Clinical characteristics.

Hypophosphatasia is characterized by defective mineralization of bone and/or teeth 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. Although the disease spectrum is a continuum, six clinical forms are usually recognized based on age at diagnosis and severity of features:

• Perinatal (severe) hypophosphatasia characterized by respiratory insufficiency and hypercalcemia
• Perinatal (benign) hypophosphatasia with prenatal skeletal manifestations that slowly resolve into one of the milder forms
• Infantile hypophosphatasia with onset between birth and age six months of rickets without elevated serum alkaline phosphatase activity
• Childhood (juvenile) hypophosphatasia that ranges from low bone mineral density for age with unexplained fractures to rickets, and premature loss of primary teeth with intact roots
• Adult hypophosphatasia 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.

Although formal diagnostic criteria are not established, all forms of hypophosphatasia (except pseudohypophosphatasia) share in common reduced activity of unfractionated serum alkaline phosphatase (ALP) and presence of either one or two pathogenic variants in ALPL, the gene encoding alkaline phosphatase, tissue-nonspecific isozyme (TNSALP).

Management.

Treatment of manifestations: Perinatal (severe) type: limited experience with enzyme replacement therapy (ERT); expectant management and family support. Infantile and early childhood (juvenile) types: enzyme replacement therapy (asfotase alfa), respiratory support, treatment of hypercalcemia/hypercalciuria, treatment of seizures with vitamin B₆, routine treatment of craniosynostosis. All other types: routine dental care starting at age one year; nonsteroidal anti-inflammatory drugs (NSAID) for osteoarthritis, bone pain, and osteomalacia; internal fixation for pseudofractures and stress fractures.

Surveillance: Dental visits twice yearly starting at age one year; monitoring children with infantile type for increased intracranial pressure secondary to craniosynostosis.

Agents/circumstances to avoid: Bisphosphonates, excess vitamin D.

Genetic counseling.

Perinatal and most infantile cases of hypophosphatasia are 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 activity.

• Autosomal recessive hypophosphatasia. Heterozygotes (carriers) either are asymptomatic (manifesting biochemical but not clinical abnormality) or may manifest milder symptoms, depending on the variant. Although de novo pathogenic variants have been reported, in most instances each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an "asymptomatic" carrier, and a 25% chance of being unaffected and not a carrier.
• Autosomal dominant hypophosphatasia. To date, all probands have inherited a pathogenic variant from a parent; de novo pathogenic variants have not been reported. Each child of an individual with the autosomal dominant form of hypophosphatasia has a 50% chance of inheriting the pathogenic variant.

Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant(s) have been identified in an affected family member. Recurrence of perinatal and infantile hypophosphatasia may reliably be identified by prenatal ultrasound examination.

Suggestive Findings

Hypophosphatasia should be suspected in individuals with:

• Defective mineralization of bone and/or teeth;
• Premature loss of teeth with intact roots;
• Reduced serum alkaline phosphatase (ALP) activity.

At least six clinical forms are currently recognized based on age at diagnosis and severity of features (see Table 1). Clinical features include the following:

• Prenatal long-bone bowing with osteochondral spurs and pretibial dimpling
• Infantile rickets without elevated serum alkaline phosphatase activity. Features can include growth failure, craniotabes, craniosynostosis, blue sclerae, costochondral enlargement ("rachitic rosary"), scoliosis, thickening of wrists and ankles, bowing of long bones, lax ligaments, and hypotonia.
• Hypercalcemia and hypercalciuria particularly during the first year of life
• Pathologic fractures and bone pain. Growing children may have a predilection to metaphyseal fractures; however, epiphyseal and diaphyseal fractures are also seen. In adults, metatarsal stress fractures and femoral pseudofractures prevail.
• Premature loss of deciduous teeth beginning with the incisors. Unusually and characteristically, the dental root remains attached to the lost tooth. Dental caries and early loss or extraction of adult teeth is also seen.
• Family history of any of the forms of hypophosphatasia consistent with autosomal recessive inheritance or autosomal dominant inheritance with variable expressivity

The radiographic signs of hypophosphatasia vary with age and type, and may be quite distinctive. Perinatal lethal hypophosphatasia is radiographically distinct. In milder cases, the combination of clinical, laboratory, and radiographic findings are required for diagnosis because the radiographic signs are not pathognomonic.

