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Diencephalic syndromes of infancy
March, 1967 T h e ]ournal o[ P E D I A T R I C S
383
DienceDhalicsyndromes of infancy Report of 3 children with emaciation syndrome and disproportionately large hands and feet
Three infants with diencephalic syndromes had abnormally large hands and leer without general gigantism. In two of them the cause was an optic glioma involving the chiasma; in each instance the spinal fluid protein was increased. The third patient had brain atrophy, probably due to a perinatal lesion; the spinal fluid protein concentration was normal. In one patient growth of the tumor was accompanied by a change [rom emaciation to obesity and by disappearance of previous locomotor overactivity. The specificity of certain clinical manifestations in the diencephalic syndromes of infancy is discussed.
Ingrid Gamstorp, M.D.,* Bengt Kjellman, M.D., and Bertil Palmgren, M.D. LUND, SWEDEN
T H E E M A C I A T I O N S Y N D R O M E Of Russell, 1 the syndrome of gigantism and lipodystrophy2, 3, 4 and the syndrome of cerebral gigantism 5, 6 represent different constellations of clinical symptoms due to a proved or suspected diencephalic lesion. The characteristics of these syndromes are summarized in Table I. Acromegaloid features, including disproportionately large hands and feet, occur in cerebral gigantism and in the syndrome of gigantism and lipodystrophy, but apparently have not been described previously in the emaciation syndrome. During the last few years we have investigated some infants with dieneephalic symptoms of different etiology. Three of these infants, who are described below, had sympFrom the Department of Pediatrics, University Hospital, Lund, Sweden. ~Address. Barnkllnlken, Lasarettet, Lund, Sweden.
toms of emaciation and abnormal overgrowth of the hands and feet without general gigantism. Two of the patients had glioma of the optic chiasm, the third had a nonprogressive central cerebral atrophy, possibly of traumatic origin. CASE REPORTS Case 1. History and physical findings. Y. N., female,
born Nov. 16, 1962, was admitted for the first time at the age of 8 months because of prolonged failure to gain weight and acute gastroenteritis. Her mother and a maternal aunt had thyroid adenomas. The family history was otherwise noncontributory. The child was born at term after a normal pregnancy, labor, and delivery. Birth weight was 3,100 grams. Early development was normal and there were no feeding difficulties, vomiting, or diarrhea until the acute attack of gastroenteritis. Her mother had for Vol. 70, No. 3, part 1, pp. 383-390
3 8 4' Gamstorp, Kjellman, and Palmgren
some time observed locomotor overactivity and depletion of subcutaneous fat. On admission the patient was severely emaciated, euphoric, ahnost maniac, and had permanent locomotor overactivity. Her hands and feet were disproportionately large (Fig. 1). Body weight was 5,900 grams, length 71 cm., head circumference 41.5 cm. No enlargement of liver or spleen was noted. Neurological and ophthalmological examinations revealed nothing remarkable. Her mental development seemed normal. During observation in the ward there were initially no feeding difficulties, but after one week the child began to vomit. A high caloric diet failed to produce weight gain. Laboratory findings. Routine blood and urine analyses and serum protein electrophoresis revealed no abnormalities. The serum levels of electrolytes (Na, K, Ca, P, C1), serum transaminases, alkaline phosphatase, and serum lipids (triglycerides, cholesterol) were normal. Intestinal absorption of fat and xylose was normal. The values for serum protein-bound iodine and the urinary corticosteroids were within usual ranges. The spinal fluid protein was increased (82 rag. per 100 ml.), the cell count was
Fig. 1. Patient 1. Age 8 months. Note the disproportionately large hands and feet, the depletion of subcutaneous fat, and the expression of the face with its retraction of the eyelids (Collier's sign).
T a b l e I. S y m p t o m s in d i e n c e p h a l i c s y n d r o m e s
Emaciation syndrome (Russell 1)
Lipodystrophy and gigantism (Berardinelli, e Seip s)
Cerebral gigantism (Sotos et al.,* Kjellman ~)
Etiology
Hereditary metabolic dis- Idiopathic, nonprogresDiencephalic tumor ease? sive brain damage (mostly optic glioma)
Age at onset
0 to 2 years
Birth
0 to 2 years
Gigantism
Initially accelerated growth may occur
Present
Present
Large hands and feet
Present (previously not described )
Present
Present
Emaciation
Present
Present
Absent
Bone age
Normal or advanced
Advanced
Advanced
Mental symptoms
Euphoria and locomotor Normal or slightly suboveractivity may occur normal intelligence
Mental retardation
Hepatosplenomegaly
Absent
Absent
Other symptoms
Paleness in spite of nor- Hypertrichosis, hyperpigmal blood values, hypo- mentation tension, hypoglycemia
Serum lipids
Normal
Hyperlipemia
Normal
Somatotropin in serum
....
High ?
High ?
Pneumoencephalography
Diencephalic tumor
Enlarged lateral ventricles Enlarged lateral ventriand third ventricle cles and third ventricle
Present
Diencephalic syndromes o/ in/ancy 3 8 5
normal. The electroencephalogram was normal. Roentgen examinations of the skeleton, cranium, sella turcica, and optic foramina revealed no abnormalities. A pneumoencephalogram showed a distortion o f the frontal part of the third ventricle by a tumor mass, expanding from the floor of the third ventricle (Fig. 4). At operation a firm tumor the size of a walnut was found. It contained the two optic nerves, and only part of it could be removed. Histologic examination showed optic glioma. Course after operation. The patient received postoperative radiation treatment. She did not need hormone substitution therapy. One month after operation bilateral miosis and slight paleness of the optic disks were observed. Her cheerfulness and locomotor overactivity slowly decreased and she became ill-tempered. From the age of 2 years and 1 month, i.e., 1 year after the operation, she had a ravenous appetite and grew plump (Figs. 2 and 3). At the age of 1 year she could walk unaided and at 2 years she started to use single words. At a follow-up examination at the age of 2 years, 10 months, she appeared slightly retarded in development. She was no longer euphoric or hyperactive but good-natured and friendly, but did have occasional temper tantrums, particularly when she was hungry. She had no abnormal neurologic signs except bilateral miosis and optic atrophy but with no demonstrable impairment of vision. Apart from obesity she had no endocrine symptoms or signs. Roentgenograms of the
Fig. 2. Patient 1. Age 2 years and 10 months, 1 year and 9 months after operation.
