American Journal of Medical Genetics 39:19-24 (1991)
Lethal Congenital Muscular Dystrophy With Cataracts and a Minor Brain Anomaly: New Entity or Variant of Walker-Warburg Syndrome? David S. Wargowski, David Chitayat, R. Wes I’yson, Margaret G. Norman, and J.M. Friedman Departments of Medical Genetics (D.S.W.. D.C.. J.M.F.1 and Pathology (R.W.T.,M.G.N.), University of British Columbia, Vancouver, British Columbia ~
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A term newborn male with severe hypotonia and contractures was found to have dense bilateral cataracts. He died at age 3 days of respiratory failure. Amino acidopathies and disorders of peroxisome function were excluded, and results of serologic studies and placental histopathology, specifically seeking evidence of intrauterine infection, were normal. Autopsy showed changes in the skeletal muscles consistent with congenital muscular dystrophy and a small focal anomaly of the cerebral cortex. These findings either represent a new syndrome or raise further questions about broadening the spectrum of known congenital muscular dystrophy syndromes with associated eye and brain anomalies.
KEY WORDS: gyral anomalies; Fukuyama congenital muscular dystrophy; cerebrooculomuscular syndrome; muscle, eye, and brain disease
period is indicated by diminished fetal movement, congenital contractures, and other stigmata of fetal dyskinesia [Dambska et al., 1982; Federico et al., 1988; Fukuyama et al., 1981; Heggie et al., 1987; Korinthenberg et al., 19841. Other cases have followed a much less malignant course, with milder motor impairment of later onset [F’ukuyama et al., 1981; Kamoshita et al., 1976; Korinthenberg et al., 19841. In many cases, CMD is associated with developmental anomalies of the eyes and brain [Dambska et al., 1982; Dobyns et al., 1989; Fukuyama et al., 1981; Santavuori et al., 1977;Towfighi et al., 19841. Recurrence within sibships has been reported on numerous occasions [Dambska et al., 1982; Dobyns et al., 1985, 1989; Heggie et al., 1987; Korinthenberg et al., 19841, and the nosology has been extensively discussed [Dambska et al., 1982; Federico et al., 1988; Heggie et al., 1987; Heyer et al., 1986; Korinthenberg e t al., 1984; Pavone et al., 1986; Santavuori et al., 1977; Towfighi et al., 19841.Most recently, Dobyns et al. [19891 reviewed the described CMD syndromes with associated brain abnormalities and proposed that the spectrum of the Walker-Warburg syndrome (WWS) encompasses many of them. The patient described here had congenital muscle weakness with respiratory failure and was found on autopsy to have the characteristic muscle changes of CMD. Dense cataracts, indistinguishable from those caused by intrauterine rubella infection, and a focal cortical brain abnormality were also found.
INTRODUCTION Congenital muscular dystrophy (CMD) is a component of several disorders characterized by hypotonia, muscle weakness, and characteristic histological findings, including variable size of muscle fibers, central nuclei, fiber necrosis with or without macrophage infilCLINICAL REPORT tration, regenerative changes, and an excess of fatty and This male infant was born after a 39 week gestation to connective tissues in endomysial and perimysial spaces a 35-year-old rubella-immune G3P2SA1 mother of [Dambska et al., 1982; Federico et al., 1988; Fukuyama Ukrainian origin who had undergone radioactive thyet al., 1981; Heggie et al., 1987; Heyer et al., 1986; roid ablation a t age 15 years and maintained a euthyNonaka and Chou, 19791. Enormous clinical variability roid state throughout the pregnancy with replacement has been observed; in some cases, onset in the prenatal therapy. The father was a healthy 40-year-old man of Polish origin. The parents are not related. Their first Received for publication February 13, 1990; revision received pregnancy produced a boy who was alive and well a t age 5 years. Their second pregnancy ended spontaneously June 26, 1990. Address reprint requests to David S. Wargowski, MD, Univer- during week 6 of gestation and was not investigated. sity of Wisconsin Clinical Genetics Center, 1500 Highland Avenue, The maternal grandmother had lost 3 female children in Madison, WI 53705-2280. their infancy, but no information regarding the causes of 0 1991 Wiley-Liss, Inc.
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Wargowski et al.