• Osteopenia, osteoporosis, or low bone mineral content for age detected by dual-energy x-ray absorptiometry (DEXA). Bone mineral content increases with age, and there may be improvement during adolescence with recurrence in middle age.
• Infantile rickets. Findings include undermineralized bones, widened-appearing sutures, brachycephaly, flail chest, rachitic costochondral rib changes (see Figure 1A), flared metaphyses (resulting in enlarged wrists, knees, and ankles), poorly ossified epiphyses, and bowed legs.
• Alveolar bone loss resulting in premature loss of deciduous teeth. This most typically involves the anterior mandible, with the central incisors lost first. However, any tooth may be affected (see Figure 1B).
• Focal bony defects of the metaphyses resembling radiolucent "tongues" (see Figure 1C). This feature is fairly specific for childhood (juvenile) hypophosphatasia.
• Metatarsal stress fractures in childhood (juvenile) and adult hypophosphatasia
• Osteomalacia with lateral pseudofractures (Looser zones) in adult hypophosphatasia (see Figure 1D)

Figure 1.

Radiographic signs of hypophosphatasia A. Rachitic rib changes, flail chest, and metaphyseal dysplasia (proximal humerus) in infantile hypophosphatasia B. Alveolar bone loss surrounding molars in childhood (juvenile) hypophosphatasia C. Hypolucent "tongue" (more...)

Laboratory Testing

Total serum alkaline phosphatase (ALP) activity: low. In all the types of hypophosphatasia, serum ALP activity is low.

• Laboratories both within and across countries use different methods and thus have very different reference ranges; the gender- and age-specific reference range determined by each reference laboratory should be used. See Table 2 (pdf) for typical lowest normal reference values.
• Transient increases in serum ALP activity in affected individuals invariably occur during pregnancy. Small increases in serum ALP activity may be seen with liver disease and acute fracture or surgery. Thus, serial measurement of serum ALP activity may be necessary when the diagnosis is suspected in toddlers with unexplained fractures.
• Quantitation of the activity of the bone isoform of ALP in serum is generally unnecessary; however, in the setting of liver disease, the serum activity of ALP may be "falsely" normal. The bone isoform is heat labile; the liver isoform heat stable.

Urine concentration of phosphoethanolamine (PEA): elevated

• This is the most commonly obtained secondary screen for hypophosphatasia. It may be obtained as part of a urine amino acid chromatogram.
• An elevated urine concentration of PEA supports the diagnosis of hypophosphatasia; however, the concentration in urine may be elevated with other metabolic bone disease and may be normal in affected individuals.
  Note: Finding an elevated urine concentration of proline adds specificity in interpretation of test results.
• Asymptomatic heterozygotes may have reduced serum ALP activity and increased urine PEA concentration.

Serum concentration of pyridoxal 5'-phosphate (PLP): elevated

• This biologically active metabolite of vitamin B₆ may be the most sensitive indicator of hypophosphatasia [Cole et al 1986].
• Many reference laboratories measuring vitamin B₆ either (1) measure PLP and report as “vitamin B₆” or (2) report the PLP level; thus, ordering “vitamin B₆” may suffice if PLP is not an option.
• Use of vitamin supplements within a week of assaying serum concentration of PLP may lead to false positive results.

Serum concentration of calcium, ionized calcium, and inorganic phosphate: normal

• Normal levels distinguish hypophosphatasia from other forms of rickets.
• Hypercalciuria may be present with or without elevated serum concentration of calcium.
• Although inorganic phosphate concentration in serum or urine is most typically normal, it may be elevated and thus is too variable to be used in diagnosis.

