The proband was born at 36 weeks, appropriate for gestational age, to nonconsanguineous white parents. There was no evidence of hyperbilirubinemia or intrahepatic cholestasis in the neonatal period, and she had normal newborn screen results. She presented with 3 episodes of life-threatening bleeding and anemia. The diagnostic evaluation for her bleeding diathesis revealed an abnormal clotting profile with no biochemical evidence for hepatocellular damage. She was incidentally noted to have severe growth deceleration that failed to respond to 502 kJ/kg (120 kcal/kg) per day of protein-hydrolyzed formula. An extensive diagnostic workup for failure to thrive, which was otherwise normal, included plasma amino acid analysis that revealed hyperglutaminemia and citrulline levels within the reference range. Testing of a repeat sample revealed isolated hypercitrullinemia. No argininosuccinic acid was detected. Her ammonia level and urine orotic acid were within the reference ranges. Subsequent plasma amino acid analysis exhibited a profile suggestive of neonatal intrahepatic cholestasis caused by citrin deficiency with elevations in citrulline, methionine, and threonine. Western blotting of fibroblasts demonstrated citrin deficiency, and a deletion for exon 3 was found in the patient's coding DNA of the SLC25A13 gene. On the basis of the experience with adults carrying this condition, the patient was given a high-protein, low-carbohydrate diet. The failure to thrive and bleeding diathesis resolved. When compliance with the dietary prescription was relaxed, growth deceleration was again noted, although significant bleeding did not recur. This is the first report of an infant of Northern European descent with citrin deficiency. The later age at presentation with failure to thrive and bleeding diathesis and without obvious evidence of neonatal intrahepatic cholestasis expands the clinical spectrum of citrin deficiency. This case emphasizes the importance of continued dietary control and growth monitoring in children with neonatal intrahepatic cholestasis caused by citrin deficiency and identifies a new metabolic entity responsible for failure to thrive.
Failure to thrive (FTT) is a common pediatric condition, with 10% of children in 1 study showing transitory FTT and 4% showing sustained FTT.1 Investigation of such weight loss is a frequent cause of hospital admissions. Recent reviews have emphasized that this entity most commonly reflects a lack of adequate energy intake and is rarely caused by an organic disease.2
Conversely, citrin deficiency is an inborn error of metabolism previously reported to have a carrier prevalence of 1 in 70 in the Southeast Asian population.3 It has not been described previously in North America or in a subject of Northern European descent. This disorder is caused by mutations in the SLC25A13 gene, which encodes an aspartate glutamate carrier. The same mutations cause 2 different age-dependent clinical phenotypes: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD [Online Mendelian Inheritance in Man No. 605814])4 and adult-onset type II citrullinemia (Online Mendelian Inheritance in Man No. 603471).5 In both cases, individuals have an abnormal amino acid chromatogram with an elevated citrulline level. Severe intrahepatic cholestasis with fatty liver is the most common presenting feature in NICCD. However, neonatal hepatitis; positive newborn screen results for galactosemia, tyrosinemia, and phenylketonuria; hemolytic anemia; and bleeding diathesis have been described previously as presenting features.6
The proband was born at 36 weeks' gestation via normal vaginal delivery. The pregnancy had been complicated by vaginal bleeding at 12 weeks' gestation. The mother reported that all of her other antenatal tests were within reference limits. The infant's anthropometric measurements were appropriate for gestational age. She was born to nonconsanguineous white parents. There was no family history of jaundice, bleeding disorders, or FTT.
There was no evidence of hyperbilirubinemia or intrahepatic cholestasis in the neonatal period. No elevations of tyrosine and galactose levels were detected by newborn screening.
At 2 months of age, failure to gain weight was noted. The infant was diagnosed clinically with gastroesophageal reflux and treated with ranitidine and metoclopramide for 3 weeks without clinical benefit. Her parents reported good oral intake of formula.
The infant presented at 7 months of age with an episode of bleeding associated with a decrease in her hemoglobin level to 2 g/dL. This incident was treated with fresh-frozen plasma and packed red blood cells.
