低ホスファターゼ症

BACKGROUND: Alkaline phosphatase (ALP) plays an essential role in skeletal mineralization and bone metabolism. While elevated ALP levels are commonly investigated in clinical practice, persistently low ALP values are often overlooked despite their potential association with hypophosphatasia (HPP), a rare metabolic bone disorder caused by pathogenic variants in the ALPL gene. This study aimed to determine the prevalence and clinical characteristics of adults with persistently low ALP in a large tertiary care hospital. METHODS: We conducted a retrospective review of adult patients who underwent serum ALP testing at King Abdulaziz Medical City, Riyadh, between January 2017 and December 2024. Patients with ≥ 2 ALP measurements < 40 IU/L separated by at least 30 days were identified. Secondary causes of low ALP were excluded through review of clinical history, laboratory data, and medication records. Demographic, clinical, biochemical, and imaging data were analyzed. RESULTS: Among 243,362 adults with 928,403 ALP measurements, 7,307 patients (3.0%) had at least one ALP value < 40 IU/L. A total of 179 patients had ≥ 2 ALP measurements < 40 IU/L. After excluding 154 patients with secondary causes or incomplete data, 25 patients were identified with unexplained persistently low ALP (0.01% of the total tested population). The mean age was 52.2 years (range 18-92), and 68% were female. The mean nadir ALP was 30.2 IU/L. Musculoskeletal (MSK) symptoms (92%) and fatigue (79%) were the most common clinical manifestations, followed by dental abnormalities (50%), anxiety (33%), and depression (29%). Fractures were reported in 46% of patients, most commonly affecting the vertebrae, hips, and metatarsals. In subgroup analysis, patients with MSK symptoms had significantly lower nadir ALP levels (p = 0.021). Familial clustering of persistently low ALP was observed in 25% of patients. Notably, none of the reviewed electronic medical records documented recognition of persistently low ALP or consideration of hypophosphatasia. CONCLUSION: Persistently low ALP is uncommon but clinically relevant. Many affected patients demonstrated clinical features compatible with possible adult hypophosphatasia, and familial clustering suggests a possible genetic contribution. Greater awareness of this biochemical finding may improve recognition of potential HPP, prevent inappropriate antiresorptive therapy, and facilitate earlier diagnostic evaluation, including biochemical and genetic testing.

Hypophosphatasia (HPP) is a rare metabolic disorder caused by loss-of-function ALPL variants and characterized by heterogeneous skeletal and extra-skeletal manifestations. Although recent diagnostic criteria include ALPL variants, the diagnosis can be made based solely on clinical features. In adult-onset HPP, however, symptoms are often mild or nonspecific, including musculoskeletal symptoms and fatigue, making it difficult to differentiate from other conditions. This retrospective, cross-sectional study aimed to integrate genetic and biochemical data to enhance the clinical interpretation of low alkaline phosphatase (ALP) in patients with bone disorders. Among 865 consecutive adults visiting a bone-specialized outpatient department, patients with persistent hypophosphatasemia underwent ALPL sequencing. Clinical and biochemical characteristics were compared among three groups: biallelic or monoallelic variants with dominant-negative effect (DNE), monoallelic variants without DNE, and variant-negative individuals. Fifty-six patients (6.5%) showed persistent hypophosphatasemia. Two (0.2%) were compound heterozygotes, and 29 (3.4%) carried monoallelic variants without DNE. Clinical symptoms and secondary causes of hypophosphatasemia were similar between monoallelic without DNE and variant-negative patients, whereas serum ALP, urinary phosphoethanolamine (PEA), and plasma inorganic pyrophosphate (PPi) differed significantly. A model using thresholds of ALP < 35 IU/L, urinary PEA > 91 µmol/gCr, and plasma PPi > 1.96 µmol/L demonstrated high diagnostic performance for identifying patients with monoallelic variants without DNE. This study elucidated the complex clinical spectrum of patients with low ALP. Although clinical manifestations were comparable between monoallelic individuals without DNE and variant-negative individuals, distinct biochemical profiles were observed. Integrating genetic nosology into current diagnostic criteria may refine clinical decision-making.