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Fig. 3. Patient 1. Weight, length, and head circumference. Note the rapid increase in weight from about 2 years of age.
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386
Gamstorp, Kjellman, and PaImgren
The Journal of Pediatrics March 1967
Fig. 4. Patient 1. Pneumoencephalogram (A, lateral, and B, frontal view) at the age of 1 year and before operation. Note impression in and displacement of anterior part of third ventricle, most marked in the right circumference.
Fig. 5. Patient 1. Pneumoencephalogram (A, Tateral view, B, frontal view) at the age of 2 years and 10 months, about 1 year and 10 months after operation. Note the progression of the tumor as compared with Fig. 4.
sella turcica, optic foramina, and cranium discIosed no abnormality. Pneumoencephalography revealed severe progression of the tumor (Fig. 5). The height, weight, and head circumference are shown in Fig. 3. Comment. This patient thus had the typical features of the Russell's syndrome, viz., emaciation, hyperkinesia, and euphoria. In addition she had disproportionally large hands and feet. The possibilities of a psychosis, malabsorption disease, and thyrotoxicosis were considered, but the clinical picture together with the increased spinal fluid protein suggested a diencephalic tumor. This diagnosis was confirmed by pneumo-
encephalography and operation. That emaciation was followed by obesity during the progress of the tumor is noteworthy. Case 2. History and physical findings. K. G. D., born Aug. 27, I963, was referred to us because of retarded development, emaciation, and poor vision. A male cousin of the mother had died at the age of 18 months in 1937. He had had a variety of symptoms including emaciation, nystagmus, strabismus, dilated pupils, pale optic disks, and poor vision. Necropsy was not done. The family history was otherwise noncontributory.
Volume 7'0 Number 3, part 1
The patient here reported was born at term after a normal pregnancy, labor, and delivery. Birth weight was 3,100 grams. Strabismus and nystagmus were noticed from the first month of life. Psychomotor development appeared normal during the first 6 months, but later was retarded, and then signs of poor vision also became evident. There were no feeding difficulties. On admission, at the age of 17 months, he was pale and thin and had excessively large hands and feet (Fig. 6). Body weight was 9,080 grams, length 80.5 cm., and head circumference 53 cm. Length was thus normal for age, body weight was below the 2 sigma limit, and head circumference was above the upper limit of the normal range. 7, 8 The liver and spleen were not enlarged. The patient could sit, but not stand, unaided. He had convergent strabismus, bilateral nystagmus, large pupils which reacted only slightly to light, pale optic disks, exaggerated tendon reflexes, aad general ataxia. Laboratory data. Routine blood and urine analyses were normal, as were the values for serum electrolytes (K, Na, Ca, P, C1) and lipids (triglyeerides, cholesterol). Serologic tests for syphilis, listeriosis, and toxoplasmosis were negative. Urine excretion of neutral 17-KS and 17-OH CS, an intravenous ACTH test, and an oral methopyranone test were normal. The spinal fluid contained 102 mg. protein per 100 ml. and 32 white blood cells per milliliter. Electroencephalography, and x-ray examination of skeleton, sella turclca, and optic foramina disclosed no abnormalities. A pneumoencephalogram revealed enlarged lateral ventricles and a suprasellar tumor, which dislocated the aqueduct and third ventricle (Fig. 7). At operation a tumor mass was subtotally resected. The tumor involved the optic chiasm. Histologic examination showed optic glioma. Course after operation. The postoperative sourse was complicated by left-sided weakness. The patient received postoperative radiation therapy and substitution treatment with hydrocortisone, DOCA, and NaC1. Ventricular-cardiac shunt for the relief of intracranial hypertension was performed 1 month after operation. Eight months after operation he was in good nutritional condition and had no clinical signs of progression of the tumor. The head circumference was 55 cm. He could not walk. Comment. In this case of diencephalic tumor, emaciation and paleness without anemia were
Diencephalic syndromes of infancy
387
Fig. 6. Patient 2. Age 1 year and 5 months, with a normal child of the same age. Note the large hands and feet and the depletion of subcutaneous fat.
Fig. 7. Patient 2. Pneumoencephalogram (lateral view) at the age of 1 year and 6 months, and before operation. Note large, expansive, suprasellar tumor, partly circumscribed by air, in third ventricles and cisterns. combined with disproportionately large hands and feet. There was, however, no hyperkinesia or euphoria. Neurologic and ophthalmologic signs indicated the nature and site of the tumor.
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Gamstorp, Kjelbnan, and Palmgren
The Journal o[ Pediatrics March 1967
The spinal fluid protein was increased. The diagnosis was confirmed by pneumoencephalography and operation. It is noteworthy that another member of the family also probably had a diencephalic tumor in infancy.
Case 3.
