SHORT COMMUNICATION: HEPATOLOGY
Ornithine Transcarbamylase Deficiency Presenting as
Acute Liver Failure in Girls: A Paediatric Case Series
y
Arthavan Selvanathan, zAshley Hertzog,
ABSTRACT
Ornithine transcarbamylase deficiency (OTCD) is the most common of the
urea cycle disorders and follows an X-linked inheritance pattern. The
classical form in male infants causes vomiting and lethargy in the neonatal
period; if untreated the severe hyperammonaemia can cause acute neuro-
toxic complications and permanent disability. OTCD may also occur in
heterozygote female individuals, though the manifestations are variable. We
report 2 cases of female paediatric patients with OTCD, who presented with
acute liver failure. Both patients had limited oral intake at the time of
presentation, causing an absence of orotic aciduria, which delayed the
diagnosis. These cases demonstrate the need to consider urea cycle disorders
in children presenting with acute liver failure, and that repeating the urine
metabolic screen at the time of an unrestricted diet is warranted if there is a
high clinical suspicion.
Key Words: inborn errors of metabolism, paediatric liver disease, urea
cycle disorder
(JPGN 2020;71: 208–210)
Received September 29, 2019; accepted March 16, 2020.
From the Clinical Genetics and Genetic Pathology, Genetic Metabolic
Disorders Service, Sydney Children’s Hospital Network, the yDiscipline
Child and Adolescent Health, University of Sydney, the zNSW Bio-
chemical Genetics Service, Sydney Children’s Hospital Network, the
§Department of Gastroenterology, Sydney Children’s Hospital, the
jjSchool of Women’s and Children’s Health, University of New South
Wales, the ôGenetic Metabolic Disorders Service, Sydney Children’s
Hospital Network, and the #Disciplines of Child and Adolescent Health
and Genetic Medicine, University of Sydney, Sydney, Australia.
Address correspondence and reprint requests to Arthavan Selvanathan,
BMed, MD, Advanced Trainee, Clinical Genetics and Genetic
Pathology, Genetic Metabolic Disorders Service, Sydney Children’s
Hospital Network. Clinical Associate Lecturer, Discipline of Child and
Adolescent Health, University of Sydney, Sydney, Australia
(e-mail: arthavan.selvanathan@health.nsw.gov.au).
Supplemental digital content is available for this article. Direct URL
citations appear in the printed text, and links to the digital files are
provided in the HTML text of this article on the journal’s Web site
(www.jpgn.org).
Compliance with Ethics Guidelines: Ethics approval was granted by the
Sydney Children’s Hospital Network Research Ethics and Governance
Team (HREC Reference Number: CCR2019/26). All procedures fol-
lowed were in accordance with the ethical standards of the responsible
committee on human experimentation (institutional and national) and
with the Helsinki Declaration of 1975, as revised in 2000. Informed
consent was obtained from all patients’ families in order to review
medical records, and publish their cases anonymized.
The authors report no conflicts of interest.
Copyright # 2020 by European Society for Pediatric Gastroenterology,
Hepatology, and Nutrition and North American Society for Pediatric
Gastroenterology, Hepatology, and Nutrition
DOI: 10.1097/MPG.0000000000002716
208
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
§jj
Daniel A. Lemberg, and ô#
Carolyn Ellaway
What Is Known
 Ornithine transcarbamylase deficiency has a wide
phenotypic spectrum in female patients, ranging
from the classical neonatal presentation to asymp-
tomatic carrier status.
 Ornithine transcarbamylase deficiency can cause
acute liver failure in female heterozygotes.
What Is New
 We report 2 additional female paediatric patients
presenting with acute liver failure as the first mani-
festation of ornithine transcarbamylase deficiency.
 Both patients did not have orotic aciduria on the
initial urine metabolic screen.
 It is important to consider urea cycle disorders in
patients presenting with acute liver failure, and to
repeat urine testing on an unrestricted diet if there is
high clinical suspicion.
O rnithine transcarbamylase deficiency (OTCD) is an X-
linked urea cycle disorder (UCD), which causes hyperam-
monaemia because of an inability to convert carbamoylphosphate
and ornithine to citrulline (see Figure, Supplementary Digital
Content 1, http://links.lww.com/MPG/B811, demonstrating the urea
cycle). The classic form presents in male infants, with poor feeding,
vomiting, and lethargy after a symptom-free interval. Without
appropriate management, children develop neurotoxic complica-
tions from hyperammonaemia (seizures and coma), often leading to
long-term disability and even death.
Despite its inheritance pattern, OTCD also presents in girls,
with variable manifestations including similar acute decompensa-
tions, recurrent vomiting, progressive developmental delay, and/or
protein aversion. It is increasingly recognized that girls have
atypical presentations, including acute liver failure (ALF) (1).
We herein report 2 girls with OTCD presenting initially in ALF,
without orotic aciduria. It is important for OTCD to be considered,
therefore, as a cause of ALF.
PATIENT 1
Patient 1, now ages 2.5 years, was born after a normal
pregnancy and delivery, with no relevant family history. From
12 months of age, she had recurrent episodes (6–7 times per day) of
vomiting, with accompanying developmental and growth arrest.
She presented at ages 18 months with worsening oral intake,
hypotonia, and hypothermia (34.7 8C). She had sluggish pupil
reactions and rightward eye deviation, with a modified Glasgow
Coma Score of 6; these parameters improved with midazolam.
JPGN  Volume 71, Number 2, August 2020
JPGN  Volume 71, Number 2, August 2020 OTCD Presenting as Acute Liver Failure in Girls

