From Hypertransaminasemia to Mucopolysaccharidosis IIIA
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Krawiec et al. Italian Journal of Pediatrics 2014, 40:97 http://www.ijponline.net/content/40/1/97 ITALIAN JOURNAL OF PEDIATRICS CASE REPORT Open Access From hypertransaminasemia to mucopolysaccharidosis IIIA Paulina Krawiec1,2*,Elżbieta Pac-Kożuchowska1,2, Beata Mełges1,2, Agnieszka Mroczkowska-Juchkiewicz1,2, Stanisław Skomra2, Agnieszka Pawłowska-Kamieniak1,2 and Katarzyna Kominek1,2 Abstract Mucopolysaccharidosis type III (MPS III; Sanfilippo syndrome) is a metabolic disorder characterized by the deficiency of a lysosomal enzyme catalyzing the catabolic pathway of heparan sulphate. MPS III presents with progressive mental deterioration, speech delay and behavioural problems with subtle somatic features, which can often lead to misdiagnosis with idiopathic developmental/speech delay, attention deficit/hyperactivity disorder or autism. We report a case of a 5-year-old boy with developmental delay and behaviour problems admitted to the Department of Paediatrics due to chronic hypertransaminasemia. The patient developed normally until the age of 2 years when he was referred to a paediatric neurologist for suspected motor and speech delay. Liver function tests were unexpectedly found elevated at the age of 3.5 years. Physical examination revealed obesity, mildly coarse facial features and stocky hands. He showed mental retardation and mild motor delay. The clinical picture strongly suggested mucopolysaccharidosis. The diagnosis of MPS IIIA was confirmed by decreased activity of heparan N-sulfatase in leucocytes. Conclusion: We strongly recommend screening for MPS III in children with severe behavioural abnormalities with hyperactivity, psychomotor or speech deterioration and failure to achieve early developmental milestones particularly with facial dysmorphism. Keywords: Mucopolysaccharidosis type IIIA, Sanfilippo syndrome, Hypertransaminasemia Background idiopathic developmental/speech delay, attention deficit/ Mucopolysaccharidosis (MPS) type III, also known as Sanfi- hyperactivity disorder (ADHD) or autism spectrum disor- lippo syndrome, is an autosomal recessive metabolic dis- ders [2]. order characterized by the deficiency of a lysosomal enzyme We report a rare case of a boy with unexpected MPS IIIA catalyzing the catabolic pathway of glycosaminoglycan diagnosis to highlight the importance of paediatric history (GAG) - heparan sulfate. Based on the deficiency of a spe- and physical examination for the diagnostic process and to cific enzyme in the degradation of heparan sulphate, four indicate that patients with metabolic disorders may develop different subtypes of MPS III are distinguished, i.e. MPS III any other chronic diseases. A (heparan N-sulfatase), MPS III B (α-N-acetylglucosamini- dase), MPS III C (heparan acetyl-CoA: alpha-glucosaminide Case report N-acetyltransferase) and MPS III D (N-acetylglucosamine 6- A 5-year-old boy with developmental delay was admitted sulfatase) [1,2]. to the hospital for persistent hypertransaminasemia of MPS III presents with progressive mental deterioration, 18 months’ duration. speech delay and behavioural problems with only subtle The boy was born at term after the uncomplicated preg- somatic features, which can often lead to misdiagnosis with nancy by caesarean section due to the ultrasound con- firmed large foetus weight and dehiscence of the pubic * Correspondence: [email protected] symphysis. His birth weight was 4,570 g and birth length 1 Department of Paediatrics, Medical University of Lublin, Racławickie 1, was 59 cm. At the first minute after birth the Apgar score 20-059 Lublin, Poland 2Department of Paediatrics, Children’s University Hospital in Lublin, Gębali 6, was 10. No neonatal problems were reported. The boy was 20-093 Lublin, Poland the second child in the family and had the older healthy © 2014 Krawiec et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Krawiec et al. Italian Journal of Pediatrics 2014, 40:97 Page 2 of 5 http://www.ijponline.net/content/40/1/97 sister. The parents were healthy and non-consanguineous. Liver function tests were unexpectedly found to be ele- However, his mother had the history of 2 miscarriages in vated at the age 3.5 years when he was hospitalized due to the first trimester. pneumonia. Alanine aminotransferase (ALT) was 144 U/L According to his parents, the child’s development was (normal <29 U/L) and aspartate aminotransferase (AST) normal until the age of 2 years. Head control was was 90 U/L (normal <36 U/L). Thereafter, elevated ALT and achieved by the 3rd month of life, sitting without assist- AST were observed in follow-up laboratory tests. ance in the 6th month of life and walking in the 9th On admission to our Department his weight was 36.3 kg month of life. However, he began using single, simple (> > 97th percentile) and height 115 cm (75th percentile). words (i.e. mum, dad) at the