The association of chromosomal imbalances and neurologic abnormalities is well known.
To describe a family with 2 brothers presenting with 15q trisomy due to a maternal equilibrated translocation involving chromosomes 12 and 15.
Design, Setting, and Patients
Among patients with epilepsy followed up in our hospital, we identified 2 brothers with epilepsy and mental retardation who presented dysmorphic features. Detailed clinical, electroencephalographic, and magnetic resonance imaging investigation was performed. In addition, we collected blood samples for karyotyping.
Clinical findings included minor dysmorphic features, mental retardation, abnormal behavior, and secondary generalized epilepsy. Electroencephalography showed left temporal slow waves in the older brother and background abnormality associated with generalized and multifocal epileptiform discharges in the other. Their magnetic resonance images showed mesial temporal lobe malformation, including the hippocampus and parahippocampal and fusiform gyri, with abnormal shape and axis.
To our knowledge, this is the first report of mesial temporal lobe malformation associated with chromosomal abnormalities. Our finding may contribute to the understanding of the genetic mechanisms involved in central nervous system malformations, especially in the mesial temporal lobe structures.
THE NEUROBIOLOGICAL aspects of abnormal cortical development and epilepsy have been poorly understood and represent a high priority in clinical neuroscience. Identifiable harmful events that may lead to these disorders include prenatal infections, vascular failure, and genetic factors such as single gene mutations, polygenic or multifactorial influences, and chromosome imbalances.
Since the development of new cytogenetic techniques, many partial trisomies and monosomies have been described in malformative syndromes, allowing a better definition of these disorders. The distal 15q trisomy is associated with a clinical picture characterized mainly by mental retardation, postnatal growth retardation, epilepsy (usually generalized seizures), and additional malformations. To date, no magnetic resonance (MR) imaging studies in patients with 15q trisomy have been reported, and computed tomographic scans detected only cranial abnormalities such as microcephaly or craniosynostosis.1 We describe herein the clinical presentation, MR imaging findings, and cytogenetic findings in 2 brothers with 15q trisomy due to a maternal equilibrated translocation involving chromosomes 12 and 15. In addition, we present data on the extended family.
Among patients with epilepsy followed up in our hospital, we identified 2 brothers (Figure 1) with epilepsy and mental retardation who presented dysmorphic features. The seizures and epilepsy syndrome, as well as the development milestones, were characterized by clinical history. In addition, we performed detailed neurologic and dysmorphologic examinations, including cognitive evaluation with estimated IQ (Wechsler Adult Intelligence Scale–Revised and Wechsler Intelligence Scale for Children–Revised) in both patients and all available relatives.
Pedigree of the family studied. Proband is indicated by an arrow (IV:10). Squares indicate males; circles, females; triangles in generation III, spontaneous abortions; half-filled symbols, individuals with the balanced translocation, ie, 46,X_,t(12;15)(p13.3;q26.2); symbols filled with dark gray shading, individuals with partial trisomy of chromosome 15, 46,X_,der(12)t(12;15)(p13.3;q26.2); and double line, consanguineous marriage. Individual IV:7 was referred as having a normal karyotype (46,XY?); however, it was performed almost 20 years ago with no banding.
After obtaining informed consent, we collected blood samples for cytogenetic studies on short-term culture of peripheric blood lymphocytes by means of standard G-banding technique. In addition, we performed routine interictal electroencephalograms using the international 10-20 system for electrode placement and MR images. Imaging studies were conducted in a 2-T scanner (Elscint-Prestige; Elscint Ltd, Haifa, Israel) including T1- and T2-weighted images in 3 orthogonal planes with 3- to 6-mm slices. We also performed a T1 volumetric acquisition with 1-mm thickness. The MR imaging analyses included detailed visual evaluation and multiplanar reconstruction using a workstation for 3-dimensional image reformatting.
