Disorders of phosphorus metabolism (Hypophosphatasia): Clinical Guidelines

List of Abbreviations

HPP – hypophosphatasia

BBB – blood-brain barrier

GER – gastroesophageal reflux

GI – gastrointestinal tract

CT – clinical trials

CS – craniosynostosis

CT – computed tomography

BMD – bone mineral density

OI – osteogenesis imperfecta

PTH – parathyroid hormone

GFR – glomerular filtration rate

TNSALP – tissue-nonspecific alkaline phosphatase

PEA - phosphoethanolamine

ALP - alkaline phosphatase

AIMS - Alberta Infant Motor Scale

BiPAP – bilevel positive airway pressure

Ca/Cr calcium/creatinine ratio

CPAP - continuous positive airway pressure

GMFM - Gross Motor Function Measure

…** – drug is included in the list of vital and essential drugs (Order of the Government of the Russian Federation No. 2406-r dated October 12, 2019 "On approval of the list of vital and essential drugs, as well as lists of drugs for medical use and the minimum assortment of drugs required for medical care")

# - off-label use – outside the indications registered in the drug instructions, carried out by decision of the medical commission, with the permission of the Local Ethics Committee of the medical organization (if any), subject to the signed informed consent of the parents (legal representative) and the patient over 15 years of age;

Terms and Definitions

Enzyme replacement therapy – treatment consisting of the administration of a drug (recombinant enzyme) to patients with an inherited metabolic defect.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Hypophosphatasia (HPP) is a progressive inherited metabolic disorder caused by tissue-nonspecific alkaline phosphatase (TNSALP) deficiency resulting from a mutation in the ALPL gene. The disease can manifest prenatally, in childhood, or in adulthood. Early age of onset is usually associated with a more severe course, while late onset is associated with a milder course. Reduced TNSALP activity primarily manifests as impaired bone mineralization and the development of rachitic changes.

HPP is characterized by wide variability of clinical manifestations and prognosis for the patient — from a mild course with minor bone involvement or exclusively dental system lesions, to severe forms with marked skeletal deformations, nervous system, lung, and kidney damage leading to disability and death, including intrauterine death [1].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Hypophosphatasia (HPP) develops as a result of a mutation in the ALPL gene encoding the TNSALP enzyme. The ALPL gene is located on the short arm of chromosome 1 (1p36.12), comprising 12 exons; more than 400 mutations are known. Most defects are missense mutations, but deletions, insertions, in-frame shift mutations, and intronic mutations also occur.

Severe forms of HPP typically occur in the presence of a homozygous or compound heterozygous mutation in the ALPL gene (OMIM 171760). Mild forms of HPP result from a heterozygous mutation of this gene. These are specific mutations for which a significant impact on protein function has been proven. TNSALP is expressed on the cell surface as a homodimer, so some heterozygous mutations can lead to a dominant-negative effect, reducing the activity of the entire homodimer. The presence of a mutation in even a single allele can provoke the development of the disease. The vast majority of heterozygous carriers are asymptomatic.

The best-studied function of TNSALP is ensuring the formation of hydroxyapatite, the main mineral component of bone tissue.

TNSALP catalyzes the cleavage of phosphate from a number of substrates, the most functionally important of which are inorganic pyrophosphate and pyridoxal-5-phosphate. TNSALP generates adenosine from adenosine monophosphate in dorsal root ganglion neurons [1]. Adenosine has an antinociceptive effect and plays a key role in pain signaling. Adenosine deficiency provokes severe bone and muscle pain in HPP patients (the role of other substrates in pathogenesis has not been studied). When the phosphate group is cleaved from inorganic pyrophosphate with the participation of TNSALP, the released phosphate binds to calcium to form hydroxyapatite crystals necessary to increase bone mineral density.

In HPP, inorganic pyrophosphate is not cleaved, its concentration in the extracellular fluid increases significantly, and hydroxyapatite crystals are not formed. This leads to impaired bone formation and skeletal deformations. Inorganic pyrophosphate accumulating in plasma and tissues, in turn, is a potent inhibitor of mineralization, further exacerbating the impaired bone formation process. In addition, inorganic pyrophosphate combining with amorphous calcium phosphate forms calcium pyrophosphate crystals, which can deposit in renal tissue (causing nephrocalcinosis) or joints (causing crystalline arthritis and pseudogout).

