A NOVEL MUTATION IN ALPL GENE CAUSING ADULT AUTOSOMAL DOMINANT HYPOPHOSPHATASIA IN A FAMILY OF SOUTHERN SPAIN: PHENOTYPE CHARACTERIZATION

S. Leal Rodriguez, N. Roldan Ruiz, L. Mayordomo, J. Bobillo-LobatoLa Fe University and Polytechnic Hospital, Rheumatology, València, Spain Hospital Universitario Nuestra Señora de Valme, Rheumatology, Sevilla, Spain Hospital Universitario Nuestra Señora de Valme, Clinical Analysis Laboratory, Sevilla, Spain  Background Tissue non-specific alkaline phosphatase (TNSALP) is essential for bone and tooth extracellular matrix mineralization. The gene encoding TNSALP (ALPL) is located on the long arm of chromosome 2. More than 400 ALPL variants exist. Low enzymatic activity of serum alkaline phosphatase (ALP) due to gene mutations leads to hypophosphatasia (HPP), a heterogeneous clinical condition ranging from asymptomatic or mild adult forms to severe perinatal disease. Adult’s HPP most typical features are stress fractures and early loss of dentition. Objectives To describe the clinical phenotype and laboratory features in a family suffering from HPP in which a new gene variant was detected. Methods A descriptive observational study of a family belonging to the Virgen de Valme Hospital area (Seville) was conducted through a primary identification of an index case with low level of ALP in whom a novel ALPL gene mutation was found. Members from three family generations were screened for low level of ALP to select patients meeting laboratory criteria for HPP. To assess family segregation, phenotype and clinical relevance of this mutation, genetic analysis of those with confirmed low ALP and a selection of members with normal ALP levels was done. Epidemiological, clinical, laboratory and genetic study variables were collected. A descriptive quantitative analysis of the data was performed. Results We studied 16 members corresponding to three generations of the same family suspected to have familial hypophosphatasia. The index case was a 57-year-old male with chronic pain, problems with dentition and previous history of fractures. ALP screening found 8/16 (50%) patients with low level. Genetic testing was performed for 7/16 patients and 3/16 with low and normal ALP levels, respectively. A familial carrier variant c.786A>G heterozygotic single-nucleotide polymorphism (SNP) in the ALPL gene was found in all patients with low ALP (Graph 1). Clinical and laboratory features for the seven positive carriers are shown in Table 1. Most fractures were due to non-minor trauma. Chronic arthralgia was the main articular complaint. All laboratory values were within normal range, ruling out secondary causes of HPP. Only one patient presented with high pyridoxal-5’-phosphate (PLP). Conclusion We present a new autosomal dominant inheritance mutation in the ALPL gene that causes HPP. Variable clinical expressivity is observed. Dentition problems and recurrent fractures predominate, associated with chronic pain. Early diagnosis and genetic counselling may be important, although further studies and a larger population are required to establish the definitive pathologic relevance of this variant. Table 1. Epidemiological, clinical and laboratory characteristics of positive mutation carriers (n = 7). ALP: alkaline phosphatase; PLP: pyridoxal-5’- phosphate; 25-OH-VitD: 25-hydroxy-vitamin D; PTH: parathyroid hormone; TSH: thyroid stimulating hormone. Baseline characteristics (n = 7) Sex Male 3 (42.8%) Female 4 (57.2%) Age (mean, sd) 55.6 ± 13.2 years Early dentition loss Yes 1 (14.3%) No 6 (85.7%) Fracture history Yes 4 (57.1%) No 3 (42.9%) Articular manifestations Yes 7 (100%) No 0 (0%) Laboratory values Mean, sd Minimum Maximum ALP (U/l) 28 ± 4.16 22 33 PLP (nmol/l) 88 ± 49.1 26.5 178 Calcium (mg/dl) 9.83 ± 0.43 9.3 10.4 Phosphorus (mg/dl) 3.72 ± 0.53 2.7 4.2 Magnesium (mg/dl) 1.91 ± 0.15 1.7 2.1 25-OH-Vit-D (ng/ml) 71.2 ± 10.8 57.5 87.2 PTH (pg/ml) 28.6 ± 8.01 15.3 34.5 Vitamin B12 (pg/ml) 489 ± 135 285 645 TSH (µU/ml) 1.73 ± 0.92 0.84 3.64 Cortisol (µg/dl) 13.3 ± 3.48 7.9 18 Image/graph:Graph 1. ALP enzymatic activity according to gene mutation carrier status. Red dotted line represents the lower laboratory limit for ALP. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests None Declared. Keywords: Genetics/Epigenetics, Rare/orphan diseases, Bone diseases DOI: 10.1136/annrheumdis-2023-eular.6178Citation: , volume 82, supplement 1, year 2023, page 428Session: Genetic Determinants of Clinical Phenotypes (Poster Tours)