Hypophosphatasia (HPP) is a rare osteometabolic disease. Enzyme replacement therapy (ERT) for HPP was approved in 2015 and has significantly improved the survival and quality of life of patients. Poor responses to ERT have been reported; however, detailed information is limited. We encountered a case of severe perinatal HPP refractory to ERT with neutralizing antibody (NAb) expression that possibly affected bone mineralization. Asfotase alfa (AA) (6 mg/kg/wk) was initiated 2 mo after birth and resulted in complete resolution of rickets by age 7 mo. However, rickets recurred at age 18 mo without any other identifiable cause than NAbs detected. The AA dose was increased to 9 mg/kg/wk based on the United States prescribing guidelines when the patient was age 3 yr. By ages 4 yr and 8 yr, rickets in the upper limbs and lower limbs, respectively, had nearly disappeared. NAbs were not detected at age 6 yr. We reduced the AA dose (6 mg/kg/wk) at age 8 yr. Rickets recurrence was not observed. Changes in bone mineralization corresponded to NAb expression, suggesting that NAbs may have influenced the therapeutic effect. The optimal AA dose may vary based on clinical findings and the NAb status.

Hypophosphatasia (HPP) is a rare inherited metabolic bone disorder caused by pathogenic variants in the ALPL gene, with a wide clinical spectrum ranging from severe pediatric forms to mild adult-onset disease. In contrast, heterozygous variants in ACAN are a recognized cause of autosomal dominant short stature, often associated with advanced bone age and premature growth plate closure. We report a 16-yr-old girl evaluated for severe disproportionate short stature with growth arrest during early adolescence. Her medical history included benign childhood epilepsy, mild intellectual disability, and enamel abnormalities. Biochemical evaluation revealed persistently low serum and bone-specific alkaline phosphatase levels, while calcium-phosphate metabolism was otherwise normal. Genetic testing identified a heterozygous pathogenic ALPL variant (c.1426G>A; p.Glu476Lys), inherited from an asymptomatic father, consistent with autosomal dominant HPP with minimal clinical expression. Additionally, a maternally inherited ACAN variant of uncertain significance (c.511G>C; p.Ala171Pro) was detected. Based on phenotypic correlation and family segregation, the growth phenotype is more plausibly explained by ACAN-related growth plate dysfunction, while the ALPL variant likely represents an incidental or mildly expressed finding. This case highlights the importance of careful genotype-phenotype correlation and cautious interpretation of multiple genetic findings in the evaluation of severe short stature.

Proximal muscle weakness is a recognized feature of hypophosphatasia (HPP), although significant structural muscle pathology is not typically observed. We report a 48-year-old woman with a 20-year history of progressive gait disturbance, proximal muscle weakness (Medical Research Council grade 2-4), and recurrent low-trauma fractures. Laboratory evaluation revealed persistently low serum alkaline phosphatase, and genetic testing identified a heterozygous likely pathogenic variant in ALPL (NM_000478.6:c.1559del; p.[Leu520Argfs*86]), confirming the diagnosis of HPP. However, severe muscle weakness and extensive fatty infiltration on muscle magnetic resonance imaging were disproportionate to what would be expected from HPP alone, prompting further evaluation. Additional genetic analysis identified a previously unreported homozygous intronic deletion in COL6A2 (NM_001849.4:c.1771-18_1771-3del), classified as likely pathogenic and predicted to affect splicing with uncertain protein consequences, confirming concurrent collagen VI-related muscular dystrophy (COL6-RD). Family genetic testing identified the same ALPL variant in the proband's 16-year-old daughter, who was subsequently diagnosed with HPP and found to be a carrier of COL6-RD. This case highlights that HPP and muscular dystrophy can coexist and underscores the importance of comprehensive neuromuscular evaluation when muscle weakness is present in patients with HPP.