Fatigue, Decreased Interest in Play, Motor Delay, and Elevated -Function Tests in a 4-Year-Old Boy*

CASE scoliosis. His extremities were thin with normal sub- At a 4-year-old health-supervision visit, J.B.’s cutaneous tissue; there was no joint tenderness, mother expressed concern about his sluggishness swelling, or erythema. There was no rash, , and lack of energy during the past few months. or scleral icterus. Neurological examination revealed Occasionally, he asked to be carried instead of walk- normal tone and deep tendon reflexes. Although J.B. ing. He showed less interest in play, although he appeared to have symmetrically decreased muscle continued to enjoy watching television. J.B.’s appe- strength, he was not cooperative during the exami- tite was good, and he had not experienced a recent nation. His gait was broad-based without ataxia. illness or physical trauma. Cranial nerve examination was normal. J.B. is a healthy child without significant illnesses, Because of the hepatosplenomegaly, the pediatri- hospitalizations, or surgery. He was born at full cian assessed J.B.’s liver function. The total and direct term, of appropriate size for gestational age, and and were normal. The without prenatal or perinatal complications. His only aspartate aminotransferase (AST) and alanine ami- medications were a multivitamin and fluoride. He notransferase (ALT) enzyme levels were elevated; has no known allergies, and his immunizations are the AST was 557 units/mL, and the ALT was 360 up to date. He lives at home with his mother, father, units/mL. The hemoglobin was 12.5 mg/dL. A total and 6-year-old sister, who are all healthy. The par- white blood cell count and platelet count were nor- ents are employed, and his mother denied any sig- mal. A, B, and C serologies were negative nificant stress, marital conflicts, or recent change in with the exception of the presence of hepatitis B the family’s pattern of living. J.B.’s family history is surface antigen (HepBsAg) antibody (consistent with significant for in 2 maternal Hepatitis B vaccine-induced immunity). uncles during their early thirties. A developmental At this point, J.B.’s pediatrician was uncertain history revealed that J.B. sat without support at 6 about a diagnosis that would take into account leth- months of age and crawled at about the same time. argy, temper tantrums, delayed motor development, His mother noted that he had difficulty pulling to a and hepatosplenomegaly associated with elevated stand before his first birthday, and he did not walk transaminase levels. The abnormal gait and until 2 years of age. Social, fine motor, and language possible weakness on examination added further development were achieved at appropriate times. He confusion to the diagnostic dilemma. Uncertain was toilet-trained a few months before the visit, and about the next step, the pediatrician referred JB to a there were no recent changes in bowel or bladder pediatric gastroenterologist. habits. A physical examination at the pediatrician’s office INDEX TERMS. hepatomegaly, muscular dystrophy, fatigue, motor demonstrated normal vital signs and height and developmental delay. weight measurements between the 5th and 10th per- centiles (head circumference was not measured). We need the whole physical for the whole patient. Throughout the history and examination, J.B. sat qui- Plato etly in his mother’s lap. He appeared tired and did not make any significant effort to engage in sponta- Dr Martin T. Stein neous play activities. His head and neck examination A delay in development or a persistent behavioral were unremarkable. His thorax was barrel-shaped, condition may, on examination, be associated with and a grade 2–3/6 systolic murmur was auscultated other physical symptoms or signs that may provide a at the apex; it was musical in quality and decreased clue to a diagnosis. At times, the finding on physical when J.B. was placed in a sitting position. Peripheral examination and a subsequent laboratory test are so pulses were normal. His abdomen was flat and non- striking that the next step is an immediate referral to tender, and normal bowel sounds were present. A a subspecialist. J.B. presented with a constellation of soft, nontender liver edge was palpable 4 cm below concerns, including fatigue (“sluggishness and lack the right costal margin; the spleen was 2 cm below of energy” for several months), diminished interest the left costal margin. An abdominal mass was not in play and spontaneous activities, and a delay in palpated. In a standing position, his back appeared motor development. The finding on physical exami- straight, with a mild lumbar lordosis, but without nation of mild hepatosplenomegaly and elevated se- rum transaminases led the primary pediatrician to consider an underlying liver disorder. A referral to a * Originally published in J Dev Behav Pediatr. 