russell's diencephalic syndrome early childhood · ofthe frontothalamic-hypothalamic pathway...

Journal of Neurology, Neurosurgery, and Psychiatry, 1972, 35, 196-201

Russell's diencephalic syndrome of early childhood

MICHAEL A. SALMON

From the Park Hospitalfor Children, Oxford, and Stoke Mandeville Hospital

SUMMARY A case of Russell's diencephalic syndrome of early childhood is presented and theworld literature reviewed. Assays of serum growth hormone (HGH) and fat mobilizing substance(FMS) were performed and gave very abnormal results. The role of these two substances is discussedand their value in the diagnosis of this syndrome is emphasized.

Within the last two decades interest has beenfocused on the diencephalon and its pathology,and it is now known that discrete organic lesionsof the hypothalamus and adjacent structuresmay produce characteristic symptoms. Thus, ithas been known for very many years thatposteriorly placed tumours of the hypothalamusmay be associated with precocious puberty,somnolence, obesity, diabetes insipidus, dys-thermia, and various emotional disturbances.Some conditions, however, such as leprechaun-ism (Donohue's syndrome), cerebral gigantism(Soto's syndrome), generalized lipodystrophywith gigantism, and possibly progeria (Hutchin-son-Gilford syndrome) may be due to a func-tional disorder of the diencephalon rather thanto a discrete organic lesion within one or moreof its component structures. It was not, how-ever, until 1951 that Russell described anapparently specific syndrome of early childhoodresulting from a neoplastic lesion of the anteriorhypothalamus, and not until 1957 that LorimerDods became the second author to reportfurther examples of the syndrome. Russellwould appear to be the only author to reportcases from the United Kingdom.

Russell's syndrome is probably much morecommon than the 50 cases in the literature wouldsuggest and the purpose of this paper is todescribe a further case from the United Kingdomwith the results of relevant investigations andtreatment.

CASE REPORT

S.H., a girl aged 23 months, was the first child ofelderly parents (maternal age, 43 years; paternalage, 45 years). She presented with a three monthhistory of rapid, progressive weight loss and sleep

reversal. The mother had been a ward sister on awell-known neurological unit. The first 20 months oflife had been uncomplicated but after this time therewas a dramatic change (Figs 1 and 2). In spite of anapparently normal dietary intake she rapidly lostweight (Fig. 3) and at the same time became hyper-active by night with long periods of sleep by day.While in the ward she appeared affectionate, withoutaggression, but hyperkinetic. She talked and sang toherself incessantly and demonstrated slight ataxia on

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FIG. 1. S.H. at age 20 moniths.196

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turning and reaching out for objects. Clinical 97examination revealed, apart from gross marasmus, HeightCins.)nystagmus and numerous caf&-au-lait patches overher upper trunk. Her body temperature was consis- /.tently about 35 60C (96°F) and never exceeded this. . 50There was no polydipsia or polyuria and her appetite 34/was usually normal. Her height and weight, frommeasurements kept by the parents, both followedthe 97th percentile, but the weight dropped to wellbelow the 3rd percentile in just over three months.During this period of time her height did not leave Weight (lbs.) 75the 97th percentile.

30 50INVESTIGATIONS The results of the following in- */vestigations were within normal limits: Haemo- 2.5.globin, sedimentation rate, urea, plasma electrolytes,cholesterol, calcium, phosphorus, alkaline phospha-tase, plasma proteins, random and fasting blood 25

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glucose, D-xylose absorption test, serum lead,protein bound iodine, and electroencephalograph.Urine specific gravity was consistently over 1,010. 20

20-

18 ' 24 ' 30 6age

(months)FIG. 3. Height and weight chart.

Abnormal results The cerebrospinal fluid containedprotein 100 mg/100 ml. A pneumoencephalogramshowed a large and mainly left-sided anterior hypo-thalamic tumour (Figs 4 and 5) indenting the thirdventricle.The cisterna lamina terminalis was displaced

forwards and the interpeduncular system wasobliterated. The tumour also encroached on theupper part of the prepontine cisterns and displacedthe lower margin of the left frontal horn upwardsand forwards. The aqueduct was rather more up-right than normal and the midbrain was displacedbackwards.Serum growth hormone (HGH) was assayed using

a double antibody radioimmunoassay technique as:7^-+XFE1 described by Jackson, Grant, and Clayton (1968);

HGH production was stimulated with oral BovrilM2(20 g/1-5 m given in 160 ml. warm water) and

estimated in venous blood samples taken from anindwelling intravenous cannula. The results obtainedwere comparable with those expected in an adultsubject with acromegaly (Table 1). A similar assaywas performed eight months after radiotherapy.