age of 18 months. Toilet The Cole’s index was 181.5% and the body mass index was control was achieved at 3 years of age. Since the 2nd year 27.4 kg/m2 (>>97th percentile). of life progressive psychomotor developmental delay, On physical examination, the boy appeared to have restlessness and impulsivity with hyperactivity became mildly coarse facial features, the slightly depressed nasal apparent, therefore he was referred to a paediatric neur- bridge, prominent eyebrows, low set ears, malocclusion, ologist. About the age of 5 years lack of speech and toi- full cheeks, wiry and dry hair and the short neck (Figure 1). let control were noticed. The boy had excessive lumbosacral lordosis, genu valga The clinical history revealed recurrent upper respira- (knock-knee deformity) and varus feet. He had broad-base tory tract infections and recurrent diarrhoea. At present, gait with anteversion. His hands were stocky with short his stools are rather constipated. He had adenotomy at fingers. The liver and the spleen were not palpable. the age of 2 years. Since birth, the boy had the tendency The boy showed mental retardation and mild motor to excessive weight. delay. His speech was limited to incomprehensible Figure 1 Dysmorphic features of our patient. Facial dysmorphism (coarse facial features, the slightly depressed nasal bridge, prominent eyebrows, low set ears, malocclusion, full cheeks, wiry and dry hair and the short neck) and skeletal symptoms (genu valga, varus feet, and stocky hands) seen in our patient. Krawiec et al. Italian Journal of Pediatrics 2014, 40:97 Page 3 of 5 http://www.ijponline.net/content/40/1/97 sounds. The boy presented anxious and restless Table 1 Laboratory results of our patient behaviour. Parameter Result Reference range The clinical picture strongly suggested mucopolysacchari- ALT [U/L] 144 <29 dosis. The daily urinary glycosaminoglycans (GAGs) excre- AST [U/L] 73 <36 tion was 895 mg GAG/g creatinine, i.e. elevated compared Bilirubin [mg/dL] 1.7 1.5 to the normal reference level (<88 mg GAG/g creatinine). Elevated GAGs were identified as chondroitin sulphate and GGT [U/L] 34 <29 heparan sulphate, which suggested mucopolysaccharidosis CK [U/L] 98 <149 III. To confirm the diagnosis and to determine the type of IgG [mg/dL] 521 504-1464 MPS the lysosomal enzyme activity was assessed in Total cholesterol [mg/dL] 111 <170 leucocytes. Heparan N-sulfatase activity was decreased Triglyceride [mg/dL] 58 <75 (1.29 nmol/mg protein/18 h) compared to the normal refer- HBs-Antigen Negative Negative ence range (4.1 ± 1.4 nmol/mg protein/18 h). The activities of other lysosomal enzymes i.e. α-iduronidase, α-N- Anti-HCV antibodies Negative Negative acetylglucosaminidase, N-acetyl-transferase, glucosamine Anti-EBV antibodies Negative Negative sulfatase, galactosamine sulfatase, β-glucoronidase, arylsul- Anti-CMV antibodies Negative Negative fatase and iduronide sulfatase were within normal limits. Lysosomal acid lipase [pmol/punch/hr] 0.61 0.37-2.3 The diagnosis of mucopolysaccharydosis III type A was α-1-antitrypsin [g/L] 1.3 0.9-2.0 confirmed. Ceruloplasmin [g/L] 0.3 0.15-0.3 Moreover, laboratory results revealed hypertransaminase- mia with slightly elevated γ-glutamyltranspeptydase. De- Serum copper [ug/L] 1106 900-1900 tailed diagnostic examinations were performed to determine 24-hour urinary copper [ug/24 h] <10 <60 the cause of hypertransaminasemia. Based on the serological tests viral hepatitis caused by hepatitis B virus (HBV), hepa- titis C virus (HCV), cytomegalovirus (CMV) and Ebstein – progression of symptoms and shorter survival than the Barr virus (EBV) were excluded. The serum level of creatine other subtypes [1]. kinase, total immunoglobulin G (IgG), α1-antitrypsin, lyso- The majority of children with MPS IIIA were born somal acid lipase, ceruloplasmin, copper and 24-hour urin- after uneventful pregnancies [1,3]. Buhrman et al. found ary copper were within the normal range. Thus, muscular that the most common pregnancy complication was cae- dystrophy, autoimmune hepatitis, α1-antitrypsin deficiency, sarean section due to failure to progress, macrocephaly lysosomal acid lipase deficiency and Wilson’sdiseasewe and breech position, suggesting that the GAGs storage excluded. Table 1 presents the laboratory results of our already occur before birth, which was also found in our patient. patient’s perinatal history [4]. On the abdominal ultrasound examination, the bright Interestingly, Meyer et al. noticed a high number of mis- liver echo pattern was found; the liver and spleen were carriages in mothers of children with MPS IIIA (29%). The not enlarged. above data need to be interpreted with caution as the inci- Chronic hypertransaminasemia in our patient might dence of miscarriages is age-dependent and the exact age of be related to mucopolysaccharidosis or result from coex- mothers at the time of miscarriage was unknown. However, isting non-alcoholic steatohepatitis (NASH).