Hypophosphatasia

Actionability Adult Summary Report

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Gene: ALPL (HGNC:438)
• Mode(s) of Inheritance: Autosomal Recessive
• Literature Search: 01/09/2025
• Curation Status: Released (1.0.0)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
ALPL	hypophosphatasia (0018570)	241500	Moderate Actionability
ALPL	hypophosphatasia (0018570)	241510	Moderate Actionability
ALPL	hypophosphatasia (0018570)	146300	Moderate Actionability

Actionability Assertion Rationale

• All experts agreed with the assertion computed according to the rubric, recognizing that there is limited effectiveness data in adult onset disease and ERT is not approved specifically in adults.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Morbidity from hypophosphatasia / Referral to specialist for management including enzyme replacement therapy as appropriate.	1	3N	2D	2	8ND

Severity of Outcome

Prevalence of the Genetic Condition

Prevalence of the severe forms (perinatal and infantile) of hypophosphatasia (HP) have 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.

Clinical Features (Signs / symptoms)

HP 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. 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. While the disease spectrum is a continuum, seven clinical forms of HP are recognized based on age at diagnosis and severity of features. The perinatal (severe) form is characterized by pulmonary insufficiency and hypercalcemia and is typically identified by prenatal ultrasound examination. The prenatal (benign) form has prenatal skeletal manifestations that slowly resolve into one of the milder forms. The infantile form includes rickets, nephrocalcinosis due to hypercalciuria, and loss of deciduous teeth, and clinical severity depends on the degree of pulmonary insufficiency. Other complications include hypercalcemia, irritability, poor feeding, failure to thrive, hypotonia, and more rarely vitamin B6-responsive seizures. Craniosynostosis and intracranial hypertension are potential complications, and older children may have kidney damage. The severe childhood (juvenile) form has variable presenting features that progress to rickets; more severely affected toddlers have short stature and delays in walking; bone and joint pain are typical. Diaphyseal and metaphyseal fractures may occur. The mild childhood form has low bone mineral density for age, increased risk of fractures and premature loss of deciduous teeth (prior to age 5 years) with the dental root characteristically remaining attached to the lost tooth. The adult form presents with pseudofractures and stress fractures in the lower extremities in middle age and can be associated with early loss of adult dentition. Foot pain and slow-to-heal stress fractures of the metatarsals are common. Chondrocalcinosis and osteoarthropathy may develop with age. Osteomalacia distinguishes adult HP from odonto-HP. Odonto-HP is characterized by premature exfoliation of primary teeth (with first teeth usually lost by age two years) and/or severe dental caries, as well as abnormal color, shape and structure of the teeth, without skeletal manifestations, or it can be variably seen in the other forms of HP.

Natural History (Important subgroups & survival / recovery)

The emergence of enzyme replacement therapy (ERT) with asfotase alfa has altered the natural history of severe perinatal and infantile HP. A new phenotype of “treated perinatal and infantile HP” is emerging. However, even when the diagnosis is made expediently, unfavorable outcomes with ERT are possible. Clinical signs of the infantile form appear during the first 6 months of life and has high mortality. Prior to the availability of ERT, survival rates of 42 and 27% at age 1 and 5 years, respectively, were reported due to respiratory failure in perinatal and infantile HP. 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 and/or premature loss of deciduous teeth. Prognosis depends on clinical course and severity; disease burden throughout an individual patient's life is not well understood. Substantial morbidities may develop during the lifetime of a patient with HP, who may have increasing disease burden resulting from joint problems, fractures, orthopedic/dental surgeries, pain, muscular insufficiency, decreased functional status, and impaired mobility. Patients with adult or odonto-HP are believed to have a normal lifespan. Loss of teeth may have functional and aesthetic consequences.

Likelihood of Outcome

Mode of Inheritance

Autosomal Recessive

Prevalence of Genetic Variants

Unknown

In individuals with severe (perinatal and infantile) HP, sequence analysis detects biallelic ALPL pathogenic variants in approximately 95% of individuals of European ancestry. In other clinical phenotypes, the proportion of pathogenic variants detected is difficult to estimate.

