Medical Student Medical University of South Carolina, United States
Introduction : Hypophosphatasia (HPP) is a rare disease characterized by low activity of tissue nonspecific alkaline phosphatase (TNAP) due to loss-of-function mutations in the alkaline phosphatase (ALPL) gene. We present a unique case of a patient who was incidentally noted to have a pathogenic mutation in the ALPL gene found on a salivary DNA test performed by an online ancestry service.
Case(s) Description : A 20 year old woman with complaints of chronic fatigue and musculoskeletal pain due to scoliosis and hip pseudoarthrosis was referred to our endocrinology clinic for evaluation of recurrent low serum ALP in 2022. She recalled losing two primary teeth with roots intact at an early age but denied a history of recurrent dental issues or pathological fractures. Interestingly, the patient had submitted salivary DNA to an ancestry service in 2016 and was incidentally found to be a carrier for a c.1250A >G mutation of the ALPL gene that is pathogenic for perinatal HPP. Patient underwent extensive diagnostic lab work which revealed a low serum ALP 21 U/L (normal 35-104), low bone specific ALP 4.5 ug/L (normal 7.7-16.8) and high vitamin B6 167.1 ug/L (normal 3.4-65.2). Other testing revealed normal serum values of calcium, parathyroid hormone, phosphorus, magnesium, zinc, copper, ceruloplasmin, vitamin B12, folate, iron panel, thyroid stimulating hormone, complete blood count, renal and liver panels. Dual x-ray absorptiometry (DEXA) scan revealed normal bone density for age. Asfotase alfa is an enzyme replacement therapy approved for treatment of HPP but given our patient’s current asymptomatic status, this treatment is not indicated at this time. Clinical symptoms of HPP were reviewed and the importance of regular dental care and avoiding bisphosphonates was emphasized. Genetic counseling for the patient and her family was recommended.
Discussion : HPP is a rare bone disease with an incidence of 1 per 100,000 and is often identified by low ALP in lab work-up following repetitive or low impact stress fractures. Asymptomatic patients will benefit from close monitoring to assist in clinical decision making. Patient education should focus on recognizing clinical symptoms, maintaining dental hygiene, and avoiding bisphosphonates. This is a case in which ancestry testing was able to identify a pathogenic mutation associated with HPP before any clinical phenotype was expressed, showcasing potential clinical utility of such testing. Additionally, this case emphasizes the importance of diagnostic work-up following low ALP facilitating early identification of HPP and treatment to prevent bone demineralization, reducing lifelong morbidity.
.jpg "Delaney N. Walden, BSC (she/her/hers) photo")