Pediatric Summary Report Secondary Findings in Pediatric Subjects Non-diagnostic, excludes newborn screening & prenatal testing/screening P Current Version Rule-Out Dashboard Release History Status (Pediatric): Passed (Consensus scoring is Complete) Curation Status (Pediatric): Released

Condition: Hypophosphatasia
Narrative Description of Evidence
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
The prevalence of severe forms (perinatal and infantile) of hypophosphatasia (HP) has been estimated to be between 1:300,000 to 1:100,000. For mild forms (prenatal benign, childhood, adult, and odonto-HP), the prevalence is expected to be around 1:6300.
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Clinical Features
(Signs / symptoms)
HP is characterized by defective mineralization of bone and/or teeth and reduced serum and bone alkaline phosphatase activity. Although the disease spectrum is a continuum, from stillbirth without mineralized bone to pathologic fractures in later adulthood, HP has been divided to six subtypes based on clinical course and severity. The perinatal (severe) form results in stillbirth or death shortly after birth. The prenatal (benign form), despite skeletal abnormalities on ultrasound, has spontaneous improvement after birth and patients slowly resolve to a non-lethal form. The infantile form includes rickets, nephrocalcinosis due to hypercalciuria, and loss of deciduous teeth. The childhood (juvenile) form ranges in severity from low bone mineral density for age with unexplained fractures to rickets as well as premature loss of teeth. Adult HP presents with pseudofractures and stress fractures in the lower extremities. Many patients present with early loss of permanent teeth. Odonto-HP is characterized by dental anomalies without abnormalities of the skeletal system. Dental anomalies are common in all forms of HP. These include abnormal tooth shape, abnormal tooth structure, tooth color, dental anomalies of tooth eruption/exfoliation with premature loss of predominantly the primary and also permanent dentition; delayed eruption of teeth and primary teeth impaction are also recorded.
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Natural History
(Important subgroups & survival / recovery)
Clinical signs of the infantile form appear during the first 6 months of life and has high mortality, with 50% succumbing to respiratory failure due to undermineralization of the ribs. The emergence of tissue-nonspecific alkaline phosphatase (TNSALP) enzyme replacement therapy (ERT) with asfotase alfa has altered the natural history of severe perinatal and infantile HP cases. A new phenotype of “treated perinatal and infantile HPP” is emerging, and the prior designation of “perinatal lethal HP” may no longer universally apply in the developed world. The childhood form in most cases presents after the first 6 months of life and before 5 years. Adult HP presents during middle age, though the patient may have had mild rickets in childhood. Prognosis depends on clinical course and severity. Patients with adult or odonto-HP are believed to have a normal lifespan. The prevalence in Canadian Mennonites may be higher, at up to 1 in 2500 persons, with a carrier frequency of 1/25. African-American individuals with HP are rare.
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2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
To establish the extent of disease and needs in an individual diagnosed with HP, 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
•Baseline dental evaluation
•Baseline orthopedic evaluation (Tier 4)
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 (Tier 4)
TNSALP ERT has received FDA approval in three settings: perinatal, infantile, and juvenile onset HP. However, the long-term effects of treatment are not fully known. In two prospective, single-arm studies, 68 individuals with severe, perinatal/infantile HP completed 24-weeks of ERT beginning at age 1 day – 78 months. Of patients requiring respiratory support (n = 26), 81% (n = 21) survived through the last date of assessment (median age 3.2 years) versus a 5% survival rate in historical controls. Further, 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 48 historical controls. Radiographs from 64 of these individuals indicated improvement on the Radiographic Global Impression of Change (RGI-C) scale (defined as “responders”) in 74% at last assessment, though comparative historical data does not exist. Eighteen individuals with perinatal/infantile HP experienced fractures during treatment; the effect of ERT on fractures remains unclear. In a prospective open-label, single arm study, 8 patients with juvenile HP completed at least 48 months of therapy and were compared to 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. Gait also improved in patients treated with ERT, with a 6-minute walk test improving to the normal range in six of six patients assessed by month 48, from none at baseline. The data are at present are insufficient to assess the effect of ERT on fractures in juvenile HP. The long-term effects of treatment are not fully known. (Tier 3)
In the dental setting, emphasis is placed on oral hygiene, appropriate use of fluoride and preventive treatment. Early loss of both primary and/or permanent teeth may be very distressful and may impair maxillary or mandibular development and therefore could be managed through prosthetic appliances (Tier 4)
Low-impact physical activity and exercise may improve general bone health, build muscle, and stabilize skeleton. Supervision by a physician specialist familiar with hypophosphatasia is suggested. (Tier 4)
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Children with hypophosphatasia should be seen by a pediatric dentist twice yearly, beginning at age one year to preserve primary dentition (to support nutrition) and to preserve or replace secondary dentition (Tier 4)
Children with the infantile type of hypophosphatasia are at elevated risk for increased intracranial pressure secondary to craniosynostosis and should be monitored by a neurosurgeon for this complication. Surveillance should include ophthalmic reassessment, neurological examination and radiographic imaging throughout childhood until adolescence, and, in presence of Chiari I malformation or hydrosyringomyelia, probably throughout lifetime. (Tier 4)
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Circumstances to Avoid
Treatment with bisphosphonates, commonly used for rickets, may be detrimental. Although adverse outcomes have not been identified in the infantile type, there is a plausible molecular mechanism for adverse outcomes based on the structure of bisphosphonates. Further, in adults with HP and osteomalacia treated with bisphosphonates, lateral subtrochanteric femoral pseudofractures have been described. As the prevalence of adult HP is not known and many undiagnosed adult patients undoubtedly are treated with bisphosphonates, the frequency of this unusual complication is not known. (Tier 3)
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Excess vitamin D can exacerbate hypercalcemia/hypercalciuria in children with infantile HP who have hypercalcemia. As such vitamin D therapy regimens for rickets should also be avoided. (Tier 4)
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Trauma to the skeleton should be avoided due to the fact that fractures may take a long time to heal and be difficult to treat. (Tier 4)
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 HP. (Tier 4)
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Recessive
The perinatal and infantile-onset forms are inherited in an autosomal recessive manner, while milder childhood and adulthood onset forms can be inherited in either an autosomal dominant or recessive manner.