2002;23:37–41. doi:10.1542/peds.2004-1721H pediatric gastroenterologist followed these observa- PEDIATRICS (ISSN 0031 4005). Copyright © 2004 by the American Acad- tions. emy of Pediatrics and Lippincott Williams & Wilkins. It is a credit to the pediatric gastroenterologist that

Downloaded from www.aappublications.org/newsPEDIATRICS by guest on September Vol.114 29, 2021 No. 5 November 2004 1437 J.B.’s evaluation was comprehensive. As described in 1). Cell injury results in the liberation of these intra- detail in the first commentary, the child’s abnormal cellular enzymes and raises serum aminotransferase liver-function studies were integrated with other im- levels. Therefore, the differential diagnosis of ele- portant observations, including a delay in motor de- vated aminotransferase enzymes is broad. velopment, a family history that suggested a genetic Investigating hepatic causes of chronic elevated disorder, and a more detailed evaluation of weak- aminotransferase enzymes is a reasonable place to ness during the physical examination. A careful syn- start in J.B. because of the hepatosplenomegaly dis- thesis of the facts available to the primary care clini- covered on physical examination. Chronic liver in- cian led to a suspicion of a diagnosis outside of the fection, passive congestion, cholestatic liver disease, gastrointestinal system. This kind of medical prac- hepatobiliary tumors, and inappropriate storage of tice, where the patient is seen as a whole person and fat, glycogen, and metals are possible etiologies. Car- not in terms of individual organs and systems, was diac disorders such as acute myocardial infarction, described several years ago by the British pediatri- myocarditis, pericarditis, and cardiomyopathy often cian, John Apley.1 Using cardiology as an example, cause elevations of aminotransferase enzymes. Ac- he wrote: “The cardiologist, however expert in phys- tive injury from disorders such as iology and cardiac function, is incomplete as a diag- rhabdomyolysis, viral or pyomyositis, muscular dys- nostician and doctor if he fails to look beyond the trophy, or rheumatic myositis causes elevations in functioning of the heart to the functioning of the serum aminotransferase enzymes. Other disorders patient as a person. On the whole, good diagnosti- including renal infarcts, intestinal infarcts, shock, cians are good listeners. History-taking can be cru- pancreatitis, cholecystitis, endocrinopathies, and cial, and further questions to highlight the develop- heparin therapy may also lead to elevations of ami- mental history, which can be added to see if anything notransferases. suspicious emerges, should not be omitted with any The additional findings of muscle weakness and one child…” isolated gross motor delay with hepatomegaly help I asked Dr Neelesh Tipnis to provide the initial narrow the potential etiologies in J.B. For example, commentary. Dr Tipnis is a Fellow in Pediatric Gas- liver storage diseases typically present in this fash- troenterology at Children’s Hospital San Diego, Uni- ion.2 Glycogen storage disease, particularly type II versity of California, where J.B. was evaluated. Dr (Pompe’s disease) and type III (Cori-Fabry), presents Paul Schultz, a senior pediatric neurologist at the with progressive hepatosplenomegaly, fasting hypo- same institution, wrote the second commentary. The glycemia, and variable degrees of muscle weakness. discussion on the Developmental-Behavioral Pediat- Niemann-Pick disease is the result of a defect in ric Web site yielded important additional comments sphingomyelinase. Four variants of Niemann-Pick from Dr Richard Jacobson. are associated with hepatosplenomegaly during in- fancy, often with prolonged jaundice. Types A and B Martin T. Stein, MD present during early infancy with failure to thrive Professor of Pediatrics and progressive muscle weakness and global devel- University of California opmental delay. Types C and D Niemann-Pick Children’s Hospital San Diego San Diego, California present during the toddler years with predominant gaze disturbances and extrapyramidal signs, fol- REFERENCE lowed by muscle weakness and gross motor delay. 