Acute liver failure (ALF) is a life-threatening condition in the absence of preexisting liver disease in children. The main clinical presentation comprises hepatic dysfunction, elevated liver biochemical values, and coagulopathy. The etiology of ALF remains unclear in most affected children; however, the recent identification of mutations in the neuroblastoma amplified sequence (NBAS) gene in autosomal recessively inherited ALF has shed light on the cause of a subgroup of fever-triggered pediatric ALF episodes. Previously, biallelic mutations in NBAS have been reported to be associated with a syndrome comprising short stature, optic atrophy, and Pelger-Huët anomaly (SOPH) specifically occurring in the Yakut population. No hepatic phenotype has been observed in individuals with this disorder who all carry the homozygous NBAS founder mutation c.5741G>A [p.(Arg1914His)]. We present the case of a 4-year-old girl with the cardinal features of SOPH syndrome: characteristic facial dysmorphism, postnatal growth retardation, delay of bone age, slender long bones, optic atrophy, and Pelger-Huët anomaly. During the first 2 years of her life, a series of infections with episodes of fever were accompanied by elevated liver enzyme levels, but hyperammonemia, hypoglycemia, coagulopathy, or encephalopathy suggestive of acute and severe liver disease were never observed. Whole exome sequencing in the patient revealed compound heterozygosity of the 2 NBAS variants, p.(Arg1914His) and p.(Glu943*). This case highlights the variability of clinical presentation associated with NBAS deficiency. Absence of severe liver problems in this case and SOPH-affected Yakut subjects suggests that individuals carrying the NBAS missense mutation p.(Arg1914His) are less susceptible to developing ALF.
- ALT —
- alanine aminotransferase
- ALF —
- acute liver failure
- AST —
- aspartate aminotransferase
- GGT —
- γ-glutamyl transpeptidase
- Ig —
- NBAS —
- neuroblastoma amplified sequence
- SOPH —
- short stature, optic atrophy, and Pelger-Huët anomaly
Acute liver failure (ALF) in early infancy and childhood is a devastating condition associated with a high mortality. Timely and appropriate medical management is essential in pediatric ALF for complete recovery of liver function.1 Although the underlying cause remains unknown in ∼50% of cases of ALF,2 novel and known inborn errors of metabolism possibly account for a significant number of individuals with ALF.3 The recent discovery of mutations in the neuroblastoma amplified sequence (NBAS) gene in individuals with autosomal recessively inherited ALF has shed light on previously unexplained episodes of fever-triggered ALF in infants and children (OMIM #616483).4 NBAS deficiency is reportedly a relatively frequent cause of pediatric ALF and may account for recurrent, milder liver crises and mild hepatopathy in infants and children.5 Early antipyretic therapy and induction of anabolism have been shown to effectively ameliorate the course of liver crises, leading to complete liver recovery in most cases; however, severe hepatic failure can also lead to early death.5,6
With the previous discovery of NBAS mutations in subjects with a new syndrome comprising short stature, optic atrophy, and Pelger-Huët anomaly (SOPH) as the main features (OMIM #614800),7 ALF has been linked to SOPH syndrome, with the latter occurring in the Yakut population. The clinical spectrum associated with NBAS mutations ranges from isolated ALF to a multisystem disorder involving the skeletal, immune, and eye system.5,8 Importantly, no hepatic involvement has yet been reported in individuals with SOPH syndrome who all carry the homozygous NBAS founder mutation c.5741G>A [p.(Arg1914His)].7 Recent reports on 2 unrelated cases and 3 siblings with biallelic NBAS mutations indicated a broad phenotypic spectrum associated with NBAS deficiency, including fever-triggered acute liver disease.6,8,9 The case we reported here further demonstrates high clinical variability in patients with NBAS mutations and suggests that individuals with the missense variant p.(Arg1914His) could have abnormal liver function, but possibly are less prone to develop ALF.