History and physical findings. T. K., male, born Sept. 22, I964, was admitted at the age of 4 months because of fever, increased muscle tone, and heart disease. The family history was noncontributory. During pregnancy his mother had arterial hypertension and slight albuminuria. Labor and delivery were uncomplicated. Birth weight was 4,200 grams. Generally increased muscle tone and left-sided facial weakness were observed on the second day of life. The following day he had an attack of dyspnea for 2 hours. At the age of one week a systolic heart murmur was heard. Body temperature fluctuated between 37 ~ and 39 ~ C. There were no feeding difficulties. On admission at the age of 4 months, the boy was of heavy build with hypertrophic muscles and excessively l a n e hands and feet (Fig. 8). The subcutaneous fat layer was practically absent. Body weight was 6,600 grams, length 67 cm., and head circumference 45 cm. Thus, measurements were within normal limits for age. He had no enlargement of liver or spleen. A systolic heart murmur was heard; it was loudest over the pulmonary area. The cranium was scaphocephalic with pronounced occipital bones, and the anterior fontanel was open but not bulging. The optic disks were normal, and the pupils reacted norma!ly to light. Muscle tone was generally increased, and the tendon reflexes were exaggerated. Laboratory data. The hemoglobin rose from 9.3 Gin. per 100 ml. to 11.4. Values obtained on routine analyses of the blood and urine, and determination of the aminoacids, acid mucopolysaccharides, and steroid hormones in the urine were normal. So were the serum electrolytes (Na, K, Ca, P. C1), serum enzymes (transaminases, alkaline phosphatase), serum lipids (triglycerides, cholesterol), and somatotropin in serum.* Serologic tests for syphilis and toxoplasmosis were negative. Spinal fluid protein and white cell count were within normal limits. Roentgen examinations of cranium, sella turcica, optic foramina, and a carotid angiogram revealed no abnormalities. A pneumoencephalo~DetermJnatlon performed by E. Cerasl; M.D., Stockholm.
Fig. 8. Patient 3. A, Hand. B, Foot at the age of 5 months; the smaller hand and foot of a normal child of the same age are shown for comparison. Note also the rough texture of the skin.
gram showed symmetrical enlargement of the lateral ventricles and some dilatation of the third ventricle. There were no signs of a tumor (Fig. 9). Skeletal x-ray disclosed normal bone age and thick diaphyses. An electrocardiogram showed right ventricular hypertrophy, and a chest x-ray revealed cardiac enlargement. Course. The patient spent 2 months in the hopsital, during which time his body weight increased from 6,600 to 7,400 grams and length from 67 to 70 cm. The head circumference
Volume 70 Number 3, part 1
Fig. 9. Patient 3. Pneumoencephalogram (lateral
view) at the age of 5 months. Slight central atrophy with normal third ventricle. increased by 1 cm. There were no feeding difficulties. The increased muscle tone diminished. At re-examination at 11 months the patient could sit without support, he could crawl, and he showed no signs of increased intracraniM pressure. The subcutaneous fat had increased. The excessive size of his hands and feet was still striking. Comment. This case was interpreted as a neonatal traumatic lesion with diencephalic involvement. Since emaciation, hypertrophic muscles, and acromegaloid hands and feet indicated a possible diencephalic lesion, the patient was examined neuroradiologically for a diencephalic tumor. In contrast to Cases 1 and 2, this boy, in whom no tumor was found, had a normal spinal fluid protein. The patient's congenital heart disease, probably pulmonary stenosis, was considered a malformation unrelated to the diencephalic syndrome. DISCUSSION
Tumors in the floor of the third ventricle represent only a small proportion of the intracranial tumors of childhood2 Diencephalic tumors are, however, more common in
Diencephalic syndromes of in[ancy
3 89
children than in adults2 Hamartomas, pinealomas, craniopharyngeomas, and gliomas of the optic chiasm are the commonest histologic types. The incidence of endocrine disturbances in patients with diencephalic tumors varies in different reports. Faur6, Debrun, and Le GaP stressed the high incidence of endocrine symptoms, whereas Chutorian and co-workers 1~ reported that, among 56 patients with optic gliomas, 30 of which were chiasmal, only 3 showed endocrine abnormalities. Sexual precocity, diabetes insipidus, hypogonadism, and obesity seem to be the common manifestation of endocrine disturbances in diencephalic tumors of childhood2, 10 However, at least 42 cases of the emaciation syndrome in children with diencephalic tumors are on record.:' o, 11-3o The onset of symptoms was invariably in infancy or early childhood, occasionally during the first months of life. In this respect, our 3 patients resemble those described previously. An interesting finding in the present material of the emaciation syndrome is the disproportionally large hands and feet without general gigantism. Judging from published photographs this feature may have been present in previously reported cases but it has not been commented on by the authors. Initially increased growth in length was described in 1951 by Russell in the emaciation syndrome? The finding of disproportionally large hands and feet in the same syndrome underlines the overlapping of the various clinical syndromes described in association with diencephalic lesions (Table I ) . The close anatomic connection between different types of disturbed growth is illustrated by Case 1, in which emaciation was followed by obesity in conjunction with enlargement of the tumor. Russell has recently recorded the same observation. 2s In 2 of his patients in whom the methopyrapone test was performed, there was an abnormal response, 28 whereas a normal response was observed in the one patient tested by us. The clinical picture gives no clue to the type of the diencephalic lesion. Two of our patients had tumors, the third had a cerebral lesion probably due to a perinatal traumatic
