in monozygotic twins discordant for OCS, using a Tower of London planning paradigm. Despite only mild evidence for impairment at the behavioral level, twins with OCS showed significantly decreased brain activation during planning in dorsolateral prefrontal cortex, thalamus pulvinar, and inferior parietal cortex. These findings are consistent with the hypothesis of disturbed cortico-striato-thalamo-cortical (CSTC) circuitry underlying OCS. In contrast to previous studies in patients with obsessive-compulsive disorder (OCD) we did not find robust evidence for reduced responsiveness in striatal brain regions. Together, these findings suggest that neurobiological mechanisms underlying OCS of environmental origin partly overlap with neurobiological changes in patients with OCD, where the disorder is likely caused by a combination of genetic and environmental influences. A difference between genetical and environmental etiologies may relate to the amount of reduced striatal responsiveness.     

Cognitive processing in monozygotic twins discordant for chronic fatigue syndrome

Twenty-one pairs of monozygotic twins discordant for chronic fatigue syndrome (CFS) and 21 matched healthy control (HC) subjects were assessed with 5 untimed tests and 5 timed tests from the computer-based NeuroCognitive Assessment Battery (R. K. Mahurin, 1993). Random effects regression showed no difference between CFS and healthy twins on any of the cognitive tests. Further, the twin groups did not differ from the HC group on any content-dependent measure. In contrast, both sets of twins performed worse than the HC group on all speed-dependent tests except Finger Tapping. Self-rated fatigue and dysphoric mood were only weakly correlated with cognitive performance. These data point toward a shared genetic trait related to information processing that is manifest in the CFS context. The findings have implications for differentiating genetic and acquired vulnerability in the symptomatic expression of the disorder. ((c) 2004 APA, all rights reserved)     

fMRI and corpus callosum relationships in monozygotic twins discordant for handedness

To further investigate brain structure and function in 26 handedness discordant monozygotic twin pairs (MzHd), MRI and behavioural assessments were carried out. These showed significant correlation between language-specific functional laterality in inferior and middle frontal gyri, and anterior corpus callosum. Previous studies of handedness discordant monozygotic twins failed to resolve the issue concerning handedness and hemispheric laterality for language due to methodological disparities. The results would be relevant to genetic theories as well as to brain structure:function explanations. MzHd twins underwent MRI and fMRI scanning as well as behavioural assessment of motor performance and cognition. There were significant differences on MRI and fMRI laterality measures, as well as a significant correlation between anterior callosal widths and functional laterality. LH twins showed higher frequencies of atypical functional laterality. There was no significant within-twin pair correlation on fMRI verbal laterality, nor did results show within-twin pair differences on verbal fluency or IQ. Implications for the field of laterality research pertain to frontal hemispheric equipotentiality for verbal processes in healthy individuals. In particular, there can be an apparent lack of cognitive `cost’ to atypical laterality. An fMRI verbal laterality index correlated significantly with corpus callosum widths near Broca’s area.     

Anatomical abnormalities in the brains of monozygotic twins discordant for schizophrenia

Recent neuroradiologic and neuropathological studies indicate that at least some patients with schizophrenia have slightly enlarged cerebral ventricles and subtle anatomical abnormalities in the region of the anterior hippocampus. Using magnetic resonance imaging (MRI), we studied 15 sets of monozygotic twins who were discordant for schizophrenia (age range, 25 to 44 years; 8 male and 7 female pairs). For each pair of twins, T1-weighted contiguous coronal sections (5 mm thick) were compared blindly, and quantitative measurements of brain structures were made with a computerized image-analysis system. In 12 of the 15 discordant pairs, the twin with schizophrenia was identified by visual inspection of cerebrospinal fluid spaces. In two pairs no difference could be discerned visually, and in one the twin with schizophrenia was misidentified. Quantitative analysis of sections through the level of the pes hippocampi showed the hippocampus to be smaller on the left in 14 of the 15 affected twins, as compared with their normal twins, and smaller on the right in 13 affected twins (both P less than 0.001). In the twins with schizophrenia, as compared with their normal twins, the lateral ventricles were larger on the left in 14 (P less than 0.003) and on the right in 13 (P less than 0.001). The third ventricle also was larger in 13 of the twins with schizophrenia (P less than 0.001). None of these differences were found in seven sets of monozygotic twins without schizophrenia who were studied similarly as controls. We conclude that subtle abnormalities of cerebral anatomy (namely, small anterior hippocampi and enlarged lateral and third ventricles) are consistent neuropathologic features of schizophrenia and that their cause is at least in part not genetic. Further study is required to determine whether these changes are primary or secondary to the disease.     

