DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY.
1977, 19
RESUMEN
Sindrome de Smith-Lemli-Opitz: observaciones neuroldgicas y oftalmoldgicas Se aporta el caso de un niiio de tres aiios con sindrome de Smith-Lemli-Opitz. Como adicion a la constelacibn de anomalias esquelkticas y genitales descritas clasicamente en este sindrome, este paciente tenia movimientos oculares espontaneos semejantes a 10s opsoclbnicos, estrabismo, falta de respuesta visual de seguimiento y falta de reflejos optokineticos. A la autopsia se observb ausencia del vermis cerebeloso. Existian hemangiomas retinianos. Se notaron microscbpicamente perdida de cClulas de Purkinje y degeneracibn neuronal extensa en 10s nucleos dentados, con asociacibn de una desmielinizacibn en placas de 10s pedhculos cerebelosos y de la substancia blanca central. Estos hallazgos pueden contribuir a la explicacibn de la fisiopatologia del opsoclonus y de algunos de 10s hallazgos neurooftalmolbgicos. REFERENCES Bienfang, D. C. (1974) ‘Opsoclonus in infancy.’ Archives of Oph/halmology, 91, 203-205. Bray, P. F., Ziter, F. A., Lahey, M. E., Myers, G . G. (1969) ‘The coincidence of neuroblastoma and acute cerebellar encephalopathy.’ Journal of Pediatrics. 75, 983-990. Dallaire, L. (1969) ‘Syndrome of retardation with urogenital and skeletal anomalies (Smith-Lemli-Opitz syndrome)+linical features and mode of inheritance.’ Journal of Medical Generics. 6, 113-120. Ellenberger, C., Campa, J. F., Netsky, M. G. (1968) ‘Opsoclonus and parenchymatous degeneration of the cerebellum. The cerebellar origin of an abnormal ocular movement.’ Neuro1og.v. 18, 104-1046. - Keltner, J. L., Stroud, M. H. (1972) ‘Ocular dyskinesia in cerebellar disease: evidence for the similarity of opsoclonus, ocular dysmetria and flutter-like oscillations.’ Brain, 95, 685-692. Garcia, C. A.. McGarry, P. A., Voirol, M., Duncan, C. (1973) ‘Neurological involvement in the SmithLemli-Opitz syndrome: clinical and neuropathological findings.’ Developnienral Medicine and Child Neurology, 15,48-55. Joubert, M., Eisenring, J. J., Robb, J. P., Andermann, F. (1969) ‘Familial agenesis of the cerebellar vermis. A syndrome of episodic hyperpnea, abnormal eye movements, ataxia and retardation.‘ Neurology, 19, 8 1 3-825. Keane, J. R., Devereaux, M. W. (1974) ‘Opsoclonus associated with an intracranial tumor.’ Archives of Ophthalmology, 92, 4 4 3 4 5 . Ross, A. T., Zeman, W. (1967) ‘Opsoclonus, occult carcinoma and chemical pathology in dentate nuclei.’ Archives of Neurology, 17, 546551. Ruvalcaba, R. H. A., Reichert, A., Smith, D. W. (1968) ‘Smith-Lemli-Opitz syndrome.’ Archives of Disease in Childhood, 43, 620-622. Smith, D. W., Lemli, L., Opitz, J. M. (1964) ‘A newly recognized syndrome of multiple congenital anomalies.’ Journal of Pediurrics, 64, 210-217. Winick. M. (1969) ‘Malnutrition and brain development.’ Journal of Pediatrics, 74, 667-679.
Congenital Hypocupraemia Syndrome With and Without Steely Hair: Report of Two Japanese Infants Kunihiko Osaka Noriko Sat0 Satoshi Matsumoto Hitoshi Ogino Soichi Kodama Sumiyoshi Yokoyama Taketoshi Sugiyama Introduction Menkes and associates (1962) described a new neurodegenerative disorder of infancy, inherited in the sex-linked recessive mode. The boys appeared to be normal at birth but developed seizures in early -
~~
~~~
~~
infancy and gradually deteriorated to a vegetative state. The hair of these patients was kinky, coarse and white, and microscopic examination showed pili torti (twisting of the hair shaft), monilethrix (irregular diameter of the hair shaft) and trichorrhexis (fractures of the hair shaft). Such hair abnormalities were thought to be the most characteristic feature of the syndrome and led to it being called
~~
Correspondence to Kunihiko Osaka, M.D., Department of Neurosurgery, Kobe University School of Medicine, I2 Kusunoki-cho 7-Chome, Ikuta-ku, Kobe 650, Japan.
62
CASE REPORTS
Menkes’ kinky (or steely) hair syndrome (Aguilar et a/. 1966; Wesenberg et a/. 1969; Danks et a/. 1972a, b ; Singh and Bresnan 1973; Adams et a/. 1974), or ‘trichopoliodystrophy’ (French et a/. 1972, Ghatak et a/. 1972). Danks and colleagues (1972a, b) found the copper content in serum and liver to be extremely low in these patients and claimed that the disorder was induced by defective intestinal absorption of copper. More than 30 patients with Menkes’ kinky hair syndrome have been reported, almost all of whom were Caucasian. The only patient of Oriental origin was recently reported by Sat0 et a/. (1975). The present paper reports two new patients of Japanese origin and discusses the problems encountered in making the diagnoses. CASE 1 A six-month-old boy was admitted to Kobe University Hospital for evaluation of his seizures. He was the only boy born to healthy, nonconsanguineous parents. A three-year-old sister
E
was normal. The family history revealed no mentally retarded children, nor any with seizures. The boy had been born uneventfully after a normal, full-term pregnancy. His early development was normal. Neurological symptoms began at three months of age with grand ma1 seizures. During the following three months he had frequent convulsions, despite anticonvulsant therapy, and became progressively less responsive. His mother noticed an extensive amount of hair to have fallen out. At the age of six months salaam spasms with hypsarrhythmia in EEG were noticed (Fig. 1) and the baby was admitted to hospital. On admission he presented as a chronically sick patient with noisy respiration. He appeared to be unaware of his surroundings. He could not suck milk well and eventually had to be tube-fed. His hair was coarse and scanty (Fig. 2) and among it were several curly white hairs. Microscopically most of the hairs were normal, t u t in some pili torti and monilethrix were found. The head was normal in size, with a sunken anterior fontanelle, but abnormal transillumination was seen in both sides of the head. Blood-cell count, urinalysis and routine blood-chemistry were unremarkable. Plain roentgenograms showed metaphyseal spurring in the long bones and flaring of the anterior ribs in the chest.
