Clinical Variation within Sibships in Fukuyama-type Congenital Muscular Dystrophy Mieko Yoshioka, MD, Sigekazu Kuroki, MD, Hiroyuki Nigami, MD, Toru Kawai, MD and Hajime Nakamura, MD
A family in which three siblings were affected with severe cerebral malformations in association with ocular anomalies and muscle disease is reported. One sibling was diagnosed as having Fukuyama type congenital muscular dystrophy (FCMD) because he showed severe hypotonia with dystrophic findings on a muscle biopsy in addition to pachygyria on CT. At the age of 3 years, retinal detachment developed in both eyes. Another sibling exhibited at birth such characteristic features as pachygyria, cephalocele, hydrocephalus, retinal detachment in both eyes, elevated serum creatine kinase activity and arthrogryposis multiplex congenita. We consider these findings to be more consistent with WalkerWarburg syndrome (WWS) than with FCMD. Anencephaly found in the third sibling was regarded as WWS with extreme brain abnormality. The appearance of two syndromes (FCMD and WWS) in the three members of the !lame family suggests that these syndromes could be allelic with variable phenotypes. Key words: Fukuyama type congenital muscular dystrophy, Walker-Warburg syndrome, autosomal recessive inheritance. Yoshioka M, Kuroki S, Nigami H, Kawai T, Nakamura H. Clinical variation within sibships in Fukuyama-type congenital muscular dystrophy. Brain Dev 1992; 14: 334-7
The association of type II lissencephaly with ocular anomalies and congenital muscular dystrophy (CMD) is found in Fukuyama-type CMD (FCMD) [1], WalkerWarburg syndrome (WWS) [2], cerebro-oculo-muscular syndrome (COMS) [3] and muscle-eye-brain disease (ME B) [4]. The relationships among these disorders are not known, though similar causes appear likely. We report herein a family in which three siblings were affected with severe cerebral malformations, in association with ocular anomalies and muscle disease. The findings in this family point to the possibility that these syndromes are allelic. CASE REPORT Both parents were healthy and non consanguineous. There
From the Department of Pediatrics, Kobe General Hospital (MY, SK, HN); and Department of Pediatrics, Faculty of Medicine, Kobe University (TK, HN), Kobe. Received for publication: May 11, 1992. Accepted for publication: July 25, 1992. Correspondence address: Dr. Mieko Yoshioka, Department of Pediatrics, Kobe General Hospital, 4-6 Minatojima-Nakamachi, Chuo-ku, Kobe 650, Japan.
was no family history of neuromuscular disorders or anomalies. Patient 1 was a male infant born without complications as a result of the mother's first pregnancy. The fmdings in this patient have previously been reported in detail [5]. Birth weight was 3,114g. Psychomotor development was delayed with head control at the age of 6 months, sitting at 2 years 10 months and absence of meaningful words at 3 years. High myopia, optic atrophy, strabismus and nystagmus were found at age 4 months. At that time, poor muscle tone and high serum creatine kinase (CK) level (9,310 IU/I, normal range 15-130) were noted. At age 3, retinal detachment of the left eye was noted, and he was admitted to our hospital. On admission, neurological fmdings included distinct muscular hypotonia and pseUdohypertrophy of the calves. He had generalized weakness which was especially marked in the proximal muscles. His face was myopathic. Deep tendon reflexes could not be elicited, and there were flexion contractures of the hip and knee joints. Repeated CT scans demonstrated slight dilatation of ventricles and a low density area in the cerebral white matter (Fig 1). Muscle biopsy indicated muscular dystrophy, with marked variation in muscle fiber size, as well as fiber necrosis, central nuclei and increase of connective tissue (Fig 2). The developmental quotient on modified Binet-Simon developmental test was 13, and chromosomal analysis
Fig 1 Cranial CT scans of two siblings. Left: patient 1 at the age of 5 months. Moderate dilatation of the lateral ventricles, especially posteriorly (colpocephalic) and pachygyria in the temporo-parietal region are shown. The low density area in the white matter is apparent. Right: patient 3 at birth. Marked dilatation of lateral ventricles and occipital encephalocele are evident.