1. Apley J. One child. In: Apley J, Ounsted C, eds. One Child. Clinics in Gaucher’s disease results in characteristic radio- Developmental Medicine. No. 80. London, United Kingdom: William Hei- graphic long-bone findings (Erlenmeyer flask) and nemann Medical Books, Ltd; 1982:33 massive hepatosplenomegaly as the result of abnor- mal sphingolipid accumulation because of a defi- Dr Neelesh A. Tipnis ciency in ␤-glucosidase. The infantile, neuronopathic J.B. has 4 major problems: elevated serum amino- form includes ataxia, peripheral neuropathy, and sei- transferase levels, hepatomegaly with mild spleno- zures. The more common nonneuronopathic form of megaly, muscle weakness, and isolated gross motor Gaucher’s disease (type 1) is characterized by bone delay. Elevated serum aspartate aminotransferase marrow infiltration and hypersplenism. The diagno- (AST, SGOT) and alanine aminotransferase (ALT, sis is made by the finding of the Gaucher cell on bone SGPT) enzymes are a frequent cause of referral to a marrow biopsy and polymerase chain reaction test- pediatric gastroenterologist. AST and ALT are intra- ing. Enzyme replacement therapy is available. cellular enzymes used to catalyze the conversion of Hepatobiliary disease is the presenting sign of cys- aspartate and alanine, respectively, to glutamine and tic fibrosis in 1% of patients.3 Eighty percent of pa- acetyl-coenzyme A (CoA), which serves as an impor- tients with cystic fibrosis have fat accumulation in tant link to the citric acid cycle for energy produc- the liver on autopsy. Many will have focal biliary tion. When compared with serum, AST is found in and progress to end-stage liver disease. highest concentrations in myocardial tissues (7800:1), Chronic malnutrition from pancreatic insufficiency followed by skeletal muscle (7000:1), liver (5000:1), can lead to muscle weakness, atrophy, and loss of kidney (4500:1), (1400:1), lungs (500:1), and developmental milestones. red blood cells (15:1).1 In comparison, the ALT tis- Wilson’s disease is a progressive disorder caused sue-to-serum ratio reveals higher concentration in by a defect in copper transport. Copper and lipid liver tissue (2850:1) and kidney (1200:1), with smaller accumulation occurs in hepatocytes and neuronal levels in skeletal muscle and myocardium (300–400: cells and within joint, renal, and endocrine tissues.

1438 4-YEAR-OLD WITHDownloaded FATIGUE from AND www.aappublications.org/news ELEVATED LIVER-FUNCTION by guest on September TESTS 29, 2021 Age of presentation is variable but occurs most often crosomal antibody titer to assess for rheumatologic during adolescence. Accumulation of hepatic copper processes, a sweat chloride test, and a serum CK. results in pathologic changes in the liver such as Radiographic studies would include an ultrasound micro- and macrovesicular lipid deposition leading of the abdomen to assess the liver parenchyma for to progressive hepatic fibrosis with mild elevations evidence of abnormal storage, fibrosis, or congestion in serum aminotransferases. Occasionally, fulminant and a chest radiograph to evaluate the lungs and hepatic failure with a hemolytic anemia occurs. Mo- heart for evidence of pulmonary disease and cardio- tor symptoms generally occur late in the disease and megaly. An echocardiogram would be beneficial in include dystonia, weakness, choreiform movements, screening the child for a cardiomyopathy. dysarthria, and gait disturbances. Dystonia may pro- duce a “frozen face” appearance. Psychiatric mani- Neelesh A. Tipnis, MD festations are a result of copper accumulation in the Fellow in Pediatric Gastroenterology cerebral cortex and basal ganglion. Inattentiveness, University of California Children’s Hospital San Diego diminished social functioning, deterioration in San Diego, California school performance, and psychosis may occur. Searching for a hepatic cause of elevated amin- REFERENCES otransferases in this case is a logical first step in the 1. Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Phil- presence of hepatosplenomegaly. However, elevated adelphia, PA: W. B. Saunders; 1991:248–284 AST and/or ALT have been reported in children 2. Teckman JH, Perlmutter DH. Metabolic disorders of the liver. In: Wyllie with muscular dystrophy.4 Duchenne muscular dys- R, Hyams JS, eds. Pediatric Gastrointestinal Disease: Pathophysiology, Diag- nosis, Management. Philadelphia, PA: W. B. Saunders; 1999:579–599 trophy (DD) is an X-linked disorder that is the most 3. Schwachman H. Gastrointestinal manifestations of cystic fibrosis. Pediatr common hereditary neuromuscular disease, occur- Clin North Am. 1975;22:787–805 ring in all races, with an incidence of 1:3600 male live 4. Munsat TL, Baloh R, Pearson CM, Fowler W Jr. Serum enzyme alter- births. Elevations of aminotransferase enzymes are ations in neuromuscular disorders. JAMA. 1973;226:1536–1543 5. Zamora S, Adams C, Butzner JD, Machida H, Scott RB. Elevated amino- found during the early asymptomatic period when transferase activity as an indication of muscular dystrophy: case reports the greatest amount of muscular degeneration oc- and review of the literature. Can J Gastroenterol. 1996;10:389–393 curs. Hepatomegaly was a feature in 8 of 24 patients 6. Tsung SH. isoenzymes patterns in human tissue ob- with muscular dystrophy referred to a gastroenter- tained at surgery. Clin Chem. 1976;22:173–175 ologist for evaluation of elevated AST.5 In these cases, no clinical evidence of hepatic disease was Dr Paul Schultz found. All children had a history of delayed walking J.B. presented with reduced motor function, inter- and signs of muscular dystrophy, including calf preted as “lethargy.” At 4 years of age, he was re- pseudohypertrophy and proximal muscle weakness. cently toilet-trained. His inability to walk indepen- Creatine kinase (CK) is principally found in skeletal dently until 2 years of age should have been an muscle and only in small amounts in the liver.6 The alarming symptom in a child with a normal birth presence of an elevated CK (often Ͼ240 times normal history. Hepatosplenomegaly led to an evaluation of values) with the appropriate history and physical liver function, which revealed elevations of AST and findings should raise suspicion for the diagnosis of ALT. A subsequent examiner noted pseudohypertro- muscular dystrophy. The diagnosis of DD can be phy of the calf muscles and ordered a serum CK confirmed by gene testing for the characteristic dys- level, which was markedly elevated. The constella- trophin gene deletions and histopathologic changes tion of gross motor developmental delay, proximal on muscle biopsy. Affected children should be weakness, subsequently apparent pseudohypertro- screened for cardiac, pulmonary, and cognitive se- phy of the calf muscles, and elevation of the CK led quelae of muscular dystrophy. to the diagnosis of DD. The diagnosis was confirmed My evaluation of J.B. would begin with a careful by a molecular genetic test that demonstrated a char- review of the history, paying careful attention to the acteristic deletion of the DD locus.1 onset of weakness, a developmental history for clues The most common initial signs or symptoms of DD of more global developmental delay, a family history are delayed gait development, expressive language of other affected males, and the ascertainment of the delay, and abnormal liver-function tests performed height of immediate relatives to evaluate his short during an evaluation of other conditions such as stature. A neurological examination should include gastrointestinal symptoms or hepatosplenomegaly.2 an assessment of upper and lower motor neuron For years we have advocated the performance of a function; the determination of muscle strength, tone, CK determination on any boy with a normal birth bulk, and reflexes are very important in a child with history who is not walking independently by 18 delayed motor development. Cardiac murmurs or months of age and the determination of proximal leg extra heart sounds might be indicative of a cardio- strength in any boy with delayed speech develop- myopathy associated with a global myopathic pro- ment.3 The latter is performed by asking the child to cess. The abdominal