Puzzler of the month
GEORGE K. SIBERRY, MD, MPH, SECTION EDITOR
Today is not the first time you are seeing this 2-year-old boy, a challenging patient who has been brought to the clinic by his parents with a low-grade fever that began two days ago. He has been cranky and irritable for a few days, they tell you, and they "want to make sure he doesn't have another ear infection."
In fact, you have been seeing their son for the past eight months for different reasons, including upper respiratory infections and otitis media, after they came to you from another pediatric practice because of a change in health insurance. The boy was born at term by normal vaginal delivery; his mother did not experience any problems during her pregnancy. According to his parents, he was noted at an early age to exhibit abnormal movements and was investigated for the possibility of a seizure disorder. A magnetic resonance imaging scan of the brain was normal for age and the tracing of an electroencephalogram was labeled "nonspecific." His record indicates that, because all other "routine tests" were normal and he did not have any additional problems, his first pediatrician decided to observe him rather than start anticonvulsant therapy.
The child had, for some time, been noted to display significant delays in motor milestones and speech. He had been referred to a clinical geneticist because of concern over his facial appearance and microcephaly. Findings of a karyotyping were reported as "normal," however, and the consultant concluded that the distinctive facial features were familial. He was referred to an early intervention program, and was evaluated by an otolaryngologist and an ophthalmologist, who found that his hearing and vision are normal. At 2 years of age now, his speech is limited to moaning and groaning sounds. He receives speech, occupational, and physical therapy.
This patient has never been easy to examine and, considering all his difficulties, your relatively brief time as his pediatrician seems much longer because of that. Today, you hear him crying as soon as he is brought into the examining room. You've started to understand his personality by now: He is, as most children would be, less agitated when his family is around, and he clings to his father or mother during your attempts to examine him. Once you start examining him, he will try to calm himself down. He has never stood or walked; trunk control was delayed and even now he sits in his mother's lap with his body curved and neck tilted to one side. He does not drool. He observes objects that are shown to him but often kicks at them in obvious irritation.
Recently, the boy was given a diagnosis of autism spectrum disorder by a consulting neurologist. When his parents still expressed confusion over why he is not developing as they expect him to, you arranged consultation with an academic neurologist in another state. The diagnosis was confirmed and expanded: autism and spastic cerebral palsy. You, the boy, and his parents have begun to adjust to this uncomfortable diagnosis. He is taking baclofen to provide muscle relaxation and is still in the early intervention program.
Today, your patient is afebrile and lying on the examining table; his mother reports that she gave him acetaminophen two hours before they left the house to see you. He allows you to examine him, although he is clearly uncomfortable with the unfamiliar faces of several medical students peering at him. Legs are spastic; no contractures are noted. Head circumference is well below the 5th percentile for age; height is at the 25th percentile; and weight, at the 25th percentile. He does not have a rash or cutaneous stigmata of a neurologic disease. Mouth and throat are normal. Nostrils are clear of discharge; tympanic membranes appear normal; eyes move normally, without evidence of infection. You find no lymphadenopathy or neck masses. Breath sounds are normal on auscultation; so are heart sounds. No murmurs are audible.
The boy's abdomen is normal; you do not detect any enlargement of the liver or spleen, or masses. The central nervous system examination is remarkable only for spasticity of upper and lower limbs, hyperreflexia, and dystonic movements of the upper limbs. He holds your prescription pad without damaging it. His lower limbs do not cross when he is suspended vertically. Spasticity appears to occur intermittently. You find neither neck stiffness nor signs of meningeal irritation. You see no changes in his behavior or neurologic status from the last visit. Because he begins crying insistently, you decide to stop your examination. The question remains: What is the origin of his fever?
Because examination of his upper and lower respiratory tract was of no help, you turn to other possibilities. A viral syndrome and a urinary tract infection are high on the list.
You explain to the boy's parents that it is necessary to catheterize their son's bladder and obtain a sterile specimen for urinalysis. As you clean his groin with Betadine, you notice a powdery yellow substance in his diaper and on the surrounding skin. His mother knows about this: "It happens whenever he gets sick," she explains.