death was available. The family history was otherwise unremarkable. Poor fetal movement was noted throughout the pregnancy, and the infant was delivered by cesarean section because of breech position and a previous cesarean section. His birth weight was 2,880 g (10th-25th centile), length 50 cm (25th-50th centile), and OFC 35.5 cm (75th-90th centile). At birth he was flaccid and had minimal respiratory effort. Diminished muscle mass, multiple contractures, bilateral cataracts, and facial abnormalities were immediately apparent (Fig. 1).His occiput was prominent, and the anterior fontanelle was almost closed. His forehead was high, with a ridged metopic suture. The palpebral fissures were small and deeply set, and the density of the cataracts precluded further examination of the eyes. Both ears were small (3.5 cm, 5th centile), with notched and underfolded helices. The nasal bridge and tip were broad; there was malar hypoplasia, a long but well-formed philtrum, and a small and triangular mouth with down-turned corners, micrognathia, and broad alveolar ridges. The nipples were hypoplastic, and the internipple distance and sternum were short (6.7 cm and 4.7 cm, respectively; both
Lethal Congenital Muscular Dystrophy With Cataracts and a Minor Brain Anomaly: New Entity or Variant of Walker-Warburg Syndrome? David S. Wargowski, David Chitayat, R. Wes I’yson, Margaret G. Norman, and J.M. Friedman Departments of Medical Genetics (D.S.W.. D.C.. J.M.F.1 and Pathology (R.W.T.,M.G.N.), University of British Columbia, Vancouver, British Columbia ~
~
~
~~
~
~
A term newborn male with severe hypotonia and contractures was found to have dense bilateral cataracts. He died at age 3 days of respiratory failure. Amino acidopathies and disorders of peroxisome function were excluded, and results of serologic studies and placental histopathology, specifically seeking evidence of intrauterine infection, were normal. Autopsy showed changes in the skeletal muscles consistent with congenital muscular dystrophy and a small focal anomaly of the cerebral cortex. These findings either represent a new syndrome or raise further questions about broadening the spectrum of known congenital muscular dystrophy syndromes with associated eye and brain anomalies.
KEY WORDS: gyral anomalies; Fukuyama congenital muscular dystrophy; cerebrooculomuscular syndrome; muscle, eye, and brain disease
period is indicated by diminished fetal movement, congenital contractures, and other stigmata of fetal dyskinesia [Dambska et al., 1982; Federico et al., 1988; Fukuyama et al., 1981; Heggie et al., 1987; Korinthenberg et al., 19841. Other cases have followed a much less malignant course, with milder motor impairment of later onset [F’ukuyama et al., 1981; Kamoshita et al., 1976; Korinthenberg et al., 19841. In many cases, CMD is associated with developmental anomalies of the eyes and brain [Dambska et al., 1982; Dobyns et al., 1989; Fukuyama et al., 1981; Santavuori et al., 1977;Towfighi et al., 19841. Recurrence within sibships has been reported on numerous occasions [Dambska et al., 1982; Dobyns et al., 1985, 1989; Heggie et al., 1987; Korinthenberg et al., 19841, and the nosology has been extensively discussed [Dambska et al., 1982; Federico et al., 1988; Heggie et al., 1987; Heyer et al., 1986; Korinthenberg e t al., 1984; Pavone et al., 1986; Santavuori et al., 1977; Towfighi et al., 19841.Most recently, Dobyns et al. [19891 reviewed the described CMD syndromes with associated brain abnormalities and proposed that the spectrum of the Walker-Warburg syndrome (WWS) encompasses many of them. The patient described here had congenital muscle weakness with respiratory failure and was found on autopsy to have the characteristic muscle changes of CMD. Dense cataracts, indistinguishable from those caused by intrauterine rubella infection, and a focal cortical brain abnormality were also found.
INTRODUCTION Congenital muscular dystrophy (CMD) is a component of several disorders characterized by hypotonia, muscle weakness, and characteristic histological findings, including variable size of muscle fibers, central nuclei, fiber necrosis with or without macrophage infilCLINICAL REPORT tration, regenerative changes, and an excess of fatty and This male infant was born after a 39 week gestation to connective tissues in endomysial and perimysial spaces a 35-year-old rubella-immune G3P2SA1 mother of [Dambska et al., 1982; Federico et al., 1988; Fukuyama Ukrainian origin who had undergone radioactive thyet al., 1981; Heggie et al., 1987; Heyer et al., 1986; roid ablation a t age 15 years and maintained a euthyNonaka and Chou, 19791. Enormous clinical variability roid state throughout the pregnancy with replacement has been observed; in some cases, onset in the prenatal therapy. The father was a healthy 40-year-old man of Polish origin. The parents are not related. Their first Received for publication February 13, 1990; revision received pregnancy produced a boy who was alive and well a t age 5 years. Their second pregnancy ended spontaneously June 26, 1990. Address reprint requests to David S. Wargowski, MD, Univer- during week 6 of gestation and was not investigated. sity of Wisconsin Clinical Genetics Center, 1500 Highland Avenue, The maternal grandmother had lost 3 female children in Madison, WI 53705-2280. their infancy, but no information regarding the causes of 0 1991 Wiley-Liss, Inc.
20
Wargowski et al.
death was available. The family history was otherwise unremarkable. Poor fetal movement was noted throughout the pregnancy, and the infant was delivered by cesarean section because of breech position and a previous cesarean section. His birth weight was 2,880 g (10th-25th centile), length 50 cm (25th-50th centile), and OFC 35.5 cm (75th-90th centile). At birth he was flaccid and had minimal respiratory effort. Diminished muscle mass, multiple contractures, bilateral cataracts, and facial abnormalities were immediately apparent (Fig. 1).His occiput was prominent, and the anterior fontanelle was almost closed. His forehead was high, with a ridged metopic suture. The palpebral fissures were small and deeply set, and the density of the cataracts precluded further examination of the eyes. Both ears were small (3.5 cm, 5th centile), with notched and underfolded helices. The nasal bridge and tip were broad; there was malar hypoplasia, a long but well-formed philtrum, and a small and triangular mouth with down-turned corners, micrognathia, and broad alveolar ridges. The nipples were hypoplastic, and the internipple distance and sternum were short (6.7 cm and 4.7 cm, respectively; both