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Prevalence of Genetic Mutations
Applying the Hardy-Weinberg equation to prevalence estimates of the disorder, carrier frequency for severe forms (perinatal and infantile) is estimated between 1:275-1:150. (Tier 3)
(Include any high risk racial or ethnic subgroups)
The penetrance is suggested to be 100% for persons inheriting the condition recessively. The penetrance for mild forms with dominant inheritance is 30-40%, depending on the mutation. (Tier 4)
The infantile form has high mortality, with 50% succumbing to respiratory failure due to undermineralization of the ribs. (Tier 4)
Relative Risk
(Include any high risk racial or ethnic subgroups)
Information on relative risk was not available for the Pediatric context.
Within some families, expression can be highly variable, with several forms seen in family members with heterozygous or homozygous variants. Parents of even markedly affected children may show no or extremely mild symptoms of the disease. (Tier 4)
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4. What is the Nature of the Intervention?
Nature of Intervention
Enzyme replacement therapy requires once weekly subcutaneous injection administration. The most common adverse events seen in clinical trials leading to FDA approval were injection site reactions (63%), lipodystrophy (28%), ectopic calcifications (14%), and hypersensitivity reactions (12%). Eye and kidney monitoring is required for ectopic calcification at baseline and periodically during treatment. In clinical trials, 1% of patients experienced signs and symptoms consistent with anaphylaxis.
The involvement of multiple specialists treating complex interrelated medical issues mandates case management and social work support.
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
Even in the setting of a symptomatic patient, differential diagnosis without genetic testing is difficult, especially in the case of an adult or childhood presentation. (Tier 4)
Despite having signs or symptoms (such as transient rickets and premature loss of deciduous teeth) in childhood or adolescence, the “adulthood onset” form is typically not diagnosed until middle age. (Tier 4)
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Scoring Groups Info
Scoring Group
Gene Disease Pair(s)

Final Consensus Scores
OutcomeScoring Group / InterventionScoring GroupPair
Nature of the
Rickets/fractures GroupA / Enzyme Replacement Therapy GroupA
Adverse events (e.g., atypical femoral fractures) GroupA / Avoid bisphosphonates GroupA
Respiratory failure that can lead to long-term ventilatory support or death (infantile) GroupB / Enzyme Replacement Therapy GroupB
To see the scoring key, please go to:
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Reference List
1. Mornet E, Hofmann C, Bloch-Zupan A, Girschick H, Le Merrer M. Clinical utility gene card for: hypophosphatasia - update 2013. Eur J Hum Genet. (2014) 22(4).
2. Hypophosphatasia. Orphanet encyclopedia,
3. E Mornet, ME Nunes. Hypophosphatasia. 2007 Nov 20 [Updated 2016 Feb 04]. In: MP Adam, HH Ardinger, RA Pagon, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from:
4. Infantile hypophosphatasia. Orphanet encyclopedia,
5. Childhood-onset hypophosphatasia. Orphanet encyclopedia,
6. Perinatal lethal hypophosphatasia. Orphanet encyclopedia,
7. Adult hypophosphatasia. Orphanet encyclopedia,
8. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. HYPOPHOSPHATASIA, INFANTILE. MIM: 241500: 2016 Oct 13. World Wide Web URL:
9. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. HYPOPHOSPHATASIA, CHILDHOOD. MIM: 241510: 2012 Apr 02. World Wide Web URL:
10. Prenatal benign hypophosphatasia. Orphanet encyclopedia,
11. Odontohypophosphatasia. Orphanet encyclopedia,
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