You wonder about that yellow powder as you proceed, and inquire about his medications and diet in detail. He drinks a lot fruit juice, his mother reports, and is taking the baclofen. You catheterize the bladder and make a mental note to look up the side effects of baclofen. Urine is pale yellow with some sediment. Dipstick testing reveals a specific gravity of 1.015; pH, 6.0; protein, glucose, nitrites, white blood cells, and ketones, absent; and blood, present.
It may take two days to get the results of the urine culture and microscopy, but you decide to hold off treatment for the moment and counsel the boy's parents on fever control and hydration. You check the side-effect profile of baclofen; nothing jumps out that fits this picture.
Next day, urine microscopy results arrive. In addition to what you already knew from the dipstick test, the laboratory reports occult blood as 3+; WBCs, RBCs, and epithelial cells all at 0-3 cells per high-powered field; no casts; a moderate concentration of uric acid crystals; and few bacteria. Nothing helpful here; for your efforts, all you know is that he does not have a urinary tract infection.
But what about the yellow powder in the boy's diaper? It occurs to you: Could it be uric acid crystals? You've heard about red diaper syndrome, especially in newborns. It's a benign condition, so this is likely nothing to worry about.
Nevertheless, you look through the laboratory results from the boy's previous visits. The record of another urinalysis, three months back, in the emergency room, notes "many amorphous crystals" in his diaper. Might something in the urine be causing this crystalluria? Your mind leaps ahead: Are there conditions that cause crystalluria associated with neurologic problems? Yeshyperuricemia, gout, developmental delay, and even self-mutilation can be aspects of a syndrome! Are you hearing the hoof beats of a zebra in a herd of horses? Where should your investigation begin?
You call the boy's parents and ask about a family history of gout and kidney stones. He is the only child of healthy, nonconsanguineous parents. They report no history of neurologic problems in the family. One of the patient's uncles has had kidney stones; another has "some kidney problems," but they can't be more specific.
You ask them to bring the boy in for further testing. Blood is drawn for complete blood count, a comprehensive metabolic panel, and tests of phosphate and uric acid.
But the boy's mother is becoming agitated. What's going on? she asks. You tell her about uric acid, kidney stones, and inherited problems, and promise that, if her son's uric acid level is high, you'll order just one more testone that isn't available locally but that you think is justified, whatever the cost or trouble of getting it.
Results arrive the next day. All parameters of the CBC and metabolic panel are within normal limits, but the uric acid level is elevated at 9.5 mg/dL (normal range, 2.48.2 mg/dL). So the boy does have hyperuricemia, which presumably is causing the uricosuria. Urine culture results also arrive: No growth after 48 hours.
The next day, you call the biochemical genetics laboratory in a distant city to find out details about the test you want performed next.
You call the boy's parents and discuss the implications of the results you have in hand. They agree to the additional test and prepare for the ultimate diagnosis. A 3 mL specimen of their son's blood is packed in ice and shipped to the lab by express courier. Then, the wait.
The result comes in a week: RBC hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzymatic activity is 13 nmol/min/g Hb (normal range, 4002,200). You have the diagnosis: This child has Lesch-Nyhan syndrome.
Drs. Michael Lesch and William L. Nyhan described this syndrome in 1964. It is caused by a deficiency of HPRT, an enzyme in the purine salvage pathway. HPRT catalyzes the conversion of hypoxanthine to inosine monophosphate and of guanine to guanine monophosphate in the presence of phosphoribosyl pyrophosphate. Purine bases can be produced de novo in the human body, but the steps involve a great expenditure of energy. So we utilize a so-called salvage pathway to recycle what we can get from cells ordinarily destroyed in the body, such as RBCs. Because HPRT enzymatic activity is deficient (less than 1.5% of normal) in persons who have Lesch-Nyhan syndrome, they develop an elevated level of hypoxanthine, which damages basal ganglia. Hypoxanthine is converted into uric acid and excreted via the kidneys and gut. Persons with hyperuricemia are prone to develop uric acid stones and kidney failure.
Lesch-Nyhan syndrome is inherited in an X-linked recessive pattern, although spontaneous mutations also occur. Prevalence is approximately 1 case among every 380,000 live births. Maternal carriers of the gene have a 50% chance of transmitting the HPRT1 mutation (chromosomal locus Xq26-q27.2) in each pregnancy. Sons who inherit the mutation are affected; daughters who inherit it become a carrier. Prenatal testing by chorionic villous sampling is available to make the diagnosis.
