NBAS mutations cause a multisystem disorder involving bone, connective tissue, liver, immune system, and retina.
We report two unrelated patients with a multisystem disease involving liver, eye, immune system, connective tissue, and bone, caused by biallelic mutations in the neuroblastoma amplified sequence (NBAS) gene. Both presented as infants with recurrent episodes triggered by fever with vomiting, dehydration, and elevated transaminases. They had frequent infections, hypogammaglobulinemia, reduced natural killer cells, and the Pelger-Huët anomaly of their granulocytes. Their facial features were similar with a pointed chin and proptosis; loose skin and reduced subcutaneous fat gave them a progeroid appearance. Skeletal features included short stature, slender bones, epiphyseal dysplasia with multiple phalangeal pseudo-epiphyses, and small C1-C2 vertebrae causing cervical instability and myelopathy. Retinal dystrophy and optic atrophy were present in one patient. NBAS is a component of the synthaxin-18 complex and is involved in nonsense-mediated mRNA decay control. Putative loss-of-function mutations in NBAS are already known to cause disease in humans. A specific founder mutation has been associated with short stature, optic nerve atrophy and Pelger-Huët anomaly of granulocytes (SOPH) in the Siberian Yakut population. A more recent report associates NBAS mutations with recurrent acute liver failure in infancy in a group of patients of European descent. Our observations indicate that the phenotypic spectrum of NBAS deficiency is wider than previously known and includes skeletal, hepatic, metabolic, and immunologic aspects. Early recognition of the skeletal phenotype is important for preventive management of cervical instability.
Center for Molecular Diseases, Lausanne University Hospital, Lausanne, Switzerland.
Nuria Garcia
NG
Segarra
Center for Molecular Diseases, Lausanne University Hospital, Lausanne, Switzerland.
Diana
D
Ballhausen
Clinical Metabolic Genetics, Cook Children's Health Care System, Fort Worth, Texas, USA.
Heather
H
Crawford
Division of Immunology and Allergy, Lausanne University Hospital, Lausanne, Switzerland.
Matthieu
M
Perreau
Center for Molecular Diseases, Lausanne University Hospital, Lausanne, Switzerland.
Belinda
B
Campos-Xavier
Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
Karin
K
van Spaendonck-Zwarts
VitaK and Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands.
Cees
C
Vermeer
Pediatric Service, Centre Hospitalier du Centre Valais, Sion, Switzerland.
Michel
M
Russo
Service of Pediatric Surgery, Lausanne University Hospital, Lausanne, Switzerland.
Pierre-Yves
PY
Zambelli
Vital-IT group, Swiss Institute of Bioinformatics, University of Lausanne, Switzerland.
Brian
B
Stevenson
Department of Medical Genetics, Lausanne University Hospital, Lausanne, Switzerland.
Beryl
B
Royer-Bertrand
Department of Medical Genetics, Lausanne University Hospital, Lausanne, Switzerland.
Carlo
C
Rivolta
Division of Immunology and Allergy, Lausanne University Hospital, Lausanne, Switzerland.
Fabio
F
Candotti
Department of Medical Genetics, Lausanne University Hospital, Lausanne, Switzerland.
Sheila
S
Unger
Jules-Gonin Eye Hospital, Lausanne, Switzerland.
Francis L
FL
Munier
Department of Pediatrics, Lausanne University Hospital, Lausanne, Switzerland.
Andrea
A
Superti-Furga
Center for Molecular Diseases, Lausanne University Hospital, Lausanne, Switzerland.
Luisa
L
Bonafé
D000015:Abnormalities, Multiple / Q000209:etiology / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007107:Immune System / Q000503:physiopathology; D007223:Infant; D008107:Liver Diseases / Q000235:genetics; D008297:Male; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D009896:Optic Atrophy / Q000235:genetics; D010381:Pelger-Huet Anomaly / Q000209:etiology; D011247:Pregnancy; D012160:Retina / Q000473:pathology; D012867:Skin / Q000473:pathology
C117339:NBAS protein, human; D009363:Neoplasm Proteins
NBAS; Pelger-Huët anomaly; cervical instability; fatty acid oxidation; immunodeficiency; liver disease; optic atrophy; retinal dystrophy; skeletal dysplasia; transaminase