Fig 2 Skeletal muscle of patient I showing marked variation in muscle fiber size, degenerated muscle fibers and proliferated connective tissue and fat (hematoxylin and eosin , x 200).
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Fig 3 MR i11'Ulges of patient 3 at one month of age (after the operation). demonstrating aqueductal stenosis (arrow 1). agenesis of corpus callosum (arrow 2). tectal beaking (arrow 3). large massa intermedia (arrow 4). and pachygyria of the temporal lobe (arrow 5).
revealed 46, XY (normal male) karyotype. Diathermy and an encircling procedure were performed for the retinal detachment of the left eye, but reattachment was not obtained. Ten months later, retinal detachment of the right eye occurred. The second pregnancy resulted in a male infant (patient 2) who survived for five minutes. He had been diagnosed as having anencephaly by ultrasound during pregnancy and was delivered prematurely at the seventh gestational month. His serum CK activity was 325 IU/l. Chromosomal study revealed normal karyotype. His muscles and eyes were not examined. No further information was available . The third pregnancy resulted in a male infant (patient 3) with birth weight of 3,518 g delivered at 41 weeks' gestation. At birth he had a 6 cm parieto-occipital encephalocele uncovered by skin with a defect in the right parietal bone. Noncommunicating hydrocephalus that required shunting was also present (Fig 1). He had exophthalmos, low set ears and flexion contractures of the elbow, hip and knee joints. Evaluation of deep tendon reflexes was equivocal because of joint contractures, but light reflex was preserved, and rooting, sucking and grasp reflexes were normal. Laboratory examination one day after birth revealed serum CK of 151 ,520 IU/l with 100% of MM and below 1% of MB isozyme, GOT 748 TU/1 (normal range 9-36), GPT 193 IU/l (7-34) and LDH
336 Brain & Development. Vol 14. No 5, 1992
11,520 IU/I (227-416). These muscle enzyme levels decreased gradually with serum CK of 5,280, GOT 103 and GPT 109 IU/I on the 50th day after birth. Chromosomal analysis revealed 46,XY (normal male) karyotype. Repair of cranium bifid urn, intracranial transposition of encephalocele and right ventriculo-peritoneal shunt was done on the eighth day after birth. Occipitofrontal circumference was 39 cm on that day . MRI after the operation revealed aqueductal stenosis and pachygyria (Fig 3). The initial ophthalmological evaluation at 18 days of age disclosed retinal detachment of both eyes. Optic disc was pale with sharp margin. Neither corneal opacities nor cataracts were observed.
DISCUSSION Cortical abnormalities are known to occur in association with muscle disease and ocular changes [1-4]. Type II lissencephaly is an integral part ofWWS, COMS and MEB. Indeed, the relationship between these syndromes is so close that these conditions can probably be considered identical [2]. The muscle lesions in such cases are dystrophic in type and do not differ from those of the congenital muscular dystrophies. In FCMD, the second most common type of muscular dystrophy in Japan, an abnormal gyrational pattern is present in all pathologically verified cases [6] and is recognizable on MRl in most patients [7].
Recent studies by Dobyns et aI, however , have revealed that FCMD differs from WW~ in manifesting consistently less frequent and severe cerebellar and retinal abnormalities [2]. For patient 1 in the present family, the fmdings have been reported as FCMD [5], because he showed severe hypotonia with dystrophic fIndings on the muscle biopsy in addition to pachygyria on CT. The only fmding atypical of FCMD was that he presented retinal detachment of both eyes at age 3 years. On the other hand, patient 3 exhibited such characteristic features as pachygyria recognized by CT and MRI, cephalocele, hydrocephalus and retinal detachment of both eyes. His signs of muscle disease consisted of elevated serum CK and arthrogryposis multiplex congenita. We consider all of these fIndings to be more consistent with WWS than with FCMD. Anencephaly may in some cases be combined with eye signs identical to retinal dysplasia and thus may be considered as WWS with extreme brain abnormality [8]. Our patient 2 had no information about eye signs, but his anencephaly may be some relation to WWS. Thus, a spectrum of cortical malformations was seen in these three siblings. It is important to note that, although the recurrence rate of similar malformations in siblings is generally very low, autosomal recessive disorders have a 25% rate of recurrence [9]. From this perspective, we speculate that the three siblings in the present family may have had a single gene disorder. The appearance of two syndromes (FCMD and WWS) in three members of the same family suggests that these syndromes could be allelic with variable phenotypes.
