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Macrocephaly and chromosome disorders: a case report
ELSEVIER
Brain & Development 1996; 18:312-315
Case report
Macrocephaly and chromosome disorders: a case report Paola Drigo *, Sabina CarrY, Anna Maria Laverda, Lina Artifoni Department of Pediatrics, University of Padua, Via Giustiniani 3, 35128 Padova, Italy Received 5 October 1995; accepted 13 February 1996
We report the case of a young patient with macrocephaly. After excluding the most frequent causes of macrocephaly (hereditary disorders, degenerative, osseous and metabolic diseases, neurocutaneous syndromes and cerebral malformations), the likelihood of a chromosome disorder was investigated, revealing an unbalanced de novo translocation: 46,X,der(X),t(X;7) (q13 or q13.2; q11.23 or q21.11), i.e., a partial trisomy of the long arm of chromosome 7, associated with a partial monosomy of the long arm of chromosome X. Though this chromosome disorder is relatively rare, it should be considered in the differential diagnosis of patients under one year of age presenting with macrocephaly, scoliosis and non-progressive psychomotor retardation. Keywords: Macrocephaly; Scoliosis; Chromosome disorder; Unbalanced translocation X;7
1. I N T R O D U C T I O N Macrocephaly is one of the most common reasons for consulting a neuropediatrician and may be due to degenerative, osseous and metabolic diseases, neurocutaneous syndromes and cerebral malformations. This case report describes a young patient whose macrocephaly was associated with a chromosome disorder, which is a relatively rare finding [1].
2. C A S E R E P O R T The patient is the first-born daughter of unrelated parents. The mother has generalized epilepsy and goiter; she received no medication during the pregnancy, which culminated in normal delivery at the 36th week of gestation. At birth, the child's weight was in the 5th percentile, her length was in the 25th percentile and her head circumference was in the 10th percentile [2]; the Apgar score was 9 at 1 rain and 10 at 5 min. The neonatal period was marked by hypotonia, hyporeactivity and sucking problems. At 2 months old, when first seen, the child presented macrocephaly (head circumference in the 95th percentile), with a weight between the 25th and 50th percentile and a length in the 25th percentile. On neurological examination, it was found that she failed to fix or follow a visual target and she did not smile;
* Corresponding author. Fax: (39) (49) 8213509.
she had axial hypotonia and lower limb hypertonia with hyperactive reflexes. The ophthalmological examination showed normal ocular findings. Visual evoked potentials to flash stimuli at two months and at follow-up during the first year of life were normal. Brainstem auditory evoked potentials at two months showed a normal morphology, with interpeak latency (IPL) I - V at the third SD corresponding to a normal child of less than one month of age. At follow-up, a progressive reduction in IPL I - V was observed, without achieving normal values at the latest check-up (1 year). The CT scan revealed diffuse white matter hypodensity with normal ventricles and scarce evidence of the cerebral sulci (Fig. 1A). Since the clinical picture was suggestive of a degenerative disease of leukodystrophic type, particularly Canavan disease, we measured the lysosomal enzymes and N-acetylaspartic acid in urine: these were found to be within the normal range. At 6 months old, the child showed macrocephaly (head circumference beyond the 95th percentile) with a weight in the 10th percentile and length in the 50th percentile and signs of minor dysmorphism like a prominent forehead, epicanthus, 'anti-Down' palpebral fissures, small nose, an elongated filtrum, high arched palate, normally shaped low-set ears (Fig. 2); furthermore signs of scoliosis, due to an abnormal muscle tone, were present; X-ray and CT scan of the spine excluded vertebral abnormalities or malformations. The neurological picture remained unchanged. CT scan of the brain showed no densitometric anomaly in the white matter, though there was a slight ventricular dilatation (Fig. 1B).