Chest bone hypomineralization leads to prenatal lung development impairment (secondary hypoplasia), which causes respiratory failure and determines the prognosis in newborns and infants. Another important function of TNSALP is regulating the entry of vitamin B6 into the brain by cleaving phosphate from pyridoxal-5-phosphate. This facilitates the penetration of pyridoxal across the blood-brain barrier into the central nervous system, where phosphate is reattached to pyridoxal to form pyridoxal-5-phosphate. The latter is a cofactor for many neurotransmitters, such as serotonin, dopamine, gamma-aminobutyric acid, etc.; its deficiency in the central nervous system leads to seizures, which are stopped by the administration of #pyridoxine. The presence of seizures in HPP is a prognostic sign of a more severe course and a high probability of a fatal outcome [1, 2].

1.3 Epidemiology of the Disease or Condition

The exact prevalence of the disease remains unknown and may vary depending on the population, assessment method, and form of HPP. The ethnic group with the highest HPP incidence rate is the Mennonites in Manitoba, Canada. It is reported that in this population, 1 in 25 people carries an ALPL mutation and approximately 1 in 2,500 newborns has a lethal form of HPP. The prevalence of severe forms of HPP is estimated at 1 in 100,000 births in Canada. Molecular studies have shown that the frequency of severe forms of HPP in Europe is 1 in 300,000, but moderate forms of HPP, according to the same study, are 50 times more common. Data on prevalence in Russia are lacking, but the estimated frequency of severe forms is 1 in 100,000 [2, 3, 19].

1.4 Features of Coding the Disease or Condition

E83.3 – Disorders of phosphorus metabolism and phosphatases

Hypophosphatasia

1.5 Classification of the disease or condition

Depending on the age of hypophosphatasia onset, the following forms are distinguished:

• perinatal (development of symptoms in utero or at birth);

• infantile (up to 6 months of age);

• childhood (6 months − 18 years);

• adult (over 18 years).

As a rule, the form of the disease determines the severity of the course — from the most severe in the perinatal form to relatively mild in the adult form.

Odontohypophosphatasia is a separate form characterized exclusively by dental involvement [1].

1.6 Clinical presentation of the disease or condition

Perinatal form (sometimes called perinatal lethal) is characterized by the most severe course, high mortality, and can be diagnosed prenatally by fetal ultrasound or immediately after birth. Newborns exhibit:

• skeletal hypomineralization with limb shortening and severe deformations of the ribs, spine, and chest;

• pulmonary hypoplasia, respiratory failure, need for respiratory support;

• marked muscular hypotonia, poor suckling;

• vomiting, dehydration, fever, anorexia, constipation;

• membranous skull;

• intracranial hemorrhage;

• seizures (vitamin B6-dependent);

• myelophthisic anemia (likely due to a reduction in functioning bone marrow volume);

• growth retardation, poor weight gain;

• hypercalciuria;

• nephrocalcinosis;

• fractures occurring in utero.

The infantile form is also characterized by a severe course, featuring:

• marked bone hypomineralization;

• severe skeletal deformations similar to those in the perinatal form;

• pulmonary hypoplasia, respiratory failure requiring respiratory support;

• increased neuro-reflex excitability, vitamin B6-dependent seizures;

• muscular hypotonia;

• hypercalcemia and nephrocalcinosis;

• physical and motor developmental delay;

• muscle and bone pain;

In children with perinatal and infantile forms of the disease, abnormal skull bone formation often leads to craniosynostosis and increased intracranial pressure, which may require neurosurgical treatment.

At an early age, death most commonly results from severe skeletal hypomineralization, leading to chest deformity, pulmonary hypoplasia, and respiratory failure.

