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A rare, moderate form of hypophosphatasia (HPP) characterized by onset after six months of age and widely variable clinical features from low bone mineral density for age, to unexplained fractures, skeletal deformities, and rickets with short stature and waddling gait.
ORPHA:247667Classification level: Subtype of disorder
The prevalence is unknown. About 130 cases have been reported to date.
Patients develop manifestations after six months of age and generally before five years of age. Clinical manifestations cover a wide spectrum. Commonly, patients have rickets leading to short stature, with delay in walking and a waddling gait, and bone and joint pain. Skeletal deformities may include dolichocephalic skull and enlarged joints. Other common features are signs of intracranial hypertension and failure to thrive. Diaphyseal and metaphyseal fractures are common. Some affected children have premature loss of deciduous teeth, starting with incisors and then loss of other teeth with intact roots, before five years of age. The disease may follow an intermittent course with remission and recurrence in later life. There may be some clinical overlap between childhood-onset HPP and moderately severe infantile HPP.
Mutations in the ALPL gene (1p36.12) are known to cause hypophosphatasia.
Diagnosis is based on clinical presentation, alkaline phosphatase assay and confirmed by genetic testing.
Osteogenesis imperfecta is the most common differential diagnosis of HPP.
Autosomal recessive and autosomal dominant patterns of inheritance are reported, potentially explaining clinical variability. Genetic counseling is recommended for affected individuals.
Management and treatment
Treatment has traditionally been supportive rehabilitative strategies to minimize functional limitations, and surgery to manage some fractures. However, there is evidence that enzyme replacement therapy with asfotase alfa, approved for pediatric onset HPP (Europe and USA), improves function in childhood-HPP.
Affected individuals may have significant disease, with poor mobility, chronic pain, and short stature. In addition, significant rickets, long bone deformity, and non-traumatic fractures are possible. Fractures may heal poorly and can reoccur.
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