0387-7604/96//$15.00 Copyright © 1996 Elsevier Science B.V. All rights reserved. PII S03 87-7604(96)00025-3
P. Drigo et al./Brain & Development 1996; 18:312-315
313
Given the lack of elements compatible with degenerative disease or any apparent metabolic causes or malformations to explain the macrocephaly, and also in view of the minor dysmorphic signs, a cytogenetic investigation was performed. This revealed an unbalanced de novo translocation: 46,X,der(X),t(X;7) (q13 or q13.2; q11.23 or q21.11), i.e., a partial trisomy of the long arm of chromosome 7 associated with a partial monosomy of the long arm of chromosome X (Fig. 3 and Fig. 4). The child is now 5 years old; her neurological situation is characterized by tetraparesis with axial hypotonia and some improvement in psychomotor performance: she smiles on social contact, listens to voices, is able to make repetitive consonant sounds, such as ba-ba, ma-ma, and to transfer an object from one hand to the other. She can keep her head erect, but is unable to sit alone, stand or walk. The patient has persistent severe scoliosis and macrocephaly (95th %ile).
3. D I S C U S S I O N
Fig. 2. Patient at age 5 years: macrocephaly, prominent forehead, epicanthus, 'anti-Down' palpebral fissures, small nose, elongated filtrum, normally shaped low-set ears. Reproduced with mother's written consent.
Macrocephaly is commonly defined as a skull circumference that exceeds the mean by two or more standard deviations for the age and sex [3]. Gooskens et al. [4] suggest that there are three main pathogenic alterations: (i) anatomical (neuron proliferation or a reduction in the neuron component, possibly due to glial growth), as in the case of neurocutaneous syndromes, growth disorders (achondroplasia, Beckwith-Wiedemann syndrome, etc.), Klinefelter syndrome, familial megalencephalia, etc.;
Fig. 1. A: CT: diffuse white matter hypodensity with normal ventricles and scarce evidence of the cerebral sulci. B: CT: no densitometric anomaly in the white matter; slight ventricular dilatation.
314
P. Drigo et al. / Brain & Development 1996; 18:312-315
(ii) dynamic (alterations in cerebrospinal fluid dynamics), as in hydrocephalus; (iii) metabolic (lysosomal or demyelinating pathologies), such as in mucolipidosis, mucopolysaccharidosis, sphingolipidosis, amino acid disorders, leukodystrophies, etc. Our patient's macrocephaly was associated with a chromosome disorder and should consequently be included in the first of these groups. The etiologic diagnosis of a chromosome disorder in the patient reported here was reached after excluding the more common causes of macrocephaly. The clinical picture was open to various diagnostic interpretations: (a) at the age of 2 months, a cerebral malformation or hydrocephalus was suggested by the finding of macrocephaly and hypotonia: both possibilities were excluded by ultrasound and the CT scan. The finding of a developmental delay, together with the hypodense CT images prompted the hypothesis of a leukodystrophy due to a degenerative disease of neonatal onset. However, lysosomal enzyme measurements within the normal range and the finding that N-acetylaspartic acid in the urine was not increased enabled us to exclude Canavan disease and other degenerative pathologies typical of this age group. (b) at the age of 6 months, the presence of macrocephaly, axial hypotonia with ,hyperactive reflexes, and mental retardation led to a diagnosis of non-progressive encephalopathy, though this
Fig. 4. Partial Q-bandedkaryotypes of the three differentmetaphases: on the right, chromosomesX; on the left, chromosomes7. Arrow designates the der(X),t(X;7) (q13 or q13.2; ql 1.23 or q21.11).
Fig. 3. Proband's karyotype (QFQ banding).