One month later, at 8 months of age, she was admitted to a different hospital with oozing of blood from her mouth. She had a mildly elevated protime (PT) (15.4 seconds) and a low albumin level (3.2 g/dL). Her hemoglobin level dropped to 7 g/dL, which required another transfusion of packed red blood cells. She had normal liver transaminase levels at this point. A computed tomography scan of her abdomen and pelvis revealed no arteriovenous malformations. Bronchoscopy and esophagogastroduodenoscopy did not identify the source of the blood loss.
She was readmitted 1 month later, at 9 months of age, with hematochezia and profuse bleeding from her rectum. Her hemoglobin level was 5.6 g/dL, and she required additional transfusions and fresh-frozen plasma. Her PT was elevated at 19.4 seconds, and her partial thromboplastin time was elevated at 36.7 seconds.
The workup for her bleeding diathesis revealed an abnormal clotting profile with a low factor 2 (44% of control) and low factor 5 (35% of control). We failed to find a source of bleeding with repeat imaging, including angiography and a Meckel scan. She was noted on this admission to have a very low albumin level (2.8 g/dL), although her liver transaminase levels remained within the reference range. Severe growth deceleration was also noted (see Figs 1 and 2).
An extensive workup for FTT (Table 1) was essentially normal except for the plasma amino acids, which on hospital day 7 showed nonspecific elevations in several amino acids (see Table 2, plasma amino acid 1).
The infant was given an observed calorie challenge using a free amino acid formula (120 kcal/kg [502 kJ/kg] per day: 41% fat, 12% protein, 47% carbohydrate) for 12 days. This intake is significantly in excess of the dietary reference intakes for a typical 9-month-old (81 kcal/kg [340.2 kJ/kg] per day: 39% fat, 6% protein, 45% carbohydrate).9 Despite this formula, she failed to gain weight.
On hospital day 20, a repeat plasma amino acid assay revealed a modest and isolated elevation of citrulline with no detected argininosuccinic acid (see Table 2, plasma amino acid 2). She had a serum lactate level within the reference range (1.4 mmol/L) and a normal urinary organic acid analysis. The result of an assay for argininosuccinate synthetase activity in cultured fibroblasts was within the reference range (4.1 nmol/min per mg protein [reference range: 0.8–3.8 nmol/min per mg protein]). The patient had ammonia (8 μmol/L [reference range: <50 μmol/L]) and urine orotic acid (0.4 mg/mL [reference range: 0.3–2.82 mg/mL]) levels within the reference ranges. A subsequent amino acid analysis was performed on hospital day 31. This test revealed a biochemical profile suggestive of NICCD (elevated citrulline, threonine, and methionine), although no elevations of tyrosine and arginine were observed (see Table 2, plasma amino acid 3).
On the basis of the experience of Imamura et al10 in adults with citrin deficiency, a high-protein/low-carbohydrate diet was initiated. This 6-kg infant was given 4 g/kg per day of protein, 9.3 g/kg per day of carbohydrate, and 6 g/kg per day of fat (113 kcal/kg [475 kJ/kg] per day: 15% protein; 35% carbohydrate, 50% lipids). The infant immediately began gaining weight, and energy intake was reduced to 103 kcal/kg (433 kJ/kg) per day. Full correction of growth velocity and weight was subsequently seen (see Figs 1 and 2). Plasma amino acids and the coagulation profile normalized (see Table 2, plasma amino acid 4). At 20 months of age she had a reduced protein intake (11% protein, 35% carbohydrate, and 54% fat). Her growth and weight became static. Furthermore, her mother reported some minor rectal bleeding. Her linear growth velocity resumed with no additional bleeding episodes when the protein was again increased to 15%.
Western blotting performed on the patient's fibroblasts showed the absence of citrin protein with a normal adenosine triphosphate synthase band. Complementary DNA (cDNA) was prepared by using total RNA extracted from cultured skin fibroblasts, and sequencing of the coding regions was performed as described previously.5 This test revealed a deletion of exon 3 when sequenced in both directions.
