Acute Liver Failure Meets SOPH Syndrome: A Case Report on an Intermediate Phenotype

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.

[1]  J. Cáceres,et al.  Mechanism and regulation of the nonsense-mediated decay pathway , 2016, Nucleic acids research.

[2]  R. Plasterk,et al.  Mechanistic insights and identification of two novel factors in the C. elegans NMD pathway. , 2007, Genes & development.

[3]  K. Böker,et al.  Akutes Leberversagen , 2001, Der Internist.

[4]  Sheila Unger,et al.  NBAS mutations cause a multisystem disorder involving bone, connective tissue, liver, immune system, and retina , 2015, American journal of medical genetics. Part A.

[5]  A. Mégarbané,et al.  Neuroblastoma Amplified Sequence (NBAS) mutation in recurrent acute liver failure: Confirmatory report in a sibship with very early onset, osteoporosis and developmental delay. , 2015, European journal of medical genetics.

[6]  Song Zhang,et al.  Pattern of diagnostic evaluation for the causes of pediatric acute liver failure: an opportunity for quality improvement. , 2009, The Journal of pediatrics.

[7]  T. Isobe,et al.  Identification of the neuroblastoma-amplified gene product as a component of the syntaxin 18 complex implicated in Golgi-to-endoplasmic reticulum retrograde transport. , 2009, Molecular biology of the cell.

[8]  W. Bernal,et al.  Update on acute liver failure , 2015, Current opinion in critical care.

[9]  Thomas Meitinger,et al.  Biallelic Mutations in NBAS Cause Recurrent Acute Liver Failure with Onset in Infancy , 2015, American journal of human genetics.

[10]  E. Chouery,et al.  Developmental delay, dysmorphic features, neonatal spontaneous fractures, wrinkled skin, and hepatic failure: A new metabolic syndrome? , 2008, American journal of medical genetics. Part A.

[11]  Gustavo Boldrini,et al.  Management and Prognosis of Acute Liver Failure in Children , 2012, Current Gastroenterology Reports.

[12]  Osamu Onodera,et al.  Neuroblastoma amplified sequence gene is associated with a novel short stature syndrome characterised by optic nerve atrophy and Pelger–Huët anomaly , 2010, Journal of Medical Genetics.

[13]  Robert W. Taylor,et al.  Recurrent acute liver failure due to NBAS deficiency: phenotypic spectrum, disease mechanisms, and therapeutic concepts , 2016, Journal of Inherited Metabolic Disease.

[14]  D. Jain,et al.  Individual exome analysis in diagnosis and management of paediatric liver failure of indeterminate aetiology. , 2014, Journal of hepatology.