Two novel COL2A1 mutations associated with a Legg-Calvé-Perthes disease-like presentation

Abstract

Background: Abnormal development and growth of the capital femoral epiphysis and acetabulum are associated with a wide variety of underlying etiologies, one of which is Legg-Calvé-Perthes disease.

Case description: We report the cases of two children who presented with abnormal development of both hips and in whom novel mutations in the COL2A1 gene were found. These cases illustrate the importance of identifying individuals with a type II collagen abnormality, as it informs management, allows investigation for other complications, and provides the opportunity for accurate genetic counseling and consideration of other family members who might be at risk.

Literature review: The literature documents numerous private mutations in COL2A1 associated with diverse clinical phenotypes including bilateral hip dysplasia and premature osteoarthritis. Some of these mutations are associated with a joint-specific phenotype but few other skeletal or extraskeletal manifestations. Only careful clinical examination of children presenting with hip anomalies therefore will reveal additional findings that warrant an evaluation by a clinical geneticist. DNA mutation analysis may be useful for making a specific diagnosis and identifying other at-risk family members.

Purposes and clinical relevance: The purpose of our report is to alert clinicians to the possibility that children who present with bilateral Perthes-like disease of the hip might have an underlying mutation in the gene encoding type II collagen. It is important to consider this in the differential diagnosis and workup of such children as it has specific prognostic, clinical, genetic counseling, and reproductive sequelae.

Fig. 1A–F

(A) An AP radiograph shows the patient’s pelvis and lower spine at age 5.5 years. Abnormalities of the proximal femoral epiphyses, which are more pronounced on the right than on the left are seen. (B) There was no evidence of platyspondyly. (C) The left proximal humeral epiphysis was flattened with an unusual convex appearance. (D) No abnormalities of the hand were seen on an AP radiograph. (E) An AP view of the left knee shows mild broadening of the distal femoral and proximal tibial metaphyses and broad, flattened epiphyses at the knees. (F) A left lateral knee radiograph shows delayed ossification of the left patella.

Fig. 2A–B

(A) An AP radiograph of the pelvis of Patient 2, aged 2 years 9 months, show bilateral dysplastic changes of the hips. (B) No evidence of platyspondyly is seen on this radiograph but the vertebral end plates were ragged.