Metabolism
abstract
Failure to thrive (FTT) is a common symptom, not a diagnosis, of a wide range of childhood diseases. Although FTT is usually caused by inade-quate energy intake in diet or constitutional small size, organic pathol-ogy should be considered in some cases of FTT. This article is intended to guide primary care physicians for when to suspect inborn errors of metabolism in children who present with FTT.Pediatrics2009;124:972– 979
Failure to thrive (FTT), usually identified during the first 3 years of life, is not a diagnosis but a symptom of a wide variety of conditions.1FTT is
widely used to describe inadequate growth in early childhood, but no consensus exists concerning the definition of FTT. Some authors define FTT in absolute terms as height or weight below the third or fifth percentiles for age on more than 1 occasion. Others define it in relative terms for each patient as height or weight measurements that de-crease 2 major percentiles using the standard growth charts.2As many
as 10% of children seen in primary care settings show signs of FTT.3
Although FTT is one of the most common problems that primary care physicians confront, its underlying causes often remain elusive and difficult to identify. It is important to detect the underlying pathology to start appropriate treatment as soon as possible and reduce long-term sequelae. FTT is most commonly a result of inadequate energy intake in diet or constitutional or genetic small size and is rarely caused by an organic disease.4When children exhibit persistent FTT that does not
respond to increased energy intake through diet, primary care physi-cians should consider organic causes including inborn errors of metabolism (IEM).
Individually rare conditions, IEM are usually caused by partial or full enzyme deficiencies or transport defects that result in either accumu-lation of toxic products or lack of an important end product. Some IEM can be easily treated, which underscores the value of including them in the differential diagnosis of FTT. The manifesting symptoms depend on the particular metabolic pathway that is affected.
FTT may be part of the clinical picture at presentation of a metabolic disease. Because those children have a compromised metabolic pathway, they show defective utilization and nutritional imbalances, leading eventu-ally to FTT.
In this article we clarify for primary care physicians when they should consider IEM in a patient with FTT and refer the patient to a metabolic specialist for further metabolic workup. The complete differential di-agnosis of IEM in patients with FTT is well beyond the scope of this article.
CONTRIBUTORS:Can Ficicioglu, MD, PhD, and Kristina an Haack, MD
Section of Biochemical Genetics, Department of Pediatrics, Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
KEY WORDS
failure to thrive, metabolic disorders
ABBREVIATIONS
FTT—failure to thrive
IEM—inborn error of metabolism GSD— glycogen-storage disease
www.pediatrics.org/cgi/doi/10.1542/peds.2008-3724
doi:10.1542/peds.2008-3724
Accepted for publication Feb 27, 2009
Address correspondence to Can Ficicioglu, MD, PhD, Children’s Hospital of Philadelphia, Section of Biochemical Genetics, 34th Street and Civic Center Boulevard, 9S23, Philadelphia, PA 19104. E-mail: fi[email protected]
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2009 by the American Academy of Pediatrics
WHEN TO SUSPECT A METABOLIC DIAGNOSIS IN A CHILD WHO PRESENTS WITH FTT
Because FTT is rarely an isolated symp-tom in metabolic disorders, one must estimate the full spectrum of clinical findings when considering the possi-bility of an underlying metabolic dis-ease. Primary care physicians whose patients with FTT present with a his-tory of clinical signs from 1 or more of the following categories should con-sider the possibility of IEM as a stan-dard part of differential diagnosis. We include short case reports drawn from our clinical practice to highlight differ-ent scenarios of presdiffer-entation of vari-ous metabolic disorders. In our com-ments about each case, we point out the red flags that could have led to an earlier referral for a complete meta-bolic workup and diagnosis.
History of Acute, Severe, and Potentially Life-Threatening Symptoms
Because of the accumulation of toxic products in disorders such as amino acid disorders, organic acid disor-ders, and urea cycle defects, some pa-tients have a catastrophic neonatal presentation. They present with a sepsis-like picture after an initial nor-mal period of 24 to 48 hours: the infant stops feeding well, begins vomiting, and becomes lethargic. High anion gap acidosis, hypoglycemia or hyperglyce-mia, or hyperammonemia are usually present. Neurologic signs develop and can be accompanied by liver failure and cardiac decompensation. If left undiagnosed and untreated, most of these patients die in the newborn period. Some patients, especially those with some residual enzyme activity, may sur-vive this crash and go on to have other metabolic crises or develop a chronic picture of developmental and neurologic sequelae that may include FTT (case 1). Thus, examining the infant’s past
medi-cal history for episodes of “presumed sepsis” is of great importance.