would fail to explain the macrocephaly and scoliosis (the latter is frequent in children with cerebral palsy, but only after the child has begun to sit or stand). The negative findings emerging from the tests and from the neonatal clinical history, combined with the dysmorphic signs, led to the performance of cytogenetic investigations, which enabled us to attribute the macrocephaly and scoliosis to the chromosome 7 alterations. In fact, as mentioned by Forabosco et al. [1], macrocephaly is rare in chromosome syndromes generally, but it is found in 51% of cases with duplication of the long arm of chromosome 7. The kyphoscoliosis observed by the authors in 23% of these cases had already been associated with duplication of the chromosomal segment 7 q32 ~ qter [5], which was found in triplicate in our patient. The correlation between phenotypic alterations and partial trisomy of the long arm of chromosome 7 remains a controversial matter, however: while some authors [5,6] indicate distinct dysmorphic syndromes as being associated with the duplication of various chromosomal segments, Forabosco et al. [1] consider the majority of the clinical symptoms as non-specific. On the other hand, there is a correlation between the evolution and survival of these subjects and the extent of the chromosome segment involved in the rearrangement: 60% of cases with duplications comparable with the one observed in our patient do not survive beyond the neonatal period [1]. Our case differs from others in the literature, however, both because the trisomy includes almost all of the long arm of chromosome 7, and because it is the only case (to our knowl-
P. Drigo et al./Brain & Development 1996; 18:312-315
edge) of an unbalanced translocation X;7. Involvement of the X chromosome obliges us to consider the problems related to inactivation of the spreading effect. In females with unbalanced X / A translocations, a balanced gene dosage is frequently achieved by inactivation of the abnormal X and its attached autosome segment. The inactivation center on the long arm of chromosome X, located in the q13 region [7-9] has a spreading effect that has been reported for several chromosomes [10]. Most of them showed attenuated effects of the trisomic autosome. It has been suggested that the effects are probably related to the spreading of the inactivation center [ 10,11 ]. The association, in the first year of life, of macrocephaly, scoliosis and non-progressive psychomotor retardation without any brain anomalies consequently deserves the pediatrician's attention: it is worth performing a cytogenetic study in such cases to seek any chromosomal disorder involving the long a n n of chromosome 7 - - also with a view to enabling prenatal diagnosis in a subsequent pregnancy.
REFERENCES 1. Forabosco A, Baroncini A, Dalprh L, et al. The phenotype of partial dup(7q) reconsidered: a report of five new cases. Clin Genet 1988; 34: 48-59. 2. Hamill PVV, Drizd TA, Johnson CL, et al. Physical growth: national center for health statistics percentiles. Am J Clin Nutr 1979; 32: 607-29.
315
3. De Myer W. Microcephaly, micrencephaly, megalocephaly and megalencephaly. In: Swaiman KF, ed. Pediatric neurology, 2nd ed., St Louis, MO: Mosby, 1994: 208-10. 4. Gooskens RHJM, Willemse J, Bijlsma JB, Hanlo PW. Megalencephaly: definition and classification. Brain Dev (Tokyo) 1988; 10: 1-7. 5. Novales MA, Femfindez-Novoa C, Hevia A, San Martin V, Galera H. Partial trisomy for the long arm of chromosome 7. Case report and review. Hum Genet 1982; 62: 378-81. 6. Bartsch O, Kalbe U, Nhan Ngo TK, Lettau R, Schwinger E. Clinical diagnosis of partial duplication 7q. Am J Med Genet 1990; 37: 254-7. 7. Pettigrew AL, McCabe ER, Elder FF, Ledbener DH. Isodicentric X chromosome in a patient with Turner syndrome - - implications for localization of the X-inactivation center. Hum Genet 1991; 87: 498-502. 8. Muscatelli F, Lena D, Mettei MG, Fontes M. A male with two contiguous inactivation centers on a single X chromosome: study of inactivation and XIST expression. Hum Mol Genet 1992; 1:115-9. 9. Turner Z, Tommerup N, Tonnesen T, Kreuder J, Craig IW, Horn N. Mapping of the Menkes locus to Xq13.3 distal to the X-inactivation center by an intrachromosomal insertion of the segment Xq13.3q21.2. Hum Genet 1992; 88: 668-72. 10. Elejalde BR, de Elejalde MM. Phenotypic manifestations of the X-autosome translocations. In: Sandberg AA, ed. Cytogenetics of the mammalian X chromosome. Part B: X chromosome anomalies and their clinical manifestations. New York: Alan R Liss, 1983: 225-44.
11. Couturier J, Dutrillaux B, Garber P, et al. Evidence for a correlation between late replication and autosomal gene inactivation in a familial translocation t (X;21). Hum Genet 1979; 49: 319-26.
