Hypophosphatasia

Excerpt

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 (ALP). Biallelic ALPL pathogenic variants often result in severe hypophosphatasia that can result in stillbirth without mineralized bone, while heterozygous ALPL pathogenic variants are more likely to manifest as modest, mild, or even asymptomatic disease. Regardless of the number of ALPL pathogenic variants, many individuals with hypophosphatasia suffer from pain, disability, and reduced quality of life. Variability of clinical manifestations is common in both childhood and adult forms of hypophosphatasia and even occurs within affected families. 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 restrictive lung disease, respiratory failure, vitamin B₆-dependent seizures, hypercalcemia with high morbidity, and mortality

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 ALP activity

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

Mild childhood: Present later in childhood without rachitic disease, low bone mineral density for age, increased risk of fracture, and premature loss of primary teeth with intact roots

Adult: Characterized by osteomalacia and stress fractures and pseudofractures of the lower extremities in middle age, sometimes associated with early loss of adult dentition. Adults with hypophosphatasia may also have significant bone pain and pronounced non-skeletal disease, with muscle weakness, dental problems, and reduced quality of life.

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 based on clinical diagnostic criteria. The molecular diagnosis of hypophosphatasia can be established in a proband with one major or two minor criteria and biallelic loss-of-function ALPL pathogenic variants or a heterozygous ALPL pathogenic variant with dominant-negative effect identified by molecular genetic testing.

Management: Targeted therapy: Asfotase alfa enzyme replacement therapy (ERT)

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. For all types: psychological support, social work support, and referral to mental health professionals as needed.

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; renal ultrasound annually and 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, denosumab, and excess vitamin D; teriparatide is contraindicated in children.

Pregnancy management: The use of asfotase alfa 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. Milder forms of hypophosphatasia, 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 alkaline phosphatase, tissue-nonspecific isozyme (TNSALP) 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 manifestations than the proband.

Autosomal dominant 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 and prenatal/preimplantation genetic testing for hypophosphatasia are possible. Recurrence of perinatal hypophosphatasia may reliably be identified by prenatal ultrasound examination.