A case report of pycnodysostosis with atypical femur fracture diagnosed by next-generation sequencing of candidate genes.
BACKGROUND
Pycnodysostosis is a rare autosomal recessive skeletal dysplasia characterized by short stature, craniofacial dysmorphism, acro-osteolysis, osteosclerosis, and brittle bone with poor healing. Pycnodysostosis results from the deficient activity of cathepsin K, a lysosomal cysteine protease that is encoded by CTSK.


METHODS
We report a Korean adult patient with pycnodysostosis and atypical femur fracture whose diagnosis was confirmed by next-generation sequencing (NGS) of candidate genes. A 41-year-old female patient was presented with a left femur fracture after falling down. Underlying sclerotic bone disease was suspected as a radiographic skeletal survey showed thickened cortical bones, and the total body bone density was increased (T score was 5.3, and Z score was 4.9).


METHODS
We performed candidate gene sequencing of various sclerotic bone diseases for the differential molecular diagnosis of underlying sclerosing bone disease. Two heterozygous variants of CTSK were detected. One was a frameshift variant in exon 5, c.426delT (p.Phe142Leufs*19), which was previously reported, and the other was a novel missense variant in exon 6, c.755G>A (p.Ser252Asn). Sanger sequencing of CTSK confirmed the 2 heterozygous variants and thus the patient was diagnosed with pycnodysostosis.


METHODS
The patient had emergency surgery for subtrochantic femoral fracture.


RESULTS
After 4 months of surgery, the patient had almost a full range of hip and knee movements and radiographs show the substantial bridging callus across the fracture.


CONCLUSIONS
Candidate gene sequencing could be a useful diagnostic tool for the genetically heterogeneous skeletal dysplasia group, especially in cases with a mild or atypical clinical phenotype.
Department of Orthopedic Surgery Department of Medical Genetics Department of Endocrinology and Metabolism, Ajou University Hospital, Ajou University School of Medicine, Suwon Green Cross Genome, Yongin, Republic of Korea.
Hyung Keun
HK
Song
Young Bae
YB
Sohn
Yong Jun
YJ
Choi
Yoon-Sok
YS
Chung
Ja-Hyun
JH
Jang
D000058:Accidental Falls; D000328:Adult; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000601:surgery; D056657:Cathepsin K / Q000235:genetics*; D003937:Diagnosis, Differential; D005260:Female; D005264:Femoral Fractures / Q000175:diagnosis* / Q000209:etiology / Q000235:genetics* / Q000601:surgery; D016368:Frameshift Mutation; D006801:Humans; D020125:Mutation, Missense; D058631:Pycnodysostosis / Q000175:diagnosis* / Q000235:genetics*; D017421:Sequence Analysis
C534130:CTSK protein, human; D056657:Cathepsin K