We previously reported exome sequencing in a short-rib thoracic dystrophy (SRTD) cohort, in whom recessive mutations were identified in SRTD-associated genes in 10 of 11 cases. A heterozygous stop mutation in the known SRTD gene WDR60 was identified in the remaining case; no novel candidate gene/s were suggested by homozygous/compound heterozygous analysis. This case was thus considered unsolved. Re-analysis following an analysis pipeline update identified a homozygous mutation in C21orf2 (c.218G > C; p.Arg73Pro). This homozygous variant was previously removed at the quality control stage by the default GATK parameter \"in-breeding co-efficient.\" C21orf2 was recently associated with both Jeune asphyxiating thoracic dystrophy (JATD) and axial spondylometaphyseal dysplasia (axial SMD); this particular mutation was reported in homozygous and compound heterozygous state in both conditions. Our case has phenotypic features of both JATD and axial SMD; and the extent of thoracic involvement appears more severe than in other C21orf2-positive cases. Identification of a homozygous C21orf2 mutation in this case emphasizes the value of exome sequencing for simultaneously screening known genes and identifying novel genes. Additionally, it highlights the importance of re-interrogating data both as novel gene associations are identified and as analysis pipelines are refined. Finally, the severity of thoracic restriction in this case adds to the phenotypic spectrum attributable to C21orf2 mutations.

BACKGROUND: The Kozlowski type of spondylometaphyseal dysplasia (SMD-K) is characterized by vertebral and metaphyseal abnormalities. The longitudinal evolution of thoracolumbar kyphosis associated with vertebral anomalies in SMD-K is unclear.
OBJECTIVE: To document the longitudinal changes in sagittal alignment and vertebral morphology in a patient with SMD-K treated nonoperatively with a Milwaukee brace.
METHODS: Case report.
METHODS: Patient with SMD-K having multiple vertebral anomalies and a thoracolumbar kyphosis.
METHODS: A girl with SMD-K seen initially at 21 months old was followed for 14 years. She presented with thoracolumbar kyphosis associated with multiple vertebral anomalies consisting primarily of hypoplasia at L1, beaking at L2, and ovoid shape of adjacent vertebrae. The patient was treated with a Milwaukee brace and followed until she was 16 years old.
RESULTS: After initiation of brace treatment, the thoracolumbar kyphosis gradually resolved and she had a normal sagittal alignment at last follow-up. Normal vertebral morphology was also completely restored in the sagittal plane. The patient developed a main thoracic scoliosis that did not require additional treatment.
CONCLUSIONS: Nonoperative treatment with bracing can be attempted in patients with SMD-K affected by thoracolumbar kyphosis and multiple vertebral anomalies, because full restoration of normal sagittal alignment and vertebral morphology is possible.