DEVELOPMENTAL MEDICINEAND CHILD NEUROLOGY.
1977, 19
Fig. 2 (lefi). Case 1. The hair is sparse and stiff. Fig. 3 (right). Case 2. Hair is not sparse or steely.
regression and repeated convulsions of unknown origin. The boy was the product of a normal pregnancy and delivery and his early development had been normal. He had his first convulsion at two months of age, limited to the right side of the body. Soon afterwards he began to suffer repeated, generalized seizures, despite anticonvulsant therapy. Subsequently, severe psychomotor regression was noticed. On admission he was apathetic with irregular respiration. Results of physical examination were unremarkable. He did not laugh and his eyes did not follow a moving object. His head circumference was 39'5cm and the anterior fontanelle was sunken. No abnormality of the hair was found microscopically, nor was it sparse or white (Fig. 3), and although it appeared to be rather stiff the stiffness apparently was within the normal range for Japanese hair. The child's head control was almost nonexistent, all his extremities were atonic and deep tendon reflexes were suppressed. No abnormalities were found in routine laboratory studies, including quantitative analysis of urine and serum for amino acid. Convulsions were well controlled after admission by increased doses of anticonvulsants, but no neurological improvement occurred. Because the EEG suggested greater involvement in the left side of the brain, a left carotid angiogram was performed. Excessive lengthening and tortuosity were found (Fig. 4). There was no avascular area. Excessive lengthening and tortuosity were also found in the right side of the brain and in the spinal cord (Fig. 5). Because of these angiographic findings. copper metabolism was studied and extremely low ceruloplasmin and serum copper
The salaam spasms were well controlled with ACTH treatment and the pattern of hypsarrhythmia disappeared, but his psychomotor retardation progressed relentlessly. Retrograde right brachial angiography revealed a diffuse avascular area of about 2cm thickness in both hemispheres. There was also extreme lengthening and tortuosity of all arteries. The same abnormalities were seen in the arteries of the neck, right arm, legs and abdomen. Serum copper and ceruloplasmin were found to be extremely low (Table I). TABLE I Copper metabolism
Serum (pg/dl)
..
1
94
By atomic absorption technique
t By M-Partigen-CeruloplasmineEkhring Institut Two months later a right carotid angiogram revealed an increased avascular area. A burr hole was made and it was noted that there was retention of xanthrochromic fluid under a thin, transparent membrane. The fluid was not under abnormal tension. A subdural peritoneal shunt was inserted but there was no improvement in the child's condition. CASE
2
This four-month-old boy was admitted because of repeated convulsions. He was the parents' third child. The elder daughter was healthy but his brother had died of progressive psychomotor
64
CASE RFPORTS
Fig. 4. (/t.ft)Case 2. Left carotid angiogram showing tortuosity and lengthening of arteries. Fig. 5. (right) Case 2. Retrograde right brachial angiogram showing dilated and tortuous anterior spinal artery (arrow). levels were found (Table I). Biopsy material was including his brother’s death after an taken from the superficial temporal artery, the identical clinical course, were consistent lymph node and the skin. The artery showed with the syndrome: i.e. the peculiar marked tortuosity, aneurysmal dilatation and changes Of the arteries and atrophy splitting of elastic lamina (Fig. 6), but the lymph node and skin were normal microscopically. of the brain, with massive accumulation After discharge from hospital, the child deterof subdural fluid. In particular, the exiorated progressively and had repeated bouts of tremely low levels of ceruloplasmin and pneumonia. No changes occurred in the hair. He serum copper are important for the diagdied suddenly at home at the age of 13 months. nosis. Low serum copper also occurs with At autopsy the prominent findings were severe nutritional depletion of copper (Karpel atrophy of the brain, bilateral subdural hygroma covered with thick membrane, and peculiar and Peden 1972, Ashkenazi et al. 1973), tortuosity of the major arteries (Fig. 7). but nutritional copper deficiency occurs
in infancy only when a pre-term baby with less copper reserves in the liver is deprived of copper by prolonged intravenous infusion and without oral intake, as after surgery: more than enough copper is contained in the usual food (Shields et al. 1962, Karpel and Peden 1972, Ashkenazi et al. 1973). Case 2 was not born prematurely and had been fed with
Discussion There were no difficulties in diagnosing Case 1 because of the seizures, progressive psychomotor retardation, obvious hair abnormalities and the disturbed copper metabolism. Case 2 was devoid of the hair abnormality which is the key diagnostic feature of the syndrome, but other features, 65
DEVELOPMENTAL MEDICINE A N D CHILD NEUROLOGY.