ACKNOW LEDGMENTS We thank Drs. M. Yonetani, Y. Uetani and S. Oi, Kobe University, School of Medicine for clinical information. This study was supported by the research grant (2A-3) for nervous and mental disorders from the Ministry of Health and Welfare, Japan.
REFERENCES 1. Fukuyama Y, Haruna H, Kawazura M. A peculiar form of congenital progressive muscular dystrophy. Paediatr Univ Tokyo (Tokyo) 1960;4:5-8. 2. Dobyns WB, Pagon RA, Armstrong D et al. Diagnostic criteria for Walker-Warburg syndrome. Am J Med Genet 1989;32: 195-210. 3. Dambska M, Wisniewski K, Sher J, Solish G. Cerebra-oculomuscular syndrome: a variant of Fukuyama congenital cerebro-muscular dystrophy. Gin Neuropathol 1982; 1: 93-8. 4. Santavuori P, Somer H, Sainio K et al. Muscle-Eye-Brain Disease (MEB). Brain Dev 1989;11:147-53. 5. Yoshioka M, Kuroki S, Kondo T. Ocular manifestations in Fukuyama type congenital muscular dystrophy. Brain Dev 1990; 12:423-6. 6. Takada K, Nakamura H, Tanaka J . Cortical dysplasia in congenital muscular dystrophy with central nervous system involvement (Fukuyama type). J Neuropathol Exp Neurol 1984;43:395-407. 7. Yoshioka M, Saiwai S, Kuroki S, Nigami H. MR imaging of the brain in Fukuyama-type congenital muscular dystrophy. AJNR 1991;12:63-5. 8. Svedberg B. Retrolental fibroplasia or congenital encephaloophthalmic dysplasia? Acta Pediatr Scan 1975 ;64: 891-4. 9. Holmes LB, Driscoll SG, Atkins L. Etiologic heterogeneity of neural-tube defects. N EnglJ Med 1976;294:365-9.
Yoshioka et al: Variation within sibs in FCMD 337
A family in which three siblings were affected with severe cerebral malformations in association with ocular anomalies and muscle disease is reported. One sibling was diagnosed as having Fukuyama type congenital muscular dystrophy (FCMD) because he showed severe hypotonia with dystrophic findings on a muscle biopsy in addition to pachygyria on CT. At the age of 3 years, retinal detachment developed in both eyes. Another sibling exhibited at birth such characteristic features as pachygyria, cephalocele, hydrocephalus, retinal detachment in both eyes, elevated serum creatine kinase activity and arthrogryposis multiplex congenita. We consider these findings to be more consistent with WalkerWarburg syndrome (WWS) than with FCMD. Anencephaly found in the third sibling was regarded as WWS with extreme brain abnormality. The appearance of two syndromes (FCMD and WWS) in the three members of the !lame family suggests that these syndromes could be allelic with variable phenotypes. Key words: Fukuyama type congenital muscular dystrophy, Walker-Warburg syndrome, autosomal recessive inheritance. Yoshioka M, Kuroki S, Nigami H, Kawai T, Nakamura H. Clinical variation within sibships in Fukuyama-type congenital muscular dystrophy. Brain Dev 1992; 14: 334-7
The association of type II lissencephaly with ocular anomalies and congenital muscular dystrophy (CMD) is found in Fukuyama-type CMD (FCMD) [1], WalkerWarburg syndrome (WWS) [2], cerebro-oculo-muscular syndrome (COMS) [3] and muscle-eye-brain disease (ME B) [4]. The relationships among these disorders are not known, though similar causes appear likely. We report herein a family in which three siblings were affected with severe cerebral malformations, in association with ocular anomalies and muscle disease. The findings in this family point to the possibility that these syndromes are allelic. CASE REPORT Both parents were healthy and non consanguineous. There
From the Department of Pediatrics, Kobe General Hospital (MY, SK, HN); and Department of Pediatrics, Faculty of Medicine, Kobe University (TK, HN), Kobe. Received for publication: May 11, 1992. Accepted for publication: July 25, 1992. Correspondence address: Dr. Mieko Yoshioka, Department of Pediatrics, Kobe General Hospital, 4-6 Minatojima-Nakamachi, Chuo-ku, Kobe 650, Japan.