Individual III:8 was a 42-year-old woman who was asymptomatic and had a normal IQ. Cytogenetic evaluation identified a chromosomal translocation, with 46,XX,t(12:15)(p13.3;q26.2) constitution. Her MR image showed only diffuse subcortical T2 hyperintense lines, with temporal predominance and small temporal pole arachnoid cysts.
Individual IV:7 was a male, born at term with a birth weight of 2260 g and length of 44 cm. He had died at 6 months of age. We assessed his medical records, including pictures, and determined that he had had multiple malformations detected at birth. These included severe microcephaly, low frontal hairline, arched eyebrows, left microphthalmos, right anophthalmos, prominent upper lip with thin lips, micrognathia, malformed external ears, umbilical hernia, ectopic testes, and balanoprepucial hypospadia (Figure 2A). A low-resolution cytogenetic evaluation performed at the time of death, 20 years earlier, was considered normal; however, his clinical features suggest that he had a 15q monosomy.
A, Individual IV:7, showing severe microcephaly, low frontal hairline, arched eyebrows, left microphthalmos, right anophthalmos, prominent upper lip with thin lips, micrognathia, and malformed external ears, suggestive of 15q monosomy. B, Individual IV:8, showing dysmorphic ears and broad nasal bridge. C, Patient IV:10, with dysmorphic ears, broad nasal bridge, hypertelorism, and long nasolabial philtrum.
Individual IV:8 (Figure 2B), a 19-year-old man, had been born at term after an uncomplicated pregnancy and delivery; birth weight was 3110 g and length was 47 cm. Neuropsychomotor milestones showed no abnormalities, but a borderline IQ (70) was identified. He developed generalized tonic-clonic seizures at age 3 years, with satisfactory control on medication. In addition, he showed abnormal behavior with heteroaggressivity, controlled with medication. Dysmorphologic evaluation showed short stature, dysmorphic ears, broad nasal bridge, and scoliosis. His electroencephalogram showed left temporal slow waves. The MR image showed mesial temporal region malformation (more evident on the left side), with altered axis and shape of the hippocampus and fusiform and parahippocampal gyri (Figure 3). An additional imaging finding was corpus callosum malformation (not shown). Cytogenetic evaluation showed a 46,XY,der(12)t(12;15)(p13.3; q26.2) constitution resulting in a partial 15q trisomy.
Magnetic resonance imaging findings in individuals IV:8 (A) and IV:10 (B), showing the mesial temporal malformation pattern (arrows), with abnormal axis and shape including the hippocampus and parahippocampal and fusiform giri.
Individual IV:10 (Figure 2C), an 18-year-old man, had been born at term after an uncomplicated pregnancy and delivery; birth weight was 3530 g and length was 49 cm. He had an abnormal neuropsychomotor development with severe mental retardation and abnormal behavior. Estimated IQ could not be determined because he was not able to perform the requested tests. At age 8 years he began to have generalized seizures with poor control despite medication. Dysmorphologic evaluation showed short stature, dysmorphic ears, broad nasal bridge, hypertelorism, long nasolabial philtrum, high arched palate, scoliosis, and short fingers. His electroencephalogram showed abnormal background activity with generalized and multifocal epileptiform activity. The MR image showed mesial temporal region malformation (more evident on the left side), with altered axis and shape of the hippocampus and fusiform and parahippocampal gyri (Figure 3), as well as corpus callosum malformation. Additional findings were bilateral temporal pole arachnoid cysts and diffuse subcortical T2 hyperintense lines, perpendicular to the gyri. Cytogenetic evaluation showed a 46,XY,der(12)t(12;15)(p13.3;q26.2) constitution resulting in a partial 15q trisomy. This patient died suddenly while sleeping at age 18 years, but autopsy was not performed.
