Normal Uricemia in Lesch–Nyhan Syndrome and the Association with Pulmonary Embolism in a Young Child—A Case Report and Literature Review

Deficiency of hypoxanthine phosphoribosyltransferase activity is a rare inborn error of purine metabolism with subsequent uric acid overproduction and neurologic presentations. The diagnosis of Lesch–Nyhan syndrome (LNS) is frequently delayed until self-mutilation becomes evident. We report the case of a boy aged 1 year and 10 months who was diagnosed with profound global developmental delay, persistent chorea, and compulsive self-mutilation since the age of 1 year. Serial serum uric acid levels showed normal uric acid level, and the spot urine uric acid/creatinine ratio was >2. The hypoxanthine phosphoribosyltransferase cDNA showed the deletion of exon 6, and the boy was subsequently diagnosed to have LNS. He also had respiratory distress due to pulmonary embolism documented by chest computed tomography scan. This report highlights the need to determine the uric acid/creatinine ratio caused by increased renal clearance in LNS in young children. The presence of pulmonary embolism is unusual and may be the consequence of prolonged immobilization. Deficiency of hypoxanthine phosphoribosyltransferase activity is a rare inborn error of purine metabolism with subsequent uric acid overproduction and neurologic presentations. The diagnosis of Lesch–Nyhan syndrome (LNS) is frequently delayed until self-mutilation becomes evident. We report the case of a boy aged 1 year and 10 months who was diagnosed with profound global developmental delay, persistent chorea, and compulsive self-mutilation since the age of 1 year. Serial serum uric acid levels showed normal uric acid level, and the spot urine uric acid/creatinine ratio was >2. The hypoxanthine phosphoribosyltransferase cDNA showed the deletion of exon 6, and the boy was subsequently diagnosed to have LNS. He also had respiratory distress due to pulmonary embolism documented by chest computed tomography scan. This report highlights the need to determine the uric acid/creatinine ratio caused by increased renal clearance in LNS in young children. The presence of pulmonary embolism is unusual and may be the consequence of prolonged immobilization. 1. IntroductionLesch–Nyhan syndrome (LNS) is a genetic disorder of purine salvage caused by a complete deficiency of hypoxanthine phosphoribosyltransferase (HPRT) activity resulting from a mutation in the corresponding gene on the long arm of the X chromosome.1Nyhan W.L. Inherited hyperuricemic disorders.Contrib Nephrol. 2005; 147: 22-34PubMed Google Scholar Affected individuals usually suffer from overproduction of uric acid that may lead to hyperuricemia or nephrolithiasis.2Lesch M. Nyhan W.L. A familial disorder of uric acid metabolism and central nervous system function.Am J Med. 1964; 36: 561-570Abstract Full Text PDF PubMed Scopus (888) Google Scholar High serum uric acid level is usually the biochemical finding that prompts special testing for the specific diagnosis. However, infants with LNS may have borderline serum uric acid levels because of an increased renal clearance of uric acid.3Rinat C. Zoref-Shani E. Ben-Neriah Z. Bromberg Y. Becker-Cohen R. Feinstein S. et al.Molecular, biochemical, and genetic characterization of a female patient with Lesch–Nyhan disease.Mol Genet Metab. 2006; 87: 249-252Crossref PubMed Scopus (20) Google Scholar Diagnosis can be made by clinical features and further confirmed by direct sequencing of all exons of the HPRT gene.4Jinnah H.A. Harris J.C. Nyhan W.L. O'Neill J.P. The spectrum of mutations causing HPRT deficiency: an update.Nucleosides Nucleotides Nucleic Acids. 2004; 23: 1153-1160Crossref PubMed Scopus (50) Google Scholar, 5Yamada Y. Nomura N. Yamada K. Wakamatsu N. Molecular analysis of HPRT deficiencies: an update of the spectrum of Asian mutations with novel mutations.Mol Genet Metab. 2007; 90: 70-76Crossref PubMed Scopus (19) Google ScholarPulmonary embolism is more commonly found in adults with underlying predisposing factors and conditions that interfere with normal venous blood flow. In children, pulmonary embolism is rare. The few reports about pediatric pulmonary embolism reflect its relative rarity and difficult evaluation.6Monagle P. Adams M. Mahoney M. Ali K. Barnard D. Bernstein M. et al.Outcome of pediatric thromboembolic disease: a report from the Canadian Childhood Thrombophilia Registry.Pediatr Res. 2000; 47: 763-766Crossref PubMed Scopus (441) Google Scholar Imaging evaluation of pulmonary embolism is crucial for diagnosis. The use of a multidetector computed tomography (MDCT) shortens the time of the study and greatly improves its resolution.7Schoepf U.J. Diagnosing pulmonary embolism: time to rewrite the textbooks.Int J Cardiovasc Imaging. 