Serum concentration of vitamin D (25-hydroxy and 1,25-dihydroxy) and parathyroid hormone (nPTH): normal

Urine inorganic pyrophosphate (PPi): elevated

• This is a sensitive marker in affected individuals and asymptomatic heterozygotes.

Establishing the Diagnosis

Except in prenatal context where genetic diagnosis is essential, hypophosphatasia can be often diagnosed by routine clinical, biochemical, and radiographic means. The diagnosis is confirmed in a proband with identification of biallelic pathogenic variants or a heterozygous pathogenic variant in ALPL on molecular genetic testing (see Table 1).

Molecular testing approaches can include serial single-gene testing, use of a multi-gene panel, and more comprehensive genomic testing.

• Single-gene testing. Sequence analysis of ALPL is performed first, followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
• A multi-gene panel that includes ALPL and other genes of interest (see Differential Diagnosis) may also be considered. Note: The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time.
  For more information on multi-gene panels click here.
• More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if single-gene testing (and/or use of a multi-gene panel that includes ALPL) fails to confirm a diagnosis in an individual with features of hypophosphatasia. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene that results in a similar clinical presentation). For more information on comprehensive genome sequencing click here.

Test characteristics. See Clinical Utility Gene Card [Mornet et al 2014] for information on test characteristics including sensitivity and specificity.

Clinical Description

The clinical features of hypophosphatasia represent a spectrum ranging from stillbirth without mineralized bone to pathologic fractures of the lower extremities in later adulthood [Whyte 1994].

General features of hypophosphatasia. Clinical features of rickets or osteomalacia, of varying severity, are seen at all ages. Within families, several forms may be seen in family members with heterozygous or homozygous variants. Stillbirth without mineralized bone defines the most severe phenotype. “Paradoxical” rickets, in which the serum alkaline phosphatase is not elevated (as it would be in nutritional or renal rickets) is typical. Pathologic stress fractures of the lower extremities (femoral head, tibia, and metatarsals) in older adults define the mild end. All cases are characterized by:

• Defective mineralization of bone and/or teeth;
• Reduced serum alkaline phosphatase (ALP) activity.

Histologic evaluation

• Bone histology reveals rachitic abnormalities of the growth plate. Histochemical testing of osteoclasts reveals lack of membrane-associated ALP activity. Osteoclasts and osteoblasts otherwise appear normal.
• Tooth histology reveals a decrease in cementum, which varies with the severity of the disease.

Specific phenotypes include the following:

• 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 liveborn and stillborn infants. A flail chest may be present (Figure 1A). 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.
• 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 [Pauli et al 1999, Wenkert et al 2011].
• Infantile hypophosphatasia cases may be normal at birth. Clinical signs may be recognized between birth and age six months and resemble rickets (Figure 1A). 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.
  Clinical severity depends on the degree of pulmonary insufficiency; the infantile phenotype has high mortality, with 50% of individuals succumbing to respiratory failure caused by undermineralization of the ribs. Other complications include hypercalcemia, irritability, poor feeding, failure to thrive, hypotonia, and more rarely vitamin B₆-dependent seizures (see Management). Older children may have renal damage.
• Childhood (juvenile) hypophosphatasia displays wide variability in clinical presentation, ranging from low bone mineral density for age with unexplained fractures to rickets. Children may have premature loss of deciduous teeth (age <5 years), usually beginning with incisors, with the dental root characteristically remaining attached to the lost tooth. More severely affected toddlers have short stature and delay in walking, and develop a waddling myopathic gait. Bone and joint pain are typical. Diaphyseal and metaphyseal fractures may occur.
• Adult hypophosphatasia is sometimes associated with a history of transient rickets in childhood (“juvenile onset”) and/or premature loss of deciduous teeth. Early loss of adult dentition is common. 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. Foot pain and slow-to-heal stress fractures of the metatarsals are common. Thigh and hip pain may reflect pseudofractures ("Looser zones") in the lateral cortex of the femoral diaphysis (Figure 1C). Chondrocalcinosis and osteoarthropathy may develop with age. Osteomalacia distinguishes adult hypophosphatasia from odontohypophosphatasia.
• Odontohypophosphatasia can be seen as an isolated finding without additional abnormalities of the skeletal system or can be variably seen in the above forms of hypophosphatasia. Premature exfoliation of primary teeth and/or severe dental caries may be seen, with the incisors most frequently lost.