The childhood form has a more favorable course. Rachitic skeletal deformities (most commonly genu valgum) develop gradually and vary in severity. Characteristic features include:

• rachitic bone lesions manifested as shortening and deformities;

• craniosynostosis;

• recurrent fractures;

• bone and joint pain;

• joint stiffness;

• delayed onset of walking and waddling gait;

• reduced chest volume due to rib shortening;

• delayed physical and motor development;

• non-progressive myopathy;

• hypercalcemia and nephrocalcinosis (less frequent than in the infantile form);

• premature shedding of deciduous and permanent teeth without bleeding, with unformed or formed roots (sometimes showing signs of external cementum and root dentin resorption).

There is also evidence that when HPP is combined with severe neurological pathology, such as cerebral palsy in children, the condition may be misdiagnosed as severe osteoporosis, leading to inappropriate treatment strategies [55].

The adult form of HPP is characterized by pseudofractures, as well as multiple poorly healing bone fractures that frequently require surgical intervention. The lower extremities are primarily affected, presenting shortening and deformities of long tubular bones, impaired gait, and reduced height. Chondrocalcinosis, pseudogout, and arthropathy accompanied by severe pain, leading to disability and loss of working capacity, are frequently detected.

If tooth loss (with an intact root) is the sole manifestation of the disease, a diagnosis of odontohypophosphatasia is established [1, 5, 6, 7, 8, 9, 12, 13, 14, 15, 16, 17].

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis of HPP is established based on a combination of clinical data, laboratory and instrumental test results, and molecular genetic analysis.

Diagnostic Criteria

The diagnosis of HPP can be confirmed based on:

• Characteristic clinical manifestations in the form of rachitic skeletal changes, neurological and respiratory disorders, renal damage, growth and developmental delay;

• Persistent decrease in alkaline phosphatase activity (adjusted for the patient's age and sex) in the absence of other potential causes for reduced activity;

• Characteristic radiographic pattern of impaired bone formation and growth — widened metaphases, irregular ossification, radiolucent areas extending from growth plates into the diaphyses, thinning and hypomineralization of bone tissue;

Differential diagnosis is performed with other bone dysplasias, as well as with diseases presenting with rachitic deformities and/or osteomalacia.

2.1 Complaints and Anamnesis

When taking the medical history and assessing complaints, attention should be paid to the following complaints and anamnestic events:

• positive family history (similar symptoms in siblings of the proband, consanguineous marriage);

• growth retardation, poor weight gain;

• skeletal deformities;

• psychomotor retardation;

• decreased exercise tolerance;

• limb weakness;

• gait abnormalities;

• muscle, bone, and joint pain;

• premature tooth loss.

2.2 Physical Examination

Physical examination should focus on the main clinical manifestations of HPP:

• delayed physical and motor development;

• rachitic skeletal deformities;

• skull deformities;

• reduced chest volume due to rib shortening;

• muscular hypotonia;

• joint stiffness;

• delayed onset of walking and waddling gait.

2.3 Laboratory Diagnostics

Laboratory diagnostics include determining ALP activity and calcium-phosphate metabolism parameters (calcium, phosphorus, vitamin D, parathyroid hormone).

Comment: Blood alkaline phosphatase activity is determined using standard methods. In HPP, alkaline phosphatase activity is found to be below the lower limit of normal; interpretation of the results must take into account the patient's age and sex, as well as the reagent used and its reference values [21].

In addition, it is important to exclude other factors that can modulate ALP activity, both downwards (hypothyroidism, vitamin D intoxication, improper blood sampling techniques, etc.) and upwards (rickets, hyperparathyroidism, Paget's disease, biliary tract diseases, etc.) [1].

The physician must ensure the accuracy of the enzyme activity measurement results provided by the laboratory [22].

Comments: Molecular genetic testing helps verify the diagnosis; however, standard genetic testing methods have limitations, and mutations are not detected in 10% of patients with hypophosphatasia [4]. Common mutations for the ALPL gene have not been described, so complete analysis of the ALPL gene by direct sequencing is required. To date, more than 400 mutations have been discovered and described, mostly missense variants (74%) [23], leading to disease onset at various ages and with varying degrees of severity. Large deletions and insertions are also described in the gene, which are detected using MLPA (multiplex ligation-dependent probe amplification).

