Diagnosis and Treatment of Hypophosphatasia

Abstract

Hypophosphatasia (HPP) is a rare inherited metabolic disorder characterized by deficient activity of tissue-nonspecific alkaline phosphatase (TNAP) caused by variants in the ALPL gene. Disease manifestations encompass skeletal hypomineralization with rickets and lung hypoplasia, vitamin B6-dependent seizures, craniosynostosis, and premature loss of deciduous teeth. The clinical presentation can comprise failure to thrive with muscular hypotonia, delayed motor development, and gait disturbances later in childhood. In adults, pseudofractures are a characteristic indicator of severely compromised enzyme activity, but non-canonical symptoms like generalized musculoskeletal pain, weakness, and fatigue, frequently accompanied by neuropsychiatric and gastrointestinal issues are increasingly recognized as key findings in patients with HPP. The diagnosis is based on clinical manifestations in combination with persistently low alkaline phosphatase (ALP) activity, elevated levels of ALP substrates, specifically inorganic pyrophosphate (PPi), pyridoxal 5'-phosphate (PLP) or urine phosphoethanolamine (PEA), and genetic confirmation of a causative ALPL variant. Considering the wide range of manifestations, treatment must be multimodal and tailored to individual needs. The multidisciplinary team for comprehensive management of HPP patients should include expertise to ensure disease state metabolic and musculoskeletal treatment, dental care, neurological and neurosurgical surveillance, pain management, physical therapy, and psychological care. Asfotase alfa as first-in-class enzyme replacement therapy (ERT) for HPP has been shown to improve survival, rickets, and functional outcomes in severely affected children, but further research is needed to refine how enzyme replacement can also address emerging manifestations of the disease. Prospectively, further elucidating the pathophysiology behind the diverse clinical manifestations of HPP is instrumental for improving diagnostic concepts, establishing novel means for substituting enzyme activity, and developing integrative, multimodal care.

Keywords: Alkaline phosphatase; Canonical; Diagnostic criteria; Hypophosphatasia; Non-canonical; Phenotypes; Subclinical; Treatment.

Fig. 1

Currently recommended diagnostic criteria for HPP in children (left column) and adults (rights column). HPP 2 major criteria or 1 major and 2 minor criteria. Low ALP activity is an obligate criterion and requires exclusion of other conditions that can cause low ALP activity and repeated measures to avoid misinterpretation of situational reductions. HPP, hypophosphatasia; TNSALP, tissue-nonspecific alkaline phosphatase (According to Rush et al., Osteoporos Int. 2023, Brandi ML, et al. Osteoporos Int. 2023; Khan AA, et al. Osteoporosis Int. 2023)

Fig. 2

Graphic depiction of clinical signs and symptoms of Hypophosphatasia. Low circulating ALP activity, and elevated substrates due genetic ALPL variants reflect the pathophysiology of the disease and are thus considered the diagnostic core. The inner circle comprises canonical clinical manifestations that were unambiguously associated with severe HPP over decades, while the outer circle represents less specific manifestations

Fig. 3

Hypophosphatasia assessment, differentiating “subclinical-HPP” with an ALPL Variant with or without a biochemical signature but no clinical manifestation from patients with additional non-canonical clinical manifestations. Patients with the fully evolved picture of HPP including and one or more “canonical” manifestations in most instances also experience non-canonical” signs and symptoms

Fig. 4

Components of multimodal care for HPP patients, depicted as building blocks to reflect the need for individualized composition of different modules depending on clinical manifestation and age to enable optimal personalized management