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https://www.sciencedirect.com/science/article/pii/S1094695018302440
Journal of Clinical Densitometry
Available online 21 December 2018
In Press, Accepted Manuscript
What are Accepted Manuscript articles?
Hypophosphatasia in adults: clinical spectrum and its association with genetics and metabolic substrates
EvelineLefever1PeterWitters23EvelienGielen45AnnickVanclooster2WouterMeersseman2EvaMorava267DavidCassiman25†Michaël R.Laurent45†
https://doi.org/10.1016/j.jocd.2018.12.006Get rights and content
Abstract
Background
Hypophosphatasia (HPP) is a rare metabolic bone disorder caused by mutations in the alkaline phosphatase (ALPL) gene, and characterized by low circulating alkaline phosphatase (ALP) levels and bone, muscle, dental and systemic manifestations. In this case series we investigate the clinical spectrum, genetic and biochemical profile of adult HPP patients from the University Hospitals Leuven, Belgium.
Methodology
Adults with HPP were identified through medical record review. Inclusion criteria were: 1) age ≥ 16 years; 2) consecutively low ALP levels not explained by secondary causes; 3) one or more of the following supporting criteria: biochemical evidence of elevated enzyme substrates; subtrochanteric fractures, metatarsal fractures or other typical clinical features; family history of HPP; a known or likely pathogenic ALPL mutation.
Results
19 patients met our inclusion criteria (n=2 infantile, n=6 childhood, n=10 adult-onset HPP and one asymptomatic carrier). Fractures and dental abnormalities were the most reported symptoms. Fatigue was reported in n=7/19 patients (37%), three of which had previously been misdiagnosed as having chronic fatigue syndrome and/or fibromyalgia. Empirical pyridoxine therapy in four patients (without seizures) did not provide symptomatic relief. N=7/19 patients (37%) were inappropriately treated or planned to be treated with antiresorptive treatment. Two patients developed atypical femoral fractures following exposure to bisphosphonates and/or denosumab. Patients detected by screening were less severely affected, while patients with homozygous or compound heterozygous mutations had the most severe symptoms, significantly lower circulating ALP levels (p=0.013) and significantly higher pyridoxal-5’-phosphate (p=0.0018) and urinary phosphoethanolamine (p=0.0001) concentrations.
Conclusions
Screening may detect mainly less severely affected individuals, which may nevertheless avoid misdiagnosis and inappropriate antiresorptive drug exposure. Patients with biallelic mutations had more severe symptoms, significantly lower ALP and higher substrate levels. Whether the latter finding has implications for the classification and treatment of HPP should be investigated further in larger cohorts.
Keywords
Adults
Alkaline phosphatase
Fractures
Hypophospatasia
Phosphoethanolamine
Pyridoxal-5’-phosphate
Disclosure statement: PW and DC have received research support and consultancy fees from Alexion during the conduct of the study. DC also reports research grants from Shire and Genzyme, outside the submitted work. EG reports consultancy fees and non-financial support from Amgen, and consultancy fees from UCB, outside the submitted work. MRL has received consultancy fees from Alexion, Kyowa Kirin, Sandoz and UCB, and lecture fees and travel support from Amgen. All other authors report no conflicts of interest.
†
These authors share senior authorship.
© 2018 The International Society for Clinical Densitometry. Published by Elsevier Inc.