The disease can be inherited in an autosomal dominant or recessive manner. More severe clinical phenotypes (perinatal lethal / infantile) are inherited in an autosomal recessive manner, while milder forms may be caused by a dominant-negative effect (DNE). Mutations causing DNE are localized in three domains: the homodimer-binding region, the active site, and the crown domain. Consequently, a mutation located outside these domains does not exhibit a DNE [24]. The frequent variant c.571G>A (p.Glu191Lys) is a functional polymorphism; in vitro studies have shown a residual enzyme activity of 68% and no DNE [25]. It should also be noted that there is a high variability of phenotypic manifestations of the disease (allelic heterogeneity), meaning that the same mutations in the ALPL gene can have different phenotypic manifestations in different carriers, even within the same family [25]. To date, there is no convincing evidence allowing a strict correlation between mutations and disease severity. Extensive phenotypic variability has been described for carriers with identical genotypes; therefore, the severity of the mutation effect must be considered in conjunction with various additional factors—epigenetic and environmental factors [26]. Thus, diagnosis cannot be based solely on ALPL gene mutation analysis; a comprehensive assessment of clinical, laboratory, and instrumental data is required.

The presence of a single mutation in the gene is not a strict basis for confirming or excluding the diagnosis. If a mutation is detected in a heterozygous state, the type of mutation and its effect on protein function must be taken into account.

Comments: the study is performed in all patients during diagnosis, and subsequently during follow-up in patients receiving asfotase alfa.

Comments: the test is mandatory in the presence of hypercalcemia and/or signs of nephrocalcinosis.

2.4 Instrumental Diagnostics

Comments: Characteristic radiographic bone changes include deformation and shortening of tubular bones, and osteochondral spurs of the long tubular bones (Raber-Bower spurs / hypophosphatasia spurs). Widening of growth plates, irregularity of the zone of provisional calcification, and widening of the metaphysis with alternating areas of osteoporosis and osteosclerosis can be detected. So-called "flame-shaped" areas or lucencies projecting from the growth plates into the diaphysis distinguish hypophosphatasia from rickets and/or metaphyseal osteodysplasia. Bone age generally lags behind chronological age. Skull examination reveals bone hypomineralization (membranous skull), craniosynostosis, and "digital markings" (rarefaction/beaten copper appearance), which are characteristic radiographic signs of increased intracranial pressure. Adult patients may show chondrocalcinosis, pseudofractures, and pseudogout.

Comments: amplitude-integrated electroencephalography and video-EEG monitoring are also performed.

Comment: If increased intracranial pressure is suspected in a patient, any available neuroimaging method should be performed, along with a neurosurgical consultation. To date, computed tomography remains the "gold standard" for diagnosing cranial suture disorders. It not only accurately verifies the affected suture but also evaluates other signs of developing craniocerebral disproportion (thinning of skull bones, "digital markings" pattern). Another informative finding on computed tomography is the calcification of areas of the dura mater, which is also pathognomonic for HPP.

A significant drawback of radiological diagnostic methods is radiation exposure. To reduce it, infants may undergo neurosonography with visualization of cranial sutures and measurement of diastasis between skull bones. If cranial suture visualization is not possible or significant asymmetry between paired sutures is detected, a neurosurgical consultation is recommended.

The least informative neuroimaging method for craniosynostosis

is magnetic resonance imaging, which does not visualize the affected suture, but allows assessment of the position of the cerebellar tonsils relative to the foramen magnum, associated cerebrospinal fluid circulation disorders, and the deformation of CSF-containing spaces (brain ventricles, basal cisterns, and subarachnoid spaces). An important criterion for assessing the patient's clinical status is their neuro-ophthalmological status, specifically checking for papilledema. Anesthesia is administered as indicated.

Comments: pulse oximetry may be performed as indicated.

Comments: performed with caution, at the physician's discretion. Mainly used in patients with additional fracture risk, such as chronic kidney disease, a history of frequent fractures, or a very low body mass index.

Testing during asfotase alfa therapy may be useful when it is necessary to determine treatment efficacy regarding bone quality and structural characteristics.

There is a potential risk of fracture at the biopsy site.

It must not be performed prior to patient mobility tests.

Assessment should be performed by experienced specialists.

