An Unexpected Hurdle in the Race: Hypophosphatasia Unmasked By the Female Athlete Triad

Presentation Number: LB MON 45
Date of Presentation: April 3rd, 2017

Karin Katz*, Rosa Pasculli, Yelena Karbinovskaya, Nidhi Agrawal and Dorothy A. Fink
New York University Langone Medical Center, New York, NY


Background: In a young woman with bone pain and repeated stress fractures, the female athlete triad unmasked a rare genetic disorder, hypophosphatasia, which impairs bone mineralization and up until recently had no definitive therapy.

Clinical case: A 20-year female division 1 cross-country runner was referred for evaluation of bone health in the setting of three metatarsal stress fractures over three months. She had normal developmental milestones and no premature loss of teeth. She noted painful shins after prolonged standing since age 9. Menarche was at age 13, followed by irregular cycles for which she started oral contraceptives at age 16. She joined the cross-country team in college and increased her running during her sophomore year, up to 60 miles per week. She also initiated a vegetarian diet at this time.

On presentation, she had a left second metatarsal fracture and a right second and third metatarsal fracture with delayed healing. On exam, her BMI was 19.5 kg/m2. She was thin and had tenderness to palpation over her right third metatarsal joint. Laboratory evaluation was notable for an undetectable alkaline phosphatase <25 (normal: 39-117 U/L), calcium 9.5 (normal: 8.3-10.3 mg/dL), phosphorus 3.9 (normal: 2.5-4.5 mg/dL), and PTH 10 (normal: 15-75 pg/mL). Repeat labs showed an undetectable alkaline phosphatase with vitamin B6 of 195.9 (normal: 20-125 nmol/L). A bone density scan revealed a Z-score of -1.6 in the lumbar spine, 0.2 in the left femoral neck, and 1.0 in the right femoral neck. Based on this evaluation, there was high suspicion for hypophosphatasia. A TNSALP mutation analysis was sent and the gene analysis report showed an ALPL exon 4 heterozygous mutation.

The patient met with a nutritionist to discuss energy intake and balance, and three months after her first visit gained weight and her BMI improved to 20.7 kg/m2. She initiated treatment with asfotase alpha and was able to complete her cross-country season.

Conclusion: In this patient with bone pain, irregular menstruation and early bone loss, her initial symptoms were attributed to an energy imbalance in the setting of her intense exercise and vegetarian diet. It is likely that her new lifestyle unmasked her underlying metabolic bone disease. Adult hypophosphatasia is a rare, heterogeneous disease that may present with a variety of symptoms. While treatment was previously directed towards treating the symptoms of hypophosphatasia, enzyme replacement with asfotase alpha is a new therapy that may improve bone health and improve quality of life.


Nothing to Disclose: KK, RP, YK, NA, DAF