The female patient currently aged 4 years 9 months was born at 38 weeks’ gestation to healthy nonconsanguineous parents. Pregnancy was complicated by fetal growth retardation and oligohydramnios starting at week 32 of gestation. Birth weight was 2308 g (–2 SDs), length was 47 cm (–1.5 SDs), and occipital frontal circumference was 29 cm (–3 SDs). Early postnatal failure to thrive led to the first medical consultation at 5 weeks of age. In addition to short stature and poor weight, laboratory evaluation revealed neutropenia (403/µL [normal, >1000/µL]), elevated liver enzyme levels (lactate dehydrogenase, 581 U/L [normal, <300 U/L]); aspartate aminotransferase [AST], 587 U/L [normal, 0–19 U/L]; alanine aminotransferase [ALT], 544 U/L [normal, 0–23 U/L]; γ-glutamyl transpeptidase [GGT], 211 U/L [normal, 6–55 U/L]; glutamate dehydrogenase, 362 U/L [normal, 0–5 U/L]; and cholinesterase, 10.8 kU/L [normal, 3.5–8.5 kU/L]) and elevated ferritin in serum (1173 µg/L [normal, 30–200 µg/L]). However, the patient had no symptoms of cholestatic liver disease and no hyperammonemia, coagulopathy, or jaundice. Her abdominal ultrasound was normal.
Reexamination at age 7 months revealed dystrophy (4565 g; –2 SDs, according to height) and short stature (60 cm; –3 SDs). Subcutaneous fat was reduced, and skin appeared loose. Facial dysmorphism comprised a triangular face with high and broad forehead, large-appearing eyes due to proptosis, convergent strabismus, thick eyebrows (medial part), and small mouth with thin lips (Fig 1). Fontanels were strikingly large, and skull radiography showed hypoplastic maxilla, poor ossification of the calvarium, wide open sutures, and large fontanels, as well as multiple occipital Wormian bones. Her hands and feet were small; her elbow and knee joints showed flexion contractures, and sonography disclosed hip dysplasia on the left. Muscle tone was low. Results of additional laboratory testing revealed no evidence of a metabolic disorder, and cerebrospinal fluid and cerebral MRI assessments were normal. Occipital frontal circumference at age 12 months and 19 months was –1 SDs and at age 3 years 3 months was –2 SDs.
The girl’s psychomotor development was delayed: she started to walk at age 2.5 years and spoke her first words at age 3 years. Intellectual development, however, appeared to be normal.
Short stature and dystrophy became more evident at the age of 4 years 9 months: height was 81 cm (–6 SDs) and weight 9 kg (–2 SDs, according to height). Hand radiographs at age 3 years 2 months (Fig 1) and 4 years 9 months revealed delayed bone maturation by ∼9 months. A radiograph of the girl’s right shoulder at age 13 months demonstrated mild epiphyseal delay and slender humerus. A radiograph of her left pelvis and leg at age 15 months showed normal configuration of the os ilium, mild delay of the femoral and tibial epiphyseal maturation, and slender long tubular bones but no signs of osteochondrodysplasia. Endocrinologic examination was normal; in particular, there was no evidence of hypothyroidism or growth hormone deficiency.
During the first 2 years of life, the girl had a series of airway infections with fever accompanied by elevated liver enzyme levels (age 8 months: AST, 515 U/L; ALT, 371 U/L; GGT, 92 U/L; age 12 months: AST, 545 U/L; ALT, 441 U/L; GGT, 85 U/L). In the intervals between episodes of infection, liver enzyme levels decreased (AST, 136–224 U/L; ALT, 226–261 U/L; GGT, 25–116 U/L) but not to normal range. Results of liver biopsy testing, however, revealed nearly normal histologic findings with only mild fatty infiltration of the parenchyma but no signs of any storage material. During the past 2 years, hepatic involvement became less severe. Results of coagulation studies were repeatedly normal in the girl (last follow-up at age 4 years 10 months: Quick’s value, 102%; international normalized ratio, 1.0; and partial thromboplastin time, 31 seconds).
At the age of 3 years, the patient had an acute infection with tonsillitis, mycosis by Candida, and herpes simplex virus (perioral and cheeks). Laboratory evaluation revealed hypogammaglobulinemia with low immunoglobulin (Ig) G (215 mg% [normal, 504–1464 mg%]), IgG1 (1.73 g/L [normal, 2.4–7.8 g/L]), IgG2 (0.23 g/L [normal, 0.55–2.0 g/L]), IgG4 (<0.01 g/L [normal >0.69 g/L]), IgM (26 mg% [normal, 24–216 mg%]), and IgA (11 mg% [normal, 27–195 mg%]), as well as reduced B lymphocytes (12% [261/µL]; normal, 14%–44%). Results of serologic studies revealed no antibodies against tetanus or diphtheria. Subsequent subcutaneous Ig replacement therapy prevented recurrent infections in the patient. Blood evaluation at age 4.5 years disclosed a Pelger-Huët anomaly of neutrophil granulocytes. Eye examination at the age of 4 years 1 month revealed progressive loss of visual acuity within the last 6 months (visus 0.12 right and <0.1 left) and pale optic disc confirming optic atrophy.