2005; 21: 155-163Crossref PubMed Scopus (30) Google Scholar2. Case ReportA boy aged 1 year and 10 months presented with developmental delay. He was born to nonconsanguineous healthy parents, and had been diagnosed with nephrolithiasis at the age of 5 months. When the patient was 6 months old, recurrent airway infection and respiratory distress complicated by laryngomalacia required repeated hospital admission and central catheterization during hospitalization. He was diagnosed with profound psychomotor retardation and was bed-ridden since 1 year of age. He also had chorea when awake, and compulsive self-destructive behavior such as biting fingers, lips, and buccal mucosa were noted for about 6 months.Laboratory tests showed normal complete blood count, electrolytes, blood gas, ammonia, and lactate. Although serial serum uric acid level showed normal uric acid level (7.6 mg/dL), the spot urine uric acid/creatinine ratio was 116/50 or >2.0, which subsequently pointed to a diagnosis of LNS. There were no particular findings on brain magnetic resonance image and electroencephalography.The patient and his family, as well as control individuals were analyzed using multiplex quantitative polymerase chain reaction (PCR) to amplify the FGFR2 gene, the KRIT1 gene, and the HPRT gene simultaneously. The HPRT cDNA, amplified from the total RNA of the patient's peripheral blood by multiple specific primers for multiplex PCR, showed the deletion of exon 6. The family study revealed that the patient's mother was a heterozygous carrier (Figure 1). He was put on allopurinol for his uric acid overproduction and nephrolithiasis.Because of his persistent respiratory distress, the study of chest MDCT with intravenous contrast injection was performed. The images of chest MDCT showed pulmonary embolism with nonobstructive lobar and segmental arterial thrombi in the basal segments of the left lower lobe. This may explain the persistent respiratory distress of the patient (Figure 2).Figure 2Chest images using a 320-MDCT (multidetector computed tomography) scanner with a nonhelical one-volume scan mode. (A) Oblique coronal thin-slab maximum-intensity projection image shows a tubular filling defect (arrow) in the branch of the left pulmonary artery in the left lower lobe. (B) 3D image using volume rendering techniques shows eccentric thinning of the embolismic artery (arrow). The distal branches (arrowheads) of the left pulmonary artery are still patent.View Large Image Figure ViewerDownload Hi-res image Download (PPT)3. DiscussionThe diagnosis of LNS is frequently delayed until self-mutilation becomes evident.8Nyhan W.L. Lesch–Nyhan disease.Nucleosides Nucleotides Nucleic Acids. 2008; 27: 559-563Crossref PubMed Scopus (10) Google Scholar It is the most striking feature of LNS and is only present in patients with the complete enzyme defect, although some patients never show this type of behavior. The self-mutilation associated with LNS typically first appears with the emergence of teeth, and steadily worsens with increasing age.9Anderson L.T. Ernst M. Self-injury in Lesch–Nyhan disease.J Autism Dev Disord. 1994; 24: 67-81Crossref PubMed Scopus (132) Google Scholar In the current patient, such behavior prompted the investigation of his uric acid under the suspicion of LNS. Patients with HPRT deficiency must be confirmed by clinical, biochemical, enzymatic, and molecular analyses. In this case, despite fulfilling the diagnosis criteria of LNS, the patient's serial serum uric acid only showed normal uric acid. Thus, the uric acid/creatinine ratio was used to corroborate the clinical diagnosis. In young children, renal function is quite efficient in eliminating uric acid into the bladder, and hence, they may have borderline hyperuricemia due to increased renal clearance. As such, the urinary uric acid/creatinine ratio can be used as a screening test for inherited disorders of purine metabolism based on the age of the patient. Values for the urinary ratio should be <1.0 after the age of 3 years.10Kaufman J.M. Greene M.L. Seegmiller J.E. Urine uric acid to creatinine rtio – a screening test for inherited disorders of purine metabolism. Phosphoribosyltransferase (PRT) deficiency in X-linked cerebral palsy and in a variant of gout.J Pediatr. 1968; 73: 583-592Abstract Full Text PDF PubMed Scopus (113) Google ScholarThe HPRT gene is localized to the Xq26 region, and the complete amino acid sequence for HPRT is known to be 44 kb, which consists of nine exons with a coding for a 219-amino acid protein that converts hypoxanthine into inosinic acid and guanine into guanylic acid. To date, more than 300 disease-associated mutations in the HPRT gene have been identified,5Yamada Y. Nomura N. Yamada K. Wakamatsu N. Molecular analysis of HPRT deficiencies: an update of the spectrum of Asian mutations with novel mutations.Mol Genet Metab. 2007; 90: 70-76Crossref PubMed Scopus (19) Google Scholar but reports of LNS in Taiwan remains limited. Mak et al11Mak B.S. Chi C.S. Tsai C.R. Lee W.J. Lin H.Y. New mutations of the HPRT gene in Lesch–Nyhan syndrome.Pediatr Neurol. 2000; 23: 332-335Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar reported a case series of four patients with LNS from three families. Three patients in two families were revealed to have novel missense mutation in exons 3 and 8, and in one patient, a splicing region of intron 4 of the HPRT encoding region was reported. Hou12Hou J.W. Atlantoaxial subluxation with recurrent consciousness disturbance in a boy with Lesch–Nyhan syndrome.Acta Paediatr. 