Clinical case LESCH-NYHAN SYNDROME – LATE DIAGNOSIS OF RARE DISEASE: CLINICAL CASE

Background. Lesch-Nyhan syndrome is inherent X-linked recessive genetic disorder with decreased activity of hypoxanthine-guanine phosphoribosyltransferase (HGPRT). The disease is characterized by presence of the classical triad: hyperuricemia, neurological and behavioral changes. In the article we present a clinical case of Lesch-Nyhan syndrome first diagnosed only at 16 years old despite the fact that the clinical clues were already found at the patient`s early age. Case presentation. An 18-year-old Caucasian man was admitted to the rheumatology department because of gouty arthritis. In neonatal period he was diagnosed with mild intrauterine growth restriction by hypoplastic type. Uric acid crystals were found in our patient`s urine at 6-month-old. In the first year of life, delayed motor development was noted together with permanent neurological changes which were referred to rickets. During school years, severe dysgraphia, dyslexia, dysarthria, logoneurosis warranted observation by a speech therapist. At his 12 he had been diagnosed with nephrocalcinosis, at 14 – with chronic kidney disease and symptomatic arterial hypertension. The family history was remarkable for gout in grandmother and great-grandmother, chronic pyelonephritis – in mother, urate nephropathy – in both brothers. In physical examination hyperemia and edema of the left first metatarsophalangeal joint, left ankle defiguration, funnel chest, gynecomastia, tophi on the ears were noted. On examination, some neurological disorders and mild cognitive impairment were found. In investigations hyperuricemia, arthritis of the first metatarsophalangeal joint, diffuse changes in the renal parenchyma with impaired renal excretory function were detected. Despite the clues in patient`s anamnesis, objective examination and additional investigation, as well as the presence of a family anamnesis suggesting the hereditary nature of hyperuricemia, the diagnosis of HGPRT deficiency was not made until the age of 16 years. Conclusion. The presence of Lesch-Nyhan syndrome can be assumed with the progression of muscle tone impairment and movement disorders in a child after the first six months of life in combination with high plasma uric acid concentration and its increased urinary excretion. Difficulties in the syndrome diagnosis are associated not only with a rare occurrence, but with a slight or moderate degree of central nervous system impairment that is often related by doctors to rickets or delivery trauma, as well as low accessibility of molecular genetic testing.


BACKGROUND
The incidence of gout is rare in childhood, and most children with hyperuricemia have an underlying disease, such as metabolic or genetic disease, acute conditions, malignant disorders, as well as drug side effects and predisposing dietary habits [1,2]. Thus, the detection of hyperuricemia in child should alert the practitioner and force him to the search for possible cause in a particular patient. In the context of modern preventive medicine, special attention should be drawn to the timely detection of primary gout, in particular, its earliest manifestationhyperuricemia [1,2]. In around 80 % of cases gout can be characterized as a primary disease associated with genetic defects in the enzymes regulating purine metabolism, and first signs of the disturbance could be seen in early childhood [2].
In case of HGPRT deficiency, the process of free guanine and hypoxanthine reuse in the synthesis of guanosine monophosphate and inosine monophosphate is broken, resulting in more rapid conversion of guanine and hypoxanthine into uric acid. This, consequently, leads to hyperuricemia and gout development. Neurological disorders in Lesch-Nyhan syndrome are thought to be caused by a disturbance of neurotransmitters synthesis in the brain dopaminergic systems, which explains the behavioral and motor disorders in such patients [3][4][5][6][8][9][10]. Kidneys affection is characterized by a similar to gouty nephropathy clinical picture and includes urate crystalluria, recurrent pyelonephritis on the urolithiasis background and, if left untreated, it leads to the development of chronic kidney failure [5,8].
In the article we present a clinical case of Lesch-Nyhan syndrome first diagnosed only at 16 years old despite the fact that the classical clinical clues were already found at the patient`s first year.

CASE PRESENTATION
An 18-year-old Caucasian man was admitted to the rheumatology department with complaints of pain, swelling, hyperemia of the left first metatarsophalangeal joint and the left ankle swelling accompanied by limitation of active and passive movements in both joints.
According to the anamnesis, the child was born from the first pregnancy threatened by miscarriage in the first trimester, polyhydramnios; delivery on time. Birth weight -2600 g, height -48 cm, head circumference 32 cm, chest circumference 31 cm. Neonatologist conclusion: mild intrauterine growth restriction by hypoplastic type.
At the age of 6 months, during inpatient treatment for bilateral otitis media patient first was diagnosed with metabolic nephropathy (uric acid crystals were found in the urine analysis). During the hospitalization he was consulted by a neurologist who confirmed hyperexcitability syndrome, initial manifestations of rickets.
In the first year of life, delayed motor development was noted (began to crawl at 11 months, walk at 18 months) together with permanent neurological changes in the form of pronounced hypotonia of the upper and lower extremities. During school years, he was observed by a speech therapist due to severe dysgraphia, dyslexia, dysarthria, logoneurosis. He was diagnosed with nephrocalcinosis at 12 years. At 14 years the I stage of chronic kidney disease and symptomatic arterial hypertension were first established. Since then he has been constantly taking enalapril 5 mg per day. At his 16 hyperparathyroidism was revealed. Same year, 2017, he was examined in the clinic «Ohmatdyt» in Kiev, where a genetic testing was carried out and Lesch-Nyhan syndrome was diagnosed without description of the mutation nature. The treatment with febuxostat 120 mg daily and enalapril 5 mg daily were prescribed. The level of uric acid from 2017 to 2019 years has varied from 400 to 700 μmol/L, creatinine -from 90 to 135 μmol/L.
The family history was remarkable for gout in grandmother and great-grandmother, chronic pyelonephritisin mother, urate nephropathyin both brothers.
On examination, the general condition was satisfactory. Body weight -60 kg, height -175 cm. Body mass index was 19.59 kg/m2. He limped when walking because of pain in the small joints of the left foot. Hyperemia and edema of the left first metatarsophalangeal joint, left ankle defiguration. Subcutaneous tophi on the ear (Picture 1). Gynecomastia (Picture 2). Funnel chest (Picture 3).