Genotype-Phenotype Correlations

Most patients with hypophosphatasia have unique genotypes, making genotype-phenotype correlation difficult. However site-directed mutagenesis experiments identified alleles producing significant residual enzymatic activity and alleles showing a dominant negative effect (see Molecular Genetics). Less severe phenotypes are correlated with alleles allowing residual enzymatic activity in recessive hypophosphatasia, and with alleles exhibiting a dominant negative effect in dominant hypophosphatasia [Fauvert et al 2009]. Clinical features of patients with reported variants, as well as residual enzyme activity for some of those variants, can be found at www.sesep.uvsq.fr.

Nomenclature

Hypophosphatasia takes its name from low activity of the enzyme alkaline phosphatase, 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 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 1:2500, for a carrier frequency of 1:25.

On the basis of molecular diagnosis in France and in Europe, the prevalence of severe forms has been estimated at 1:300,000 [Mornet et al 2011]. For mild forms (prenatal benign, childhood [juvenile], adult and odontohypophosphatasia), the prevalence is expected to be as high as 1:6300 [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 frequency of heterozygotes for ALPL pathogenic variants in France is about 1:275.

In Japan, the birth prevalence of severe hypophosphatasia may be estimated at 1:150,000 on the basis on the frequency of individuals homozygous for the pathogenic variant c.1559delT (1:900,000 [Watanabe et al 2011]) and on the proportion of this allele in Japanese patients (40.9% [Michigami et al 2005])

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 outside of North Africa; however, clinical ascertainment bias is likely significant. African American individuals with hypophosphatasia are rare; it is assumed that pathogenic variants in this population represent European admixture.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with hypophosphatasia, the following evaluations are recommended:

• Blood urea nitrogen and serum creatinine concentration to assess renal function
• Serum concentration of calcium, phosphorus, magnesium
• Serum concentration of 25(OH) and 1,25(OH)2 vitamin D, nPTH (parathyroid hormone, N-terminal part) to assess rickets
• Assessment of pulmonary function in infants with the perinatal type to assist in prognosis and distinguishing between the perinatal (severe) type and the perinatal (benign) type
• Radiographs of the skull to assess for craniosynostosis in young children with the infantile form of hypophosphatasia
• Baseline dental evaluation
• Baseline orthopedic evaluation
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Management at all ages focuses on supportive therapy to minimize disease-related complications.

Multidisciplinary management at various ages may include:

• Endocrinology to optimize bone homeostasis and avoid exacerbating treatments
• Nephrology to monitor calcium homeostasis and examine for nephrocalcinosis
• Neurology to prophylactically or prospectively treat seizures and manage myopathy
• Neurosurgery or craniofacial team to manage pseudocraniosynostosis
• Orthopedics to manage primary and secondary skeletal manifestations
• Physical medicine and rehabilitation (PM&R), physical therapy, and occupational therapy to optimize mobility and autonomy
• Pain management
• Psychological support
• Pediatric and adult dentistry to manage tooth loss

The involvement of multiple specialists treating complex interrelated medical issues mandates case management and social work support.

Enzyme Replacement Therapy

The emergence of tissue-nonspecific alkaline phosphatase (TNSALP) enzyme replacement therapy (ERT) with asfotase alfa (Strensiq™) has altered the natural history of severe perinatal and infantile HPP cases; the long-term effects of treatment are not fully known. A new phenotype of “treated perinatal and infantile HPP” is emerging, and the prior designation of “perinatal lethal HPP” may no longer universally apply in the developed world.