Urinary fat mobilizing substance (FMS) wasassayed by the method of Pawan (1969). Plasma

FIG. 2. S.H. at age 23 months to show extreme levels of ketones (as acetone) and free fatty acidswasting. (FFA) were measured in mice injected with prepared

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Michael A. Salmon

FIG. 4. Pneumoencephalogram to show distortionof third ventricle.

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FIG. 5. Pneumoencephalogram to showdistortion of ventricular system byanterior hypothalamic tumour.

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TABLE 1SERUM GROWTH HORMONE (HGH) ASSAY

Time Normal values Before treatment Three months after(min) (plu/ml.) (Mlu/ml.) radiotherapy

(glZulrnl.)

Fasting 0-10 93.5 48-8

30 > 200 68-860 maximum rise > 200 71-690 30-40 > 165 54-8120 > 143 40-0150 84 5 27-4

urine (see Kekwick and Pawan, 1967) and comparedwith results obtained from a control series of miceinjected with saline. From the increase in plasmaketones the assay revealed a very great deal (740Oincrease) of FMS activity. Unfortunately, the assaywas performed three months after radiotherapy andit would have been interesting to have measuredFMS activity before treatment.

Control miceTest mice

Ketones(as acetone)2-21 mg/100 ml.3-85 mg/100 ml.

(740 inc.)

Free fattyacids558 ,uE/l.599 ,uE/l.

(70 0 inc.)

At the time of this assay the patient was on a

normal diet and eating well. In Pawan's series of 72normal subjects there was no percentage increase ofketones or free fatty acids in mouse plasma, and a

similar finding was reported in six subjects afterpituitary ablation.

TREATMENT AND PROGRESS Once the diagnosis of a

large anterior hypothalamic tumour was confirmedradiotherapy was given as surgery was consideredimpossible. A total of 4,650 r were delivered bycobalt y-ray therapy to the tumour over 19 sessions(44 days). After this course of radiation a slightimprovement was noticed in the succeeding months.Three months after treatment she had gained a littleweight and was much less hyperkinetic. There was,however, a sinister decrease in the child's visualacuity and it is likely that there is considerableinvolvement of the optic chiasma. Formal perimetrywas not attempted.

DISCUSSION

The case described conforms to the originaldescription by Russell (1951) of the diencephalicsyndrome which bears his name. In reviewingthe world literature there is found to be a greatsimilarity between the described cases and the

definition of a specific syndrome must be con-firmed (Table 2).

Children with Russell's diencephalic syndromecommonly present in the first year of life andprobably never after the age of 5 years. Theyoungest reported cases were those of Dods(1957) and Smith, Weinburg, and McAlister(1964) who presented at the age of 2 months.

TABLE 2REPORTED FINDINGS IN 29 CASES OFRUSSELL'S DIENCEPHALIC SYNDROME

1. Profound cachexia 29/292. Sex incidence 18d/1I?3. Euphoria mentioned in 16/294. Hyperactivity mentioned in 20/295. Nystagmus mentioned in 16/296. Optic atrophy 9/297. Pallor without anaemia mentioned in 14/298. Anterior hypothalamic tumour 29/299. Age at presentation 2-32 months

In virtually all the cases profound emaciationwith hyperactivity, apparent well-being, andeuphoria were prominent and, apart from nystag-mus, there was a gross paucity of neurologicalsigns. In no case was there evidence of raisedintracranial pressure, but extension of the tumourto involve the optic discs was present in aboutone fifth of the cases. Paradoxical obesity andincreased height occurred in a case described byFishman and Peake (1970) and was thought tobe secondary to extension of the tumour toinvolve hypothalamic centres regulating foodintake. Similar changes occurred in one of thecases described by Gamstorp, Kjellman, andPalmgren (1967) after partial surgical removalof an anterior hypothalamic tumour.Apart from gross, progressive subcutaneous

wasting, these children exhibit a curious euphoriaand lack of aggression which Spiegel, Wycis,Marks, and Lee (1947) attribute to interruptionof the frontothalamic-hypothalamic pathway oreven to discrete involvement, by the tumour, ofthe dorsomedial thalamic nuclei.Growth hormone (HGH) assay has been

made in only two patients other than thatpresented here, but the exact levels of HGH inone of these (Smith et al., 1964) is not recorded.In both cases the levels were markedly raised. Inthe present case the levels recorded, both in thefasting state and after stimulation with Bovril