Tier 4

1-2 in 500

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

Penetrance (Includes any high-risk racial or ethnic subgroups)

>= 40 %

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 pathogenic variant.

Tier 4

>= 40 %

Using case report data, a systematic review evaluated the frequency and timing (age at occurrence) of clinical manifestations/events related to HP in 265 patients (median age 4 [0-34] years) with ≥1 year of longitudinal follow-up and found that 94% experienced ≥1 manifestation/event, regardless of when the disease first manifested. They also found that the most reported clinical manifestations/events were:

• Across all age groups: premature tooth loss: 53%, fractures: 35.8%, pain 33.6%, gross motor/ambulation difficulties: 30.9%

• In utero age range (n=30): one or more fractures (40.0%), gross motor/ambulation difficulties (23.3.%), cranial abnormalities (40.0%), respiratory symptoms (16.7%), premature loss of teeth (10.0%), pain (3.3%)

• Infancy age range (n=102): premature loss of teeth (61.8%), cranial abnormalities (43.1%), gross motor/ambulation difficulties (40.2%), pain (24.5%), one or more fractures (18.8%), respiratory symptoms (13.7%)

• Childhood age range (n=78): premature loss of teeth (74.4%), pain (41.0%), one or more fractures (34.6%), gross motor/ambulation difficulties (23.1%), cranial abnormalities (12.8%)

• Adolescence age range (n=9): pain (66.7%), premature loss of teeth (33.3%), one or more fractures (33.3%), gross motor/ambulation difficulties (11.0%)

• Adulthood age range (n=46): one or more fractures (73.9%), pain (54.3%), gross motor/ambulation difficulties (32.6%), premature loss of teeth (30.4%)

Tier 5

>= 40 %

Of adult patients with pediatric onset HP:

• 95% experienced pain

• 86% experienced fragility fractures

• 62% had muscle weakness

• 60% used gait aids

Tier 3

Expressivity

Intrafamilial clinical variability is common, particularly when some affected family members have a heterozygous pathogenic variant and other affected family members have biallelic pathogenic variants. Siblings 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.

Tier 4

Most individuals with HP have unique ALPL pathogenic variants, preventing the identification of genotype-phenotype correlations.

Tier 4

A study of 44 adolescents and adults with childhood or adult HP compared clinical characteristics between patients with autosomal recessive disease (30 patients) and autosomal dominant disease (14 patients). Median age of onset of symptoms in patients with recessive disease was 1 year, with a range of 0-4 years, and the median age of onset of symptoms in patients with dominant disease was 4 years, with a range of 0 to 36 years. A large percentage of both groups experienced bone pain, abnormal gait, and fractures. Abnormally shaped head or chest, bowing of the limbs, and delayed walking were more common in patients with recessive disease. Patients with dominant disease had a higher number of fractures.

Tier 3

Less severe phenotypes have been observed in individuals with biallelic loss-of-function variants that allow residual enzymatic activity or heterozygous variants exhibiting a dominant-negative effect.

Tier 3

Intervention Effectiveness

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 (all ages)

• Serum concentration of calcium, phosphorus, magnesium (infants)

• Serum concentration of 25(OH) and 1,25(OH)2 vitamin D, nPTH (parathyroid hormone, N-terminal part) to assess for confounding comorbidity (older individuals)

• Assessment of pulmonary function to assist in prognosis and distinguishing between the perinatal types (infants)

• Radiographs of the skull to assess for craniosynostosis (all ages)

• Baseline dental evaluation (by 1 year of age)

• Baseline orthopedic evaluation (all ages)

Tier 4

At all ages, supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields:

• Endocrinology to optimize bone homeostasis and avoid exacerbating treatments

• Respiratory support per pulmonologist

• Nephrology to monitor calcium homeostasis and assess for nephrocalcinosis

• Neurology to prophylactically or prospectively treat seizures and manage myopathy

• Neurosurgery or craniofacial team to manage complications including intracranial hypertension and indication for surgical release