In October 2015, the FDA approved asfotase alfa for treatment of patients with perinatal, infantile, and juvenile onset HPP [Alexion –10-23-2015].

• Perinatal/infantile HPP study outcomes. In two prospective, single-arm studies (with historical controls used for survival analysis), 68 individuals with severe, perinatal/infantile-onset HPP (age at treatment onset: 1 day – 78 months) completed at least 24-weeks of TNSALP ERT (≤9 mg/kg weekly, administered subcutaneously) [Whyte et al 2016] (final data).
  • Survival. Of those requiring respiratory support (n = 26), 21 (81%) survived through the last date of assessment (median age 3.2 years), in comparison to 1:20 (5%) in historical controls.
  • In the mixed cohort of 68 patients with perinatal/infantile onset HPP receiving asfotase alfa ERT, 54 required mechanical ventilation and of these, 91% survived and 85% were ventilator free at last contact, in comparison to 27% overall survival and 25% ventilator free in the 48 historical controls [Whyte et al 2016] (final data). Clinical trials with ERT have shown improvement in developmental milestones and pulmonary function [Whyte et al 2012].
  • Bone findings. Radiographs from 64 of these individuals, and four from a third prospective open-label study of juvenile-onset HPP, were evaluated for HPP-related rickets using the 7-point Radiographic Global Impression of Change (RGI-C) scale. Radiographic change of at least +2 (defined as “responders”) were seen in 50/68 (74%) of those treated (see Figure 2), at last assessment (historical comparative data does not exist). Eighteen individuals with perinatal/infantile-onset HPP experienced fractures during the course of treatment; the effect of asfotase alfa on fractures remaining unclear [Whyte et al 2016] (final data).
• Juvenile-onset HPP study outcomes. One prospective open-label, single arm study included eight patients with juvenile-onset HPP and five patients with perinatal/infantile-onset HPP; age at treatment onset was six to 12 years. The patients with juvenile-onset HPP completed at least 48 months of TNSALP ERT (6 mg/kg weekly, administered subcutaneously). The eight juvenile-onset patients were compared with 32 historical controls. By the RGI-C rating of radiographs, all eight patients were deemed responders; two (6%) of the historical controls were rated responders with an improvement of +2 or more at month 54. Gait, assessed using a modified Performance Oriented Mobility Assessment Gait (MPOMA-G), six-minute walk test (6MWT), and step length improved in patients treated with asfotase alfa. 6MWT improved to the normal range in six of six patients assessed by month 48, from none at baseline. The data are at present insufficient to assess the effect of asfotase alfa on fractures in juvenile-onset HPP [Whyte et al 2016] (final data).

Figure 2.

Radiograph of treated hypophosphatasia A. Patient from Figure 1A after 12 months asfotase alfa enzyme replacement therapy B. Note tracheostomy tube, placed for laryngomalacia and bronchomalacia, features of the treated disease C. Rachitic rib and metaphyseal (more...)

Prevention of Primary Manifestations

Low-impact physical activity and exercise may improve general bone health. Supervision by a physician specialist familiar with hypophosphatasia is suggested.

Prevention of Secondary Complications

Calcium supplementation and vitamin D therapy may prevent secondary hyperparathyroidism in adults. This should only be pursued with close monitoring by a physician specialist familiar with hypophosphatasia.

Surveillance

Children with hypophosphatasia should be seen by a pediatric dentist twice yearly, beginning at age one year.

Children with the infantile type of hypophosphatasia are at elevated risk for increased intracranial pressure secondary to craniosynostosis, and should be monitored for this complication.