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Gamstorp, Kjellman, and PaImgren
or anoxic episode. D e t e r m i n a t i o n of the spinal fluid p r o t e i n m a y be of diagnostic help; it was n o r m a l in the p a t i e n t who h a d no t u m o r a n d increased in the 2 w h o h a d tumors. I n 12 of 16 published cases of the e m a c i a t i o n syndrome with diencephalic tumors, spinal fluid analyses revealed excessive p r o t e i n values, n-21 T h e emaciation syndrome in diencephalic lesions does not a p p e a r to be h e r e d i t a r y , e.g., it has been described in one of a p a i r o{ identical twins. 27 T h e possible occurrence of the s y n d r o m e in a relative of Case 2 is notew o r t h y t h o u g h p r e s u m a b l y coincidental. The radiological examinations were performed by Sten Cronquist, M.D., Division of Neuroradiology, Department of Radiology, University Hospital, Lund, Sweden. REFERENCES
1. Russell, A.: A diencephalic syndrome of emaciation in infancy and childhood, Arch. Dis. Childhood 26: 274, 1951. 2. Berardinelli, W.: An undiagnosed endocrinometabolic syndrome: Report of 2 cases, J. Clin. Endocrinol. 14: 193, 1954. 3. Seip, M.: Lipodystrophy and gigantism with associated endocrine manifestation. A new diencephatio syndrome? Acta paediat. 48: 555, 1959. 4. Seip, M., and Trygstad, O.: Generalized lipodystrophy, Arch. Dis. Childhood 38: 447, 1963. 5. Sotos, J. F., Dodge, P. R., Muirhead, D., Crawford, J. D., and Talbot, N. B.: Cerebral gigantism in childhood. A syndrome of excessively rapid growth with acromegalic features and a nonprogressive neurologic disorder, New England J. Med. 271: 109, 1964. 6. Kjellman, B.: Cerebral gigantism, Acta paediat, scandinav. 54: 603, 1965. 7. Broman, B., Dahlberg, G., and Liehtenstein, A.: Height and weight during growth, Acta paediat. 30: 1, 1942. 8. Karlberg, P., and Perman, A.: Some physical measurements (weight, length, head circumference and chest circumference) in healthy Swedish children in the first two years of life, Acta paediat. Suppl. 117: 128, 1959. 9. Faur6, C., Debrun, G., and Le Gal, J.: t~tude neuro-radiologique des tumeurs du pIancher du 3 e ventricle chez l'enfant, Ann. radiol. 6: 111, 1963. I0. Chutorian, A. M., Schwartz, J. F., Evans, R. A., and Carter~ S.: Optic gliomas in chiIdren, Neurology 14: 83, 1964. 11. Aas, K.: Dieneephalie syndrome of emaciation. Report of a case, Acta paediat. 52: 161, 1963.
The Journal o[ Pediatrics March 1967
12. Cussen, L. J.: Diencephalic syndrome of early infancy--case report, M. J. Australia 1: 881, 1964.
13. Dechene, E., Jacob, D., Carrier, C., and Jean, C.: Un syndrome dienc6phalique associ~ g une tumeur c6r6brale chez un nourrisson, Canad. M. J. 93: 319, 1965. 14. Diamond, E. F., and Averich, N.: Marasmus and the diencephalic syndrome, Arch. Neurol. 14: 270, 1966. 15. Gareis, F. J., and Johnson, J. A.: Inanition in infants associated with diencephalic neoplasms, Am. J. Dis. Child. 109: 349, 1965. 16. Kagan, H.: Anorexia and severe inanition associated with a tumor involving the hypothalamus, Arch. Dis. Childhood 33" 257, 1958. 17. Marie, J., Lepintre, J~ Faur6, C., L~v~que, B., Perelman, R., and Jean, R.: Cachexie progressive du nourrisson li~e ~k une tumeur diencephalique, Arch. franw p6diat. 18: 319, 1961. 18. Olbing, H.: Dienzephales Abmagerungssyndrom im S~iuglings- und Kleinkindealter, Arch. kinderh. 170: 268, 1964. 19. Pitlyk, P. J., and Miller, R. H.: Diencephalic syndrome of infancy presenting with anorexia and emaciation: Report of case, Proc. Mayo Clin. 10: 327, 1965. 20. Poznanski, A. K., and Manson, G.: Radiographic appearance of the soft tissues in the diencephalic syndrome of infancy, Radiology 31: 101, 1963. 21. White, P. T., and Ross, A. T.: Inanition syndrome in infants with anterior hypothalamic neoplasms, Neurology 13: 974, 1963. 22. Braun, F. C., and Forney, W. R.: Diencephalic syndrome of early infancy associated with brain tumor, Pediatrics 24: 609, 1959. 23. Caldera, R., and Rossier, A.: Cachexie du jeune enfant par tnmeur de l'hypothalamus, Ann. p6diat. 9: 319, 1962. 24. Dods, L.: A diencephalic syndrome of early infancy, J. Australia 2: 689, 1957. 25. Gilbert, Y., Jaillard, M., Butin, L., and Beaudonig, A.: Cachexia in an infant with brain stem tumor, Arch. fran~, p6diat. 22: 734, 1965. 26. Manciaux, J., Montaut, J., Thiriet, M., and Charles, J. M.: A propos d'un cas de caehexie diencdphalique du nourrisson, M6d. inf. 71: 671, 1964. 27. Russell, A.: A diencephalic syndrome of hyperkinetic emaciation typically linked to predominant elation in infancy and early childhood, Excerpta Med., See. VIII, p. 111, 1957. 28. Russell, A.: Syndrome of diencephalic emaciation, Summaries of communications, XI InternationaI Congress of Pediatrics, Tokyo, 1965, p. 483, 29. Seringe, Ph., Lepintre, J., Plainfosse, B., and Inigufz, M.: Cachexie du nourrisson par tumeur de I'hypothalamus ant6rieur: un nouveau cas, Ann. pddiat. 40: 346, 1964. 30. Torrey, E. F., and Uyeda, C. I.: The diencephalic syndrome of infancy, Am. J. Dis. Child. 110: 689, 1965.