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Michael A. Salmon

(Jackson et al., 1968) were greatly raised andequivalent to those expected in adults withacromegaly. These high levels were not associa-ted with any increase in height although sus-tained high levels of growth hormone shouldincrease linear growth (Daughaday, 1968).Three months after treatment with radio-therapy a second HGH assay was performed andshowed a substantial drop in HGH levels whencompared with the first assay. The levels were,however, still above those expected in normalsubjects. The effect of excess HGH productionin this syndrome is not fully understood but it isprobable that its described lipolytic action(Zierler and Rabinowitz, 1963) is, in part,responsible for dispersing subcutaneous fat,which Poznanski and Manson (1963) showed tobe completely absent. Similar loss of subcutane-ous fat is seen in other conditions of presumeddiencephalic origin-namely, leprechaunism(Donohue and Uchida, 1954; Salmon andWebb, 1963), progeria (Schinz, Baensch, Friedl,and Uehlinger, 1952; Thomson and Forfar,1950), and generalized lipodystrophy (Berardi-nelli, 1954; Seip and Trygstad, 1963; Fairney,Lewis, and Cottom, 1969). It is of interest torecall that Villee, Nichols, and Talbot (1969)showed that growth in progeria was also un-responsive to HGH. In leprechaunism the onlyreport ofHGH assay is an isolated measurementreported by Dekaban (1965) which is at theupper level of the normal fasting range (1-10tlu/ml). The total lack of subcutaneous fat inRussell's diencephalic syndrome may be partlyattributable to increased production of HGH,but the lipid mobilizing fraction (LM) isolatedby Zarafonetis, Seifter, Baeder, and Kalas (1959)from the pituitary and the fat mobilizingpolypeptide (FMS) isolated from urine byChalmers, Pawan, and Kekwick (1960) may alsoplay their part. These last two substances may bequite unrelated to HGH but Pawan (1971)suggests that FMS may in fact prove to be adegradation product of HGH. FMS activity wasestimated in the present case and found to besignificantly raised. The estimation was madethree months after radiotherapy had producedclinical improvement and a slight gain in weight.At this time HGH assay (Table 1) revealed aconsiderable drop from the pretreatment levels.It would be of the greatest interest to assayFMS before treatment in this syndrome.

In 1960 Murray found that specific stimulationof the anterior hypothalamus in dogs produced

fluctuating levels of blood lipids. Since allpituitary hormones are thought to be underhypothalamic control, it is possible that lipiddepletion may result from the action, direct orotherwise, of a specific humoral substance pro-duced by the presence of the anterior hypo-thalamic tumour in this syndrome.With the exception of one case seen by Dods

(1957) where a clinical picture resemblingRussell's syndrome resulted from a midlinecerebellar astrocytoma, all the lesions wereaccurately located in the anterior hypothalamusand extended upwards to displace the floor ofthe third ventricle. Extension forwards to involvethe optic tracts was common. The tumours werecommonly astrocytomas but oligodendroglio-mas, spongioblastomas, and ependymomas haveall been recorded. In one case (Braun andForney, 1959) a perforated duodenal ulcer withmassive haemorrhage complicated the mainpresentation, although we should recall that theassociation of peptic ulceration with intracranialneoplasm was noticed as long ago as 1850 byRokitansky and again in 1932 by Cushing.The presentation of Russell's syndrome is so

stereotyped that diagnosis should not bedifficult. The profound cachexia with hyper-activity and a happy affectionate child should becontrasted with the cachectic picture of chronicstarvation, severe malabsorption, gastroenteritis,neoplasia in general, anorexia nervosa, thyro-toxicosis, and chronic diabetes.The absence of neurological signs is important,

although nystagmus may be present. Air studiesand growth hormone assay should confirm thediagnosis. Treatment is at the best palliative andneurosurgery may be impossible. Fishman andPeake (1970) record a six year survival afterradiotherapy in one case, but few patients sur-vive one year after the initial diagnosis.

My special thanks are due to Mrs. D. B. Jackson(Institute of Child Health, London) for HGH assaysand to Dr. Gaston Pawan (Medical Unit, TheMiddlesex Hospital, London) for FMS assays. Iwould like to thank Dr. Dermod MacCarthy, towhom this patient was initially referred, and Dr.Hugh Ellis, who provided facilities for many of theinvestigations.

REFERENCES

Berardinelli, W. (1954). An undiagnosed endocrinometabolicsyndrome. Report of 2 cases. Journal of Clinical Endo-crinology and Metabolism, 14, 193-204.