However, some infants may not dem-onstrate recognizable symptoms in the newborn period. They may present later when dietary changes add more protein to the diet (such as changing from breast milk to formula or adding protein solids) or, commonly, during a period of catabolism such as an inter-current illness or extended fast. In some cases, at the initial presentation the infant may demonstrate symptoms of metabolic crisis such as lethargy, high anion gap acidosis, hyperam-monemia, or hypoketotic hypoglyce-mia, although their absence does not rule out the presence of an IEM.
Case 1
A 4-month-old boy was transferred to our center because of lethargy and sei-zures. He was born at term after a nor-mal pregnancy. He had vomiting and mild high anion gap metabolic acidosis on the third day of life and was treated for sepsis with antibiotics and intrave-nous fluids. He was discharged from the NICU at 16 days of life. He continued to have recurrent vomiting and poor weight gain. He was diagnosed as having gastroesophageal reflux and treated with antireflux mediations. At 3 months of age he had FTT, developmen-tal delay, and recurrent vomiting. At 4 months of age he developed seizures and lethargy when he had fever and an upper respiratory infection and was transferred to our hospital. He had high anion gap acidosis and ke-tonuria, and his physical examina-tion was remarkable for lethargy, ax-ial hypotonia, and choreoathetosis. Results of plasma amino acid, urine organic acid, and plasma acylcarni-tine analyses were consistent with propionic acidemia.
Comments
High anion gap acidosis warranted metabolic workup at 3 days of life, and
FTT, developmental delay, and recur-rent vomiting warranted metabolic workup at 3 months of age.
Recurrent Vomiting
Vomiting is commonly episodic in met-abolic disorders and leads frequently to FTT. Although gastroesophageal re-flux or formula intolerance typically and appropriately are the chief clinical considerations for a patient with recur-rent vomiting, symptoms related to the times and contents of food intake (eg, period of fasting, high-protein meals, meals containing fructose), worsening of vomiting during intercurrent ill-nesses, or a finding of lethargy or acido-sis are highly suggestive of an underly-ing metabolic disease such as urea cycle defects, organic acid disorders, amino acid disorders, hereditary fructosemia, galactosemia, fatty acid oxidation de-fects, or mitochondrial disorders.6,8,9
Liver Dysfunction
Inborn errors may present with any of the characteristic features of liver dis-ease.7,10Conjugated or unconjugated
thromboplastin time, and fibrinogen.
Case 2
A 16-month-old infant born in Nigeria was referred for evaluation of develop-mental delay and FTT. There was no newborn screening for any metabolic disorders. He was breastfed and has been on solid foods and cow’s milk since 9 months of age. On examination he had hepatomegaly. Initial basic lab-oratory test results showed elevated plasma transaminase activities, direct bilirubinemia, and abnormal coagula-tion. Results of urinalysis for reducing substances were positive, and there was generalized aminoaciduria. The galactose-1-phosphate level was ele-vated at 18 mg/dL (normal:⬍1 mg/dL), and galactose-1-phosphate uridyltrans-ferase enzyme activity was⬍0.07mol/ hour per g hemoglobin (normal range: 15.9 –26.4mol/hour per g), thus con-firming a diagnosis of classical galac-tosemia. He was compound heterozy-gous for S135L/Q188R.
Comments
FTT, liver dysfunction with coagulopa-thy, hepatomegaly, and vomiting could be caused by galactosemia. These symp-toms by themselves should trigger refer-ral for a metabolic workup. However, pri-mary care physicians could also test urine for reducing substance. If the re-sult is positive, start a lactose-restricted diet and immediately refer the patient for further metabolic workup.