383
DienceDhalicsyndromes of infancy Report of 3 children with emaciation syndrome and disproportionately large hands and feet
Three infants with diencephalic syndromes had abnormally large hands and leer without general gigantism. In two of them the cause was an optic glioma involving the chiasma; in each instance the spinal fluid protein was increased. The third patient had brain atrophy, probably due to a perinatal lesion; the spinal fluid protein concentration was normal. In one patient growth of the tumor was accompanied by a change [rom emaciation to obesity and by disappearance of previous locomotor overactivity. The specificity of certain clinical manifestations in the diencephalic syndromes of infancy is discussed.
Ingrid Gamstorp, M.D.,* Bengt Kjellman, M.D., and Bertil Palmgren, M.D. LUND, SWEDEN
T H E E M A C I A T I O N S Y N D R O M E Of Russell, 1 the syndrome of gigantism and lipodystrophy2, 3, 4 and the syndrome of cerebral gigantism 5, 6 represent different constellations of clinical symptoms due to a proved or suspected diencephalic lesion. The characteristics of these syndromes are summarized in Table I. Acromegaloid features, including disproportionately large hands and feet, occur in cerebral gigantism and in the syndrome of gigantism and lipodystrophy, but apparently have not been described previously in the emaciation syndrome. During the last few years we have investigated some infants with dieneephalic symptoms of different etiology. Three of these infants, who are described below, had sympFrom the Department of Pediatrics, University Hospital, Lund, Sweden. ~Address. Barnkllnlken, Lasarettet, Lund, Sweden.
toms of emaciation and abnormal overgrowth of the hands and feet without general gigantism. Two of the patients had glioma of the optic chiasm, the third had a nonprogressive central cerebral atrophy, possibly of traumatic origin. CASE REPORTS Case 1. History and physical findings. Y. N., female,
born Nov. 16, 1962, was admitted for the first time at the age of 8 months because of prolonged failure to gain weight and acute gastroenteritis. Her mother and a maternal aunt had thyroid adenomas. The family history was otherwise noncontributory. The child was born at term after a normal pregnancy, labor, and delivery. Birth weight was 3,100 grams. Early development was normal and there were no feeding difficulties, vomiting, or diarrhea until the acute attack of gastroenteritis. Her mother had for Vol. 70, No. 3, part 1, pp. 383-390
3 8 4' Gamstorp, Kjellman, and Palmgren
some time observed locomotor overactivity and depletion of subcutaneous fat. On admission the patient was severely emaciated, euphoric, ahnost maniac, and had permanent locomotor overactivity. Her hands and feet were disproportionately large (Fig. 1). Body weight was 5,900 grams, length 71 cm., head circumference 41.5 cm. No enlargement of liver or spleen was noted. Neurological and ophthalmological examinations revealed nothing remarkable. Her mental development seemed normal. During observation in the ward there were initially no feeding difficulties, but after one week the child began to vomit. A high caloric diet failed to produce weight gain. Laboratory findings. Routine blood and urine analyses and serum protein electrophoresis revealed no abnormalities. The serum levels of electrolytes (Na, K, Ca, P, C1), serum transaminases, alkaline phosphatase, and serum lipids (triglycerides, cholesterol) were normal. Intestinal absorption of fat and xylose was normal. The values for serum protein-bound iodine and the urinary corticosteroids were within usual ranges. The spinal fluid protein was increased (82 rag. per 100 ml.), the cell count was
Fig. 1. Patient 1. Age 8 months. Note the disproportionately large hands and feet, the depletion of subcutaneous fat, and the expression of the face with its retraction of the eyelids (Collier's sign).
T a b l e I. S y m p t o m s in d i e n c e p h a l i c s y n d r o m e s
Emaciation syndrome (Russell 1)
Lipodystrophy and gigantism (Berardinelli, e Seip s)
Cerebral gigantism (Sotos et al.,* Kjellman ~)
Etiology
Hereditary metabolic dis- Idiopathic, nonprogresDiencephalic tumor ease? sive brain damage (mostly optic glioma)
Age at onset
0 to 2 years
Birth
0 to 2 years
Gigantism
Initially accelerated growth may occur
Present
Present
Large hands and feet
Present (previously not described )
Present
Present
Emaciation
Present
Present
Absent
Bone age
Normal or advanced
Advanced
Advanced
Mental symptoms
Euphoria and locomotor Normal or slightly suboveractivity may occur normal intelligence
Mental retardation
Hepatosplenomegaly
Absent
Absent
Other symptoms
Paleness in spite of nor- Hypertrichosis, hyperpigmal blood values, hypo- mentation tension, hypoglycemia
Serum lipids
Normal
Hyperlipemia
Normal
Somatotropin in serum
....
High ?
High ?