FTT is a common pediatric problem. In most cases, the cause is thought to be insufficient energy intake or constitutional small size.1
Conversely, inborn errors of urea cycle metabolism present classically with an acute encephalopathy or neurocognitive dysfunction or as a result of abnormal newborn screening tests.11
Citrin deficiency has been reported previously in Southeast Asian populations as a result of an abnormal newborn screen, liver failure, or (later on in life) with a neuropsychiatric presentation.3,5,6,12
Our proband, the first of European ancestry reported, presented with FTT and without evidence of intrahepatic cholestasis at 6 months of age. This alternative presentation expands the clinical spectrum of citrin deficiency. Moreover, it illustrates the importance of considering rare diseases when children exhibit persistent FTT that does not respond to adequate energy intake.
It is interesting to note that our patient had a normal citrulline level at a time of low energy intake because she was on intravenous dextrose after a gastrointestinal bleed. It can be hypothesized that the protein load resulting from this bleed may have provided a source of arginine and/or aspartate, which could correct the metabolic defect because loss of citrin causes deficiency of aspartate in the cytosol.13 In addition, by restricting the carbohydrate intake, the increase in the cytosolic reduced nicotinamide-adenine dinucleotide/oxidized nicotinamide-adenine dinucleotide ratio would be reverted and a potential derangement of lipid metabolism and depletion of cytosolic aspartate would be prevented.10 Furthermore, the failure of growth after reduction in protein intake with continued carbohydrate restriction suggests the importance of maintaining a high-protein, low-carbohydrate diet for these patients. The observed decompensation illustrates the importance of ongoing health surveillance.
We hypothesize that the failure of liver synthetic dysfunction, as verified by the low albumin levels, is the cause of the bleeding disorder seen in citrin deficiency. Expansion of the newborn screening program can be expected to identify more cases,6 which would require understanding of this emerging metabolic phenotype.
This study was supported in part by Grant-in-Aid for Scientific Research (B) 16390100 from the Japan Society for the Promotion of Science and by Grant for Child Health and Development 17–2 from the Ministry of Health, Labor, and Welfare of Japan.
We thank W.E. O'Brien, PhD (Biochemical Genetics Laboratory, Baylor College of Medicine) for plasma amino acid analysis and assistance with interpretation and Suzanne D'Souza, RD, LD (Texas Children's Hospital) for assistance with dietary calculations and dietary management of this patient.
- Accepted September 18, 2006.
- Address correspondence to Fernando Scaglia, MD, Clinical Care Center, Suite 1560, 6621 Fannin St, Houston, TX 77030. E-mail:
The authors have indicated they have no financial relationships relevant to this article to disclose.
- ↵Wright CM, Parkinson KN, Drewett R. The influence of maternal socioeconomic and emotional factors on infant weight gain and weight faltering (failure to thrive): data from a prospective birth cohort. Arch Dis Child.2006;91 :312– 317
- ↵Wright CM. Identification and management of failure to thrive: a community perspective. Arch Dis Child.2000;82 :5– 9
- ↵National Academy of Science; Food and Nutrition Board; Institute of Medicine. Dietary Reference Intakes: Energy, Carbohydrates, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, DC: National Academies Press; 2002/2005
- ↵Imamura Y, Kobayashi K, Shibatou T, et al. Effectiveness of carbohydrate-restricted diet and arginine granules therapy for adult-onset type II citrullinemia: a case report of siblings showing homozygous SLC25A13 mutation with and without the disease. Hepatol Res.2003;26 :68– 72
- ↵Clarke JTR. A Clinical Guide to Inherited Metabolic Diseases. 3rd ed. Cambridge, United Kingdom: Cambridge University Press; 2006
- ↵Saheki T, Kobayashi K, Iijima M, et al. Adult-onset type II citrullinemia and idiopathic neonatal hepatitis caused by citrin deficiency: involvement of the aspartate glutamate carrier for urea synthesis and maintenance of the urea cycle. Mol Genet Metab.2004;81(suppl 1) :S20– S26
- Copyright © 2007 by the American Academy of Pediatrics