Agents/Circumstances to Avoid

Biphosphonates are relatively contraindicated in hypophosphatasia. Although adverse outcomes have not been identified in children with the severe infantile type [Deeb et al 2000], theoretic concern has long been raised based on the structure of bisphosphonates. The phosphate motifs in bisphosphonates have a similar conformation to inorganic pyrophosphate (PPi), the natural substrate of TNSALP; thus, treatment with bisphosphonates is thought to be analogous to "adding fuel to the fire." In adults with hypophosphatasia and osteomalacia treated with bisphosphonates, lateral subtrochanteric femoral pseudofractures have been described [Whyte 2009]. As the prevalence of adult hypophosphatasia is not known and many undiagnosed adult patients undoubtedly are treated with bisphosphonates, the frequency of this unusual complication is not known.

Excess vitamin D can exacerbate hypercalcemia/hypercalciuria in children with infantile hypophosphatasia who have hypercalcemia.

Teriparatide (recombinant human parathyroid hormone fragment, amino acids 1-34) at high doses induces osteosarcoma in rats, and may increase the risk of radiation-induced osteosarcoma (a pediatric growth plate tumor) in humans. It is contraindicated in children with hypophosphatasia.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Enzyme replacement therapy (ERT). Autosomal recessive hypophosphatasia remains an extremely rare and severe condition. The treatment duration and long-term effects of ERT with asfotase alfa remain unknown for perinatal and infantile HPP. Clinical trials are in Phase IV, with patients treated up to 78 months at the time of FDA approval.

For milder autosomal recessive and autosomal dominant childhood (juvenile) and adult-onset HPP, limited information about asfotase alfa exists; clinical trials are underway in children, adolescents, and adults.

Bone marrow transplantation (hematopoietic cell transplantation) was used to treat an eight-month-old girl with severe hypophosphatasia with prolonged, significant clinical and radiologic improvement [Whyte et al 2003]. Seven years after transplantation, the patient was reported to be active and growing, and to have the clinical phenotype of the more mild childhood (juvenile) form of hypophosphatasia [Cahill et al 2007]. In another trial, both bone marrow and allogenic mesenchymal stem cells were implanted in an eight-month old patient, resulting in improvement of respiratory conditions [Tadokoro et al 2009]. However,the patient developed therapy-related leukemia [Taketani et al 2013]. Transplantation of ex vivo expanded mesenchymal stem cells for patients who had previously undergone bone marrow transplantation improved bone mineralization, muscle mass, respiratory function, intellectual development, and survival [Taketani et al 2015].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Perinatal and most infantile cases of infantile hypophosphatasia are 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 of the ALPL pathogenic variant on TNSALP activity [Fauvert et al 2009].

Risk to Family Members – Autosomal Recessive Inheritance

Parents of a proband

• In most cases, the parents of a child with an autosomal recessive form of hypophosphatasia are obligate heterozygotes (i.e., carriers of one ALPL pathogenic variant).
• In extremely rare cases, only one parent of an affected child is heterozygous for an ALPL pathogenic variant.
  • Taillandier et al [2005] and Zhang et al [2012] each reported one case of a de novo pathogenic variant in the second ALPL allele in an individual with autosomal recessive hypophosphatasia.
  • Uniparental disomy of chromosome 1 was reported as the cause of recessive hypophosphatasia in two cases [Watanabe et al 2014, Hancarova et al 2015].
• Depending on the ALPL pathogenic variant, heterozygous parents are either clinically asymptomatic (manifesting only biochemical abnormality) or have milder clinical symptoms than their child. Determining the mode of inheritance in families with mildly affected parents is difficult and may lead to consideration of autosomal dominant inheritance.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being heterozygous for an ALPL pathogenic variant, and a 25% chance of being unaffected and not a carrier.
• Depending on the ALPL pathogenic variant, heterozygous sibs can be either clinically asymptomatic (manifesting only biochemical abnormality) or have milder clinical symptoms than the proband.

Offspring of a proband. The offspring of an individual with autosomal recessive hypophosphatasia are obligate heterozygotes (carriers) for a pathogenic variant in ALPL.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier of a pathogenic variant in ALPL.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the ALPL pathogenic variants in the family.

