Clinical Description
Hypophosphatasia is characterized by defective mineralization of bone and/or teeth and reduced serum 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 (see Table 2). Intrafamilial clinical variability is common, particularly when some affected family members have a heterozygous ALPL pathogenic variant and other affected family members have biallelic pathogenic variants. Sibs with compound heterozygous variants tend to display less clinical variability at the severe end of the spectrum and more variability at the milder end of the spectrum [Huggins et al 2020].
Table 2.
Select Clinical, Radiographic, and Laboratory Features of Hypophosphatasia by Type
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Type | MOI | Cardinal Features | Additional Features |
---|
Perinatal
(severe)
| AR | Hypomineralization Osteochondral spurs
|
|
Perinatal
(benign)
| AR AD | Long bone bowing Benign postnatal course
| |
Infantile
| Mostly AR |
| Additional clinical & radiographic features of infantile rickets 1, 2 Alveolar bone loss (anterior mandible) Premature loss of deciduous teeth Impaired motor skills
|
Severe
childhood
(juvenile)
| AR AD |
|
|
Mild
childhood
| AR AD | ↑ fractures | Premature loss of deciduous teeth (incisors) |
Adult
| AR AD |
|
|
Odontohypo-
phosphatasia
| AR AD | Alveolar bone loss | Exfoliation (incisors) Dental caries
|
- 1.
Clinical features of infantile rickets: growth failure, craniotabes, blue sclerae, scoliosis, thickening of wrists and ankles, bowing of lower extremities, lax ligaments, and hypotonia
- 2.
Radiographic features of infantile rickets: widened-appearing sutures, brachycephaly, flail chest, flared metaphyses, poorly ossified epiphyses, and bowed long bones in the lower extremities
Perinatal (severe) hypophosphatasia is typically identified by prenatal ultrasound examination. Pregnancies may end in stillbirth. Small thoracic cavity and short, bowed limbs are seen in both stillborn and live-born infants. A flail chest may be present (see ). Infants with perinatal hypophosphatasia may experience pulmonary insufficiency; restrictive lung disease is the most frequent cause of death. Hypercalcemia is common and may be associated with apnea or seizures. In those treated with asfotase alfa enzyme replacement therapy (ERT), a new phenotype of "treated perinatal and infantile hypophosphatasia" is emerging. However, even when the diagnosis is made expediently, unfavorable outcomes with ERT are possible [Duffus et al 2018]. Infants with perinatal (severe) hypophosphatasia started on ERT between age one day and age 78 months showed improvement in pulmonary function and survival. The effect of ERT on fractures remains unclear [Whyte et al 2019]. In the past, individuals with severe phenotypes died before dental eruption; emerging data suggest the possibility of dental features in infants treated with ERT. The oral health of children with early-onset infantile hypophosphatasia may be improved with early and continued administration of ERT, compared to initiation of therapy later in childhood [Schroth et al 2021].
Perinatal (benign) hypophosphatasia is typically identified by prenatal ultrasound examination showing short and bowed long bones but normal or slightly decreased mineralization. Postnatally, skeletal manifestations slowly resolve with a less severe hypophosphatasia phenotype [Wenkert et al 2011].
Infantile hypophosphatasia. There may be no clinical features apparent at birth. Clinical signs may be recognized between birth and age six months and resemble rickets (see ). Clinical severity depends on the degree of pulmonary insufficiency; the infantile phenotype has high mortality. Prior to the availability of ERT, 50% of individuals succumbed to respiratory failure caused by undermineralization of the ribs. Other complications include hypercalcemia, irritability, poor feeding, growth deficiency (including weight, length, and head circumference), hypotonia, and, more rarely, vitamin B6-responsive seizures (see Management). Open fontanels and wide sutures may be deceptive, in that the hypomineralized bone causing this radiographic appearance is prone to premature fusion. Craniosynostosis and intracranial hypertension are potential complications. Older children may have kidney damage. Clinical trials with ERT have shown improvement in developmental milestones and pulmonary function (see ) [Whyte et al 2019].
Radiograph of treated hypophosphatasia. Individual from Figure 2A after 12 months of asfotase alfa enzyme replacement therapy. Note tracheostomy tube, placed for laryngomalacia and bronchomalacia, features of the treated disease. Rachitic rib and metaphyseal (more...)
Severe childhood (juvenile) hypophosphatasia displays wide variability in initial clinical presentation but often progresses to rickets. More severely affected toddlers have short stature and delay in walking, developing a waddling myopathic gait. Bone and joint pain are typical. Diaphyseal and metaphyseal fractures may occur. Gait, six-minute walk test, and step length improved in individuals treated with ERT. To date, data are insufficient to assess the effect of ERT on fractures in juvenile hypophosphatasia [Whyte et al 2016].
Mild childhood hypophosphatasia. Presentation is typically later in childhood without rachitic disease. Mild childhood hypophosphatasia is characterized by low bone mineral density for age with unexplained fractures. Children may have premature loss of deciduous teeth (prior to age five years), usually beginning with incisors, with the dental root characteristically remaining attached to the lost tooth. Bone and joint pain are atypical, but behavioral features (attention-deficit/hyperactivity disorder) and sleep disturbances are overrepresented in children with hypophosphatasia [Pierpont et al 2021].