Picture 3. Funnel chest
Psycho-neurological status. The patient was oriented in time, place and person. His mood appeared labile. There was no evidence of speech disorders. Cranial nerves examination was unremarkable. Upper and lower limbs muscle strength was 5 from 5 grades. The deep tendon and periosteal reflexes of the upper and lower limbs were normal. Pathologic reflexes (Babinsky, Oppenheim, Schaefer, Chaddock) were negative bilaterally. Plastic (extrapyramidal) symmetrical muscular hypertonicity in the upper extremities with resting tremor of their distal part was found together with positive Negro's phenomenon, Noik-Ganev's phenomenon and Formann's symptom. In the lower extremitiessymmetrical normotonus. Coordination: fingerto-nose and heel-to-knee tests were performed confidently on both sides; the Romberg test was negative. When walking, there was a slight brady-and oligokinesia without postural instability. Sensation disorders were not found. The patient also had moderate cognitive impairments: the nominative function of speech was impaired, there was a working memory deficit due to coding disturbances especially in the tasks involving several functions simultaneously; mild constructive, verbal and executive dysfunctions. Visual-spatial praxis and «frontal» functions were normal. Neuropsychological testing with the Montreal Cognitive Assessment scale 18 points; Eysenck's test result was 71 points; according to the depressive states scale by V. Zung (adaptation of T. I. Balashova), the patient had a «state without depression» (40 points), the neurotization level according to L. I. Wasserman was 35 %.
Additional investigations. Laboratory data: uric acid level -550 μmol/L, creatinine 86 μmol/L, glomerular filtration rate -104 ml/min/1,73m 2 . Radiography of the left foot: marginal growths of the first nail phalanx base, narrowing of the first toe interphalangeal joint, the restructuring of the bone of the first toe main phalanx base (compatible with arthritis of the 2nd degree). Ultrasound of the urinary tract and prostate: prominent diffuse changes in the renal parenchyma, right-sided nephroptosis; bladder and prostate were unremarkable. Excretory urography: indirect signs of inflammatory kidney disease with impaired renal excretory function.
Clinical diagnosis: Lesch-Nyhan syndrome: chronic gouty arthritis, recurrent course, exacerbation stage, activity II, with a predominant affection of the small joints of the left foot, left ankle joint, with the peripheral tophi, X-ray stage II, functional impairment of joints I degree. Chronic kidney disease I stage: gouty nephropathy, nephrocalcinosis, urinary syndrome, symptomatic arterial hypertension. Chronic renal failure with impaired excretory function of the kidneys. Encephalopathy with moderate cognitive dysfunction, dysarthria.

DISCUSSION
In the «classic» variant of Lesch-Nyhan syndrome (residual activity HGPRT ≈ 1.5 %) patients` mean duration of life is about 20-30 years.
With moderate extrapyramidal insufficiency (residual activity HGPRT ≈ 8 %) life expectancy is much longer, patients are teachable and can acquire some specialties [3,5,[7][8][9]. However, in case of late diagnosis, neurological symptoms, nephrolithiasis, chronic renal failure progress resulting in patient`s disability [11]. Neurological symptoms can manifest by varying degree of severity of extrapyramidal and pyramidal motor dysfunction [5,10]. Our patient's neurological manifestations correspond to a moderate degree of extrapyramidal insufficiency and motor dysfunction, that should be characterized as a manifestation of basal ganglia lesions [10]. Hyperuricemia in his case is accompanied by clinical manifestations of gout. According to literature, the above symptomatology corresponds to the residual activity of HGPRT ≈ 8 % [3,5].
It is important for a pediatric neurologist to know that Lesch-Nyhan syndrome is often hidden under the guise of cerebral palsy clinical manifestations [3,5,8]. However, unexplained persistent hyperuricemia and progressive urate nephropathy require explanation, and could help in early diagnosis of the syndrome [11]. Uric acid crystals were primary found in our patient`s urine at 6-month-old. At his 12 he had been diagnosed with nephrocalcinosis, at 14 -with chronic kidney disease and symptomatic arterial hypertension. Despite these clues together with presence of family anamnesis suggesting hereditary character of hyperuricemia, the diagnosis of HPRT deficiency was not made until the age of 16 years. The interaction of a family doctor, pediatric neurologist, rheumatologist, genetics is extremely important and necessary for the earliest possible diagnosis [4]. Difficulties in the syndrome diagnosis are associated not only with a rare occurrence, but frequently with a slight or moderate degree of central nervous system impairment that is often related by doctors to rickets or delivery trauma, as well as low accessibility of molecular genetic studies [4,5].
The diagnosis can be confirmed by detecting a mutation in the HGPRT1 gene using direct automatic sequencing of the gene coding region. An alternative method of the diagnosis confirmation is the study of the HGPRT enzyme activity in erythrocytes, fibroblast or lymphoblast cultures [4]. In the presented case, the diagnosis was confirmed by a genetic method.