Abstract #1178966: A Rare Case of Idiopathic Osteoporosis with COL10A1 and COL27A1 Genetic Mutations in a Premenopausal Woman

Abstract

The association between bone mineral density (BMD) and fracture differs in premenopausal women when compared to the postmenopausal women. Irrespective of the BMD, any fragility fracture in those aged 20-50 requires evaluation for secondary causes of osteoporosis. In the absence of secondary causes, idiopathic osteoporosis (IOP) is considered. We present a case of a premenopausal woman with IOP whose mutational analysis revealed variants in COL10A1 and COL27A1. These genetic mutations are found in Schmid-type metaphyseal chondrodysplasia (SMCD) and Steel syndrome, respectively. To our knowledge, this is the first case report establishing a linkage between these specific mutations and IOP. A 36-year-old Hispanic woman with a history of fragility fracture of the lumbar spine at age 23 was referred to Endocrinology for further evaluation. Dual-energy x-ray absorptiometry (DEXA) reported a Z-score of -3.0 in L1-L4, consistent with osteoporosis of the lumbar spine. A careful history, physical examination, and laboratory evaluation ruled out secondary causes of osteoporosis. In the interim, the patient presented a recurrent fragility fracture of the left proximal humerus requiring surgical intervention where bone marrow (BM) was obtained for cytology. BM cytology was found normocellular without increase in blasts or lymphocytes. Notably, the mutational analysis revealed heterozygous variants of uncertain significance (VUS) in COL10A1 [variant c682 c >T (p.Pro228Ser)] and COL27A1 [variant c.1814 c >T (p.Thr 6605 Met)]. Whole exome sequencing was not able to be performed due to insurance issues. The most common secondary causes of premenopausal bone loss include estrogen deficiency as seen in hypogonadism, drug exposure such as glucocorticoids, malabsorption disorders like celiac disease, hyperthyroidism, hypercalciuria, hyperparathyroidism, and disturbances in calcium and vitamin D metabolism. Osteoporosis with no known secondary causes is known as IOP. IOP is a disorder with multiple proposed mechanisms including impairment in growth hormone and insulin like growth factor axis, osteoblast dysfunction, and genetic mutations. Mutational analysis in selected IOP cases, have shown pathogenic variants and VUS in LRP5, LRP6, COL1A1, COL1A2, PLS3, WNT1, DKK1, FKBP10, HGD, SLC34A3. Our patient was found with heterozygous VUS in COL10A1 and COL27A1. These genetic mutations are found in (SMCD) and Steel syndrome, respectively. These rare osteochondrodysplasias, more commonly found in childhood, are associated with skeletal abnormalities including scoliosis, congenital hip dislocations, short stature, and characteristic facial features. More importantly, COL10A1 encodes the alpha 1 chain of collagen type X which is involved in growth plate function, and COL27A1 gene encodes a member of the fibrillar collagen family involved in the calcification of cartilage and the transition of cartilage to bone. To our knowledge, COL10A1 and COL27A1 mutations have not been yet associated as primary causes of IOP. We report this case aiming for further research to identify additional genetic etiologies of IOP.