Pneumoencephalography
Diencephalic tumor
Enlarged lateral ventricles Enlarged lateral ventriand third ventricle cles and third ventricle
Present
Diencephalic syndromes o/ in/ancy 3 8 5
normal. The electroencephalogram was normal. Roentgen examinations of the skeleton, cranium, sella turcica, and optic foramina revealed no abnormalities. A pneumoencephalogram showed a distortion o f the frontal part of the third ventricle by a tumor mass, expanding from the floor of the third ventricle (Fig. 4). At operation a firm tumor the size of a walnut was found. It contained the two optic nerves, and only part of it could be removed. Histologic examination showed optic glioma. Course after operation. The patient received postoperative radiation treatment. She did not need hormone substitution therapy. One month after operation bilateral miosis and slight paleness of the optic disks were observed. Her cheerfulness and locomotor overactivity slowly decreased and she became ill-tempered. From the age of 2 years and 1 month, i.e., 1 year after the operation, she had a ravenous appetite and grew plump (Figs. 2 and 3). At the age of 1 year she could walk unaided and at 2 years she started to use single words. At a follow-up examination at the age of 2 years, 10 months, she appeared slightly retarded in development. She was no longer euphoric or hyperactive but good-natured and friendly, but did have occasional temper tantrums, particularly when she was hungry. She had no abnormal neurologic signs except bilateral miosis and optic atrophy but with no demonstrable impairment of vision. Apart from obesity she had no endocrine symptoms or signs. Roentgenograms of the
Fig. 2. Patient 1. Age 2 years and 10 months, 1 year and 9 months after operation.
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Fig. 3. Patient 1. Weight, length, and head circumference. Note the rapid increase in weight from about 2 years of age.
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The Journal of Pediatrics March 1967
Fig. 4. Patient 1. Pneumoencephalogram (A, lateral, and B, frontal view) at the age of 1 year and before operation. Note impression in and displacement of anterior part of third ventricle, most marked in the right circumference.
Fig. 5. Patient 1. Pneumoencephalogram (A, Tateral view, B, frontal view) at the age of 2 years and 10 months, about 1 year and 10 months after operation. Note the progression of the tumor as compared with Fig. 4.
sella turcica, optic foramina, and cranium discIosed no abnormality. Pneumoencephalography revealed severe progression of the tumor (Fig. 5). The height, weight, and head circumference are shown in Fig. 3. Comment. This patient thus had the typical features of the Russell's syndrome, viz., emaciation, hyperkinesia, and euphoria. In addition she had disproportionally large hands and feet. The possibilities of a psychosis, malabsorption disease, and thyrotoxicosis were considered, but the clinical picture together with the increased spinal fluid protein suggested a diencephalic tumor. This diagnosis was confirmed by pneumo-
encephalography and operation. That emaciation was followed by obesity during the progress of the tumor is noteworthy. Case 2. History and physical findings. K. G. D., born Aug. 27, I963, was referred to us because of retarded development, emaciation, and poor vision. A male cousin of the mother had died at the age of 18 months in 1937. He had had a variety of symptoms including emaciation, nystagmus, strabismus, dilated pupils, pale optic disks, and poor vision. Necropsy was not done. The family history was otherwise noncontributory.
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The patient here reported was born at term after a normal pregnancy, labor, and delivery. Birth weight was 3,100 grams. Strabismus and nystagmus were noticed from the first month of life. Psychomotor development appeared normal during the first 6 months, but later was retarded, and then signs of poor vision also became evident. There were no feeding difficulties. On admission, at the age of 17 months, he was pale and thin and had excessively large hands and feet (Fig. 6). Body weight was 9,080 grams, length 80.5 cm., and head circumference 53 cm. Length was thus normal for age, body weight was below the 2 sigma limit, and head circumference was above the upper limit of the normal range. 7, 8 The liver and spleen were not enlarged. The patient could sit, but not stand, unaided. He had convergent strabismus, bilateral nystagmus, large pupils which reacted only slightly to light, pale optic disks, exaggerated tendon reflexes, aad general ataxia. Laboratory data. Routine blood and urine analyses were normal, as were the values for serum electrolytes (K, Na, Ca, P, C1) and lipids (triglyeerides, cholesterol). Serologic tests for syphilis, listeriosis, and toxoplasmosis were negative. Urine excretion of neutral 17-KS and 17-OH CS, an intravenous ACTH test, and an oral methopyranone test were normal. The spinal fluid contained 102 mg. protein per 100 ml. and 32 white blood cells per milliliter. Electroencephalography, and x-ray examination of skeleton, sella turclca, and optic foramina disclosed no abnormalities. A pneumoencephalogram revealed enlarged lateral ventricles and a suprasellar tumor, which dislocated the aqueduct and third ventricle (Fig. 7). At operation a tumor mass was subtotally resected. The tumor involved the optic chiasm. Histologic examination showed optic glioma. Course after operation. The postoperative sourse was complicated by left-sided weakness. The patient received postoperative radiation therapy and substitution treatment with hydrocortisone, DOCA, and NaC1. Ventricular-cardiac shunt for the relief of intracranial hypertension was performed 1 month after operation. Eight months after operation he was in good nutritional condition and had no clinical signs of progression of the tumor. The head circumference was 55 cm. He could not walk. Comment. In this case of diencephalic tumor, emaciation and paleness without anemia were
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Fig. 6. Patient 2. Age 1 year and 5 months, with a normal child of the same age. Note the large hands and feet and the depletion of subcutaneous fat.
Fig. 7. Patient 2. Pneumoencephalogram (lateral view) at the age of 1 year and 6 months, and before operation. Note large, expansive, suprasellar tumor, partly circumscribed by air, in third ventricles and cisterns. combined with disproportionately large hands and feet. There was, however, no hyperkinesia or euphoria. Neurologic and ophthalmologic signs indicated the nature and site of the tumor.
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The Journal o[ Pediatrics March 1967
The spinal fluid protein was increased. The diagnosis was confirmed by pneumoencephalography and operation. It is noteworthy that another member of the family also probably had a diencephalic tumor in infancy.
Case 3.