examination should delineate stand up from a seated position on the floor while liver and spleen size and texture. Laboratory testing observing the use of his arms (Gower’s sign) to assist should include studies to assess the presence of in- his weak legs by pushing on his thighs. fection (hepatitis B and C and Epstein-Barr viral Early diagnosis before 4 to 5 years of age does not titers), serum ␣-1 antitrypsin levels, serum copper necessarily lead to an improved outcome, but it does and ceruloplasmin levels for Wilson’s disease, an allow for carrier detection for the mother, who has a antinuclear antibody titer and anti-liver/kidney mi- 60% to 70% chance of being a carrier of this X-linked

Downloaded from www.aappublications.org/news by guest on September 29, 2021 SUPPLEMENT 1439 recessive disorder.2 If she is a carrier, future preg- However, an enlarged liver and spleen is not a typ- nancies can be evaluated by amniocentesis to detect ical feature of dystrophinopathy, so something else the presence of DD. might be going on. There is an X-linked glycogen stor- Approximately 10% of those boys with similar age disease (type VIII) that affects the liver and is presentations have a milder form of the disease, re- associated with hypercholesterolemia (which might be ferred to as Becker dystrophy (BD).4 Prognosis de- associated with ischemic heart disease in the uncles), pends on accurately differentiating DD from BD, but this disorder is not associated with myopathy. which can often be done by molecular genetic test- So I come back to BD as the most likely explanation. ing. In the 30% of cases that have no demonstrable The diagnosis can be made with serum CK, which deletion, a muscle biopsy is needed to histologically should be in the thousands, and DNA testing for a analyze the dystrophin level, which is diminished in deletion of the dystrophin gene. If a deletion is not BD and absent in DD.5 found, a muscle biopsy, with histochemistry for glyco- gen and immunostaining for dystrophin, would be the Paul Schultz, MD next step. An electromyogram is not necessary unless Clinical Professor of Pediatrics and Neurology there is doubt about the weakness or if the CK is Children’s Hospital San Diego normal. University of California San Diego, California Dr Martin T. Stein REFERENCES New information is slow to work its way into 1. Beggs AH, Koenig M, Boyce F, Kunkel LM. Detection of 98% of DMD/ clinical practice. When I heard this case at our Grand BMD gene deletions by polymerase chain reaction. Hum Genet. 1990;86: Rounds Conference, I was certain that I knew the 45–48 origin of the elevated serum transaminase levels; it 2. Emery AEH. Duchenne Muscular Dystrophy. 2nd ed. New York, NY: Oxford University Press; 1993 must represent liver disease in J.B. A medical school 3. Schultz P. Supportive therapy in muscular dystrophy. In: Fukuyama Y, memory from more than 3 decades ago reminded me Kamoshita S, Ohtsuka L, Suzuki I, eds. Modern Perspectives in Child that, of the 2 enzymes, the serum ALT (formally Neurology. Tokyo, Japan: Japanese Society of Child Neurology; 1991: known as SGPT) was specific for the hepatocyte, 277–280 4. Mendell JR, Buzin CH, Feng J, et al. Diagnosis of Duchenne dystrophy by whereas the serum AST (formally known as SGOT) enhanced detection in small mutations. Neurology. 2001;57:645–650 was derived from muscle, hepatocyte, and a variety 5. Muntoni F. Is a muscle biopsy in Duchenne dystrophy really necessary? of other cells. The case discussion by Dr Tipnis Neurology. 2001;57:574–575 makes it clear that both enzymes may be increased in muscle injury. Knowledge of that fact may have re- Web Site Discussion directed my attention away from chronic liver dis- The case summary for the Challenging Case was ease associated with developmental delay and posted on the Developmental and Behavioral Pedi- chronic fatigue—the wrong path to be sure! atrics Web site‡ (www.dbpeds.org.list) and the Jour- Pattern recognition is the most frequent cognitive nal’s Web site (www.lww.com/DBP). Comments mechanism used by physicians when establishing a were solicited. clinical diagnosis.1 It serves our use well, in that symptoms and signs of a particular condition are Richard Jacobson, MD, PhD, Pediatric Neurology, often clustered in recognizable patterns.2 To make Medical