1977, 19
Fig. 6 (above). Case 2. Superficial temporal artery: note splitting of elastic lamina. (Van Gieson stain.) Fig. 7 (right). Case 2. Autopsy findings: note tortuous anterior cerebral arteries (arrow). C indicates optic chasm.
the usual milk, so cannot be an example of nutritional copper deficiency. Since such unusual depletion of copper is not known in any other disease process, Case 2 must be diagnosed as an atypical case of Menkes’ kinky-hair syndrome; atypical because he did not have the hair abnormalities characteristic of the disorder. Almost all cases of the syndrome reported so far have been Caucasian and all seem to have shown the characteristic hair abnormality (Menkes et al. 1962; Aguilar et a/. 1966; Billing and Degnan 1971; Danks et a/. 1 9 7 2 ~b; French et al. 1972; Ghatak et al. 1972; Singh and Bresnan 1973; Adams et al. 1974). The absence of hair abnormality in our Case 2 might be a reflection of racial difference, since Japanese hair is stiffer than Caucasian hair. Only one other patient with this disorder has been reported in Japan (Sato et a/. 1975), and that case apparently had the hair abnormality. From our experience with our two cases, from two different families and both seen over a very short period, we feel that there may be many patients with this disorder in Japan who
have not been diagnosed, probably because the hair abnormality is absent or not so conspicuous. By the same token, there might also be some Caucasian patients who do not have the abnormal hair thought to be characteristic of the syndrome. Serum copper determination is a simple laboratory procedure and should be performed routinely in all patients with unexplained deterioration, whether or not the hair is abnormal. It would seem from our Case 2 that the hair abnormality is only one of the manifestations of copper deficiency and should not be relied on for its diagnosis. If that is so, the terms ‘kinky’ or ‘steely’ hair or ‘trichopoliodystrophy’ are inappropriate and we propose ‘congenital hypocupraemia’ as the diagnostic term to encompass patients with and without hair abnormalities. The arterial changes seen in both our patients, probably induced by splitting of the internal elastic lamina, apparently is a constant finding in congenital hypocupraemia. Angiography therefore can be a useful diagnostic aid, as has been proposed by Wesenberg et a/. (1969). However,
66
CASE REPORTS
similar angiographic findings have been reported in other diseases. The cases reported by Beuren e t a / . (1969), Duquesnel et a/. (1970) and Maki et al. (1974) were probably congenital hypocupraemia since their clinical features were consistent with the syndrome. However, tortuous and lengthened arteries were also noted in a 10-year-old girl with aortic insufficiency (Ertugrul 1967) and in a one-year-old girl with Ehlers-Danlos syndrome (Lees and Menashe 1969). Therefore, even with such characteristic findings, the final diagnosis should await the study of copper metabolism. Accumulated subdural fluid has been a finding in many cases with this disease. As in our Case 1, surgical correction invariably has failed to bring about improve-
ment (Aguilar 1966, Singh and Bresnan 1973). In our Case 2, no avascular area was found at four months, but at autopsy severe brain atrophy was found and the subdural fluid collected was more than 60cc. Apparently the subdural hygroma was secondary to severe brain atrophy and little can be expected from surgical intervention. AUTHORS’ APPOINTMENT
Kunihiko Osaka, M.D., Department of Neurological Surgery; Noriko Sato, M.D., Department of Neurological Surgery; Satoshi Matsumoto, M.D., Department of Neurological Surgery; Hitoshi Ogino, M.D., Department of Paediatrics; Soichi Kodama, M.D.. Department of Paediatrics; Sumiyoshi Yokoyama, M.D., Department of Paediatrics; Taketoshi Sugiyama, M.D., Department of Pathology (11); Kobe University School of Medicine, Kobe 650. Japan.
SUMMARY
Two Japanese infants with Menkes’ kinky hair syndrome are reported. The unusual finding in one infant was the absence of the hair abnormality characteristic of this disease; other findings were consistent with the diagnosis. It is suggested that hair abnormality cannot be relied upon for the diagnosis and that the term ‘kinky hair’ is inappropriate. In its place ‘congenital hypocupraemia’ is proposed as the diagnostic term to embrace patients with and without hair abnormality. Serum copper determination is a simple and reliable test in the diagnosis of this syndrome and should be done routinely in all male patients with unexpected deterioration. The angiographic features present in these patients are characteristic but not pathognomonic of the disease. Subdural hygroma, a common finding, is the result of severe brain atrophy and little can be expected by surgical intervention. RESUME
Les cas de deux enfants japonais prisentant un syndrome de cheveux acier de Menkes sont dicrits. Le fait inhabituel chez I’un des enfants Ctait I’absence de I’anomalie des cheveux caractiristique de la maladie alors que les autres symptomes correspondaient bien au diagnostic. 11 est donc suggiri qu’au moins chez les enfants japonais I’anomalie des cheveux ne peut constituer un signe fidkle pour le diagnostic et que le terme cheveux acier est inapproprii. En remplacement, il est proposC ‘hypocuprimie conginitale’, ce terme recouvrant les malades avec ou sans anomalie des cheveux. La ditermination du taux sirique du cuivre est un test simple et fidkle pour le diagnostic de ce syndrome et devrait Ctre pratiquie systimatiquement chez tous les jeunes garcons prisentant une dittrioration inattendue. Les manifestations angiographiques prisentes chez ces sujets sont caractiristiques mais non pathognomoniques de la maladie. L’hygroma sous-durale, dicouverte commune, est le risultat de I’atrophie ciribrale grave et il ne peut Ctre attendu que peu de I’intervention chirurgicale. 67
DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY.