Self-mutilation is the classic feature of Lesch-Nyhan syndrome. Patients begin biting their fingers, lips, and tongue for no apparent reason. (Although the boy featured in this case has never exhibited self-mutilating behavior, he does sometimes bite his mother.) Pain perception is not impaired (so-called pain insensitivity syndrome is now considered a misnomer); patients may, in fact, fear their behavior. Self-mutilating behaviors can be prevented with restraints and helmets; patients sometimes are calmed by being restrained. In severe cases, teeth are extracted to prevent biting.
The degree of neurologic delay varies from patient to patient. Speech is greatly affected; most affected children never walk unaided. Patients have severe dystonia and varying degrees of spasticity. Most are given a diagnosis of cerebral palsy or autism early in childhood (see Table 1).
Spasticity and dystonia
Uric acid kidney stones
Patients excrete uric acid crystalshaving the appearance of orange sandin their urine, and are prone to uric acid kidney stones (which are radiolucent and can be missed on a plain radiograph), nephropathy, and renal failure. Gout is uncommon in children in early stages of the syndrome. Megaloblastic anemia is an associated finding.
No cure exists for Lesch-Nyhan syndrome. Bone marrow replacement has been tried, with associated complications. Medications such as baclofen and diazepam reduce muscular spasticity; L-dopa controls dystonia; and carbamazepine modifies the bizarre, self-mutilating behavior (see Table 2). Management also involves hydration, alkalinization of the urine with oral citrate preparations, and avoidance of purine-containing foods.
History (dystonia, self-injurious behavior)
Red blood cell hypoxanthine-guanine phosphoribosyltransferase (HPRT) assay
Skin fibroblast HPRT assay
Allopurinol (reduces uric acid level)
Baclofen (relaxes muscle)
Bone marrow transplant (fosters enzyme replacement)
Carbamazepine (reduces aggression)
Diazepam (allays anxiety and spasticity)
The boy whose case is described here has hyperuricemia, which can lead to early renal failure and death. Allopurinol, a xanthine oxidase inhibitor that reduces the conversion of purines to uric acid, controls hyperuricemia and uric acid nephropathy. But this treatment is a double-edged sword. Allopurinol can increase the hypoxanthine level, causing excretion of hypoxanthine through the kidneys and, thereby, xanthine stones because of the insolubility of the crystals.
The boy's fever resolved without treatment. It was probably the result of a viral illness, unrelated to his metabolic problem.
Pediatricians often care for patients who have developmental delay or cerebral palsy but in whom an underlying cause is never determined. The astute clinician remains vigilant for evidence of a specific, albeit unusual, basis for a patient's condition. When a child's diaper comes off during your exam, resist discarding its contents without a look. There, you may find a clue to your mystery.
Crawhall JC, Henderson JF, Kelley WN: Diagnosis and treatment of the Lesch-Nyhan syndrome. Pediatr Res 1972;6:504
Endres W, Helmig M, Shin YS, et al: Bone marrow transplantation in Lesch-Nyhan disease. J Inherit Metab Dis 1991;14:270
Harris JC: Disorders of purine and pyrimidine metabolism, in Behrman RE, Kliegman RM, Jenson HB (eds): Nelson Textbook of Pediatrics , ed 16. Philadelphia, Pa., W. B. Saunders, 2000, pp 423428
Lesch-Nyhan syndrome (#300322), in Online Mendelian Inheritance in Man. National Center for Biotechnology Information, US National Library of Medicine ( http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?300322 ). Visited March 27, 2003
Nicklas JA, O'Neill JP, Jinnah HA, et al: Lesch Nyhan syndrome. Gene Reviews ( http://www.geneclinics.org ). Visited March 27, 2003
Nyhan WL: The recognition of Lesch-Nyhan syndrome as an inborn error of purine metabolism. J Inherit Metab Dis 1997:20:171
George Siberry, ed. A.C. Anilkumar. Pediatric Puzzler: Autism, cerebral palsy, and fever. Contemporary Pediatrics May 2003;20:27.