Subjective and objective sleepiness in monozygotic twins discordant for chronic fatigue syndrome

STUDY OBJECTIVE: To examine the association of chronic fatigue syndrome (CFS) with measures of objective and subjective sleepiness. DESIGN: Monozygotic co-twin control study. SETTING: Academic medical center. PATIENTS AND PARTICIPANTS: Twenty monozygotic twin pairs discordant for CFS. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: All twins completed an Epworth Sleepiness Scale (ESS), 4 Stanford Sleepiness Scales (SSS), and underwent a standard 4-nap multiple sleep latency test. We compared the ESS scores, average SSS scores, and average sleep latency in CFS and healthy twins. The CFS twins reported more sleepiness as measured by mean scores on the ESS (10.9 vs 8.2; 95% confidence interval [CI] = 0.3-5.5; P = .03) and the SSS (3.4 versus 2.1; 95% CI = 0.7-1.9; P < .001). The mean sleep latency on the Multiple Sleep Latency Test was not significantly different between the CFS and healthy twins (8.9 vs 10.0 minutes; 95% CI -4.4-1.7; P = .33). Mean SSS scores increased among the CFS twins and decreased among healthy twins from nap 1 to nap 4 (P < .001). The individual ESS scores and mean sleep latencies on the Multiple Sleep Latency Test were negatively correlated for all the twins (Pearson's r = - 0.40; P = .01), with a slightly stronger association among the healthy twins (Pearson's r = -0.42, P = .07) than the CFS twins (Pearson's r = -0.36, P = .15). CONCLUSIONS: CFS twins reported significantly more subjective sleepiness than their healthy co-twins despite similar nonpathologic mean sleep latencies on the Multiple Sleep Latency Test. Patients with CFS may mistake their chronic disabling fatigue for sleepiness.     

Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder

Studies of the major psychoses, schizophrenia (SZ) and bipolar disorder (BD), have traditionally focused on genetic and environmental risk factors, although more recent work has highlighted an additional role for epigenetic processes in mediating susceptibility. Since monozygotic (MZ) twins share a common DNA sequence, their study represents an ideal design for investigating the contribution of epigenetic factors to disease etiology. We performed a genome-wide analysis of DNA methylation on peripheral blood DNA samples obtained from a unique sample of MZ twin pairs discordant for major psychosis. Numerous loci demonstrated disease-associated DNA methylation differences between twins discordant for SZ and BD individually, and together as a combined major psychosis group. Pathway analysis of our top loci highlighted a significant enrichment of epigenetic changes in biological networks and pathways directly relevant to psychiatric disorder and neurodevelopment. The top psychosis-associated, differentially methylated region, significantly hypomethylated in affected twins, was located in the promoter of ST6GALNAC1 overlapping a previously reported rare genomic duplication observed in SZ. The mean DNA methylation difference at this locus was 6%, but there was considerable heterogeneity between families, with some twin pairs showing a 20% difference in methylation. We subsequently assessed this region in an independent sample of postmortem brain tissue from affected individuals and controls, finding marked hypomethylation (>25%) in a subset of psychosis patients. Overall, our data provide further evidence to support a role for DNA methylation differences in mediating phenotypic differences between MZ twins and in the etiology of both SZ and BD.     

Holoprosencephaly in monozygotic twins – clinical and computer tomographic findings

Of monozygotic male twins with holoprosencephaly, one showed by computer tomographic (CAT) scan a mild type with orbital hypotelorism, flat nose, bilateral cleft lip, and cleft palate associated with an intermaxillary rubital hypotelorism, flat nose, absent nasal bridge, and median cleft lip. Lymphocyte chromosomes were apparently normal. A review of the literature shows a heterogenous patient material in that most pertinent cases involved dizygotic twins, and some of these presumably had chromosome abnormalties.