case report A rare mutation in hypophosphatasia: a case report of adult form and review of the literature 1 Department of Internal Medicine, 1 2 3 Hospital General Universitario Francisco Galeano-Valle , Jaime Vengoechea , Rodolfo J. Galindo Gregorio Marañón, Madrid, Spain; Instituto de investigación Sanitaria Gregorio Marañón, Madrid, Spain 2 Emory University School SUMMARY of Medicine, Departments of Human Genetics and Hypophosphatasia is a rare inborn error of metabolism characterized by low serum alkaline Medicine, Atlanta, GA, USA phosphatase activity due to loss-of-function mutations in the gene encoding the tissue-nonspecific 3 Emory University School isoenzyme of alkaline phosphatase (TNSALP). Extracellular accumulation of TNSALP substrates of Medicine, Diabetes and leads to dento-osseous and arthritic complications featuring tooth loss, rickets or osteomalacia, and Endocrinology Section, calcific arthopathies. Mild hypophosphatasia usually has autosomal dominant inheritance, severe Atlanta, GA, USA cases are either autosomal recessive or due to a dominant negative effect. Clinical manifestations Correspondence to: of hypophosphatasia are extremely variable, ranging from life threatening to asymptomatic clinical Rodolfo J. Galindo presentations. The clinical presentation of the adult-onset hypophosphatasia is highly variable. Emory University School of Medicine, Division of Endocrinology, Fractures, joint complications of chondrocalcinosis, calcifying polyarthritis and multiple pains may Diabetes and Metabolism reveal minor forms of the disease in adults. It is important to recognize the disease to provide the 69 Jesse Hill Jr. Dr., best supportive treatment and to prevent the use of anti-resorption drugs in these patients. Bone- Glenn Bld, Suite 202 30303 – Atlanta, GA, USA targeted enzyme-replacement therapy (asfotase alfa) was approved in 2015 to treat pediatric- [email protected] onset hypophosphatasia. We present a case of a 41-year-old male diagnosed with adult form of hypophosphatasia with a rare ALPL mutation that has been previously described only once and Received on Aug/26/2018 Accepted on Dec/11/2018 review the literature on the adult form of the disease and its genetic mechanism. Arch Endocrinol Metab. 2019;63(1):89-93 DOI: 10.20945/2359-3997000000108 INTRODUCTION forms were estimated at 1/300,000 and 1/6,370 patients in Europe, respectively (3). Clinical ypophosphatasia (OMIM 146300, 241500, manifestations of hypophosphatasia are extremely 241510) is a rare inborn error of metabolism H variable and seven major clinical forms are identified. characterized by low serum alkaline phosphatase Fractures, joint complications of chondrocalcinosis, (ALP) activity (hypophosphatasaemia) due to calcifying polyarthritis and multiple pains may reveal lossoffunction mutations within the gene that encodes minor forms of the disease in adults. It is important the tissue-nonspecific isoenzyme of ALP ALPL( ). to recognize the disease to provide the best treatment, In hypophosphatasia, extracellular accumulation of to prevent fractures, which are frequently complicated ALP substrates, including inorganic pyrophosphate, and associated with pseudarthrosis. Moreover, it’s an inhibitor of mineralization, explains the dento- extremely important to prevent the inappropriate use osseous and arthritic complications featuring tooth of anti-resorption drugs, frequently prescribed for loss, rickets or osteomalacia, and calcific arthropathies the fractures related to bone fragility, and attributed (1). In mild hypophosphatasia, there is functional loss to primary osteoporosis in these patients (1,4-6). of one of the copies of the gene, leading to autosomal Bone-targeted enzyme-replacement therapy with dominant inheritance. In severe hypophosphatasia, the asfotase alfa was approved in 2015 to treat pediatric- mutations affect both alleles of the gene. This could be onset hypophosphatasia. Currently, there is no well- through autosomal recessive transmission or because established treatment available for the correction of the of an autosomal dominant mutation with a dominant bone fragility in adult hypophosphatasia. We present a negative effect, in which the gene product from one case of a 41-year-old male diagnosed with adult form of AE&M all rights reserved. allele interferes with homo-dimerization (2). The hypophosphatasia with a rare ALPL gene mutation that © prevalence of severe and moderate hypophosphatasia has been previously described only once and review Copyright Arch Endocrinol Metab. 