2006; 95: 1500-1504Crossref PubMed Scopus (6) Google Scholar reported a 9-year-old boy with LNS complicated with atlantoaxial subluxation, and the direct genomic DNA sequencing of the HPRT gene revealed a single nucleotide substitution in intron 5. To the best of our knowledge, this is the first case of LNS with exon 6 deletion reported in Taiwan.Treatment of LNS remains limited for self-mutilation and motor syndrome. However, allopurinol should be started as soon as the enzyme deficiency is diagnosed, although it has no reported effect on behavioral and neurological symptoms. It should be adjusted to reduce hyperuricemia and achieve a urinary uric acid/creatinine ratio lower than 1.0. Allopurinol is efficacious and generally safe as treatment for uric acid overproduction in patients with HPRT deficiency.13Torres R.J. Prior C. Puig J.G. Efficacy and safety of allopurinol in patients with hypoxanthine–guanine phosphoribosyltransferase deficiency.Metabolism. 2007; 56: 1179-1186Abstract Full Text Full Text PDF PubMed Scopus (33) Google ScholarPediatric patients rarely present with conditions that place them at high risk for thrombus formation. When it occurs, pulmonary embolism has been shown to cause serious illness and even death. Traditional risk factors in adults may be a consequence of continuous immobilization,14Lee L.C. Shah K. Clinical manifestation of pulmonary embolism.Emerg Med Clin North Am. 2001; 19: 925-942Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar because the pathophysiology of thrombus formation is blood flow stasis.15Dalen J.E. Pulmonary embolism: what have we learned since Virchow? Natural history, pathophysiology, and diagnosis.Chest. 2002; 122: 1440-1456Crossref PubMed Scopus (234) Google Scholar Nonetheless, there is no article on LNS that suggests the complication of pulmonary embolism, and as such, it can be considered a consequence of long-term immobilization stemming from his profound retardation and recurrent central catheterization.In conclusion, this report highlights the value of the uric acid/creatinine ratio as a screening tool for young male children highly suspected to have LNS. To the best of our knowledge, this is the first case report of LNS associated with pulmonary embolism, complicated by the patient's long-term immobilization.Conflicts of interestThe authors have no conflicts of interest relevant to this article. 1. IntroductionLesch–Nyhan syndrome (LNS) is a genetic disorder of purine salvage caused by a complete deficiency of hypoxanthine phosphoribosyltransferase (HPRT) activity resulting from a mutation in the corresponding gene on the long arm of the X chromosome.1Nyhan W.L. Inherited hyperuricemic disorders.Contrib Nephrol. 2005; 147: 22-34PubMed Google Scholar Affected individuals usually suffer from overproduction of uric acid that may lead to hyperuricemia or nephrolithiasis.2Lesch M. Nyhan W.L. A familial disorder of uric acid metabolism and central nervous system function.Am J Med. 1964; 36: 561-570Abstract Full Text PDF PubMed Scopus (888) Google Scholar High serum uric acid level is usually the biochemical finding that prompts special testing for the specific diagnosis. However, infants with LNS may have borderline serum uric acid levels because of an increased renal clearance of uric acid.3Rinat C. Zoref-Shani E. Ben-Neriah Z. Bromberg Y. Becker-Cohen R. Feinstein S. et al.Molecular, biochemical, and genetic characterization of a female patient with Lesch–Nyhan disease.Mol Genet Metab. 2006; 87: 249-252Crossref PubMed Scopus (20) Google Scholar Diagnosis can be made by clinical features and further confirmed by direct sequencing of all exons of the HPRT gene.4Jinnah H.A. Harris J.C. Nyhan W.L. O'Neill J.P. The spectrum of mutations causing HPRT deficiency: an update.Nucleosides Nucleotides Nucleic Acids. 2004; 23: 1153-1160Crossref PubMed Scopus (50) Google Scholar, 5Yamada Y. Nomura N. Yamada K. Wakamatsu N. Molecular analysis of HPRT deficiencies: an update of the spectrum of Asian mutations with novel mutations.Mol Genet Metab. 2007; 90: 70-76Crossref PubMed Scopus (19) Google ScholarPulmonary embolism is more commonly found in adults with underlying predisposing factors and conditions that interfere with normal venous blood flow. In children, pulmonary embolism is rare. The few reports about pediatric pulmonary embolism reflect its relative rarity and difficult evaluation.6Monagle P. Adams M. Mahoney M. Ali K. Barnard D. Bernstein M. et al.Outcome of pediatric thromboembolic disease: a report from the Canadian Childhood Thrombophilia Registry.Pediatr Res. 2000; 47: 763-766Crossref PubMed Scopus (441) Google Scholar Imaging evaluation of pulmonary embolism is crucial for diagnosis. The use of a multidetector computed tomography (MDCT) shortens the time of the study and greatly improves its resolution.7Schoepf U.J. Diagnosing pulmonary embolism: time to rewrite the textbooks.Int J Cardiovasc Imaging. 2005; 21: 155-163Crossref PubMed Scopus (30) Google Scholar

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.