Category: Calcium/Bone Disorders
To preset the case of a patient with the rare condition of hypophosphatasia (HPP) and the workup that led to the diagnosis.
Methods : We reviewed clinical and lab data.
A 49-year-old female, with no significant past medical history, was referred to endocrinology by sports medicine specialist to rule an underlying metabolic bone disease given recurrent stress fractures.
Patient was in her usual state of health until 2 years prior to presentation when she had a metatarsal stress fracture while running. She had been an avid runner for 7 years prior to that. Her stress fracture was attributed to high-volume running. However, over the next 24 months, she had 6 other fractures, including other metatarsal fractures, femoral fracture, and a rib fracture, all associated with minimal to no trauma. Patient denies having any dental problems and never had kidney stones. She has regular menstrual cycles. Family history is negative for bone disorders, but her son has had major dental problems since childhood.
Initial workup showed a normal serum creatinine, calcium, phosphorus, PTH, and vitamin D levels. A mild reduction in alkaline phosphatase (AP) of 31 U/L (33-115) was noted. Further workup revealed a low bone-specific AP of 3.3 mcg/L (5-18.2), elevated serum PLP (vitamin B6) twice the upper limit of normal at 52ng/mL (2.1-21.7), and a normal FGF23 level. Axial DXA scan was normal.
At this point, HPP was suspected. Genetic testing revealed a heterozygous mutation in the ALPL gene for a sequence variant defined as c.407G>A which is predicted to result in the amino acid substitution pArg136His. This variant was reported in patients affected with infantile HPP, odontoHPP, and adult HPP.
Once the diagnosis of HPP carrier was confirmed, the patient was advised to avoid strenuous high-impact exercise such as long-distance running. The enzyme replacement drug asfotase alfa was not recommended given the mild presentation and since it is FDA-approved for the treatment of perinatal, infantile, and juvenile-onset HPP only. She was referred to genetic counseling.
Given its rarity and subtle presentation, the diagnosis of adult-onset HPP was not straightforward and was made after patient sustained numerous fractures over the span of 2 years. Apart from the potential repercussions on her children, establishing the diagnosis of HPP had implications on her training regimen and therapy options.
The diagnosis of HPP requires a high index of suspicion given its rarity. Once the diagnosis is made, treatment options remain limited especially in patients with adult-onset HPP. Future research is necessary to determine the efficacy and safety of treatment with asfotase alfa in adults.
University of Florida
Second-year clinical fellow in the division of Endocrinology and Metabolism at the University of Florida.
Assistant Professor of Medicine
University of Florida, Florida
Dr. Diana Barb received her medical degree from the University of Medicine and Pharmacy in Targu Mures Romania. She did a two year research fellowship, focusing on obesity, adiponectin and cancer at Beth Israel Deaconess Medical Center, Harvard Medical School in Boston, Massachusetts, followed by an Internship, Internal Medicine Residency and Endocrinology Fellowship at Emory University in Atlanta, Georgia. Subsequently, she joined the University of Florida as a Clinical Assistant Professor in the Division of Endocrinology, Diabetes & Metabolism.