To identify the genetic cause for the various clinical findings in the girl, whole exome sequencing was performed in the patient and in her parents. Two heterozygous sequence variants in the NBAS gene (c.2827G>T [p.(Glu943*)] and c.5741G>A [p.(Arg1914His)]) were detected in the girl, and both were validated by using Sanger sequencing. Parental genotyping revealed the c.5741G>A mutation in the heterozygous state in the mother and the c.2827G>T mutation in the heterozygous state in the father, indicating compound heterozygosity of the NBAS variants in the patient. The NBAS change p.(Arg1914His) represents the founder mutation in the Yakuts population associated with SOPH syndrome.7 The nonsense variant p.(Glu943*) together with another NBAS mutation have previously been reported in 2 individuals with ALF and/or additional features.4,5
ALF is a rare and life-threatening condition characterized by rapid-onset liver injury and hepatic dysfunction. Clinical presentation includes elevated liver biochemical values, coagulopathy, and encephalopathy in a patient without preexisting liver disease.10,11 The recent discovery of NBAS mutations as a molecular cause of ALF has helped explaining a significant proportion of pediatric ALF.4 Age at onset is within the first 2 years, and affected children presented with vomiting and lethargy after febrile illnesses; crises started with massively elevated AST and ALT levels (maximum range, 3510–24 721 U/L and 4001–17 700 U/L, respectively). Coagulopathy and jaundice developed in most of the cases, while hypoglycemia, hyperammonemia, and hepatic encephalopathy were present in only some (Table 1).5
NBAS mutations in patients with the severe hepatic phenotype tend to cluster in the first one-half of the encoded protein (amino acids 95–1121); however, 2 patients with ALF (numbers 12 and 13 in the study by Staufner et al5) and exon-spanning deletions affecting the C-terminal region of NBAS have recently been reported (Table 1).4–6,8 None of the ALF-associated mutations affects exon 45 in which the SOPH syndrome–specific mutation c.5741G>A has been discovered.7 The patient reported here had only moderately elevated liver enzyme levels during febrile infections, and she never developed typical symptoms of liver crises. Because individuals with SOPH syndrome and the homozygous NBAS mutation p.(Arg1914His) do not exhibit a hepatic phenotype (although no data on liver biochemical values were available),7 we hypothesize that individuals with the p.(Arg1914His) change, either in the heterozygous or homozygous state, are less prone to developing liver crises and ALF. The effect of the arginine-to-histidine substitution on NBAS function is unclear. NBAS is involved in retrograde transport of vesicles from the Golgi apparatus to the endoplasmic reticulum and the control of nonsense-mediated messenger RNA decay.12–14 Further investigations will show whether the episodes of liver disease in patients with NBAS deficiency are due to a compromised nonsense-mediated messenger RNA pathway, alterations in Golgi–endoplasmic reticulum trafficking, and/or an impaired, yet-to-be-discovered NBAS function.
The patient exhibited significant phenotypic overlap with the 2 NBAS mutation-positive cases reported by Segarra et al.8 This patient and the 2 individuals from the study by Segarra et al share similar facial features, short stature, frequent infections, Pelger-Huët anomaly, reduced natural killer cells, and various skeletal findings (Table 1). In contrast to our patient, the girl and the boy in the earlier study had acute liver disease triggered by fever and accompanied by massively elevated transaminase levels (AST and ALT with a maximum range of >7500–15 000 and 9300–9700 U/L, respectively). Similar to the girl reported here, no hepatic problems have been reported in Yakut subjects with SOPH syndrome.7 Clinical features of the patient, such as postnatal growth retardation, small hands, delay of bone age, proptosis, flat face, optic nerve atrophy, and Pelger-Huët anomaly, resemble those of SOPH syndrome.
The phenotype of this patient further broadens the clinical spectrum associated with NBAS deficiency and highlights the absence of acute liver disease in individuals carrying the NBAS founder mutation of the Yakut population.
We are grateful to the patient’s family who contributed to this study. We thank Dennis Zorndt for skillful technical assistance.
- Accepted August 31, 2016.
- Address correspondence to Kerstin Kutsche, PhD, Institute of Human Genetics, University Medical Center Hamburg–Eppendorf, Martinistraße 52, 20246 Hamburg, Germany. E-mail:
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: Supported by grants from Deutsche Forschungsgemeinschaft (KO 4576/1-1 to Dr Kortüm and KU 1240/10-1 to Dr Kutsche).
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
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- Copyright © 2017 by the American Academy of Pediatrics