TABLE 1. Blood and urine test results at different timepoints for patient 1 and patient 2

Patient 1 Patient 2 Normal range Units

Sample A B C D E F G – –

pH 7.38 – – 7.49 – 7.48 – 7.34–7.43 –

pCO2 34 – – 28 – 27 – 32–45 mmol/L
Bicarbonate 20 – – 21 – 19.6 – 18–24 mmol/L
Lactate 2.5 – – 1.6 – 2.6 – 0.7–2.0 mmol/L
Bilirubin 13 5 4 7 3 <10 5 0.7–2 mmol/L
AST – 140 145 759 1920 840 264 10–50 U/L
ALT 1704 619 73 1133 2786 819 1041 0–45 U/L
ALP 281 218 296 52 103 73 65 0–45 U/L
GGT 39 36 14 219 197 216 225 80–320 U/L
Albumin 43 35 34 36 33 38 37 33–48 g/L
INR 3.7 1.7 1.5 3 1.7 2 1.5 0.9–1.1 –
Ammonia 223 62 353 95 59 133 112 <50 mmol/L
Citrulline (plasma) 14 – 17 5 – 9 10 10–45 mmol/L
Arginine (plasma) 20 – 23 16 – 17 34 34–118 mmol/L
Glutamine (plasma) 1089 – 960 1212 – 1111 1392 385–862 mmol/L
Plasma acylcarnitine profile Normal – – Normal – – – – –
Urinary orotate (UPLC/MS/MS) 16 – 109 0.3–3.0 mmol/mmol CRT
Urinary orotate (GC/MS) 10.1 – Below limit of detection 629 <10 mmol/mmol CRT

ALP ¼ alkaline phosphatase; ALT ¼ alanine aminotransferase; AST ¼ aspartate aminotransferase; CO2 ¼ carbon dioxide; CRT ¼ creatinine; GC/MS ¼ gas
chromatography/mass spectrometry; GGT ¼ gamma-glutamyl transferase; INR ¼ international normalized ratio; UPLC/MS/MS ¼ ultraperformance liquid
chromatography/tandem mass spectrometry.

There was evidence of ALF (see Table 1: A) with synthetic
dysfunction (international normalized ratio [INR] 3.7) and hyper-
ammonaemia (223 mmol/L). She received intravenous fluids, anti-
biotics, and antiviral agents. HHV-6 serology was positive (titres:
2.83 copies/mL), but this did not explain the extent of
liver dysfunction.
The initial urine metabolic screen (UMS) showed a slightly
increased orotate (it was reported that a mild UCD could not be
excluded); the repeat screen 2 days later was normal. A liver biopsy
demonstrated a mild ductular reaction at the portolobular interface,
representing regenerative change. The child recovered, the ammo-
nia normalized (Table 1: B), and she was discharged home with
gastroenterological follow-up.
She re-presented 3 weeks later with episodic vomiting,
confusion, and ataxia, 3 days after recommencing a normal diet.
The ammonia was 353 mmol/L, there was a gross increase in urinary
orotate, and plasma amino acids showed low arginine and high
glutamine (Table 1: C). A biochemical diagnosis of OTCD was
made, with molecular testing demonstrating a de novo heterozygous
frameshift variant (OTC: c.529deljp.Leu177Serfs10). Treatment
was started with sodium benzoate, L-arginine, and a low-protein diet
(1.5 g/kg/day), with resolution of hyperammonaemia. She has had
no further metabolic decompensations. Her development is normal
except for delayed expressive language (mostly single words, with
occasional 2-word phrases).
PATIENT 2
Patient 2 is now a 9-year-old girl, who presented to the
Emergency Department at 16 months of age with a 3-week history
of vomiting, unsteadiness, and lethargy. She was noted to be in ALF
with a mild respiratory alkalosis (Table 1: D). The serum ammonia
was 95 mmol/L. Her liver function tests (LFTs) worsened over the
ensuing 4 days (Table 1: E). She had been receiving 36 mg/kg/day
of paracetamol: subacute paracetamol toxicity was the provisional
diagnosis for the ALF (the paracetamol level was normal).
The urine organic acids showed a slightly elevated orotate,
reported as being consistent with hepatic dysfunction. A DISIDA
scan showed mild intrahepatic cholestasis, and a brain magnetic
resonance imaging (MRI) showed extensive bilateral temporopar-
ietal swelling with corresponding diffusion restriction, consistent
with hepatic encephalopathy. LFTs improved and she was dis-
charged home with ongoing Vitamin K and ursodeoxycholic acid
therapy, and outpatient gastroenterology follow-up.
Two weeks later, she re-presented with poor oral intake and
vomiting. Her LFTs showed worsening synthetic dysfunction
(international normalized ratio [INR] 2) (Table 1: F). Urinary
orotate whilst on clear fluids was below the limit of detection.
She restarted a normal diet and 3 days later, urinary organic acids
demonstrated a gross increase in orotate (Table 1: G). Plasma
citrulline and arginine were low with high glutamine, consistent
with OTCD. She was treated with a low-protein diet, sodium
benzoate, and L-arginine. Molecular studies demonstrated a hetero-
zygous de novo frameshift variant (OTC: c.239delAjp.
Lys80Serfs3).
The patient has had no subsequent metabolic decompensa-
tions. Her growth parameters are on the 50th centile, and her
neurological examination is normal. There is intermittent hyper-
ammonaemia (maximum 213 umol/L) with intercurrent illnesses.
Her most recent brain MRI shows stable residual changes (mild
bilateral parietal lobe volume loss). She attends a mainstream
school, with a teacher’s aide for reading assistance.
DISCUSSION
The natural history of OTCD in girls ranges from neonatal
hyperammonaemic encephalopathy to asymptomatic carriers.
Twenty percentage of female patients are reported to experience
encephalopathic episodes (2). Of similarly symptomatic female
patients from a large Korean case series, 60% had normal develop-
ment, 30% had developmental delay, and the remaining 2 patients
died (3). Our cases demonstrate 2 atypical presenting features of