1977, 19
ZUSAMMENFASSUNG
Es werden zwei japanische Kinder mit dem Menkes’ ‘steely hair’ Syndrom beschrieben. Der ungewohnliche Befund bei einem der Kinder war das Fehlen der Haarveranderungen, die fur diese Krankheit charakteristisch sind, die anderen Befunde waren jedoch typisch fur diese Diagnose. Es wird darauf hingewiesen, dakzumindest bei japanischen Kinderndie Haarveranderungen nicht pathognomonisch sind und daB der Begriff ‘steely hair’ nicht zutreffend ist. Stattdessen wird die Bezeichnung congenitaler Kupfermangel als diagnostischer Terminus technicus vorgeschlagen, um Patienten mit und ohne Haarveranderungen zu erfassen. Kupferbestimmungen im Serum sind eine einfache und zuverlassige Methode fur die Diagnose dieses Syndroms und sollten routine-maBig bei allen mannlichen Patienten, die unerwartet eine Verschlechterung ihres allgemeinen Zustandes durchmachen, veranlant werden. Die angiographischen Befunde bei diesen Patienten sind charakteristisch, aber nicht pathognomonisch fur diese Erkrankung. Das subdurale Hygrom, ein haufiger Befund, ist das Ergebnis einer schweren Hirnatrophie und kann mit nur wenig Erfolg durch chirurgische Intervention behandelt werden. REFERENCES Adams, P. C., Strand, D. R., Bresnan, M. J., Lucky, A. W. (1974) ‘Kinky hair syndrome. Serial study of radiological findings with emphasis on the similarity to the battered child syndrome.’ Radiology, 112,401-407. Aguilar, M. J., Chadwick, D. L., Okuyama, K., Kamoshita, S. (1966) ‘Kinky hair disease. 1. Clinical and pathological features.’ Journal of Neuropathology and Experimental Neurology, 25, 507-522. Ashkenazi, A., Levin, S., Djaldetti, M.,Fishel, E.. Benvenisti, D. (1973) ‘The syndrome of neonatal copper deficiency.’ Pediatrics, 52, 525-533. Beuren, A. J., Hort, W., Kalbfleisch, H., Miiller, H., Stoermer, J. (1969) ‘Dysplasia of the systemic and pulmonary arterial system with tortuosity and lengthening of the arteries. A new entity, diagnosed during life and leading to coronary death in early childhood.’ Circulation, 39, 109-1 15. Billings, D. M., Degnan, M. (1971) ‘Kinky hair syndrome. A new case and a review.’ American Journal of Diseases of Children, 121,447-449. Danks, D. M., Campbell, P. E., Stevens, B. J., Mayne, V., Cartwright, E. (1972a) ‘Menkes’ kinky hair syndrome. An inherited defect of copper absorption with wide-spread effects.’ Pediatrics, 50, 188-201. - Stevens, B. J., Campbell, P. E., Gillespie, J. M., Walker-Smith, J., Blomfield, J., Turner, B. (1972b) ‘Menkes’ kinky hair syndrome.’ Lancet. 1, 1100-1 102. Duquesnel, J.. Monnet, P., Salles, B., David, M., Croisille, M. (1970) ‘Les dolico-art6res congenitales. (A propos de cinq observations.)’ Semaine des H6pitaux a2 Paris, Annales de Radiologie, 13, 343. Ertugrul, A. (1967) ‘Diffuse tortuosity and lengthening of the arteries.’ Circulation, 36,400-407. French, J. H., Sherard, E. S.,Lubell, H., Brotz, M., Moore, C. L. (1972) ‘Trichopoliodystrophy. I. Report of a case and biochemical studies.’ Archives of Neurology, 26, 229-244. Ghatak, N. R., Hirano, A., Poon, T. P., French, J. H. (1972) ‘Trichopoliodystrophy. Pathological changes in skeletal muscle and nervous system.’ Archives of Neurology, 26, W 7 2 . Karpel, J. T., Peden, V. H. (1972) ‘Copper deficiency in long term parenteral nutrition.’ Journal of Pediatrics, 80, 32-36. Lees, M. H., Menashe, V. D., Sunderland, C. O., Morgan, C. L., Dawson, P. J. (1969) ‘Ehlers-Danlos syndrome associated with multiple pulmonary artery stenoses and tortuous systemic arteries.’ Journal of Pediatrics, 75, 1031-1036. Maki, Y., Nakada, Y.,Shirai. S. (1974) ‘Dolichomega cerebral arteries in children.’ Clinical Neurology (Tokyo), 14, 344-352. Menkes, J. H.. Alter, M., Steigleder, G. K., Weakley. D. R.. Sung, J. H. (1962) ‘A sex-linked recessive disorders with retardation of growth, peculiar hair and focal cerebral and cerebellar degeneration.‘ Pediatrics, 29, 764-779. Sacks, J. G., Lindenberg, R. (1969) ‘Dolicho-ectatic intra-cranial arteries. Symptomatology and pathogenesis of arterial elongation and distention.’ Johns Hopkins Journal of Medicine. 125, 95-106. Sato, F.. Shimura, Y., Yokota, J., Suzuki, M., Takita, S..Yabuta, K., Fukuyama, Y. (1975) ‘Menkes kinky hair disease. A report of the first Japanese case and review of literature.’ Brain and Development. 7, 132-145. Shields, G . S.,Coulson, W. F.. Kimball, D. A., Carnes, W. H., Cartwright, G. E., Wintrobe, M. M. (1962) ‘Studies on copper metabolism. Cardiovascular lesions in copper-deficient swine.’ American Journal of Pathology, 41, 603-62 I. Singh, S., Bresnan, J. (1973) ‘Menkes kinky-hair syndrome.’ American Journal of Diseases of Children, 125, 572-518. Wesenberg, R. L.. Gwinn, J. L., Barnes, G. R . (1969) ‘Radiological findings in the kinky-hair syndrome.’ Radiology, 92, 500-506.