2.5 Other Procedures

2.5.1 Specialist Consultations and Monitoring

Comment: Due to the fact that the disease is characterized by damage to multiple organs and systems and requires comprehensive therapy, which necessitates the joint management of the patient by specialists of various profiles, initial and follow-up consultations are indicated with a geneticist, neurologist, neurosurgeon, endocrinologist, pediatric endocrinologist, trauma surgeon/orthopedist, dentist, nephrologist, pulmonologist, otolaryngologist-audiologist, ophthalmologist, pediatrician/neonatologist/general practitioner/family physician, medical rehabilitation specialist (rehabilitation physician, physical and rehabilitation medicine physician, exercise therapy physician, physical therapist, or others), as well as physicians of other specialties for patients with hypophosphatasia presenting with functional impairments of the corresponding organs and systems. The frequency of consultations is determined individually, taking into account the patient's age and the severity of the disease.

Comment: for testing guidelines, see Appendix A3.1

2.5.2 Differential Diagnosis

Clinical manifestations of hypophosphatasia must be differentiated from other bone dysplasias, as well as from conditions presenting with rickets and/or osteomalacia, including:

• vitamin D-deficient rickets;

• tubulopathies presenting with rachitic bone changes (primarily hypophosphatemic rickets);

• renal osteodystrophy;

• cleidocranial dysplasia;

• idiopathic juvenile osteoporosis;

• osteogenesis imperfecta (Table 1).

Premature tooth loss in hypophosphatasia should be differentiated from traumatic tooth dislocation and Papillon-Lefèvre syndrome. Premature shedding of deciduous teeth, as well as early loss or extraction of permanent teeth, may be an early (and sometimes the only) sign of hypophosphatasia. Tooth loss is typically unaccompanied by bleeding. Teeth in hypophosphatasia exhibit the following morphometric features: enlarged pulp chambers, widened root canals, and cementum hypoplasia. Early tooth loss is accompanied by a reduction in alveolar bone height (especially of the mandible). Permanent teeth frequently erupt with enamel hypoplasia [36, 40].

Table 1.

Differential diagnosis of hypophosphatasia

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Conservative Treatment

3.1.1 Pathogenetic therapy

Comment: Currently, the only pathogenetic treatment method for hypophosphatasia is long-term enzyme replacement therapy with asfotase alfa, which is a human recombinant tissue-nonspecific chimeric Fc-deca-aspartate alkaline phosphatase glycoprotein. Treatment achieves favorable dynamics in such parameters as levels of tissue-nonspecific alkaline phosphatase biochemical substrates (inorganic pyrophosphate and pyridoxal-5'-phosphate), bone mineralization, bone structure, growth, muscle strength, need for respiratory support, pain syndrome, and exercise tolerance.

The clinical efficacy and safety of asfotase alfa have been demonstrated in open-label, non-randomized studies involving 69 patients (primarily with childhood and infantile forms of hypophosphatasia).

In patients receiving asfotase alfa, positive radiological changes were observed during the first 6 months of therapy (scores: +2 — substantial improvement; +3 — complete or near-complete healing); bone biopsy data confirmed positive dynamics in bone mineralization indices (osteoid thickness, ratio of osteoid volume to bone volume, and bone mineralization lag time, along with an increase in growth rate approaching the age norm). Treatment with asfotase alfa demonstrated improved survival compared to a historical control group: 95% vs. 42% at one year of age, and 84% vs. 27% at 5 years of age, respectively (p < 0.0001, Kaplan-Meier model). Compared to the historical control group, in which only 1 out of 20 patients (5%) requiring mechanical ventilation survived, 76% (16/21) of patients requiring mechanical ventilation survived in the therapy group.

Following asfotase alfa treatment (1 year or more of enzyme replacement therapy), children aged 2.5 to 7 years showed positive dynamics in their dental status (periodontal complex tissues): stabilization of deciduous teeth with grade 1 mobility despite the presence of gingival recession in the area of these teeth [35].

The recommended dosage regimen for asfotase alfa is 2 mg/kg of body weight subcutaneously 3 times/week, or 1 mg/kg of body weight subcutaneously 6 times/week. The volume of the medicinal product administered per single injection must not exceed 1 ml. If a larger volume needs to be administered, multiple injections should be given at different sites.