Brain & Development 1996; 18:312-315
Case report
Macrocephaly and chromosome disorders: a case report Paola Drigo *, Sabina CarrY, Anna Maria Laverda, Lina Artifoni Department of Pediatrics, University of Padua, Via Giustiniani 3, 35128 Padova, Italy Received 5 October 1995; accepted 13 February 1996
We report the case of a young patient with macrocephaly. After excluding the most frequent causes of macrocephaly (hereditary disorders, degenerative, osseous and metabolic diseases, neurocutaneous syndromes and cerebral malformations), the likelihood of a chromosome disorder was investigated, revealing an unbalanced de novo translocation: 46,X,der(X),t(X;7) (q13 or q13.2; q11.23 or q21.11), i.e., a partial trisomy of the long arm of chromosome 7, associated with a partial monosomy of the long arm of chromosome X. Though this chromosome disorder is relatively rare, it should be considered in the differential diagnosis of patients under one year of age presenting with macrocephaly, scoliosis and non-progressive psychomotor retardation. Keywords: Macrocephaly; Scoliosis; Chromosome disorder; Unbalanced translocation X;7
1. I N T R O D U C T I O N Macrocephaly is one of the most common reasons for consulting a neuropediatrician and may be due to degenerative, osseous and metabolic diseases, neurocutaneous syndromes and cerebral malformations. This case report describes a young patient whose macrocephaly was associated with a chromosome disorder, which is a relatively rare finding [1].
2. C A S E R E P O R T The patient is the first-born daughter of unrelated parents. The mother has generalized epilepsy and goiter; she received no medication during the pregnancy, which culminated in normal delivery at the 36th week of gestation. At birth, the child's weight was in the 5th percentile, her length was in the 25th percentile and her head circumference was in the 10th percentile [2]; the Apgar score was 9 at 1 rain and 10 at 5 min. The neonatal period was marked by hypotonia, hyporeactivity and sucking problems. At 2 months old, when first seen, the child presented macrocephaly (head circumference in the 95th percentile), with a weight between the 25th and 50th percentile and a length in the 25th percentile. On neurological examination, it was found that she failed to fix or follow a visual target and she did not smile;
* Corresponding author. Fax: (39) (49) 8213509.
she had axial hypotonia and lower limb hypertonia with hyperactive reflexes. The ophthalmological examination showed normal ocular findings. Visual evoked potentials to flash stimuli at two months and at follow-up during the first year of life were normal. Brainstem auditory evoked potentials at two months showed a normal morphology, with interpeak latency (IPL) I - V at the third SD corresponding to a normal child of less than one month of age. At follow-up, a progressive reduction in IPL I - V was observed, without achieving normal values at the latest check-up (1 year). The CT scan revealed diffuse white matter hypodensity with normal ventricles and scarce evidence of the cerebral sulci (Fig. 1A). Since the clinical picture was suggestive of a degenerative disease of leukodystrophic type, particularly Canavan disease, we measured the lysosomal enzymes and N-acetylaspartic acid in urine: these were found to be within the normal range. At 6 months old, the child showed macrocephaly (head circumference beyond the 95th percentile) with a weight in the 10th percentile and length in the 50th percentile and signs of minor dysmorphism like a prominent forehead, epicanthus, 'anti-Down' palpebral fissures, small nose, an elongated filtrum, high arched palate, normally shaped low-set ears (Fig. 2); furthermore signs of scoliosis, due to an abnormal muscle tone, were present; X-ray and CT scan of the spine excluded vertebral abnormalities or malformations. The neurological picture remained unchanged. CT scan of the brain showed no densitometric anomaly in the white matter, though there was a slight ventricular dilatation (Fig. 1B).