68
1977, 19
RESUMEN
Sindrome de Smith-Lemli-Opitz: observaciones neuroldgicas y oftalmoldgicas Se aporta el caso de un niiio de tres aiios con sindrome de Smith-Lemli-Opitz. Como adicion a la constelacibn de anomalias esquelkticas y genitales descritas clasicamente en este sindrome, este paciente tenia movimientos oculares espontaneos semejantes a 10s opsoclbnicos, estrabismo, falta de respuesta visual de seguimiento y falta de reflejos optokineticos. A la autopsia se observb ausencia del vermis cerebeloso. Existian hemangiomas retinianos. Se notaron microscbpicamente perdida de cClulas de Purkinje y degeneracibn neuronal extensa en 10s nucleos dentados, con asociacibn de una desmielinizacibn en placas de 10s pedhculos cerebelosos y de la substancia blanca central. Estos hallazgos pueden contribuir a la explicacibn de la fisiopatologia del opsoclonus y de algunos de 10s hallazgos neurooftalmolbgicos. REFERENCES Bienfang, D. C. (1974) ‘Opsoclonus in infancy.’ Archives of Oph/halmology, 91, 203-205. Bray, P. F., Ziter, F. A., Lahey, M. E., Myers, G . G. (1969) ‘The coincidence of neuroblastoma and acute cerebellar encephalopathy.’ Journal of Pediatrics. 75, 983-990. Dallaire, L. (1969) ‘Syndrome of retardation with urogenital and skeletal anomalies (Smith-Lemli-Opitz syndrome)+linical features and mode of inheritance.’ Journal of Medical Generics. 6, 113-120. Ellenberger, C., Campa, J. F., Netsky, M. G. (1968) ‘Opsoclonus and parenchymatous degeneration of the cerebellum. The cerebellar origin of an abnormal ocular movement.’ Neuro1og.v. 18, 104-1046. - Keltner, J. L., Stroud, M. H. (1972) ‘Ocular dyskinesia in cerebellar disease: evidence for the similarity of opsoclonus, ocular dysmetria and flutter-like oscillations.’ Brain, 95, 685-692. Garcia, C. A.. McGarry, P. A., Voirol, M., Duncan, C. (1973) ‘Neurological involvement in the SmithLemli-Opitz syndrome: clinical and neuropathological findings.’ Developnienral Medicine and Child Neurology, 15,48-55. Joubert, M., Eisenring, J. J., Robb, J. P., Andermann, F. (1969) ‘Familial agenesis of the cerebellar vermis. A syndrome of episodic hyperpnea, abnormal eye movements, ataxia and retardation.‘ Neurology, 19, 8 1 3-825. Keane, J. R., Devereaux, M. W. (1974) ‘Opsoclonus associated with an intracranial tumor.’ Archives of Ophthalmology, 92, 4 4 3 4 5 . Ross, A. T., Zeman, W. (1967) ‘Opsoclonus, occult carcinoma and chemical pathology in dentate nuclei.’ Archives of Neurology, 17, 546551. Ruvalcaba, R. H. A., Reichert, A., Smith, D. W. (1968) ‘Smith-Lemli-Opitz syndrome.’ Archives of Disease in Childhood, 43, 620-622. Smith, D. W., Lemli, L., Opitz, J. M. (1964) ‘A newly recognized syndrome of multiple congenital anomalies.’ Journal of Pediurrics, 64, 210-217. Winick. M. (1969) ‘Malnutrition and brain development.’ Journal of Pediatrics, 74, 667-679.
Congenital Hypocupraemia Syndrome With and Without Steely Hair: Report of Two Japanese Infants Kunihiko Osaka Noriko Sat0 Satoshi Matsumoto Hitoshi Ogino Soichi Kodama Sumiyoshi Yokoyama Taketoshi Sugiyama Introduction Menkes and associates (1962) described a new neurodegenerative disorder of infancy, inherited in the sex-linked recessive mode. The boys appeared to be normal at birth but developed seizures in early -
~~
~~~
~~
infancy and gradually deteriorated to a vegetative state. The hair of these patients was kinky, coarse and white, and microscopic examination showed pili torti (twisting of the hair shaft), monilethrix (irregular diameter of the hair shaft) and trichorrhexis (fractures of the hair shaft). Such hair abnormalities were thought to be the most characteristic feature of the syndrome and led to it being called
~~
Correspondence to Kunihiko Osaka, M.D., Department of Neurosurgery, Kobe University School of Medicine, I2 Kusunoki-cho 7-Chome, Ikuta-ku, Kobe 650, Japan.
62
CASE REPORTS
Menkes’ kinky (or steely) hair syndrome (Aguilar et a/. 1966; Wesenberg et a/. 1969; Danks et a/. 1972a, b ; Singh and Bresnan 1973; Adams et a/. 1974), or ‘trichopoliodystrophy’ (French et a/. 1972, Ghatak et a/. 1972). Danks and colleagues (1972a, b) found the copper content in serum and liver to be extremely low in these patients and claimed that the disorder was induced by defective intestinal absorption of copper. More than 30 patients with Menkes’ kinky hair syndrome have been reported, almost all of whom were Caucasian. The only patient of Oriental origin was recently reported by Sat0 et a/. (1975). The present paper reports two new patients of Japanese origin and discusses the problems encountered in making the diagnoses. CASE 1 A six-month-old boy was admitted to Kobe University Hospital for evaluation of his seizures. He was the only boy born to healthy, nonconsanguineous parents. A three-year-old sister
E
was normal. The family history revealed no mentally retarded children, nor any with seizures. The boy had been born uneventfully after a normal, full-term pregnancy. His early development was normal. Neurological symptoms began at three months of age with grand ma1 seizures. During the following three months he had frequent convulsions, despite anticonvulsant therapy, and became progressively less responsive. His mother noticed an extensive amount of hair to have fallen out. At the age of six months salaam spasms with hypsarrhythmia in EEG were noticed (Fig. 1) and the baby was admitted to hospital. On admission he presented as a chronically sick patient with noisy respiration. He appeared to be unaware of his surroundings. He could not suck milk well and eventually had to be tube-fed. His hair was coarse and scanty (Fig. 2) and among it were several curly white hairs. Microscopically most of the hairs were normal, t u t in some pili torti and monilethrix were found. The head was normal in size, with a sunken anterior fontanelle, but abnormal transillumination was seen in both sides of the head. Blood-cell count, urinalysis and routine blood-chemistry were unremarkable. Plain roentgenograms showed metaphyseal spurring in the long bones and flaring of the anterior ribs in the chest.
