Endocrine Abstracts

Background: Recent advances in next-generation sequencing technology have greatly increased the number of Variants of Uncertain Significance (VUS) encountered in clinical practice. Herein, we present difficulty in diagnostic path and challenges in a premenopausal woman with an unusual fracture history and osteoporosis.

Clinical Case: A 37-year-old Thai woman with no known underlying disease was diagnosed with osteoporosis (a BMD Z-score of -2.6 at femoral neck) after having developed left proximal fracture femur from a slip and fall accident 6 months earlier. The patient came to see us for further treatments of early-onset osteoporosis. Additional history revealed that intramuscular DMPA injection was continuously used for 7 years as a hormonal contraceptive. Initial work-up for secondary osteoporosis at that time showed only low serum TSH level, vitamin D insufficiency (17 ng/ml), slightly elevated plasma iPTH level (70.5 pg/ml) with normal plasma alkaline phosphatase (ALP). The patient was started on a weekly oral bisphosphonate for 4 months before whole exome sequencing to investigate monogenic bone disorders revealed a rare heterozygous variant c.1069C>T (p.Arg357Trp) of the ALPL gene which could cause adult-onset hypophosphatasia (HPP). However, this variant was classified as VUS by the ACMG guidelines. Based on the very low allele frequency from gnomAD, the possibility of pathogenicity of this variant could not be excluded. However, additional testing revealed normal plasma pyridoxal 5′-phosphate (an ALP substrate) together with her history of prolonged use of DMPA which could have adverse bone effects from hypoestrogenism and its glucocorticoid effect did not support the diagnosis of HPP. Extended family members testing to determine whether the variant is shared by other unaffected individuals showed the patient inherited this variant from her mother and her brother without history of fracture also carries this variant. As a result, the possibility of HPP had been disregarded. At follow-up 3 months later, she developed avascular necrosis (AVN) of previous screw fixation at left femoral head and total hip arthroplasty was performed uneventfully.

Conclusions: Identification of rare ALPL VUS challenges in deciphering the clinical relevance whether this patient has HPP and bisphosphonate should be discontinued. The underrepresentation of non-European ancestry groups in current genomic databases complicates interpretation of their genetic test results. The patient’s clinical presentation remains the most important context for interpreting sequencing results. Our case also highlights the fracture risk from long-term use of DMPA which is widely used as progestogen-only contraceptive method in low and middle-income countries.