Case 3
A 6-month-old boy with FTT was re-ferred to our metabolic clinic to rule out metabolic disease. Medical history was remarkable for FTT, mild develop-mental delay, and recurrent vomiting. At 4 weeks of age, he was hospital-ized because of projectile vomiting, and pyloric stenosis was ruled out. After discharge, he was referred to
results of glucose, creatine kinase, ammonia, lactate, plasma amino acid, and acylcarnitine studies were found to be normal. In the metabolic visit at 6 months, a transferrin isoelectric fo-cusing test was ordered to rule out congenital glycosylation defects on the basis of the finding of hepatomegaly, mild liver dysfunction, FTT, and devel-opmental delay. The test revealed an abnormal glycosylation pattern with de-creased tetrasialotransferrin but pres-ence of disialotransferrin and asialo-transferrin consistent with congenital disorders of glycosylation type 1.
Comments
At 4 weeks, this patient already had symptoms such as vomiting, hepato-megaly, and FTT, which indicate poten-tial IEM. Such a patient ought to be referred for a complete metabolic eval-uation. The metabolic tests listed on Table 1 do not rule out all metabolic disorders; some patients, including this one, had normal results on these tests and required a special test to make the diagnosis.
Neurologic Symptoms
FTT may be accompanied by devel-opmental delay or regression, sei-zures, nystagmus (case 4), abnormal muscular tonus, or abnormal move-ments. Recurrent episodes of leth-argy, ataxia, seizures, or strokes can reveal an underlying metabolic dis-order such as ornithine transcarb-amylase deficiency, organic acid dis-orders, maple syrup urine disease, homocystinuria, and mitochondrial disease.6,11,12 Patients with creatine
synthesis defects may present with growth failure and seizures.13 The
presence of hepatosplenomegaly with slowly progressive psychomotor re-tardation suggests a diagnosis of a lysosomal storage disease.
intake, low muscle tone, nystagmus, and liver dysfunction was referred to our metabolic clinic. The medical history revealed that the patient had an elevated tyrosine level de-tected through newborn screening. Tyrosinemia type I was ruled out on the basis of normal plasma amino acid and urine organic acid analyses at 1 week of age. She had conjugated hy-perbilirubinemia and elevated transaminase levels and was referred to gastroenterology to rule out biliary atresia and other liver disorders. At 3 months of age she developed nystag-mus, and her neurologic examination was remarkable for hypotonia. Liver biopsy results by electron microscopy showed proliferation of mitochondria with decreased cristae, a finding con-sistent with mitochondrial depletion syndrome. Mitochondrial DNA content was below 10% of controls in liver. The patient had 2 missense mutations in the deoxyguanosine kinase (DGUOK) gene.
Comments
FTT, liver disease, hypotonia, and nys-tagmus could be caused by a mito-chondrial disease, and special tests are needed to confirm the diagnosis.
Cardiomyopathy and Myopathy
Exercise intolerance, rhabdomyolysis, recurrent muscle pain, and spasms need further testing to rule out meta-bolic origins such as fatty acid oxida-tion defects or glycogen-storage disor-ders.6 Several metabolic conditions
Impairment of Special Senses
Impaired growth and finding of hear-ing loss or visual impairment indicates need for further metabolic and genetic workup to rule out various storage dis-eases, peroxisomal defects, and mito-chondrial abnormalities.6 An infant
with FTT, cholestasis, and hearing loss may have a defect in peroxisomal bio-genesis. Ophthalmologic signs, espe-cially those such as cataracts, retinop-athy, nystagmus, or optic atrophy, are suggestive of an underlying metabolic disorder.
For example, FTT and cataracts may be caused by an IEM such as galac-tosemia, Lowe syndrome, or mitochon-drial disorders. Recommended initial tests (see Table 2) may show abnormal
liver functions and positive reducing substance in the urine. Then the next step should be to refer the patient to a metabolic specialist and send for an enzyme test to confirm the diagno-sis of galactosemia. FTT, cataracts, hy-potonia, and developmental delay in a male infant could be caused by Lowe syndrome, an X-linked disorder. Find-ing tubular dysfunction (proteinuria, glucosuria, and aminoaciduria) may increase the suspicion for this condi-tion, and it is important to ask for a metabolic consult to confirm this diag-nosis with an enzyme analysis. These examples demonstrate the usefulness of comprehensive metabolic panels and urinalysis for FTT patients in pro-viding indicators of potential IEM.