2019;63/1 89 Adult-onset hypophosphatasia the literature on the adult form of the disease and its ALPL gene (NM_000478.5) Sanger sequencing was genetic mechanism. performed at a CLIA-certified molecular diagnostic lab (Prevention Genetics, Marshfield, Wisconsin, USA). This showed that the patient was heterozygous for a CASE REPORT pathogenic variant, c.1474del, which is predicted to A 41-year-old Caucasian male presented to the result in a frameshift and premature protein termination endocrinology clinic with a long standing history (p.Ala492Profs*29). The classification as pathogenic of asthenia, constipation and depressed mood. was established by the clinical laboratory according to Additionally, the patient related he had right lower the 2015 ACMG/AMP guidelines. The diagnosis of ribs pain for several months. He denied any history of autosomal dominant hypophosphatasia (adult form) fractures, teeth loss, cavities, muscle pain, intellectual was made. The patient was not enable to use enzyme disability or vitamin supplementation. He had a family replacement therapy (ERT) and the current treatment history of premenopausal osteoporosis in several family is basically symptomatic (analgesics, antidepressants), members, with poor response to bisphosphonates, and focused on maintaining 25(OH)D within normal and fractures. In addition, the patient had one sister range and regular supervision by a multidisciplinary with long-term decreased plasmatic ALP during team including a dentist. adulthood, fractures and poor dentition (Figure 1). Physical examination revealed slight lack of enamel in teeth. Plasmatic calcium, phosphate, magnesium, DISCUSSION thyroid and parathyroid hormone, kidney function, The first case of hypophosphatasia was reported in albumin and 25-hydroxyvitamin D (25(OH)D) were 1948 by J. C. Rathbun (7) and the first identified ALPL normal. Historical test results revealed decreased ALP mutation was reported in 1988 (8). In humans, four for at least 2 years, ranging 18-20 U/L (normal range genes account for ALP. Three genes encode the tissue- 45-115 U/L). Bone-specific ALP was 4.8 μg/L specific intestinal, placental and germ-cell ALP, whereas (normal range in males 6.5-20.1 μg/L). Vitamin B6 was the fourth gene, ALPL, encodes TNSALP, which is 328.7 nmol/L (normal range 20-125 nmol/L). Vitamin abundant in the skeleton, liver, kidney and developing A, B1, B2, B3, B5 and B12 were normal. Radiograph of teeth. TNSALP is actually a family of isoforms that differ the ribs did not reveal abnormalities. Kidneys ultrasound by post-translational modifications. Homodimerization showed normal kidneys. After genetic counseling, of TNSALP monomers is required for catalytic 78 83 90 91 Suicide Diverticulitis Multiple medical Osteoporosis problerns Knee injury at 40 HTN HTN Depression 62 62 Osteoporosis Osteoporosis Rotator Rotator 50 T2DM Osteoporosis cuff injury cuff injury Knee replacernent 20 34 39 41 Depression Asymptomatic Long standing Costal pain decreased ALP asthenia, constipation, Fractures, poor depressed mood dentition 6 4 5 rnonths Asymptomatic Poor dentition AE&M all rights reserved. © Asymptomatic Copyright Figure 1. Pedigree of the patient’s family. HTN: hypertension; ALP: alkaline phosphatase; T2DM: type 2 diabetes mellitus. 90 Arch Endocrinol Metab. 2019;63/1 Adult-onset hypophosphatasia activity (9). ALPs circulate as soluble homodimers in adulthood occurred at a median age of 44 years that are cleared by the liver (10). There is deficiency and the median age at diagnosis was 49 years. At the of all TNSALP isoforms in hypophosphatasia (9). The time of presentation, one third of patients appeared prevalence of severe and moderate hypophosphatasia asymptomatic (12). forms were estimated at 1/300,000 and 1/6,370 Hypophosphatasia has been diagnosed traditionally respectively in the European population (3). when persistent hypophosphatasemia matches a medical Three TNSALP phosphocompound substrates history, physical examination, routine laboratory accumulate extracellulary in hypophosphatasia: studies, and radiographic findings consistent with the both phosphoethanolamine (PEA) and inorganic diagnosis. The degree of hypophosphatasemia and pyrophosphate (PPi) in urine and blood and pyridoxal TNSALP substrate accumulation generally reflects the 5’-phosphate (PLP) in plasma which is the active form severity of hypophosphatasia (1,6). TNSALP substrate of vitamin B6 and a cofactor for several enzymatic excess in hypophosphatasia is marked with greatest reactions including neurotransmitters (1). PPi is a potent sensitivity and specificity by elevated serum PLP (1,7). inhibitor of mineralization and its superabundance ALPL gene analysis is expected to reveal a defect in leads to the impairment of hydroxyapatite crystal all patients with hypophosphatasia (2). Although formation and growth, thereby producing rickets and persistent hypophosphatasaemia is the hallmark for the osteomalacia, respectively in children and adults, and diagnosis