Braun, F. C., Jr., and Forney, W. R. (1959). Diencephalicsyndrome of early infancy associated with brain tumor.

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Report of a case and review of the literature. Pediatrics,24, 609-615.

Chalmers, T. M., Pawan, G. L. S., and Kekwick, A. (1960).Fat-mobilising and ketogenic activity of urine extracts:relation to corticotrophin and growth hormone. Lancet, 2,6-9.

Cushing, H. (1932). Peptic ulcers and the interbrain. Surgery,Gynecology, and Obstetrics, 55, 1-34.

Daughaday, W. H. (1968). The adenohypophysis. In Text-book of Endocrinology, 4th edn, pp. 27-84. Edited by R. H.Williams. Saunders: Philadelphia.

Dekaban, A. (1965). Metabolic and chromosomal studies inleprechaunism. Archives of Disease in Childhood, 40, 632-636.

Dods, L. (1957). A diencephalic syndrome of early infancy.Medical Journal of Australia, 2, 689-691.

Donohue, W. L., and Uchida, 1. (1954). Leprechaunism. Aeuphuism for a rare familial disorder. Journal ofPediatrics,45, 505-519.

Fairney, A., Lewis, G., and Cottom, D. (1969). Total lipo-dystrophy. Archives of Disease in Children, 44, 368-372.

Fishman, M. A., and Peake, G. T. (1970). Paradoxical growthin a patient with the diencephalic syndrome. Pediatrics, 45,973-982.

CGamstorp, I., Kjellman, B., and Palmgren, B. (1967).Diencephalic syndromes of infancy. Journal of Paediatrics,70, 383-390.

Jackson, D., Grant, D. B., and Clayton, B. E. (1968). Asimple oral test of growth-hormone secretion in children.Lancet, 2, 373-375.

Kekwick, A., and Pawan, G. L. S. (1967). Fat mobilizingsubstance (FMS). Metabolism, 16, 787-796.

Murray, G. (1960). Fat embolism and a fat center. AmericanJournal of Surgery, 100, 676-681.

Pawan, G. L. S. (1969). Levels of fat mobilizing substance(FMS) in urine of human subjects in physiological andpathological conditions of increased lipid metabolism.Proceedinigs of the Nutritioni Society, 28, 17-18.

Pawan, G. L. S. (1971). Personal communication.Poznanski, A. K., and Manson, G. (1963). Radiographic

appearance of the soft tissues in the diencephalic syndromeof infancy. Radiology, 81, 101-106.

Rokitansky, C. (1850). A Manual of Pathological Anatony,Vol. 3, p. 40. Philadelphia.

Russell, A. (1951). A diencephalic syndrome of emaciationin infancy and childhood. Archives of Disease in Childhood,26, 274.

Salmon, M. A., and Webb, J. N. (1963). Dystrophic changesassociated with leprechaunism in a male infant. Archivesof Disease in Childhood, 38, 530-535.

Schinz, H. R., Baensch, W. E., Friedl, E., and Uehlinger, E.(1952). Roentgen-diagnostics, vol. 2, pp. 1122-1123.Grune and Stratton: New York.

Seip, M., and Trygstad, 0. (1963). Generalized lipodystrophy.Archives of Disease in Childhood, 38, 447-453.

Smith, K. R., Jr., Weinburg, W. A., and McAlister, W. H.(1965). Failure to thrive: the diencephalic syndrome ofinfancy and childhood. A case report. Journal of Neuro-surgery, 23, 348-351.

Spiegel, E. A., Wycis, H. T., Marks, M., and Lee, A. J.(1947). Stereotaxic apparatus for operations on the humanbrain. Science, 106, 349-350.

Thomson, J., and Forfar, J. 0. (1950). Progeria (Hutchinson-Gilford syndrome). Report of a case and review of theliterature. Archives of Disease in Childhood, 25, 224-234.

Villee, D. B., Nichols, G., Jr., and Talbot, N. B. (1969).Metabolic studies in two boys with classical progeria.Pediatrics, 43, 207-216.

Zarafonetis, C. J. D., Seifter, J., Baeder, D. H., and Kalas,J. P. (1959). Current clinical status of lipid-mobilizerhormone. Archives of Internial Medicine, 104, 974-981.

Zierler, K. L., and Rabinowitz, D. (1963). Roles of insulinand growth hormone, based on studies of forearm metab-olism in man. Medicine, 42, 385-402.

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