Differential diagnosis of cerebral palsy: Lesch-Nyhan syndrome without self-mutilation

GRANT MITCHELL, MD RODERICK R. MCINNES, MD, PH D

Athetotic cerebral palsy was diagnosed in a 6-month-old boy with no history of perinatal trauma. LeschNyhan syndrome (i.e., complete deficiency of hypoxanthine-guanine phosphoribosyltransferase [HGPRTJ) was diagnosed only when the boy began biting his lower lip at the age of 10 years. It is suggested, on the basis of this case and others like it in the literature, that the delayed onset or absence of self-mutilation in patients with Lesch-Nyhan syndrome may be more common than has been previously suspected. In all males said to have cerebral palsy, HGPRT deficiency must be ruled out, preferably by measuring the ratio of uric acid to creatinine in a random Case report urine specimen. A 10-year-old boy was referred to Une paralysie cerebrale athetosique our hospital for investigation. He a t diagnostiquee chez un gargon was the only natural child of healthy de 6 mois sans antecedent de trau- parents. His mother's pregnancy and matisme perinatal. Ce n'etait qu'a the perinatal course had been unrel'age de 10 ans, lorsque le garson markable. When he was 3 months s'est mis 'a se mordre la levre in- old his parents had noted that he ferieure, que le diagnostic de syndro- didn't raise his head and that he me de Lesch-Nyhan (i.e., une defi- showed little interest in toys placed cience complete de l'hypoxanthine- beside him. When he was 6 months guanine phosphoribosyltransferase old they had taken him to a neuro[HGPRTI) a ete pose. Si l'on se fie surgeon, who had diagnosed cereau present cas et a` d'autres cas bral palsy. At 6 years of age he could semblables decrits dans la litterature, put two words together meaningfulil semble que l'apparition tardive ou ly, and now, at the age of 10, he l'absence d'automutilation chez les could speak in simple sentences, patients atteints du syndrome de though in a dysarthric fashion. His Lesch-Nyhan soit plus frequente developmental age was estimated to qu'on ne l'avait soupsonne. Une be 5 years. He had never learned to deficience en HGPRT doit etre sit, walk or propel his wheelchair. exclue chez tous les garsons que l'on At 8 years of age, coincident with croit atteints de paralysie cerebrale. being moved from his home to an De preference, ceci se fait en institution for the retarded, he had mesurant le rapport acide urique:cre- begun banging his right ear against atinine dans un echantillon d'urine hard objects. When he was 9 years preleve au hasard. of age grand mal seizures had developed and he had become disruptive From the departments of genetics and pediat- and less attentive at school. At 10 rics, Hospital for Sick Children, University of years of age he was transferred to a Toronto rehabilitation centre for assessment Reprint requests to: Dr. Roderick R. of his behaviour, and he began bitMclnnes, Department of genetics, Hospital for Sick Children, 555 University Ave., To- ing his lower lip. He was then referred to our hospital. ronto, Ont. M5G 1X8

Patients with Lesch-Nyhan syndrome (X-linked deficiency of hypoxanthine-guanine phosphoribosyltransferase [HGPRT] are often described as having a characteristic clinical presentation, which includes self-mutilation, choreoathetoid movements, spasticity and mild to moderate mental retardation.'"2 Their macabre and compulsive selfmutilation is one of the most unforgettable signs of clinical medicine. The following report, however, describes a classic case of Lesch-Nyhan syndrome (i.e., with complete HGPRT deficiency) in a patient who did not begin to self-mutilate until he was 8 years old; he was therefore clinically indistinguishable from patients with athetoid or quadriparetic cerebral palsy.

He was emaciated, and he had a hypertrophied right "cauliflower" ear. There were mild contractures of his elbows, wrists, knees and ankles. No localizing neurologic signs were present except for intermittent athetosis and a poor gag reflex. There was generalized hyperreflexia, and the plantar responses were extensor. The palm of his left hand had been excoriated by his fingernails, and he had to be restrained from mutilating his lower lip with his fingernails. The hemoglobin level was 12.1 g/dL, the mean corpuscular volume 108 fL and the serum folate level 5.9 (normal more than 7.0) nmol/L. Serum uric acid levels were 0.43, 0.55 and 0.57 (normal 0.12 to 0.36) mmol/L and urine uric acid:creatinine ratios 1.32, 1.06 and 1.55 (normal less than 1.0 at that age).' Cultures of skin fibroblasts showed no measurable HGPRT activity (less than 0.01% of the control), whereas the activity of adenine phosphoribosyltransferase (APRT) was slightly higher than normal. Three weeks after discharge the patient was observed to have a mild fever with a cough; he unexpectedly died in his sleep 12 hours later. An autopsy showed extensive bronchopneumonia, renal and vesical calculi, and focal gliosis of the cerebellum. Brain tissue frozen less than 12 hours after death had less than 0.1% of the normal HGPRT activity but substantial activity of APRT, an enzyme that deteriorates more rapidly than HGPRT with storage.