Renal Symptoms
Renal Fanconi syndrome as well as renal tubular acidosis may be asso-ciated with an inherited metabolic condition such as galactosemia, ty-rosinemia type 1, cystinosis, glycogen-storage disease (GSD) I, hereditary fructose intolerance, Fanconi-Bickel syndrome, and Lowe syndrome.6
Ab-normal renal loss of bicarbonate leads to hyperchloremic metabolic acidosis, which can cause FTT.
Distinct Dysmorphic Features and/or Organomegaly
Structural cerebral abnormalities and/ or mild dysmorphic features can in-dicate energy-metabolism defects such
TABLE 1 Diagnostic Approach to a Patient With FTT to not Miss and IEM
as mitochondrial disorders. Patients are usually symptomatic at birth but may present at any time of life depend-ing on the severity of the defect. Some patients with pyruvate dehydro-genase deficiency, peroxisomal bio-genesis defects, or glutaric aciduria type II may present with facial dysmorphism and associated multiple congenital anomalies. Coarse facial features, bone changes (dysostosis multiplex: large skull with elongated sella, deformed, hook-shaped lower thoracic and lumbar vertebrae, pelvic dysplasia), and organomegaly are suggestive of storage diseases such as mucopolysaccharidoses, I-cell dis-ease, which may be associated with FTT. FTT and hepatomegaly with hypo-glycemia suggest glycogen-storage disorders. The nonneuronopathic form of Gaucher disease presents with splenomegaly or hepatosplenomegaly and delayed growth that results from skeletal disease.14Dysmorphic features
are necessary for developmental path-ways and networks (peroxisomal bio-genesis defects, cholesterol metabolism defects—Smith-Lemli-Opitz syndrome).6
HOW CAN NEWBORN METABOLIC SCREENING HELP?
Since the beginning of the extended newborn screening program in the United States, Australia, Germany, the Netherlands, and Canada, many IEM are detected in the newborn period before symptoms occur.15 When a
metabolic disorder is suspected in a child who presents with FTT, it is im-portant to check the results of the new-born screening test. One should al-ways remember that not all metabolic disorders can be screened for in the newborn period. The number of meta-bolic disorders screened varies from one state to another. Some metabolic disorders such as tyrosinemia type 1 and very long-chain acyl coenzyme A dehydrogenase deficiency 1 of the fatty acid oxidation defects may be missed in the newborn screening.16If a patient
has symptoms and signs of IEM, fur-ther testing should be performed even if the result of the newborn screening test was normal.
EVALUATION OF PATIENTS WITH FTT TO RULE OUT/IN IEM
Past and Current History
Obtaining a careful past and current medical history including an assess-ment of diet, eating behaviors, and so-cial, developmental, and family history is an essential first step.17 Each
pa-tient’s newborn screening report should be obtained from the newborn screening laboratories if it is not al-ready included in the records. The his-tory should largely focus around the features that make you suspicious for an IEM, such as history of acute life-threatening symptoms in the newborn
function, hypoglycemia, or acidosis, dehydration, and lethargy associ-ated with minor illnesses5(Tables 1
and 2).
Birth History
Some clues that point toward diagno-sis of IEM may be obtained in the birth history. Preeclampsia, acute fatty liver of pregnancy, or hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome) during pregnancy may indi-cate that the child has long-chain hy-droxyacyl coenzyme A dehydrogenase deficiency or carnitine palmitoyl trans-ferase I deficiency.18,19 Patients with
small-molecule disease such as amino acid disorders, urea cycle defects, or organic acid disorders usually have completely normal intrauterine devel-opment and normal growth parame-ters at birth, because accumulated toxic small molecules are removed via placenta and are metabolized by the mother. These patients have no symptoms in the first hours of life, and they usually become symptom-atic between days 2 and 4 of life as a result of accumulation of toxic me-tabolites.
Feeding History
In the diet history, it is important to ask if there is any food aversion. For exam-ple, self-restricting high-protein food, fructose, or any type of food that makes him or her sick may be caused by a metabolic disorder that results in the inability to metabolize amino acids or fructose (case 5).
Patients with amino acid disorders or urea cycle defects may self-restrict their protein intake. Patients with he-reditary fructose intolerance get sick when they eat anything containing fructose, so they self-restrict eating candies or fruits.