was no family history of neuromuscular disorders or anomalies. Patient 1 was a male infant born without complications as a result of the mother's first pregnancy. The fmdings in this patient have previously been reported in detail [5]. Birth weight was 3,114g. Psychomotor development was delayed with head control at the age of 6 months, sitting at 2 years 10 months and absence of meaningful words at 3 years. High myopia, optic atrophy, strabismus and nystagmus were found at age 4 months. At that time, poor muscle tone and high serum creatine kinase (CK) level (9,310 IU/I, normal range 15-130) were noted. At age 3, retinal detachment of the left eye was noted, and he was admitted to our hospital. On admission, neurological fmdings included distinct muscular hypotonia and pseUdohypertrophy of the calves. He had generalized weakness which was especially marked in the proximal muscles. His face was myopathic. Deep tendon reflexes could not be elicited, and there were flexion contractures of the hip and knee joints. Repeated CT scans demonstrated slight dilatation of ventricles and a low density area in the cerebral white matter (Fig 1). Muscle biopsy indicated muscular dystrophy, with marked variation in muscle fiber size, as well as fiber necrosis, central nuclei and increase of connective tissue (Fig 2). The developmental quotient on modified Binet-Simon developmental test was 13, and chromosomal analysis
Fig 1 Cranial CT scans of two siblings. Left: patient 1 at the age of 5 months. Moderate dilatation of the lateral ventricles, especially posteriorly (colpocephalic) and pachygyria in the temporo-parietal region are shown. The low density area in the white matter is apparent. Right: patient 3 at birth. Marked dilatation of lateral ventricles and occipital encephalocele are evident.
Fig 2 Skeletal muscle of patient I showing marked variation in muscle fiber size, degenerated muscle fibers and proliferated connective tissue and fat (hematoxylin and eosin , x 200).
Yoshioka et al: Variation within sibs in FCMD
335
Fig 3 MR i11'Ulges of patient 3 at one month of age (after the operation). demonstrating aqueductal stenosis (arrow 1). agenesis of corpus callosum (arrow 2). tectal beaking (arrow 3). large massa intermedia (arrow 4). and pachygyria of the temporal lobe (arrow 5).
revealed 46, XY (normal male) karyotype. Diathermy and an encircling procedure were performed for the retinal detachment of the left eye, but reattachment was not obtained. Ten months later, retinal detachment of the right eye occurred. The second pregnancy resulted in a male infant (patient 2) who survived for five minutes. He had been diagnosed as having anencephaly by ultrasound during pregnancy and was delivered prematurely at the seventh gestational month. His serum CK activity was 325 IU/l. Chromosomal study revealed normal karyotype. His muscles and eyes were not examined. No further information was available . The third pregnancy resulted in a male infant (patient 3) with birth weight of 3,518 g delivered at 41 weeks' gestation. At birth he had a 6 cm parieto-occipital encephalocele uncovered by skin with a defect in the right parietal bone. Noncommunicating hydrocephalus that required shunting was also present (Fig 1). He had exophthalmos, low set ears and flexion contractures of the elbow, hip and knee joints. Evaluation of deep tendon reflexes was equivocal because of joint contractures, but light reflex was preserved, and rooting, sucking and grasp reflexes were normal. Laboratory examination one day after birth revealed serum CK of 151 ,520 IU/l with 100% of MM and below 1% of MB isozyme, GOT 748 TU/1 (normal range 9-36), GPT 193 IU/l (7-34) and LDH
336 Brain & Development. Vol 14. No 5, 1992
11,520 IU/I (227-416). These muscle enzyme levels decreased gradually with serum CK of 5,280, GOT 103 and GPT 109 IU/I on the 50th day after birth. Chromosomal analysis revealed 46,XY (normal male) karyotype. Repair of cranium bifid urn, intracranial transposition of encephalocele and right ventriculo-peritoneal shunt was done on the eighth day after birth. Occipitofrontal circumference was 39 cm on that day . MRI after the operation revealed aqueductal stenosis and pachygyria (Fig 3). The initial ophthalmological evaluation at 18 days of age disclosed retinal detachment of both eyes. Optic disc was pale with sharp margin. Neither corneal opacities nor cataracts were observed.
