- Idiopathic Scoliosis
- Slipped Capital Femoral Epiphysis (SCFE)
- Introduction to Metabolic Bone Disorders in Children
- Hypophosphatasia
- Overview of Bone Density Disorders in Children
- Osteoporosis in Children
- Craniotubular Dysplasias
- Craniotubular Hyperostoses
- Osteosclerosis
- Introduction to Bone Modeling Disorders in Children
- Köhler Bone Disease
- Osgood-Schlatter Disease
- Scheuermann Disease
- Legg-Calvé-Perthes Disease
Hypophosphatasia is absence or low levels of serum alkaline phosphatase due to loss-of-function mutations in the gene ALPL, which encodes tissue-nonspecific alkaline phosphatase (TNSALP). Diagnosis is clinical. Treatment is with asfotase alpha and sometimes vitamin B6.
Hypophosphatasia is an inherited metabolic disease characterized by either absence or low levels of serum alkaline phosphatase causing phenotypic diversity (ie, a clinical spectrum of disease) that ranges from mild to severe. It is caused by loss-of-function mutations in the ALPL gene encoding tissue-nonspecific alkaline phosphatase (TNSALP).
Data are limited regarding the incidence or prevalence of hypophosphatasia. In one often-cited 10-year case series in Canada during the 1950s, the incidence of hypophosphatasia overall was estimated to be 1/100,000 (1). However, another study from 2000 to 2009 in France that considered phenotypic variation estimated the prevalence of severe (autosomal recessive) forms to be 1/300,000 and of moderate forms to be 1/6,370 (2).
In hypophosphatasia, defective hydrolysis of inorganic pyrophosphate by TNSALP leads to its accumulation. Inorganic pyrophosphate is a potent inhibitor of hydroxyapatite formation, which in turn leads to impaired mineralization of bones and teeth (3). The deficiency of TNSALP also affects the metabolism of pyridoxal-5’-phosphate, the active form of vitamin B6, leading to intracellular vitamin B6 deficiency, high serum B6 level, and the potential for generalized seizures.
General references
1. Fraser D. Hypophosphatasia. Am J Med. 1957;22(5):730-746. doi:10.1016/0002-9343(57)90124-9
2. Mornet E, Taillandier A, Domingues C, et al. Hypophosphatasia: a genetic-based nosology and new insights in genotype-phenotype correlation. Eur J Hum Genet. 2021;29(2):289-299. doi:10.1038/s41431-020-00732-6
3. Khan AA, Brandi ML, Rush ET, et al. Hypophosphatasia diagnosis: current state of the art and proposed diagnostic criteria for children and adults [published correction appears in Osteoporos Int. 2024 May;35(5):933-934. doi: 10.1007/s00198-024-07048-x.]. Osteoporos Int. 2024;35(3):431-438. doi:10.1007/s00198-023-06844-1
Symptoms and Signs of Hypophosphatasia
The clinical manifestations of hypophosphatasia are variable. These include early tooth loss (especially if the lost teeth have roots intact) and rickets.
Patients with severe disease may have vomiting, poor weight gain, and/or seizures.
Diagnosis of Hypophosphatasia
Decreased serum alkaline phosphatase and elevated pyridoxal-5’-phosphate or vitamin B6
Imaging studies (prenatal ultrasound, radiographs)
Genetic testing
Diagnosis is suggested by the clinical manifestations and by laboratory findings of decreased serum alkaline phosphatase level and elevated pyridoxal-5’-phosphate or vitamin B6 level (1).
Additional laboratory findings, such as hypercalcemia, hyperphosphatemia, and hypercalciuria, are more common among patients with a severe infantile form, where poor bone mineralization is pronounced; however, these findings are not present in all patients.
Imaging studies, including prenatal ultrasound and plain radiographs in children and adults, may reveal characteristic findings such as skeletal hypomineralization, rickets, or osteomalacia, which support the diagnosis (2).
Genetic testing for pathogenic variants in the ALPL gene may be performed for diagnostic confirmation of hypophosphatasia (3), particularly to aid prenatal diagnosis, and in patients with an atypical presentation or for recurrence risk assessment.
Diagnosis references
1. Whyte MP. Hypophosphatasia - aetiology, nosology, pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2016;12(4):233-246. doi:10.1038/nrendo.2016.14
2. Mannes I, Rothenbuhler A, Merzoug V, Di Rocco F, Linglart A, Adamsbaum C. Imaging patterns in pediatric hypophosphatasia. Pediatr Radiol. 2022;52(5):998-1006. doi:10.1007/s00247-021-05232-3
3. Fenn JS, Lorde N, Ward JM, Borovickova I. Hypophosphatasia. J Clin Pathol. 2021;74(10):635-640. doi:10.1136/jclinpath-2021-207426
Treatment of Hypophosphatasia
Possible asfotase alpha
For seizures, possible vitamin B6
For patients with suspected hypophosphatasia, referral to a pediatric endocrinologist for further evaluation and consideration of treatment with asfotase alfa is appropriate. Asfotase alpha is a recombinant protein carrying the catalytic domain of TNSALP. It is given by subcutaneous injection 1 to 3 times a week.
For patients with hypophosphatasia with seizures, referral to a pediatric neurologist is appropriate. Vitamin B6 in high doses may reduce seizures because although patients often have elevated circulating pyridoxal-5′-phosphate (PLP), deficiency of tissue-nonspecific alkaline phosphatase (encoded by the ALPL gene) prevents adequate pyridoxal from entering the brain. This creates a functional deficiency of active vitamin B6 in the central nervous system, impairing neurotransmitter synthesis and leading to seizures (1). Supplementation with vitamin B6 (pyridoxine or pyridoxal phosphate) bypasses this block, restores brain PLP, and helps control seizures.). Supplementation with vitamin B6 (pyridoxine or pyridoxal phosphate) bypasses this block, restores brain PLP, and helps control seizures.
Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce bone pain. Appropriate dental care and fracture prevention measures should be implemented to prevent complications of disease. Infusions of alkaline phosphatase and hematopoietic stem cell transplantation have limited roles.
Treatment reference
1. Whyte MP. Hypophosphatasia - aetiology, nosology, pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2016;12(4):233-246. doi:10.1038/nrendo.2016.14
Prognosis for Hypophosphatasia
Neurodevelopment is generally typical for age.
Patients who survive infancy or who present with less severe phenotypes often have persistent bony deformities and short stature.
Drugs Mentioned In This Article