College of Wisconsin, Milwaukee, Wisconsin the most out of this diagnostic process requires both Weakness, elevated transaminases, and a history the acquisition of sufficient clinical information, the of maternal uncles with heart disease (perhaps a ability to use as much of the information as possible cardiomyopathy rather than the reported ischemic (rather than discard critical data), and the courage to heart disease) suggests an X-linked genetic disorder, include as much of the information as possible in a in particular a dystrophinopathy. The elevated AST unifying diagnosis. John Apley had this in mind and ALT could come from muscle, and so an astute when he wrote about the “one child” noted in my gastroenterologist would check a CK even in a pa- introductory comments. tient without other features pointing to liver disease. This case also illustrates the importance of includ- This is an occasional reason for referral to our neu- ing specific information on development in all med- romuscular clinic. The uncles are not said to be weak, ical histories. Knowledge of a developmental delay which would suggest that the phenotype would be apparently limited to the motor domain was a critical the milder Becker variety of muscular dystrophy. If piece of information. It was not given the proper this is the correct diagnosis, then the child’s apparent attention when the primary care clinician discovered fatigue could simply reflect progressive proximal abnormal liver-function tests. Presumably, an un- weakness. specified hepatic disorder was the clinician’s reason for referring J.B. to a gastroenterologist. Had J.B.’s “sluggishness and lack of energy” been evaluated ‡A bimonthly discussion of an upcoming Challenging Case takes place at the Developmental and Behavioral Pediatrics Web site. This Web site is more carefully, a proximal pattern of weakness in the sponsored by the Maternal and Child Health Bureau and the American lower extremities might have been demonstrated Academy of Pediatrics section on Developmental and Behavioral Pediatrics. during the examination by the primary care clinician. Henry L. Shapiro, MD, is the editor of the Web site. Martin Stein, MD, the In my office, I have a higher-than-usual examination Challenging Case editor, incorporates comments from the Web discussion into the published Challenging Case. To become part of the discussion at table that allows a child to walk up 3 steps to reach the Developmental and Behavioral Pediatrics home page, go to www. the top. Children with proximal muscle weakness, a dbpeds.org. hallmark of DD and BD, have difficulty with this

1440 4-YEAR-OLD WITHDownloaded FATIGUE from AND www.aappublications.org/news ELEVATED LIVER-FUNCTION by guest on September TESTS 29, 2021 task. The Gower sign, the hallmark of a proximal REFERENCES muscle weakness, is described by Dr Schultz. In ad- 1. Oski F. The diagnostic process. In: Principles and Practice of Pediatrics. dition, Dr Schultz pointed out another reason to pay Philadelphia, PA: J. B. Lippincott; 1990:50–52 attention to developmental delay in this case when 2. Jones KL. Smith’s Recognizable Patterns of Malformations. 5th ed. Philadel- he suggested that, in any boy with delayed walking phia, PA: W. B. Saunders; 1997 beyond 18 months without an explanation, a serum 3. Stein MT, Bennett FC, Abbott MB. Early delay in motor development. J Dev Behav Pediatr. 1996;17:414–419 CK determination is an appropriate screening test for 4. DiMauro S, Hayes AP, Bonilla E. Hereditary myopathies. In: Rudolph 3 muscular dystrophy. In fact, the CK in children with AM, ed. Rudolph’s Pediatrics. 20th ed. Stamford, CT: Appleton and DD is elevated before the onset of weakness.4 Langue; 1996:1978–1981

Downloaded from www.aappublications.org/news by guest on September 29, 2021 SUPPLEMENT 1441 Fatigue, Decreased Interest in Play, Motor Delay, and Elevated Liver-Function Tests in a 4-Year-Old Boy Pediatrics 2004;114;1437 DOI: 10.1542/peds.2004-1721H

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Downloaded from www.aappublications.org/news by guest on September 29, 2021 Fatigue, Decreased Interest in Play, Motor Delay, and Elevated Liver-Function Tests in a 4-Year-Old Boy Pediatrics 2004;114;1437 DOI: 10.1542/peds.2004-1721H

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