DEVELOPMENTAL MEDICINEAND CHILD NEUROLOGY.
1977, 19
Fig. 2 (lefi). Case 1. The hair is sparse and stiff. Fig. 3 (right). Case 2. Hair is not sparse or steely.
regression and repeated convulsions of unknown origin. The boy was the product of a normal pregnancy and delivery and his early development had been normal. He had his first convulsion at two months of age, limited to the right side of the body. Soon afterwards he began to suffer repeated, generalized seizures, despite anticonvulsant therapy. Subsequently, severe psychomotor regression was noticed. On admission he was apathetic with irregular respiration. Results of physical examination were unremarkable. He did not laugh and his eyes did not follow a moving object. His head circumference was 39'5cm and the anterior fontanelle was sunken. No abnormality of the hair was found microscopically, nor was it sparse or white (Fig. 3), and although it appeared to be rather stiff the stiffness apparently was within the normal range for Japanese hair. The child's head control was almost nonexistent, all his extremities were atonic and deep tendon reflexes were suppressed. No abnormalities were found in routine laboratory studies, including quantitative analysis of urine and serum for amino acid. Convulsions were well controlled after admission by increased doses of anticonvulsants, but no neurological improvement occurred. Because the EEG suggested greater involvement in the left side of the brain, a left carotid angiogram was performed. Excessive lengthening and tortuosity were found (Fig. 4). There was no avascular area. Excessive lengthening and tortuosity were also found in the right side of the brain and in the spinal cord (Fig. 5). Because of these angiographic findings. copper metabolism was studied and extremely low ceruloplasmin and serum copper
The salaam spasms were well controlled with ACTH treatment and the pattern of hypsarrhythmia disappeared, but his psychomotor retardation progressed relentlessly. Retrograde right brachial angiography revealed a diffuse avascular area of about 2cm thickness in both hemispheres. There was also extreme lengthening and tortuosity of all arteries. The same abnormalities were seen in the arteries of the neck, right arm, legs and abdomen. Serum copper and ceruloplasmin were found to be extremely low (Table I). TABLE I Copper metabolism
Serum (pg/dl)
..
1
94
By atomic absorption technique
t By M-Partigen-CeruloplasmineEkhring Institut Two months later a right carotid angiogram revealed an increased avascular area. A burr hole was made and it was noted that there was retention of xanthrochromic fluid under a thin, transparent membrane. The fluid was not under abnormal tension. A subdural peritoneal shunt was inserted but there was no improvement in the child's condition. CASE
2
This four-month-old boy was admitted because of repeated convulsions. He was the parents' third child. The elder daughter was healthy but his brother had died of progressive psychomotor
64
CASE RFPORTS
Fig. 4. (/t.ft)Case 2. Left carotid angiogram showing tortuosity and lengthening of arteries. Fig. 5. (right) Case 2. Retrograde right brachial angiogram showing dilated and tortuous anterior spinal artery (arrow). levels were found (Table I). Biopsy material was including his brother’s death after an taken from the superficial temporal artery, the identical clinical course, were consistent lymph node and the skin. The artery showed with the syndrome: i.e. the peculiar marked tortuosity, aneurysmal dilatation and changes Of the arteries and atrophy splitting of elastic lamina (Fig. 6), but the lymph node and skin were normal microscopically. of the brain, with massive accumulation After discharge from hospital, the child deterof subdural fluid. In particular, the exiorated progressively and had repeated bouts of tremely low levels of ceruloplasmin and pneumonia. No changes occurred in the hair. He serum copper are important for the diagdied suddenly at home at the age of 13 months. nosis. Low serum copper also occurs with At autopsy the prominent findings were severe nutritional depletion of copper (Karpel atrophy of the brain, bilateral subdural hygroma covered with thick membrane, and peculiar and Peden 1972, Ashkenazi et al. 1973), tortuosity of the major arteries (Fig. 7). but nutritional copper deficiency occurs
in infancy only when a pre-term baby with less copper reserves in the liver is deprived of copper by prolonged intravenous infusion and without oral intake, as after surgery: more than enough copper is contained in the usual food (Shields et al. 1962, Karpel and Peden 1972, Ashkenazi et al. 1973). Case 2 was not born prematurely and had been fed with
Discussion There were no difficulties in diagnosing Case 1 because of the seizures, progressive psychomotor retardation, obvious hair abnormalities and the disturbed copper metabolism. Case 2 was devoid of the hair abnormality which is the key diagnostic feature of the syndrome, but other features, 65
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Fig. 6 (above). Case 2. Superficial temporal artery: note splitting of elastic lamina. (Van Gieson stain.) Fig. 7 (right). Case 2. Autopsy findings: note tortuous anterior cerebral arteries (arrow). C indicates optic chasm.