Discussion
A diagnosis of Lesch-Nyhan syndrome is likely to be made when all the classic features - self-mutilation, choreoathetoid movements, spasticity and mild to moderate mental retardation - are present in a boy with no history of perinatal illness. Paradoxically, however, the most distinctive feature of the disease, compulsive self-mutilation, is also the most variable in both its
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time of onset and its mode of expression.3 Although comprehensive reviews of the syndrome have described the broad variation in the time of onset of self-mutilation (from 8 months of age to the midteens3'4), some widely read pediatric and neurology texts do not mention this variability.'2 Diagnosis was delayed in our patient because he demonstrated no self-mutilation until 8 years of age, and even then the presentation was not the typical biting of lips, tongue or fingers but repetitive trauma to the right ear. Emotional stress is the'only variable known to increase the degree of self-mutilation,3 and it may also influence its initiation, since our patient manifested no self-mutilation until he was moved from his family's home to an institution. Furthermore, he began biting his lower lip only after he was transferred to another institution 2 years later. The prevalence of Lesch-Nyhan syndrome without self-mutilation may be considerably higher than previously suspected. Seegmiller (personal communication, 1981) recently identified two patients with this syndrome in a group of 1100 San Diego children in a special education program for both gifted and impaired ' children. Cerebral palsy had been diagnosed when the boys were 3 and 9 years old. Neither boy self-mutilated, and both had normal serum uric acid levels'but elevated ratios of uric acid to creatinine in the urine. Clinical suspicion of the syndrome should always be followed by biochemical screening, including calculation of this ratio (for which normal values have been published3), since the serum uric acid levels may be normal, as in these two cases and others.3'5'6 In the interval between the onset of neurologic signs and the onset of self-mutilation, recognition of Lesch-Nyhan syndrome may be very difficult. In the evaluation of a child suspected of having cerebral palsy, the absence of perinatal distress or severe hyperbilirubinemia should suggest alternative diagnoses: of 25 children with neuropathological evidence of perinatal hypoxia, only 1 child had had a normal perinatal course.7 In 60% of the patients with Lesch-Nyhan syndrome in one review, delayed devel1324

and exact biochemical characterization, and it will give the family access to genetic counselling, carrier testing and prenatal diagnosis.3'4 In summary, we suggest that the prevalence of HGPRT deficiency without self-mutilation may be higher than previously suspected and that this diagnosis must be ruled out in all males said to have cerebral palsy. Biochemical confirmation is best obtained by determining the ratio of uric acid to creatinine in a random urine specimen,3 followed by an HGPRT assay in appropriate cases. Failure to recognize this disease deprives the patient of specific drug and biochemical therapy and prevents his family from underarthria. standing the genetic basis of the Lesch-Nyhan syndrome is most disorder. easily confused with the relatively rare athetoid form of cerebral palsy. We thank Dr. B. Bakay for the HGPRT Of 462 patients with newly diag- and APRT assays performed on culnosed cerebral palsy referred to the tured fibroblasts, and Drs. R. Palmour Ontario Crippled Children's Centre and J.E. Seegmiller for those performed in the 5-year period between 1975 on brain tissue. and 1980, three quarters had a history consistent with a perinatal References cause, and 5% had athetosis (J.S. Whittaker: personal communication, 1. NYHAN WL: Disorders of purine and 1981). The episodic dystonia and pyrimidine metabolism. In RUDOLPH AM (ed): Pediatrics, Norwalk, Conn, 1982: frequent spasticity seen in patients 277 with Lesch-Nyhan syndrome can MENKES JH: Metabolic diseases of the also suggest quadriparetic cerebral 2. nervous systems. In Textbook of Child palsy. Although seizures are quite Neurology, Lea & Febiger, Philadelphia, uncommon in patients with athetoid 1980: 87-89 cerebral palsy, they occur in half of 3. SEEGMILLER JE: Lesch-Nyhan disease and its variants. In BONDY PK, ROSENchildren with Lesch-Nyhan synBERG LE (eds): Metabolic Control and drome.4 Finally, the mental retardaDisease, Saunders, Philadelphia, 1980: tion in patients with Lesch-Nyhan 827-921 syndrome is characteristically less 4. WYNGAARDEN JB, KELLEY WN: The than one would expect from the Lesch-Nyhan syndrome. In STANBURY JB, WYNGAARDEN JB, FREDRICKSON DS degree of motor impairment com(eds): The Metabolic Basis of Inherited pared with that in a similarly affectDisease, 4th ed, McGraw, New York, ed child with cerebral palsy.4 1978: 1011-1036 In a variant of HGPRT deficien- 5. PARTINGTON MW, HENNEN B: The Lesch-Nyhan syndrome: self-destructive cy, described by Bakay and colbiting, mental retardation, neurological leagues,8 the clinical presentation disorder and hyperuricaemia. Dev Med was the same as in Lesch-Nyhan Neurol 1967; 9: 563-572 syndrome except that self-mutilation 6. Child BERMAN PH, BALIS ME, DANCIS JE: Conand mental retardation were absent. genital hyperuricemia. An inborn error of purine metabolism associated with psychoDistinguishing between Lesch-Nymotor retardation, athetosis, and selfhan syndrome and other HGPRTmutilation. Arch Neurol 1969; 20: 44-53 not is deficiency variants, however, 7. MALAMUD N, ITABASHI HH, CASTOR J, the primary concern of the clinician MESSINGER HB: An etiologic and diagnostrying to identify those rare children tic study of cerebral palsy. J Pediatr 1964; 65: 270-293 with an X-linked disorder of purine metabolism in a large population of 8. BAKAY B, NISSINEN E, SWEETMAN L, FRANCKE U, NYHAN WL: Utilization of patients with cerebral palsy. Recogpurines by an HGPRT variant in an nition of the biochemical nature of intelligent, nonmutilative patient with feathe disorder will permit appropriate tures of the Lesch-Nyhan syndrome. Pemedical and behavioural therapy, diatr Res 1979; 13: 1365-1370

opment was the earliest abnormality, the mean age at onset being 6 months. In the other cases there was a variety of initial signs, including hypotonia, unusual irritability, vomiting, seizures, spasticity, choreoathetosis, urethral obstruction and spastic torticollis. The developmental delay is usually manifest as inability to support the head.3 Hypotonia becomes apparent in the first year of life,3 extrapyramidal abnormalities develop between the ages of 8 and 12 months (but are eventually masked by progressive spasticity), and pyramidal tract disease is evident by 1 year of age.4 Speech development may be considerable, but there is invariably severe dys-

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