0387-7604/96//$15.00 Copyright © 1996 Elsevier Science B.V. All rights reserved. PII S03 87-7604(96)00025-3
P. Drigo et al./Brain & Development 1996; 18:312-315
313
Given the lack of elements compatible with degenerative disease or any apparent metabolic causes or malformations to explain the macrocephaly, and also in view of the minor dysmorphic signs, a cytogenetic investigation was performed. This revealed an unbalanced de novo translocation: 46,X,der(X),t(X;7) (q13 or q13.2; q11.23 or q21.11), i.e., a partial trisomy of the long arm of chromosome 7 associated with a partial monosomy of the long arm of chromosome X (Fig. 3 and Fig. 4). The child is now 5 years old; her neurological situation is characterized by tetraparesis with axial hypotonia and some improvement in psychomotor performance: she smiles on social contact, listens to voices, is able to make repetitive consonant sounds, such as ba-ba, ma-ma, and to transfer an object from one hand to the other. She can keep her head erect, but is unable to sit alone, stand or walk. The patient has persistent severe scoliosis and macrocephaly (95th %ile).
3. D I S C U S S I O N
Fig. 2. Patient at age 5 years: macrocephaly, prominent forehead, epicanthus, 'anti-Down' palpebral fissures, small nose, elongated filtrum, normally shaped low-set ears. Reproduced with mother's written consent.
Macrocephaly is commonly defined as a skull circumference that exceeds the mean by two or more standard deviations for the age and sex [3]. Gooskens et al. [4] suggest that there are three main pathogenic alterations: (i) anatomical (neuron proliferation or a reduction in the neuron component, possibly due to glial growth), as in the case of neurocutaneous syndromes, growth disorders (achondroplasia, Beckwith-Wiedemann syndrome, etc.), Klinefelter syndrome, familial megalencephalia, etc.;
Fig. 1. A: CT: diffuse white matter hypodensity with normal ventricles and scarce evidence of the cerebral sulci. B: CT: no densitometric anomaly in the white matter; slight ventricular dilatation.
314
P. Drigo et al. / Brain & Development 1996; 18:312-315
(ii) dynamic (alterations in cerebrospinal fluid dynamics), as in hydrocephalus; (iii) metabolic (lysosomal or demyelinating pathologies), such as in mucolipidosis, mucopolysaccharidosis, sphingolipidosis, amino acid disorders, leukodystrophies, etc. Our patient's macrocephaly was associated with a chromosome disorder and should consequently be included in the first of these groups. The etiologic diagnosis of a chromosome disorder in the patient reported here was reached after excluding the more common causes of macrocephaly. The clinical picture was open to various diagnostic interpretations: (a) at the age of 2 months, a cerebral malformation or hydrocephalus was suggested by the finding of macrocephaly and hypotonia: both possibilities were excluded by ultrasound and the CT scan. The finding of a developmental delay, together with the hypodense CT images prompted the hypothesis of a leukodystrophy due to a degenerative disease of neonatal onset. However, lysosomal enzyme measurements within the normal range and the finding that N-acetylaspartic acid in the urine was not increased enabled us to exclude Canavan disease and other degenerative pathologies typical of this age group. (b) at the age of 6 months, the presence of macrocephaly, axial hypotonia with ,hyperactive reflexes, and mental retardation led to a diagnosis of non-progressive encephalopathy, though this
Fig. 4. Partial Q-bandedkaryotypes of the three differentmetaphases: on the right, chromosomesX; on the left, chromosomes7. Arrow designates the der(X),t(X;7) (q13 or q13.2; ql 1.23 or q21.11).
Fig. 3. Proband's karyotype (QFQ banding).