Risk to Family Members – Autosomal Dominant Inheritance

Parents of a proband

• To date, all reported individuals diagnosed with the autosomal dominant form of hypophosphatasia have inherited an ALPL pathogenic variant from a parent (who may or may not have symptoms).
• A de novo ALPL pathogenic variant in the autosomal dominant form of hypophosphatasia has not been reported to date.
• If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo pathogenic variant in the proband.
• Recommendations for the evaluation of parents of a proband include review of clinical history and laboratory evaluations for signs of hypophosphatasia. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome, reduced penetrance, and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• If a parent of the proband has the ALPL pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. Clinical severity is often similar in affected family members but cannot be reliably predicted by family history or molecular genetic testing due to reduced penetrance and variable expressivity.

Offspring of a proband. Each child of an individual with the autosomal dominant form of hypophosphatasia has a 50% chance of inheriting the ALPL pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has an ALPL pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

Determining the mode of inheritance can be difficult in some families as expression of the disease may be highly variable, with parents of even markedly affected children showing no or extremely mild symptoms of the disease.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Pregnancy with high a priori risk (pregnancy known to be at increased risk based on family history)

• Molecular genetic testing. Once the ALPL pathogenic variant(s) have been identified in an affected family member, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic diagnosis for hypophophatasia are possible.
• Fetal ultrasonography. Recurrence of perinatal hypophosphatasia may reliably be identified by prenatal ultrasound examination. Undermineralization, small thoracic cavity, shortened long bones, and bowing are typical features of autosomal recessive and severe hypophosphatasia. Long bone bowing has been reported prenatally in affected sibs and in children of individuals with childhood (juvenile) or adult hypophosphatasia, but the finding is not diagnostic of perinatal hypophosphatasia since it may be prenatal benign hypophosphatasia, a clinical form that can improve during later stages of pregnancy and result in nonlethal hypophosphatasia [Moore et al 1999, Pauli et al 1999, Wenkert et al 2011].
• Biochemical testing. Concentration of alkaline phosphatase in amniotic fluid, amniocytes, and chorionic villous samples is prone to misinterpretation (particularly in distinguishing unaffected heterozygotes); molecular genetic testing is the preferred method in confirming prenatal diagnosis [Mornet et al 1999].

Pregnancy with low a priori risk (pregnancy not known to be at risk)

• Fetal ultrasonography. Although perinatal hypophosphatasia may be distinguished from other skeletal dysplasias by prenatal ultrasonography, care must be taken in the interpretation of bowed long bones. Undermineralization, small thoracic cavity, shortened long bones, and bowing are typical features of autosomal recessive and severe hypophosphatasia. However, prognosis is difficult to predict based on ultrasound findings alone. Bowed and shortened long bones have been observed on prenatal ultrasound in individuals who ultimately were shown to have benign perinatal, childhood (juvenile), and adult hypophosphatasia. The bowing resolves postnatally. In 50% of the cases, when ALPL molecular testing has been performed, a single pathogenic variant in ALPL has been identified, confirming the benign nature of the phenotype and excluding perinatal (severe) hypophosphatasia.

Literature Cited

• Brun-Heath I, Lia-Baldini AS, Maillard S, Taillandier A, Utsch B, Nunes ME, Serre JL, Mornet E. Delayed transport of tissue-nonspecific alkaline phosphatase with missense mutations causing hypophosphatasia. Eur J Med Genet. 2007;50:367–78. [PubMed: 17719863]
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Suggested Reading

• Whyte MP. Hypophosphatasia. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 207. New York, NY: McGraw-Hill. Available online. Accessed 3-30-17.

Author Notes

• ALPL Mutation Database
• Pediatric Laboratory Reference Intervals for alkaline phosphatase [Colantonio et al 2012] (see Supplemental Table 2)

Revision History

• 4 February 2016 (ha) Comprehensive update posted live
• 10 November 2011 (cd) Revision: deletion/duplication analysis of ALPL available clinically
• 5 August 2010 (me) Comprehensive update posted live
• 20 November 2007 (me) Review posted to live Web site
• 18 December 2006 (men) Original submission