Hypophosphatasia

Clinical characteristics: Hypophosphatasia is characterized by defective mineralization of growing or remodeling bone, with or without root-intact tooth loss, in the presence of low activity of serum and bone alkaline phosphatase. Clinical features range from stillbirth without mineralized bone at the severe end to pathologic fractures of the lower extremities in later adulthood at the mild end. While the disease spectrum is a continuum, seven clinical forms of hypophosphatasia are usually recognized based on age at diagnosis and severity of features:

Perinatal (severe): Characterized by pulmonary insufficiency and hypercalcemia

Perinatal (benign): Prenatal skeletal manifestations that slowly resolve into one of the milder forms

Infantile: Onset between birth and age six months of clinical features of rickets without elevated serum alkaline phosphatase activity

Severe childhood (juvenile): Variable presenting features progressing to rickets

Mild childhood: Low bone mineral density for age, increased risk of fracture, and premature loss of primary teeth with intact roots

Adult: Characterized by stress fractures and pseudofractures of the lower extremities in middle age, sometimes associated with early loss of adult dentition

Odontohypophosphatasia: Characterized by premature exfoliation of primary teeth and/or severe dental caries without skeletal manifestations

Diagnosis/testing: The clinical diagnosis of hypophosphatasia can be established in a proband with suggestive clinical, laboratory, and radiographic features by identification of reduced serum unfractionated alkaline phosphatase activity and/or identification on molecular genetic testing of biallelic loss-of-function ALPL variants or a heterozygous ALPL variant with dominant-negative effect.

Management: Targeted therapy: Asfotase alfa (Strensiq^®) enzyme replacement therapy (ERT) has been shown to improve pulmonary function, calcium homeostasis / bone health, and survival in individuals with the infantile and early childhood (juvenile) type of hypophosphatasia. There is growing experience with ERT in individuals with the perinatal (severe) type and emerging experience with ERT in treating osteomalacia in adults.

Supportive care: For the perinatal (severe) type: expectant management and family support; respiratory support; management of calcium homeostasis and bone health per endocrinologist and orthopedist; pain management; neurosurgical management of craniosynostosis; management of kidney disease per nephrologist; dental care. For the infantile and early childhood (juvenile) types: respiratory support; management of calcium homeostasis and bone health per endocrinologist and orthopedist; pain management; treatment of seizures with vitamin B₆; neurosurgical management of craniosynostosis; management of kidney disease per nephrologist; dental care. For all other types: dental care starting at age one year; nonsteroidal anti-inflammatory drugs for osteoarthritis, bone pain, and osteomalacia; internal fixation for pseudofractures and stress fractures. In adult hypophosphatasia, there is limited experience in treating osteomalacia with teriparatide.

Surveillance: Monitor calcium homeostasis and bone health per endocrinologist, nephrologist, and orthopedist; physical medicine and rehabilitation, physical therapy, and occupational therapy evaluations as needed; monitor children with infantile type for increased intracranial pressure secondary to craniosynostosis; nephrology evaluations as needed for kidney disease; neurology evaluations as needed for seizures; dental visits twice yearly starting at age one year.

Agents/circumstances to avoid: Bisphosphonates and excess vitamin D; teriparatide is contraindicated in children.

Pregnancy management: The use of asfotase alfa (Strensiq^®) ERT during human pregnancy has not been extensively studied; therefore, any potential risk to the fetus of a pregnant woman taking this therapy during pregnancy is unknown.

Genetic counseling: Perinatal and infantile hypophosphatasia are typically inherited in an autosomal recessive manner. The milder forms, especially adult and odontohypophosphatasia, may be inherited in an autosomal recessive or autosomal dominant manner depending on the effect that the ALPL pathogenic variant has on TNSALP (alkaline phosphatase, tissue-nonspecific isozyme) activity.

Autosomal recessive hypophosphatasia: If both parents are known to be heterozygous for an ALPL pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Depending on the ALPL pathogenic variant, heterozygous sibs may be either clinically asymptomatic (manifesting only biochemical abnormality) or have milder clinical symptoms than the proband.

Autosomal dominant hypophosphatasia: All individuals reported to date with hypophosphatasia caused by a heterozygous ALPL variant with a dominant-negative effect inherited the ALPL pathogenic variant from a parent (who may or may not have clinical manifestations of hypophosphatasia). Unless an individual with autosomal dominant hypophosphatasia has children with an individual who has a heterozygous or biallelic ALPL pathogenic variant(s), offspring have a 50% chance of inheriting the ALPL pathogenic variant.

Once the ALPL pathogenic variant(s) have been identified in an affected family member, heterozygote testing for at-risk relatives, prenatal testing, and preimplantation genetic testing for hypophosphatasia are possible. Recurrence of perinatal and infantile hypophosphatasia may reliably be identified by prenatal ultrasound examination.