Neurologic Developmental delay Developmental regression Ataxia Seizures Stroke Hypotonia Dystonia Gastrointestinal Recurrent vomiting Hepatosplenomegaly Cholestasis Liver dysfunction Jaundice Gastrointestinal dysmotility Cardiovascular Hypertrophic/dilated cardiomyopathy Ophthalmologic Cataracts Optic atrophy Retinal degeneration Ear, nose, and throat
Hearing loss Frequent ear infections Sleep apnea
Other
Case 5
An 8-month-old boy with FTT, feeding difficulties, and recurrent vomiting was referred to a metabolic special-ist to rule out IEM. Physical exami-nation was remarkable for hepato-megaly. A detailed nutritional history showed that the onset of his symptoms coincided with the initiation of fruits in his diet at⬃5 months of age. Heredi-tary fructose intolerance was sus-pected on the basis of the diet history. Fructose-containing foods were imme-diately eliminated from his diet, and the diagnosis was confirmed by aldo-lase B gene mutation analysis.
Comments
This case highlights the importance of taking a detailed diet history for all cases of FTT.
Family History
A careful family history may reveal im-portant clues that raise the possibility of IEM. Most IEM are inherited as auto-somal recessive traits, so there may be siblings with similar illnesses or deaths from sepsis with an unidenti-fied pathogen or sudden infant death syndrome. The parents may be consan-guineous or come from a genetic iso-late such as a small village in Mexico or the Amish in Pennsylvania. There are also X-linked and mitochondrial inher-ited IEM, so a family history must in-clude information about the mother’s siblings, their children, etc. A pedigree only containing nuclear family mem-bers is inadequate. A positive family history can be helpful, but a negative family history does not lower suspi-cion for a metabolic disease.
Physical Examination
A complete physical examination is es-sential, with 4 main goals:
1. detection of hepatomegaly and/or splenomegaly (eg, lysosomal storage disorders, galactosemia,
glycogen-storage disorders, tyrosinemia type I, hereditary fructose intolerance);
2. assessment of neurologic function (eg, mitochondrial disorders, stor-age disorders, peroxisomal disor-ders, amino acid disordisor-ders, organic acid disorders, urea cycle defects); 3. identification of dysmorphic fea-tures (eg, energy-metabolism de-fects, peroxisomal disorders, mu-copolysaccharidosis, I-cell disease, glutaric aciduria type II); and 4. hair and skin abnormalities such as kinky, colorless, or steel-colored hair, alopecia, seborrheic dermati-tis (eg, Menkes disease, biotinidase deficiency).
Hearing and vision should always be included in the workup. The involve-ment of multiple organ systems in a child with FTT should increase the sus-picion for IEM.5
Laboratory and Radiologic Investigation
Routine laboratory investigations may provide clues for an IEM (Table 1). Abnormal liver test results, decreased CO2levels, hypoglycemia, positive urine
reducing substance, and ketonuria could be caused by IEM, and the patient should be referred to a metabolic spe-cialist for further metabolic investiga-tions. When there is a metabolic acido-sis, it is very important to calculate anion gap. A patient with high anion gap acidosis always requires meta-bolic workup and consultation.
Routine laboratory errors often lead to unnecessary anxieties for parents and unnecessary referrals to metabolic specialists. Handling samples properly is essential for obtaining true results. A basic metabolic panel should be per-formed in an unhemolyzed sample. Shipping samples to other states and keeping specimens for a long time at room temperature can cause falsely decreased levels of CO2.
Most metabolic disorders can be
de-tected through biochemical analysis of body fluids, mainly blood, urine, and cerebrospinal fluid. Increased or de-creased levels of metabolites may be diagnostic. In some disorders, levels of a specific metabolite increase only in acute crisis; when patients are well, levels of such metabolites may be per-fectly normal. If blood and urine meta-bolic tests are performed when pa-tients are fasting, sick with fever, or vomiting, it sometimes helps to iden-tify otherwise undetectable abnormal metabolites. Many metabolic tests can be performed by using spot urine, which preferably should be obtained in the morning when urine is more concentrated.
