Category: Calcium/Bone Disorders
Objective : Hypophosphatasia (HPP) is characterized by defective mineralization of bone due to low activity of serum bone alkaline phosphatase. Adult forms are characterized by stress fractures and pseudofractures of the lower extremities and early loss of adult dentition. Here we present a case of adult HPP with a novel variant of the ALPL gene (p.Ala105Asp) who initially presented with an elevated Vitamin B6.
Methods : A 59-year old male with past medical history of chronic pain, polyarthralgia, multiple tendon/muscle tears, severe periodontal disease, requiring multiple fillings and crowns since his early 20s, and calcium pyrophosphate deposition disease (CPPD) presents with progressively worsening peripheral neuropathy in his feet and elevated vitamin B6. He has a left fifth metatarsal small avulsion non-healing fracture and old left non-union tibial sesamoid fracture with loss of physical function impacting ADLs, requiring assistance with mobility. Vitamin B6 was 127.7 ng/mL [2.1-21.7 ng/mL] and alkaline phosphatase was 18 U/L [53-128 U/L].
Results : Genetic testing was done, revealing a heterozygous variant of ALPL gene (p.Ala105Asp). He has 3 family members with variants of ALPL gene and have since been diagnosed with hypophosphatasia. Rest of the family are asymptomatic. The patient is currently undergoing evaluation for treatment with recombinant alkaline phosphatase, asfotase alfa.
Discussion : Adult HPP may be inherited in an autosomal recessive or autosomal dominant manner, depending on the effect that the ALPL pathogenic variant has on TNSALP activity. Heterozygotes (carriers) are either asymptomatic (may manifest biochemically but not clinically) or symptomatic. This patient had a heterozygous variant in the ALPL gene (p.Ala105Asp), which, to our knowledge, has not been reported in association with ALPL-related conditions, however other variants flanking this position in the gene (p. Asn102_Asn104del, p.G1n106His) have been associated with adult, perinatal, and infantile HPP, suggesting a change at this position adversely affects protein structure and/or function. Furthermore, this variant has not been reported in the broad dataset (individuals without severe childhood onset disease).
Conclusion : Adult HPP is a rare disorder that is often underdiagnosed due to varying nonspecific symptoms. Awareness of the disease and identification of patients who have findings such as elevated vitamin B6 and low alkaline phosphatase is essential prior to confirming diagnosis with genetic testing. Diagnosis is paramount as patients with this disorder can now be treated with recombinant alkaline phosphatase. This case was remarkable as this patient has a heterozygous novel variant in the ALPL gene (p.Ala105Asp).
Gauri Behari– Endocrinology Fellow, University of Arizona College of Medicine Phoenix, Phoenix, Arizona
Ricardo Correa– Endocrinology, diabetes and metabolism fellowship director, University of Arizona College of Medicine-Phoenix and Phoenix VA, Phoenix, Arizona
University of Arizona College of Medicine Phoenix
Endocrinology, diabetes and metabolism fellowship director
University of Arizona College of Medicine-Phoenix and Phoenix VA
Ricardo Correa, M.D., Es. D., F.A.C.P., C.M.Q. is an Assistant Professor of Medicine and Program Director for the Endocrinology, Diabetes and Metabolism of the University of Arizona College of Medicine-Phoenix and the Warren Alpert Medical School of Brown University in the department of Endocrinology, Diabetes and Metabolism. He is the chair of the young physician subcommittee of the American Association of Clinical Endocrinologist (YPS-AACE). Also he is editor of Dynamed and outreach unit director of Endotext.org and Thyroid manager and editorial board of multiple endocrine and internal medicine journals.
He completed his Medical School and Education Master at University of Panama. He completed a research fellowship in Epidemiology and Tropical disease at ICGES in Panama City and his internal medicine residency at Jackson Memorial hospital-University of Miami (UM) program. In 2012, he was honored with the AOA and GoldDOC Award from the UM. Then he pursued his clinical and research fellowship in endocrinology with special focus in neuroendocrinology and adrenals at National Institute of Health.
He was trained in Evidence-based Medicine at McMaster University in Canada and in Editorial process and OJS by LATINDEX. He is co-director of the Panamanian Cochrane Center and EBM advocate.
Dr. Correa has been involved in organized medicine since medical school. He has been scientific committee chair and vice speaker for the AMA-RFS, chair of the CoA for the ACP FC, Board of Trustee of the Maryland Medical Society, National Secretary of the CoA for the NHMA, Regional Vice President of the CIR, Medical Education Officer of JDN-WMA. He has been involved with local, regional and national organization in the area of medical education, leadership and physician wellbeing including the AMA joy in medicine organization, ACGME at different level including the duty hour task force, NBME as part of the board, NBPAS and other organization.
At AACE and ACE and Endocrine Society, Dr. Correa has occupied different position from been the fellow-in-training board of director member to member and advisor of multiple committees throughout the years.
Dr. Correa has been involved in multiple academic, scientific and educational activities including article Consultant, Interpretation of the Medical Literature Project, NBME, International Committee member of the Committee on publications ethics (COPE), World Association of Medical Editors, Deputy Editor of International Archives of Medicine, Editorial board and peer reviewer of multiple journals including Annals of Public Health, PAHO journal, SGIM journal, International Journal of Endocrinology, International Journal of Diabetes, International Journal of Clinical Cases and Images, International journal of case reports, etc. Also he is consultant for Latinamerican science center including Bolivia and Panama national science department.
He is board certified in Medical Quality. He is the author of the book title “Case report: basics and publication”. His research is focus on neuroendocrinology mainly on pituitary and adrenal tumor and new genetic mutations.