Individual IV:11 16-year-old girl, had been born after an uncomplicated pregnancy and delivery; she had normal neuropsychomotor development. She had never had seizures but showed facial dysmorphism similar to her 2 brothers (individuals IV:8 and IV:10). She had an estimated IQ of 86 but had important learning difficulties; her karyotype showed an 46,XX,t(12:15)(p13.3;q26.2) constitution, which was the same chromosomal translocation seen in her mother (III:8). The MR image showed the same abnormalities observed in individuals IV:8 and IV:10.
Individual IV:12 was a 15-year-old boy who had a normal phenotype and karyotype. His MR image showed only diffuse hyperintense T2 lines.
Individual III:6, a 46-year-old woman, had been born at home and had been very small according to information obtained from her sister (III:8). During her first year of life she had a febrile convulsion and delayed neuropsychomotor development. She started having tonic-clonic seizures in adulthood, partially controlled by medication. She presented with a clear cognitive deficit; however, we were unable to perform IQ testing because of her severe mental retardation and abnormal behavior. On physical examination we observed short stature, long face, high forehead, telecanthus, prognathism, flat philtrum, thin lips, and short fifth finger with camptodactyly. Neurologic examination showed no focal signs. Her interictal electroencephalogram was considered normal, and the MR image showed multiple areas of gliosis attributed to head trauma, but no identifiable hippocampal abnormalities. The cytogenetic evaluation showed a 46,XX,der(12)t(12;15)(p13.3;q26.2) constitution (partial 15q trisomy).
Individual III:9, a 42-year-old man, showed no abnormalities on clinical examination, with a normal IQ. The MR image was normal and his karyotype showed the same balanced translocation (46,XY,t[12;15][p13.3;q26.2]) seen in his sister (individual III:8). His children, aged 7 and 18 years, who were not examined, had normal development and no seizures.
Cytogenetic abnormalities on chromosome 15 have been associated with epilepsy and mental retardation with a wide range of clinical presentations. Partial trisomy for this chromosome has been reported more often than for any other chromosome of the D-group.2 Duplications of the short arm and proximal segment of the long arm of chromosome 15 are among the most common rearrangements involving this chromosome, whereas duplications involving the distal long arm are less frequent and complete trisomy 15 is very rare in liveborn infants.3
The clinical picture of duplication of the distal half of the long arm of chromosome 15 is quite variable, including developmental delay, growth retardation, dysmorphic craniofacial appearance, skeletal abnormalities, and hand abnormalities. Some patients exhibit only a few dysmorphic features.1 Mental retardation is the most common finding,1,3,4 and the performance seems to depend directly on the size of the duplication.3 Growth retardation of postnatal onset is also a frequent sign, and seizures occur in at least 30% of these patients.1,3,4 There is a male-to-female preponderance of 1.6:1.1
After the first report of partial trisomy of the long arm of chromosome 15,5 many other patients were identified, with the proximal break point ranging from 15q21 to 15q26. The more proximal breakpoints (15q21 to 15q23) were more likely to be found.1 Most cases are due to an unbalanced segregation of a familial translocation,1,3,6 and most of these abnormalities are maternally inherited.3,7
One of the first reports of abnormal central nervous system structures in vivo was the description of a girl with partial trisomy 15.2 In this report, a pneumoencephalogram showed reduced lateral ventricules combined with an enlarged left temporal horn and some enlarged sulci in the right frontotemporal cortex. A few reports of MR images in patients with abnormalities on chromosome 15 have been published. Leonard et al8 found a significantly larger proportion of anomalous fissures among children with Angelman syndrome than in children with Prader-Willi syndrome. Battaglia et al7 described 4 patients with the inv dup(15) syndrome, which results in 15p tetrasomy and 15q partial tetrasomy including the Prader-Willi/Angelman critical region, 3 of them with normal MR images.