the usual milk, so cannot be an example of nutritional copper deficiency. Since such unusual depletion of copper is not known in any other disease process, Case 2 must be diagnosed as an atypical case of Menkes’ kinky-hair syndrome; atypical because he did not have the hair abnormalities characteristic of the disorder. Almost all cases of the syndrome reported so far have been Caucasian and all seem to have shown the characteristic hair abnormality (Menkes et al. 1962; Aguilar et a/. 1966; Billing and Degnan 1971; Danks et a/. 1 9 7 2 ~b; French et al. 1972; Ghatak et al. 1972; Singh and Bresnan 1973; Adams et al. 1974). The absence of hair abnormality in our Case 2 might be a reflection of racial difference, since Japanese hair is stiffer than Caucasian hair. Only one other patient with this disorder has been reported in Japan (Sato et a/. 1975), and that case apparently had the hair abnormality. From our experience with our two cases, from two different families and both seen over a very short period, we feel that there may be many patients with this disorder in Japan who
have not been diagnosed, probably because the hair abnormality is absent or not so conspicuous. By the same token, there might also be some Caucasian patients who do not have the abnormal hair thought to be characteristic of the syndrome. Serum copper determination is a simple laboratory procedure and should be performed routinely in all patients with unexplained deterioration, whether or not the hair is abnormal. It would seem from our Case 2 that the hair abnormality is only one of the manifestations of copper deficiency and should not be relied on for its diagnosis. If that is so, the terms ‘kinky’ or ‘steely’ hair or ‘trichopoliodystrophy’ are inappropriate and we propose ‘congenital hypocupraemia’ as the diagnostic term to encompass patients with and without hair abnormalities. The arterial changes seen in both our patients, probably induced by splitting of the internal elastic lamina, apparently is a constant finding in congenital hypocupraemia. Angiography therefore can be a useful diagnostic aid, as has been proposed by Wesenberg et a/. (1969). However,
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CASE REPORTS
similar angiographic findings have been reported in other diseases. The cases reported by Beuren e t a / . (1969), Duquesnel et a/. (1970) and Maki et al. (1974) were probably congenital hypocupraemia since their clinical features were consistent with the syndrome. However, tortuous and lengthened arteries were also noted in a 10-year-old girl with aortic insufficiency (Ertugrul 1967) and in a one-year-old girl with Ehlers-Danlos syndrome (Lees and Menashe 1969). Therefore, even with such characteristic findings, the final diagnosis should await the study of copper metabolism. Accumulated subdural fluid has been a finding in many cases with this disease. As in our Case 1, surgical correction invariably has failed to bring about improve-
ment (Aguilar 1966, Singh and Bresnan 1973). In our Case 2, no avascular area was found at four months, but at autopsy severe brain atrophy was found and the subdural fluid collected was more than 60cc. Apparently the subdural hygroma was secondary to severe brain atrophy and little can be expected from surgical intervention. AUTHORS’ APPOINTMENT
Kunihiko Osaka, M.D., Department of Neurological Surgery; Noriko Sato, M.D., Department of Neurological Surgery; Satoshi Matsumoto, M.D., Department of Neurological Surgery; Hitoshi Ogino, M.D., Department of Paediatrics; Soichi Kodama, M.D.. Department of Paediatrics; Sumiyoshi Yokoyama, M.D., Department of Paediatrics; Taketoshi Sugiyama, M.D., Department of Pathology (11); Kobe University School of Medicine, Kobe 650. Japan.
SUMMARY
Two Japanese infants with Menkes’ kinky hair syndrome are reported. The unusual finding in one infant was the absence of the hair abnormality characteristic of this disease; other findings were consistent with the diagnosis. It is suggested that hair abnormality cannot be relied upon for the diagnosis and that the term ‘kinky hair’ is inappropriate. In its place ‘congenital hypocupraemia’ is proposed as the diagnostic term to embrace patients with and without hair abnormality. Serum copper determination is a simple and reliable test in the diagnosis of this syndrome and should be done routinely in all male patients with unexpected deterioration. The angiographic features present in these patients are characteristic but not pathognomonic of the disease. Subdural hygroma, a common finding, is the result of severe brain atrophy and little can be expected by surgical intervention. RESUME
Les cas de deux enfants japonais prisentant un syndrome de cheveux acier de Menkes sont dicrits. Le fait inhabituel chez I’un des enfants Ctait I’absence de I’anomalie des cheveux caractiristique de la maladie alors que les autres symptomes correspondaient bien au diagnostic. 11 est donc suggiri qu’au moins chez les enfants japonais I’anomalie des cheveux ne peut constituer un signe fidkle pour le diagnostic et que le terme cheveux acier est inapproprii. En remplacement, il est proposC ‘hypocuprimie conginitale’, ce terme recouvrant les malades avec ou sans anomalie des cheveux. La ditermination du taux sirique du cuivre est un test simple et fidkle pour le diagnostic de ce syndrome et devrait Ctre pratiquie systimatiquement chez tous les jeunes garcons prisentant une dittrioration inattendue. Les manifestations angiographiques prisentes chez ces sujets sont caractiristiques mais non pathognomoniques de la maladie. L’hygroma sous-durale, dicouverte commune, est le risultat de I’atrophie ciribrale grave et il ne peut Ctre attendu que peu de I’intervention chirurgicale. 67