DISCUSSION Cortical abnormalities are known to occur in association with muscle disease and ocular changes [1-4]. Type II lissencephaly is an integral part ofWWS, COMS and MEB. Indeed, the relationship between these syndromes is so close that these conditions can probably be considered identical [2]. The muscle lesions in such cases are dystrophic in type and do not differ from those of the congenital muscular dystrophies. In FCMD, the second most common type of muscular dystrophy in Japan, an abnormal gyrational pattern is present in all pathologically verified cases [6] and is recognizable on MRl in most patients [7].
Recent studies by Dobyns et aI, however , have revealed that FCMD differs from WW~ in manifesting consistently less frequent and severe cerebellar and retinal abnormalities [2]. For patient 1 in the present family, the fmdings have been reported as FCMD [5], because he showed severe hypotonia with dystrophic fIndings on the muscle biopsy in addition to pachygyria on CT. The only fmding atypical of FCMD was that he presented retinal detachment of both eyes at age 3 years. On the other hand, patient 3 exhibited such characteristic features as pachygyria recognized by CT and MRI, cephalocele, hydrocephalus and retinal detachment of both eyes. His signs of muscle disease consisted of elevated serum CK and arthrogryposis multiplex congenita. We consider all of these fIndings to be more consistent with WWS than with FCMD. Anencephaly may in some cases be combined with eye signs identical to retinal dysplasia and thus may be considered as WWS with extreme brain abnormality [8]. Our patient 2 had no information about eye signs, but his anencephaly may be some relation to WWS. Thus, a spectrum of cortical malformations was seen in these three siblings. It is important to note that, although the recurrence rate of similar malformations in siblings is generally very low, autosomal recessive disorders have a 25% rate of recurrence [9]. From this perspective, we speculate that the three siblings in the present family may have had a single gene disorder. The appearance of two syndromes (FCMD and WWS) in three members of the same family suggests that these syndromes could be allelic with variable phenotypes.
ACKNOW LEDGMENTS We thank Drs. M. Yonetani, Y. Uetani and S. Oi, Kobe University, School of Medicine for clinical information. This study was supported by the research grant (2A-3) for nervous and mental disorders from the Ministry of Health and Welfare, Japan.
REFERENCES 1. Fukuyama Y, Haruna H, Kawazura M. A peculiar form of congenital progressive muscular dystrophy. Paediatr Univ Tokyo (Tokyo) 1960;4:5-8. 2. Dobyns WB, Pagon RA, Armstrong D et al. Diagnostic criteria for Walker-Warburg syndrome. Am J Med Genet 1989;32: 195-210. 3. Dambska M, Wisniewski K, Sher J, Solish G. Cerebra-oculomuscular syndrome: a variant of Fukuyama congenital cerebro-muscular dystrophy. Gin Neuropathol 1982; 1: 93-8. 4. Santavuori P, Somer H, Sainio K et al. Muscle-Eye-Brain Disease (MEB). Brain Dev 1989;11:147-53. 5. Yoshioka M, Kuroki S, Kondo T. Ocular manifestations in Fukuyama type congenital muscular dystrophy. Brain Dev 1990; 12:423-6. 6. Takada K, Nakamura H, Tanaka J . Cortical dysplasia in congenital muscular dystrophy with central nervous system involvement (Fukuyama type). J Neuropathol Exp Neurol 1984;43:395-407. 7. Yoshioka M, Saiwai S, Kuroki S, Nigami H. MR imaging of the brain in Fukuyama-type congenital muscular dystrophy. AJNR 1991;12:63-5. 8. Svedberg B. Retrolental fibroplasia or congenital encephaloophthalmic dysplasia? Acta Pediatr Scan 1975 ;64: 891-4. 9. Holmes LB, Driscoll SG, Atkins L. Etiologic heterogeneity of neural-tube defects. N EnglJ Med 1976;294:365-9.
Yoshioka et al: Variation within sibs in FCMD 337
