ESPE2024 Poster Category 1 Bone, Growth Plate and Mineral Metabolism 1 (11 abstracts)
New clinical phenotypes associated with ALPL mutations
Mariam R Farman 1 , Catherine Rehder 2 , Theodora Malli 3 , Cheryl Rockman-Greenberg 4 , Kathryn Dahir 5 , Gabriel Ángel Martos-Moreno 6,7 , Agnès Linglart 8 , Keiichi Ozono 9 , Lothar Seefried 10 , Guillermo del Angel 11 , Florian Högler 1 , Rodrigo Montero-Lopez 1 , Francesca Barbazza 1 , Erica Burner Nading 12 , Erin Huggins 12 , Eric T Rush 13 , Muhammad K Javaid 14 , Burkhard Muche 15 , Josephine T Tauer 1 , Priya S Kishnani 12 , Gerald Webersinke 3 & Wolfgang Högler 1
1Department of Paediatrics and Adolescent Medicine, Johannes Kepler University Linz, Linz, Austria. 2Duke University Medical Center, Department of Pathology, Durham, USA. 3Laboratory for Molecular Genetic Diagnostics, Ordensklinikum Linz, Linz, Austria. 4Department of Pediatrics and Child Health Max Rady College of Medicine, Rady Faculty of Health Sciences, Winnipeg, Canada. 5Vanderbilt University Medical Center, Program for Metabolic Bone Disorders, Nashville, USA. 6Departments of Pediatrics & Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain. Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain. 7CIBER Fisiopatología de la Obesidad y Nutrición. ISCIII, Madrid, Spain. 8AP-HP, Paris Saclay University, INSERM, Bicêtre Paris Saclay hospital, Le Kremlin-Bicêtre, France. 9Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan. 10Julius-Maximilian University, Wurzburg, Germany. 11Centre for Genomics Research, AstraZeneca, Boston, USA. 12Duke University Medical Center, Division of Medical Genetics, Department of Pediatrics, Durham, USA. 13Division of Clinical Genetics, Children's Mercy Hospital Kansas City, Kansas City, MO, USA; Department of Internal Medicine, University of Kansas School of Medicine, Kansas City, KS, USA; Department of Pediatrics, University of Missouri – Kansas City School of Medicine, Kansas, USA. 14Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom. 15Charité Universitätsmedizin, Department of Rheumatology & Interdisciplinary Center for Osteology, Berlin, Germany
Objectives: HPP is a multisystem disorder caused by ALPL variants that lead to ALP deficiency and excessive inorganic pyrophosphate, which inhibits mineralization of bones and teeth. A range of symptoms is associated with HPP inherited in an autosomal dominant manner that can manifest at any stage of life, making diagnosis difficult. The traditional method of classifying HPP into different types based on the onset of symptoms (prenatal benign, perinatal severe, infantile, childhood, adult, odonto) may not be completely accurate. The ALPL gene variant consortium has been created to classify ALPL variants and develop a comprehensive public database that catalogs associated genotypes and phenotypes. Here, we report on two new phenotypes.
Methods: The variant classification process involves identifying individuals with a specific ALPL variant, conducting a deep literature review of all published patients and their family members carrying this variant, and performing in vitro residual enzyme activity testing if necessary. The multi-step process for classifying ALPL variants based on ACMG/AMP criteria was recently published (Farman MR et al., Bone 2024). Here, we highlight two non-traditional phenotypes that have emerged since the project started in 2021.
Results: The first phenotype includes reportedly asymptomatic individuals who show the typical biochemical signature of HPP, including low ALP blood serum levels with elevated PLP, but do not exhibit any overt clinical symptoms. This group comprises several heterozygous ALPL variants, including c.83A>G, c.182-2A>G, c.237_238delCA, c.244G>A, c.244G>C, c.286G>C, c.299C>T, c.511C>G, c.667C>T, c.675_676insCA, c.715G>T, c.793-30_793-11del, c.818C>T, c.881A>C, c.906C>A, c.1015G>A, c.1225C>T, c.1323C>A, c.1333T>A, c.1381G>A and c.1402G>A. The second phenotype includes individuals with extensive ectopic calcifications around major joints who were found to be heterozygous of the known ALPL variants c.1001G>A, c.1250A>G, or c.1559del.
Conclusion: Our study has been able to uncover a broader range of phenotypes associated with ALPL variants than previously described, including asymptomatic heterozygotes with the typical biochemical signature and symptomatic heterozygotes with significant ectopic calcifications. Future research should focus on phenotyping, and long-term follow-up, of asymptomatic, heterozygous individuals such as family members of known affected patients. The ALPL Gene Variant Consortium continues to explore additional HPP variants, encouraging the submission of variants and detailed clinical data of patients and family members, including asymptomatic individuals, for improving the understanding of the association between genotype and phenotype in HPP.
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