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ZUSAMMENFASSUNG
Es werden zwei japanische Kinder mit dem Menkes’ ‘steely hair’ Syndrom beschrieben. Der ungewohnliche Befund bei einem der Kinder war das Fehlen der Haarveranderungen, die fur diese Krankheit charakteristisch sind, die anderen Befunde waren jedoch typisch fur diese Diagnose. Es wird darauf hingewiesen, dakzumindest bei japanischen Kinderndie Haarveranderungen nicht pathognomonisch sind und daB der Begriff ‘steely hair’ nicht zutreffend ist. Stattdessen wird die Bezeichnung congenitaler Kupfermangel als diagnostischer Terminus technicus vorgeschlagen, um Patienten mit und ohne Haarveranderungen zu erfassen. Kupferbestimmungen im Serum sind eine einfache und zuverlassige Methode fur die Diagnose dieses Syndroms und sollten routine-maBig bei allen mannlichen Patienten, die unerwartet eine Verschlechterung ihres allgemeinen Zustandes durchmachen, veranlant werden. Die angiographischen Befunde bei diesen Patienten sind charakteristisch, aber nicht pathognomonisch fur diese Erkrankung. Das subdurale Hygrom, ein haufiger Befund, ist das Ergebnis einer schweren Hirnatrophie und kann mit nur wenig Erfolg durch chirurgische Intervention behandelt werden. REFERENCES Adams, P. C., Strand, D. R., Bresnan, M. J., Lucky, A. W. (1974) ‘Kinky hair syndrome. Serial study of radiological findings with emphasis on the similarity to the battered child syndrome.’ Radiology, 112,401-407. Aguilar, M. J., Chadwick, D. L., Okuyama, K., Kamoshita, S. (1966) ‘Kinky hair disease. 1. Clinical and pathological features.’ Journal of Neuropathology and Experimental Neurology, 25, 507-522. Ashkenazi, A., Levin, S., Djaldetti, M.,Fishel, E.. Benvenisti, D. (1973) ‘The syndrome of neonatal copper deficiency.’ Pediatrics, 52, 525-533. Beuren, A. J., Hort, W., Kalbfleisch, H., Miiller, H., Stoermer, J. (1969) ‘Dysplasia of the systemic and pulmonary arterial system with tortuosity and lengthening of the arteries. A new entity, diagnosed during life and leading to coronary death in early childhood.’ Circulation, 39, 109-1 15. Billings, D. M., Degnan, M. (1971) ‘Kinky hair syndrome. A new case and a review.’ American Journal of Diseases of Children, 121,447-449. Danks, D. M., Campbell, P. E., Stevens, B. J., Mayne, V., Cartwright, E. (1972a) ‘Menkes’ kinky hair syndrome. An inherited defect of copper absorption with wide-spread effects.’ Pediatrics, 50, 188-201. - Stevens, B. J., Campbell, P. E., Gillespie, J. M., Walker-Smith, J., Blomfield, J., Turner, B. (1972b) ‘Menkes’ kinky hair syndrome.’ Lancet. 1, 1100-1 102. Duquesnel, J.. Monnet, P., Salles, B., David, M., Croisille, M. (1970) ‘Les dolico-art6res congenitales. (A propos de cinq observations.)’ Semaine des H6pitaux a2 Paris, Annales de Radiologie, 13, 343. Ertugrul, A. (1967) ‘Diffuse tortuosity and lengthening of the arteries.’ Circulation, 36,400-407. French, J. H., Sherard, E. S.,Lubell, H., Brotz, M., Moore, C. L. (1972) ‘Trichopoliodystrophy. I. Report of a case and biochemical studies.’ Archives of Neurology, 26, 229-244. Ghatak, N. R., Hirano, A., Poon, T. P., French, J. H. (1972) ‘Trichopoliodystrophy. Pathological changes in skeletal muscle and nervous system.’ Archives of Neurology, 26, W 7 2 . Karpel, J. T., Peden, V. H. (1972) ‘Copper deficiency in long term parenteral nutrition.’ Journal of Pediatrics, 80, 32-36. Lees, M. H., Menashe, V. D., Sunderland, C. O., Morgan, C. L., Dawson, P. J. (1969) ‘Ehlers-Danlos syndrome associated with multiple pulmonary artery stenoses and tortuous systemic arteries.’ Journal of Pediatrics, 75, 1031-1036. Maki, Y., Nakada, Y.,Shirai. S. (1974) ‘Dolichomega cerebral arteries in children.’ Clinical Neurology (Tokyo), 14, 344-352. Menkes, J. H.. Alter, M., Steigleder, G. K., Weakley. D. R.. Sung, J. H. (1962) ‘A sex-linked recessive disorders with retardation of growth, peculiar hair and focal cerebral and cerebellar degeneration.‘ Pediatrics, 29, 764-779. Sacks, J. G., Lindenberg, R. (1969) ‘Dolicho-ectatic intra-cranial arteries. Symptomatology and pathogenesis of arterial elongation and distention.’ Johns Hopkins Journal of Medicine. 125, 95-106. Sato, F.. Shimura, Y., Yokota, J., Suzuki, M., Takita, S..Yabuta, K., Fukuyama, Y. (1975) ‘Menkes kinky hair disease. A report of the first Japanese case and review of literature.’ Brain and Development. 7, 132-145. Shields, G . S.,Coulson, W. F.. Kimball, D. A., Carnes, W. H., Cartwright, G. E., Wintrobe, M. M. (1962) ‘Studies on copper metabolism. Cardiovascular lesions in copper-deficient swine.’ American Journal of Pathology, 41, 603-62 I. Singh, S., Bresnan, J. (1973) ‘Menkes kinky-hair syndrome.’ American Journal of Diseases of Children, 125, 572-518. Wesenberg, R. L.. Gwinn, J. L., Barnes, G. R . (1969) ‘Radiological findings in the kinky-hair syndrome.’ Radiology, 92, 500-506.
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