Adult hypophosphatasia is sometimes associated with a history of transient rickets in childhood and/or premature loss of deciduous teeth. Early loss of adult dentition is common but not present in all adults with hypophosphatasia. Other dental problems in adolescents and adults with hypophosphatasia are more poorly characterized, although enamel hypoplasia and tooth mobility have been described. Adult hypophosphatasia is usually recognized in middle age, the cardinal features being stress fractures and pseudofractures of the lower extremities (see ). Foot pain and slow-to-heal stress fractures of the metatarsals are common (see ). Thigh and hip pain may reflect pseudofractures ("Looser zones") in the lateral cortex of the femoral diaphysis (see ). Chondrocalcinosis and osteoarthropathy may develop with age (see ). Osteomalacia distinguishes adult hypophosphatasia from odontohypophosphatasia. Adults with hypophosphatasia may have significant bone pain in the absence of fractures and pronounced non-skeletal disease including muscle weakness, dental problems, and reduced quality of life [Seefried et al 2020, Dahir et al 2022].
Radiograph of left femur in a female age 62 years with hypophosphatasia, showing a transverse fracture of the proximal midshaft of the femur with varus angulation.
Radiograph of multiple healed bilateral metatarsal fractures and features of arthritic changes in a female age 56 years with hypophosphatasia.
Radiograph of treated adult hypophosphatasia: linear sclerosis in remodeling distal femur and proximal tibia, osteophytes mid-proximal tibia, and chondrocalcinosis medial lateral compartment
Odontohypophosphatasia can be seen as an isolated finding without additional abnormalities of the skeletal system or can be variably seen in the other forms of hypophosphatasia. Caution should be exercised in citing extradental manifestations of other forms of hypophosphatasia in individuals with odontohypophosphatasia, in that such features may be common and multifactorial (e.g., low bone density for age). Premature exfoliation of primary teeth and/or severe dental caries may be seen, with the incisors most frequently lost. Some individuals initially diagnosed with isolated dental manifestations in childhood may later manifest additional symptoms that constitute childhood- or adult-onset hypophosphatasia [Mori et al 2016].
Heterozygous loss-of-function variants. Heterozygous loss-of-function ALPL pathogenic variants have been identified in adults with osteoporosis, musculoskeletal pain, and an increased risk of fractures [Mornet et al 2021]. These individuals are ascertained by low serum ALP and tend to have additional biochemical evidence of hypophosphatasia (elevated serum pyridoxal 5'-phosphate [PLP] or urine phosphoethanolamine [PEA]). Those ascertained as an incidental finding on molecular testing have lower ALP activity but may not display additional biochemical evidence of hypophosphotasia. In this latter circumstance, elevated serum PLP or urine PEA may predict disease potential.
Histopathology
Nomenclature
Hypophosphatasia takes its name from low activity of the enzyme ALP, rather than reflecting serum concentration of phosphorus.
In classifications of genetic conditions, hypophosphatasia may be considered a metabolic bone disease, a skeletal dysplasia, a metaphyseal dysplasia, a dental disorder, or a disorder of membrane-bound ectoenzyme activity in the extracellular matrix.
Prevalence
Based on pediatric hospital records in Ontario, Canada, the birth prevalence of (autosomal recessive) perinatal and infantile hypophosphatasia was estimated at 1:100,000 [Fraser 1957]. Applying the Hardy-Weinberg equation to this estimate, the carrier frequency of heterozygotes for ALPL pathogenic variants in Ontario, Canada, is about 1/150.
In the Canadian Mennonite population, the prevalence of the perinatal (severe) form is 1:2,500 (carrier frequency of 1/25) due to the founder variant p.Gly334Asp [Greenberg et al 1993], which is also a founder variant in the Hutterite population [Triggs-Raine et al 2016].
On the basis of molecular diagnosis in France and elsewhere in Europe, the prevalence of severe forms of hypophosphastia has been estimated at 1:300,000. For mild forms (perinatal benign, mild childhood, adult, and odontohypophosphatasia), the prevalence is expected to be as high as 1:6,300 [Mornet et al 2011] because heterozygotes may express the disease with low selective pressure. Applying the Hardy-Weinberg equation to this estimate for severe forms, the carrier frequency of ALPL heterozygotes in France is about 1/275. Mornet et al [2021] reported the genetic characteristics of a cohort of 424 Europeans with hypophosphatasia evaluated over the course of 22 years including 3D modeling and functional testing. Based on this work, a new molecular-based classification was suggested called mild hypophosphatasia with nonspecific signs and symptoms, with an estimated carrier frequency of 1/254, assumed penetrance of 50%, and a prevalence of 1:508 [Mornet et al 2021].
In Japan, the birth prevalence of severe hypophosphatasia may be estimated at 1:150,000 on the basis of the frequency of individuals homozygous for the pathogenic variant c.1559delT (1:900,000 [Watanabe et al 2011]) and the proportion of this pathogenic variant in affected individuals of Japanese ancestry (45.4% [Michigami et al 2020]).
In China, some pathogenic variants have been reported [Wei et al 2010, Zhang et al 2012, Yang et al 2013] but the birth prevalence is unknown.
In Africa, no individuals with hypophosphatasia have been reported in the medical literature outside of North Africa and South Africa; however, clinical ascertainment bias is significant. African American individuals with hypophosphatasia are rare; it is assumed that pathogenic variants in this population represent European admixture.