We observed different MR imaging findings in patients with the same karyotype in 2 different generations: patients III:8, III:9, and IV:11 had the balanced translocation 46,X_,t(12;15)(p13.3;q26.2), but different MR imaging findings: individuals III:8 and III:9 showed no mesial temporal lobe abnormalities, whereas patient IV:11 had hippocampal malformation. Individuals III:6, IV:8, and IV:10, all with partial 15q trisomy, also had different MR imaging findings: individual III:6 presented with no mesial temporal lobe malformation, as opposed to patients IV:8 and IV:10, who had clear-cut hippocampal abnormalities. One possible explanation for this finding is the phenomenon of imprinting, in which clinical manifestation depends on the parental origin of the abnormal chromosome. In generation IV, the chromosomal abnormality was maternally inherited. However, the parental origin of the abnormal chromosome in generation III could not be determined, since none of the parents were available for testing. There is strong clinical and experimental evidence of maternal and paternal imprinted genes on chromosome 15q.9 Thus, if in generation III the chromosomal abnormality was transmitted through the paternal line, critical genes for mesial temporal structures development could be silenced and only the normal maternally transmitting genes would be active, leading to normal hippocampal structures in individuals III:6, III:8, and III:9. By contrast, the maternally inherited abnormality would have full clinical expression in individuals in the fourth generation, leading to malformations of mesial temporal structures in patients IV:8, IV:10, and IV:11. That the offspring of individual III:9 (male with balanced translocation) were asymptomatic corroborates our theory, although they have not been karyotyped. Alternatively, one should be aware of the usual clinical variability seen in patients with chromosomal syndromes, as well as a maternal effect, with possible duplication or deficiency of genes expressed in the oocyte, when there is maternal transmission of the translocation.
Our finding of clear-cut hippocampal abnormalities in patients with partial 15q trisomy and a family member with a translocation involving chromosomes 12 and 15 suggests that this chromosomal region may contain genes that are important for the development of mesial temporal lobe structures. A more comprehensive understanding of the role of this chromosomal region in central nervous system development will depend on the description of additional patients with chromosomal 15q abnormalities. Human chromosomal abnormalities have been critical to localize genes involved in many disorders, including other types of central nervous system malformations.10,11 Thus, we strongly recommend that detailed neuroimaging studies should be performed in patients with such chromosomal imbalances.
Accepted for publication December 27, 2001.
Author contributions:Study concept and design (Drs Kobayashi, Facchin, Steiner, Cendes, and Lopes-Cendes); acquisition of data (Drs Kobayashi, Facchin, Cendes, and Lopes-Cendes and Ms Leone); analysis and interpretation of data and critical revision of the manuscript for important intellectual content (Drs Kobayashi, Facchin, Steiner, Campos, Cendes, and Lopes-Cendes and Ms Leone); drafting of the manuscript (Drs Kobayashi, Facchin, Steiner, and Lopes-Cendes); obtained funding (Dr Lopes-Cendes); administrative, technical, or material support (Drs Kobayashi, Facchin, Steiner, and Campos and Ms Leone); and study supervision (Drs Cendes and Lopes-Cendes).
Dr Kobayashi is the recipient of a scholarship from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), São Paulo, Brazil, and Dr Facchin is the recipient of a scholarship from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brasília, Brazil. Drs Cendes and Lopes-Cendes are supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brasília, Brazil. This study was supported by grants from FAPESP (Drs Cendes and Lopes-Cendes).
Corresponding author and reprints: Iscia Lopes-Cendes, MD, PhD, Departamento de Genética Médica, Faculdade de Ciências Médicas—UNICAMP, Caixa Postal 6111, Cidade Universitária Zeferino Vaz, Campinas SP, Brazil, CEP 13083-970 (e-mail: firstname.lastname@example.org).
Kobayashi E, Facchin D, Steiner CE, Leone AAA, Campos NLV, Cendes F, Lopes-Cendes I. Mesial Temporal Lobe Abnormalities in a Family With 15q26qter Trisomy. Arch Neurol. 2002;59(9):1476-1479. doi:10.1001/archneur.59.9.1476