• Orthopedics to manage primary and secondary skeletal manifestations

• Physical medicine and rehabilitation, physical therapy, and occupational therapy to optimize mobility and autonomy

• Pain management

• Psychological support

• Pediatric and adult dentistry to preserve primary dentition and to preserve or replace secondary dentition

Tier 4

ERT in the form of asfotase alfa is available for individuals of any age with pediatric onset HP who meet clinical criteria for treatment. There is general agreement that children with only the odonto-HP form of the disease are not candidates for ERT. Adults can be considered for treatment with ERT if they meet specific criteria. Prior to proceeding with ERT, a confirmed diagnosis of HP is required with identification of the goals of therapy.

Tier 2

A recent systematic review evaluated the efficacy of asfotase alfa in patients with HP; 15 articles with a total of 455 patients (ages ranging from 91 days to 55 years) with HP were included. The average treatment duration ranged from 12.1 to 79.2 months. In 95.4 % of cases, HP onset occurred during the pediatric period (perinatal, infantile, and childhood), with only 22 cases occurring in adulthood. More than half of the studies were conducted in a multicenter and multinational manner. Overall findings include enhanced survival rates, relief from musculoskeletal pain, improvements in respiratory outcomes, improvement in growth parameters, and improvement in dental health:

• Survival: Improved survival rates were from one study of patients with the perinatal and infantile forms of HP evaluating asfotase alfa treatment (37 treated patients) compared to data from similar patients from a retrospective natural history study (48 historical controls of similar chronological age and HP characteristics). Asfotase alfa was associated with improved survival in treated patients vs historical controls: 95% vs 42% at age 1 year and 84% vs 27% at age 5 years, respectively (p<.0001). Whereas 5% (1/20) of the historical controls who required ventilatory assistance survived, 76% (16/21) of the ventilated and treated patients survived, among whom 75% (12/16) were weaned from ventilatory support.

• Musculoskeletal pain: Multiple studies showed improvements in muscle fatigue with treatment using asfotase alfa; among 22 patients (including children and adults) nearly half experienced significant relief from musculoskeletal pain. One study found that after 5 years of treatment, most patients described being pain free, as well as free from any disability. There were also significant improvements in various aspects of musculoskeletal health, including increases in median distance walked and muscle strength (patient populations included adolescents and adults with pediatric-onset HP). However, there is a degree of variability in treatment response, with some studies reporting no significant improvement in individual’s musculoskeletal symptoms or pain.

• Respiratory outcomes: Across three studies, improvement in respiratory outcomes was observed among patients (infants and young children) receiving asfotase alfa treatment. Among the 49 patients initially requiring respiratory support, 65.3% no longer needed such assistance following treatment. Among five perinatal patients who experienced respiratory distress at birth, there were significant improvements in all after treatment with asfotase alfa. These improvements included increased lung volume, normalized airways, the absence of dynamic collapse during breathing at rest, and breathing during the day without ventilator support.

• Growth parameters: After undergoing asfotase alfa treatment, various growth parameters exhibited notable improvements in a pediatric population (infants and young children).

• Dental health: One study evaluated impact of age of asfotase alfa treatment initiation on dental health outcomes for infantile HP. They found that infants who started treatment earlier (mean age 3.0+/- 2.3 months) had significantly fewer teeth lost compared to children who started treatment later (mean age 52.5 +/- 11.3 months).

Tier 1

In adults with HP, calcium and vitamin D supplementation may prevent secondary hyperparathyroidism. This treatment should only be pursued with close monitoring by a specialist familiar with HP.

Tier 4

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 HP is suggested.

Tier 4

Surveillance

Recommended surveillance for individuals with HP include:

• Endocrinology and/or nephrology, and orthopedic follow-up (frequency per provider)

• Neurosurgery follow-up to monitor for increased intracranial pressure secondary to craniosynostosis in infantile type (frequency per neurosurgeon)

• Physical medicine and rehabilitation, physical therapy, and occupational therapy (as needed)

• Neurology evaluation (as needed)

• Dental evaluations beginning at one year of age (every 6 months).

Tier 4

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.