History and physical findings. T. K., male, born Sept. 22, I964, was admitted at the age of 4 months because of fever, increased muscle tone, and heart disease. The family history was noncontributory. During pregnancy his mother had arterial hypertension and slight albuminuria. Labor and delivery were uncomplicated. Birth weight was 4,200 grams. Generally increased muscle tone and left-sided facial weakness were observed on the second day of life. The following day he had an attack of dyspnea for 2 hours. At the age of one week a systolic heart murmur was heard. Body temperature fluctuated between 37 ~ and 39 ~ C. There were no feeding difficulties. On admission at the age of 4 months, the boy was of heavy build with hypertrophic muscles and excessively l a n e hands and feet (Fig. 8). The subcutaneous fat layer was practically absent. Body weight was 6,600 grams, length 67 cm., and head circumference 45 cm. Thus, measurements were within normal limits for age. He had no enlargement of liver or spleen. A systolic heart murmur was heard; it was loudest over the pulmonary area. The cranium was scaphocephalic with pronounced occipital bones, and the anterior fontanel was open but not bulging. The optic disks were normal, and the pupils reacted norma!ly to light. Muscle tone was generally increased, and the tendon reflexes were exaggerated. Laboratory data. The hemoglobin rose from 9.3 Gin. per 100 ml. to 11.4. Values obtained on routine analyses of the blood and urine, and determination of the aminoacids, acid mucopolysaccharides, and steroid hormones in the urine were normal. So were the serum electrolytes (Na, K, Ca, P. C1), serum enzymes (transaminases, alkaline phosphatase), serum lipids (triglycerides, cholesterol), and somatotropin in serum.* Serologic tests for syphilis and toxoplasmosis were negative. Spinal fluid protein and white cell count were within normal limits. Roentgen examinations of cranium, sella turcica, optic foramina, and a carotid angiogram revealed no abnormalities. A pneumoencephalo~DetermJnatlon performed by E. Cerasl; M.D., Stockholm.
Fig. 8. Patient 3. A, Hand. B, Foot at the age of 5 months; the smaller hand and foot of a normal child of the same age are shown for comparison. Note also the rough texture of the skin.
gram showed symmetrical enlargement of the lateral ventricles and some dilatation of the third ventricle. There were no signs of a tumor (Fig. 9). Skeletal x-ray disclosed normal bone age and thick diaphyses. An electrocardiogram showed right ventricular hypertrophy, and a chest x-ray revealed cardiac enlargement. Course. The patient spent 2 months in the hopsital, during which time his body weight increased from 6,600 to 7,400 grams and length from 67 to 70 cm. The head circumference
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Fig. 9. Patient 3. Pneumoencephalogram (lateral
view) at the age of 5 months. Slight central atrophy with normal third ventricle. increased by 1 cm. There were no feeding difficulties. The increased muscle tone diminished. At re-examination at 11 months the patient could sit without support, he could crawl, and he showed no signs of increased intracraniM pressure. The subcutaneous fat had increased. The excessive size of his hands and feet was still striking. Comment. This case was interpreted as a neonatal traumatic lesion with diencephalic involvement. Since emaciation, hypertrophic muscles, and acromegaloid hands and feet indicated a possible diencephalic lesion, the patient was examined neuroradiologically for a diencephalic tumor. In contrast to Cases 1 and 2, this boy, in whom no tumor was found, had a normal spinal fluid protein. The patient's congenital heart disease, probably pulmonary stenosis, was considered a malformation unrelated to the diencephalic syndrome. DISCUSSION
Tumors in the floor of the third ventricle represent only a small proportion of the intracranial tumors of childhood2 Diencephalic tumors are, however, more common in
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children than in adults2 Hamartomas, pinealomas, craniopharyngeomas, and gliomas of the optic chiasm are the commonest histologic types. The incidence of endocrine disturbances in patients with diencephalic tumors varies in different reports. Faur6, Debrun, and Le GaP stressed the high incidence of endocrine symptoms, whereas Chutorian and co-workers 1~ reported that, among 56 patients with optic gliomas, 30 of which were chiasmal, only 3 showed endocrine abnormalities. Sexual precocity, diabetes insipidus, hypogonadism, and obesity seem to be the common manifestation of endocrine disturbances in diencephalic tumors of childhood2, 10 However, at least 42 cases of the emaciation syndrome in children with diencephalic tumors are on record.:' o, 11-3o The onset of symptoms was invariably in infancy or early childhood, occasionally during the first months of life. In this respect, our 3 patients resemble those described previously. An interesting finding in the present material of the emaciation syndrome is the disproportionally large hands and feet without general gigantism. Judging from published photographs this feature may have been present in previously reported cases but it has not been commented on by the authors. Initially increased growth in length was described in 1951 by Russell in the emaciation syndrome? The finding of disproportionally large hands and feet in the same syndrome underlines the overlapping of the various clinical syndromes described in association with diencephalic lesions (Table I ) . The close anatomic connection between different types of disturbed growth is illustrated by Case 1, in which emaciation was followed by obesity in conjunction with enlargement of the tumor. Russell has recently recorded the same observation. 2s In 2 of his patients in whom the methopyrapone test was performed, there was an abnormal response, 28 whereas a normal response was observed in the one patient tested by us. The clinical picture gives no clue to the type of the diencephalic lesion. Two of our patients had tumors, the third had a cerebral lesion probably due to a perinatal traumatic