would fail to explain the macrocephaly and scoliosis (the latter is frequent in children with cerebral palsy, but only after the child has begun to sit or stand). The negative findings emerging from the tests and from the neonatal clinical history, combined with the dysmorphic signs, led to the performance of cytogenetic investigations, which enabled us to attribute the macrocephaly and scoliosis to the chromosome 7 alterations. In fact, as mentioned by Forabosco et al. [1], macrocephaly is rare in chromosome syndromes generally, but it is found in 51% of cases with duplication of the long arm of chromosome 7. The kyphoscoliosis observed by the authors in 23% of these cases had already been associated with duplication of the chromosomal segment 7 q32 ~ qter [5], which was found in triplicate in our patient. The correlation between phenotypic alterations and partial trisomy of the long arm of chromosome 7 remains a controversial matter, however: while some authors [5,6] indicate distinct dysmorphic syndromes as being associated with the duplication of various chromosomal segments, Forabosco et al. [1] consider the majority of the clinical symptoms as non-specific. On the other hand, there is a correlation between the evolution and survival of these subjects and the extent of the chromosome segment involved in the rearrangement: 60% of cases with duplications comparable with the one observed in our patient do not survive beyond the neonatal period [1]. Our case differs from others in the literature, however, both because the trisomy includes almost all of the long arm of chromosome 7, and because it is the only case (to our knowl-
P. Drigo et al./Brain & Development 1996; 18:312-315
edge) of an unbalanced translocation X;7. Involvement of the X chromosome obliges us to consider the problems related to inactivation of the spreading effect. In females with unbalanced X / A translocations, a balanced gene dosage is frequently achieved by inactivation of the abnormal X and its attached autosome segment. The inactivation center on the long arm of chromosome X, located in the q13 region [7-9] has a spreading effect that has been reported for several chromosomes [10]. Most of them showed attenuated effects of the trisomic autosome. It has been suggested that the effects are probably related to the spreading of the inactivation center [ 10,11 ]. The association, in the first year of life, of macrocephaly, scoliosis and non-progressive psychomotor retardation without any brain anomalies consequently deserves the pediatrician's attention: it is worth performing a cytogenetic study in such cases to seek any chromosomal disorder involving the long a n n of chromosome 7 - - also with a view to enabling prenatal diagnosis in a subsequent pregnancy.
REFERENCES 1. Forabosco A, Baroncini A, Dalprh L, et al. The phenotype of partial dup(7q) reconsidered: a report of five new cases. Clin Genet 1988; 34: 48-59. 2. Hamill PVV, Drizd TA, Johnson CL, et al. Physical growth: national center for health statistics percentiles. Am J Clin Nutr 1979; 32: 607-29.
315
3. De Myer W. Microcephaly, micrencephaly, megalocephaly and megalencephaly. In: Swaiman KF, ed. Pediatric neurology, 2nd ed., St Louis, MO: Mosby, 1994: 208-10. 4. Gooskens RHJM, Willemse J, Bijlsma JB, Hanlo PW. Megalencephaly: definition and classification. Brain Dev (Tokyo) 1988; 10: 1-7. 5. Novales MA, Femfindez-Novoa C, Hevia A, San Martin V, Galera H. Partial trisomy for the long arm of chromosome 7. Case report and review. Hum Genet 1982; 62: 378-81. 6. Bartsch O, Kalbe U, Nhan Ngo TK, Lettau R, Schwinger E. Clinical diagnosis of partial duplication 7q. Am J Med Genet 1990; 37: 254-7. 7. Pettigrew AL, McCabe ER, Elder FF, Ledbener DH. Isodicentric X chromosome in a patient with Turner syndrome - - implications for localization of the X-inactivation center. Hum Genet 1991; 87: 498-502. 8. Muscatelli F, Lena D, Mettei MG, Fontes M. A male with two contiguous inactivation centers on a single X chromosome: study of inactivation and XIST expression. Hum Mol Genet 1992; 1:115-9. 9. Turner Z, Tommerup N, Tonnesen T, Kreuder J, Craig IW, Horn N. Mapping of the Menkes locus to Xq13.3 distal to the X-inactivation center by an intrachromosomal insertion of the segment Xq13.3q21.2. Hum Genet 1992; 88: 668-72. 10. Elejalde BR, de Elejalde MM. Phenotypic manifestations of the X-autosome translocations. In: Sandberg AA, ed. Cytogenetics of the mammalian X chromosome. Part B: X chromosome anomalies and their clinical manifestations. New York: Alan R Liss, 1983: 225-44.
11. Couturier J, Dutrillaux B, Garber P, et al. Evidence for a correlation between late replication and autosomal gene inactivation in a familial translocation t (X;21). Hum Genet 1979; 49: 319-26.