Confirmation of CAGSSS syndrome as a distinct entity in a Danish patient with a novel homozygous mutation in IARS2.
Since the original description of the IARS2-related cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, skeletal dysplasia syndrome (CAGSSS; OMIM 616007) in an extended consanguineous family of French-Canadian descent, no further patients have been reported. IARS2 (OMIM 612801) encodes the mitochondrial isoleucine-tRNA synthetase which belongs to the class-I aminoacyl-tRNA synthetase family, and has been implicated in CAGSSS and a form of Leigh syndrome. Here, we report on a female Danish patient with a novel homozygous IARS2 mutation, p.Gly874Arg, who presented at birth with bilateral hip dislocation and short stature. At 3 months, additional dysmorphic features were noted and at 18 months her radiographic skeletal abnormalities were suggestive of an underlying spondyloepimetaphyseal dysplasia (SEMD). Retrospective analysis of the neonatal radiographs confirmed that the skeletal changes were present at birth. It was only with time that several of the other manifestations of the CAGSSS emerged, namely, cataracts, peripheral neuropathy, and hearing loss. Growth hormone deficiency has not (yet) manifested. We present her clinical features and particularly highlight her skeletal findings, which confirm the presence of a primary SEMD skeletal dysplasia in a growing list of mitochondrial-related disorders including CAGSSS, CODAS, EVEN-PLUS, and X-linked SEMD-MR syndromes.
Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany.
Shahida
S
Moosa
Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark.|Regional Hospital West, Center for Research and Education, Herning, Denmark.
Annette
A
Haagerup
Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark.|Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.
Pernille Axel
PA
Gregersen
Department of Radiology, Aarhus University Hospital, Aarhus, Denmark.
Karin Kastberg
KK
Petersen
Institute of Human Genetics, University of Cologne, Cologne, Germany.|Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
Janine
J
Altmüller
Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
Holger
H
Thiele
Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
Peter
P
Nürnberg
Division of Pediatric Orthopaedics, Seoul National University Children's Hospital, Seoul, Republic of Korea.
Tae-Joon
TJ
Cho
Department of Radiology, Woorisoa Children's Hospital, Seoul, Republic of Korea.
Ok-Hwa
OH
Kim
Department of Pediatric Imaging, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.
Gen
G
Nishimura
Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany.
Bernd
B
Wollnik
Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.
Ida
I
Vogel
D002386:Cataract / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D002648:Child; D059472:Exome; D005260:Female; D015870:Gene Expression; D040181:Genetic Diseases, X-Linked / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D013006:Growth Hormone / Q000172:deficiency*; D006319:Hearing Loss, Sensorineural / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D007533:Isoleucine-tRNA Ligase / Q000235:genetics*; D009154:Mutation; D010009:Osteochondrodysplasias / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D011859:Radiography; D013577:Syndrome
D013006:Growth Hormone; D007533:Isoleucine-tRNA Ligase
CAGSSS; IARS2; SEMD; mitochondrial disorder; skeletal dysplasia