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or anoxic episode. D e t e r m i n a t i o n of the spinal fluid p r o t e i n m a y be of diagnostic help; it was n o r m a l in the p a t i e n t who h a d no t u m o r a n d increased in the 2 w h o h a d tumors. I n 12 of 16 published cases of the e m a c i a t i o n syndrome with diencephalic tumors, spinal fluid analyses revealed excessive p r o t e i n values, n-21 T h e emaciation syndrome in diencephalic lesions does not a p p e a r to be h e r e d i t a r y , e.g., it has been described in one of a p a i r o{ identical twins. 27 T h e possible occurrence of the s y n d r o m e in a relative of Case 2 is notew o r t h y t h o u g h p r e s u m a b l y coincidental. The radiological examinations were performed by Sten Cronquist, M.D., Division of Neuroradiology, Department of Radiology, University Hospital, Lund, Sweden. REFERENCES
1. Russell, A.: A diencephalic syndrome of emaciation in infancy and childhood, Arch. Dis. Childhood 26: 274, 1951. 2. Berardinelli, W.: An undiagnosed endocrinometabolic syndrome: Report of 2 cases, J. Clin. Endocrinol. 14: 193, 1954. 3. Seip, M.: Lipodystrophy and gigantism with associated endocrine manifestation. A new diencephatio syndrome? Acta paediat. 48: 555, 1959. 4. Seip, M., and Trygstad, O.: Generalized lipodystrophy, Arch. Dis. Childhood 38: 447, 1963. 5. Sotos, J. F., Dodge, P. R., Muirhead, D., Crawford, J. D., and Talbot, N. B.: Cerebral gigantism in childhood. A syndrome of excessively rapid growth with acromegalic features and a nonprogressive neurologic disorder, New England J. Med. 271: 109, 1964. 6. Kjellman, B.: Cerebral gigantism, Acta paediat, scandinav. 54: 603, 1965. 7. Broman, B., Dahlberg, G., and Liehtenstein, A.: Height and weight during growth, Acta paediat. 30: 1, 1942. 8. Karlberg, P., and Perman, A.: Some physical measurements (weight, length, head circumference and chest circumference) in healthy Swedish children in the first two years of life, Acta paediat. Suppl. 117: 128, 1959. 9. Faur6, C., Debrun, G., and Le Gal, J.: t~tude neuro-radiologique des tumeurs du pIancher du 3 e ventricle chez l'enfant, Ann. radiol. 6: 111, 1963. I0. Chutorian, A. M., Schwartz, J. F., Evans, R. A., and Carter~ S.: Optic gliomas in chiIdren, Neurology 14: 83, 1964. 11. Aas, K.: Dieneephalie syndrome of emaciation. Report of a case, Acta paediat. 52: 161, 1963.
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12. Cussen, L. J.: Diencephalic syndrome of early infancy--case report, M. J. Australia 1: 881, 1964.
13. Dechene, E., Jacob, D., Carrier, C., and Jean, C.: Un syndrome dienc6phalique associ~ g une tumeur c6r6brale chez un nourrisson, Canad. M. J. 93: 319, 1965. 14. Diamond, E. F., and Averich, N.: Marasmus and the diencephalic syndrome, Arch. Neurol. 14: 270, 1966. 15. Gareis, F. J., and Johnson, J. A.: Inanition in infants associated with diencephalic neoplasms, Am. J. Dis. Child. 109: 349, 1965. 16. Kagan, H.: Anorexia and severe inanition associated with a tumor involving the hypothalamus, Arch. Dis. Childhood 33" 257, 1958. 17. Marie, J., Lepintre, J~ Faur6, C., L~v~que, B., Perelman, R., and Jean, R.: Cachexie progressive du nourrisson li~e ~k une tumeur diencephalique, Arch. franw p6diat. 18: 319, 1961. 18. Olbing, H.: Dienzephales Abmagerungssyndrom im S~iuglings- und Kleinkindealter, Arch. kinderh. 170: 268, 1964. 19. Pitlyk, P. J., and Miller, R. H.: Diencephalic syndrome of infancy presenting with anorexia and emaciation: Report of case, Proc. Mayo Clin. 10: 327, 1965. 20. Poznanski, A. K., and Manson, G.: Radiographic appearance of the soft tissues in the diencephalic syndrome of infancy, Radiology 31: 101, 1963. 21. White, P. T., and Ross, A. T.: Inanition syndrome in infants with anterior hypothalamic neoplasms, Neurology 13: 974, 1963. 22. Braun, F. C., and Forney, W. R.: Diencephalic syndrome of early infancy associated with brain tumor, Pediatrics 24: 609, 1959. 23. Caldera, R., and Rossier, A.: Cachexie du jeune enfant par tnmeur de l'hypothalamus, Ann. p6diat. 9: 319, 1962. 24. Dods, L.: A diencephalic syndrome of early infancy, J. Australia 2: 689, 1957. 25. Gilbert, Y., Jaillard, M., Butin, L., and Beaudonig, A.: Cachexia in an infant with brain stem tumor, Arch. fran~, p6diat. 22: 734, 1965. 26. Manciaux, J., Montaut, J., Thiriet, M., and Charles, J. M.: A propos d'un cas de caehexie diencdphalique du nourrisson, M6d. inf. 71: 671, 1964. 27. Russell, A.: A diencephalic syndrome of hyperkinetic emaciation typically linked to predominant elation in infancy and early childhood, Excerpta Med., See. VIII, p. 111, 1957. 28. Russell, A.: Syndrome of diencephalic emaciation, Summaries of communications, XI InternationaI Congress of Pediatrics, Tokyo, 1965, p. 483, 29. Seringe, Ph., Lepintre, J., Plainfosse, B., and Inigufz, M.: Cachexie du nourrisson par tumeur de I'hypothalamus ant6rieur: un nouveau cas, Ann. pddiat. 40: 346, 1964. 30. Torrey, E. F., and Uyeda, C. I.: The diencephalic syndrome of infancy, Am. J. Dis. Child. 110: 689, 1965.