www.jpgn.org 209

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

Selvanathan et al
OTCD in female patients: ALF and the initial absence of
urinary orotate.
There is increasing recognition of ALF as a feature of OTCD
(4), including in 40% of female patients (1). In vitro studies suggest
that the hepatotoxicity could be because of direct damage from
ammonium chloride, or from build-up of the precursor carbamoyl-
phosphate (5). Liver disease can occur at any age; Weiss et al (6)
report a woman who presented in ALF during pregnancy, and was
subsequently diagnosed with OTCD. It is, therefore, important that
UCDs are included as differential diagnoses for ALF, as early
diagnosis alters management and outcomes.
Orotate is a pyrimidine synthesis intermediate derived from
carbamoylphosphate; orotic aciduria in the context of hyperammo-
naemia is strongly suggestive of OTCD. Fasting, however, reduces
orotate excretion by 50% (7), and absence of orotic aciduria occurs
in some adult-onset presentations (8). Our cases did not present in
the neonatal period, and were coincidentally protein-restricted at
the time of the first urine sample, explaining the initial normal
results. Following reinstatement of a full-protein diet for 2–3 days,
both had demonstrable urinary orotate. This illustrates the need to
repeat testing if clinical suspicion is high.
CONCLUSIONS
OTCD is an X-linked disorder that has substantial clinical
variability in girls; atypical presentations are more common, and
include ALF. Absence of orotic aciduria does not preclude the
210
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
JPGN  Volume 71, Number 2, August 2020
diagnosis of OTCD in paediatric patients. Early diagnosis facilitates
appropriate management and improves long-term outcomes.
REFERENCES
1. Laemmle A, Gallagher R, Keogh A, et al. Frequency and pathophysiol-
ogy of acute liver failure in ornithine transcarbamylase deficiency
(OTCD). PLoS One 2016;11:e0153358.
2. Batshaw M, Msall M, Beaudet A, et al. Risk of serious illness in
heterozygotes for ornithine transcarbamylase deficiency. J Pediatr
1986;108:236–41.
3. Choi J, Lee B, Kim J, et al. Clinical outcomes and the mutation spectrum
of the OTC gene in patients with ornithine transcarbamylase deficiency. J
Hum Genet 2015;60:501–7.
4. Gallagher R, Lam C, Wong D, et al. Significant hepatic involvement n
patients with ornithine transcarbamylase deficiency. J Pediatr
2015;164:720.e6–5.e6.
5. Rajabi F, Rodan L, Jonas M, et al. Liver failure as the presentation of
ornithine transcarbamylase deficiency in a 13-month-old female. J Inherit
Metab Dis Rep 2018;40:17–22.
6. Weiss N, Mochel F, Rudler M, et al. Peak hyperammonemia and atypical
acute liver failure: the eruption of a urea cycle disorder during hyperem-
esis gravidarum. J Hepatol 2018;68:185–92.
7. Jeevandam M, Shoemaker J, Horowitz G, et al. Orotic acid excretion
during starvation and refeeding in normal men. Metabolism
1985;34:325–9.
8. Brassier A, Gobin S, Arnoux K, et al. Long-term outcomes in ornithine
transcarbamylase deficiency: a series of 90 patients. Orphanet J Rare Dis
2015;10:58.
www.jpgn.org