Tier 3

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

Tier 4

Especially in severe forms of the disease, 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 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

Nature of Intervention

Nature of Intervention

ERT requires frequent (3-6 per week) subcutaneous injection administration. The most common adverse events in patients treated with asfotase alfa are ISRs (injection site reactions), occurring in approximately 73% of patients in clinical studies. ISRs include injection site erythema, discoloration, pain, pruritus, swelling, induration, macule, bruising, and nodules. Additional common adverse events include lipodystrophy (28%), ectopic calcifications (14%), and hypersensitivity reactions (12%). Hypersensitivity reactions, including signs and symptoms consistent with anaphylaxis, have been reported in patients receiving asfotase alfa and can occur for the first time in patients who have received treatment for > 1 year. There are detailed monitoring and management recommendations related to adverse events in patients with HP treated with ERT. There are also detailed laboratory and monitoring recommendations (including frequent clinical evaluations, radiographs, nutrition, and safety assessments) for individuals with HP treated with ERT.

Context: Adult Pediatric

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.

Context: Adult Pediatric

Tier 4

The diagnosis of HP is often delayed. Up to 68% of individuals are symptomatic at presentation of adult HP with a significant delay between the age of onset of symptoms and the diagnosis.

Context: Adult Pediatric

Tier 3

An incorrect diagnosis of idiopathic osteoporosis may be made in individuals with HP.

Context: Adult Pediatric

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.

Context: Adult Pediatric

Tier 4

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			ALPL			241500	0018570	0600011, 0600010, 0016607, 0016605, 0600009
ALPL			241510	0018570	0600011, 0600010, 0016607, 0016605, 0600009
ALPL			146300	0018570	0600011, 0600010, 0016607, 0016605, 0600009

References List

Adult hypophosphatasia. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=247676

Childhood-onset hypophosphatasia. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=247667

E Mornet, ME Nunes. Hypophosphatasia. (2007) [Updated Feb 04 2016]. In: MP Adam, HH Ardinger, RA Pagon, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1150/

HYPOPHOSPHATASIA, ADULT; HPPA. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 146300, (2021) World Wide Web URL: http://omim.org/

HYPOPHOSPHATASIA, CHILDHOOD. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 241510, (2012) World Wide Web URL: http://omim.org/

HYPOPHOSPHATASIA, INFANTILE. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 241500, (2016) World Wide Web URL: http://omim.org/

Hypophosphatasia. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=436

Infantile hypophosphatasia. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=247651

Khan AA, Josse R, Kannu P, Villeneuve J, Paul T, Van Uum S, Greenberg CR. (2019) Correction to: Hypophosphatasia: Canadian update on diagnosis and management. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 30(1433-2965):1541.

Kishnani PS, Rush ET, Arundel P, Bishop N, Dahir K, Fraser W, Harmatz P, Linglart A, Munns CF, Nunes ME, Saal HM, Seefried L, Ozono K. (2017) Monitoring guidance for patients with hypophosphatasia treated with asfotase alfa. Molecular genetics and metabolism. 122(1096-7206):4-17.

Mornet E, Hofmann C, Bloch-Zupan A, Girschick H, Le Merrer M. (2014) Clinical utility gene card for: hypophosphatasia - update 2013. European journal of human genetics : EJHG. 22(4).

Odontohypophosphatasia. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=247685

Perinatal lethal hypophosphatasia. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=247623

Prenatal benign hypophosphatasia. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=247638

Shirinezhad A, Esmaeili S, Azarboo A, Tavakoli Y, Hoveidaei AH, Zareshahi N, Ghaseminejad-Raeini A. (2024) Efficacy and safety of asfotase alfa in patients with hypophosphatasia: A systematic review. Bone. 188(1873-2763):117219.

Szabo SM, Tomazos IC, Petryk A, Powell LC, Donato BMK, Zarate YA, Tiulpakov A, Martos-Moreno GÁ. (2019) Frequency and age at occurrence of clinical manifestations of disease in patients with hypophosphatasia: a systematic literature review. Orphanet journal of rare diseases. 14(1750-1172):85.