Because of the required specificity of metabolic investigations, tests such as plasma amino acid and urine organic acid analyses should only be per-formed in experienced laboratories that process a sufficiently large num-ber of samples for these tests. Lactate and ammonia level determinations are highly sensitive measurements that are susceptible to false results. To en-sure the highest accuracy of the mea-surement, free-flow samples are re-quired with a transfer to the laboratory on ice and rapid analysis. Physicians must provide the individual clinical context to the laboratory to enhance the accuracy of the interpretation of the test results.
method for accurate diagnosis of homocystinuria.
Plasma acylcarnitine analysis helps to diagnose fatty acid oxidation defects such as medium-chain acyl coenzyme A dehydrogenase deficiency, very long-chain acyl coenzyme A dehydrogen-ase deficiency, and organic acid dis-orders such as propionic acidemia and methylmalonic acidemia. Urine or-ganic acid analysis should be ordered to diagnose mainly organic acid disor-ders and fatty acid oxidation defects. Plasma total and free carnitine levels should always be ordered with urine carnitine levels. Decreased plasma and urine carnitine levels are usually caused by nutritional carnitine defi-ciency. A decreased plasma carnitine level along with increased urinary car-nitine excretion are caused by carni-tine transport defect, which requires urgent metabolism consultation and initiation of carnitine therapy. Analysis of urine amino acids may help to de-termine if there is tubular dysfunction. It is also important to order it to rule out some metabolic disorders such as lysinuric protein intolerance.
Urine is often a key indicator of meta-bolic diseases, but several factors hinder its utility as a diagnostic clue.5
It is difficult to collect urine from in-fants; mixing of stool with urine further complicates evaluation. Nonetheless, primary care physicians should ask if parents/care providers notice any
un-the diagnosis of a number of metabolic disorders. The sweet smell of urine could be caused by ketoacidosis found in organic acidemias. Maple-syrup odor in body fluids could be caused by maple syrup urine disease. Sweaty-feet odor in urine or on the body may be noticed with isovaleric acidemia. Dark urine can be seen with alkaptonuria and myoglobin-uria. The dipstick test for hemoglobin can detect both hemoglobinuria and myoglobinuria. Myoglobinuria is often associated with elevated creatine kinase and muscle cramps or pain. An attack of myoglobinuria can be caused by a fatty acid oxidation defect or GSD type V or VII or myophosphorylase deficiency. Although a pink or red stain in the dia-pers may well indicate blood in the urine, it also could be the first sign of porphy-ries, a major metabolic disorder that causes red urine.
It is important to emphasize that the tests discussed here do not rule out all metabolic disorders; some re-quire special tests, such as enzyme analysis, typically performed by met-abolic physicians.
Patients with neurologic findings such as hypotonia, seizures, and develop-mental delay require imaging studies including plain radiographs, computed tomography scanning, and brain MRI. MRI can be very useful for separating metabolic disorders into groups on the basis of the pattern of brain in-volvement (eg, white matter versus
made. Magnetic resonance spectros-copy is used to measure the levels of different metabolites such as lactate,
N-acetyl aspartate, choline, and creat-ine in the brain. For example, an ele-vated lactate level in basal ganglia may be a sign of mitochondrial dis-ease, or the absence of creatine peak is caused by creatine transport or syn-thesis defects.
Plain radiographs may reveal a pat-tern of abnormalities that suggest a class of metabolic disorders. For ex-ample, plain radiographs often show generalized dysostosis multiplex in lysosomal storage disorders such as mucopolysaccharidosis or split epi-physes in peroxisomal biogenesis disorders.5
CONCLUSIONS
FTT is one of a great variety of present-ing symptoms of IEM. Understandably, physicians are eager to explain the un-derlying cause of FTT. The single most important factor in deciding whether to perform metabolic tests or refer the patient to a metabolic specialist is determining whether FTT is an iso-lated finding or there is additional pathology. Children with isolated mild-to-moderate FTT do not usually man-date metabolic investigation. However, multisystem progressive findings are much more likely caused by an IEM and always warrant further investigation and evaluation for IEM.
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DOI: 10.1542/peds.2008-3724 originally published online August 10, 2009;
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Failure to Thrive: When to Suspect Inborn Errors of Metabolism
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