The most frequent adverse reactions are local injection-site reactions, which were observed in 73% of patients in clinical trials. Most injection-site reactions are mild, self-limiting, and do not lead to discontinuation of therapy (Appendix A3.2).

3.1.2 Symptomatic therapy

Comments: Vitamin D preparations and their analogues may be prescribed in cases of confirmed deficiency and with regular monitoring of blood 25-OH vitamin D levels.

Comment: hypocalcemia may be observed at the start of asfotase alfa therapy.

Comment: Bisphosphonates are synthetic analogues of inorganic pyrophosphate and exacerbate bone hypomineralization.

Comments: In patients with hypophosphatasia, the dephosphorylation of pyridoxal-5-phosphate, a vitamin B6 metabolite, into pyridoxal is inhibited due to reduced TNSALP activity. Because pyridoxal can cross cell membranes while pyridoxal-5-phosphate cannot, the central nervous system experiences a vitamin B6 deficiency, which triggers seizures. Thus, seizures in hypophosphatasia are typically vitamin B6-dependent and are treated with #pyridoxine**.

However, some patients respond to #pyridoxine** only temporarily or fail to respond at all. In such situations, the administration of antiepileptic drugs may be required. The potential development of encephalopathy should also be considered in these cases. Currently, there are no data on whether #pyridoxine** can be discontinued after the initiation of enzyme replacement therapy [20].

For symptomatic and concomitant therapy, see also Appendix A3.3

3.2 Surgical Treatment

Comment: surgical treatment using osteosynthesis hardware may be required if the patient has fractures, pseudofractures, or non-unions resulting from delayed/impaired consolidation of bone fragments. If craniosynostosis develops, patients may require neurosurgical interventions [28, 52].

3.2 Other Treatment

Comments: may include: non-invasive ventilation, CPAP (continuous positive airway pressure), BiPAP (bilevel positive airway pressure), intubation and mechanical ventilation / high-frequency mechanical ventilation; inhalation and pharmacological therapy for pulmonary hypertension should be considered, e.g., inhaled nitric oxide, extracorporeal membrane oxygenation, temporary tracheostomy, etc. [28] – in accordance with the clinical guidelines for pediatric pulmonary hypertension.

Comments: services included in the Order of the Russian Ministry of Health No. 804n dated October 13, 2017, "On Approval of the Nomenclature of Medical Services": prosthetics with complete removable laminar dentures, prosthetics with partial removable laminar dentures, prosthetics with removable clasp dentures, intraosseous dental implantation.

Dental care is also necessary. Early education in strict oral hygiene is required to prevent or slow down the development of periodontitis [54]

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comment: Methods should be selected individually, according to the patient's age and functional capabilities. Activities should also be chosen in such a way that the patient/legal representatives remain compliant with them.

Water exercises provide moderate resistance in a reduced-gravity environment, which helps strengthen muscles while minimizing pain and reducing the risk of fractures.

Contact sports or other activities with potential risks of trauma should be avoided.

Jumping and leaping should only be recommended by a physician based on the condition of the bone tissue.

Orthopedic devices may be used to correct deformities and skeletal disorders (if indicated).

Rehabilitation courses (medical massage, therapeutic exercise, joint-by-joint gymnastics, postural correction, hydrotherapy, psychological and pedagogical support) should preferably be conducted in a day hospital setting 3–4 times a year.

Medical (therapeutic) massage is a method of treatment and prevention consisting of a set of metered mechanical stimulation techniques applied to various areas of the patient's body surface by the masseur's hands. Massage enhances metabolic processes in the skin and increases muscle tone. Massage should begin with stroking, followed by muscle kneading. Vibration is performed in areas of significantly reduced bone density. Massage is administered in courses daily or every other day. The course of treatment ranges from 10 to 25 procedures with intervals of 10 days to 2 months.

Therapeutic exercise is a system applying a wide variety of physical culture means for prevention, treatment, and rehabilitation. It should include both daily hygienic gymnastics (morning exercises) and therapeutic gymnastics. An individualized exercise program is drawn up, which is also performed in courses [56].

It is mandatory to include work with a clinical psychologist in the comprehensive rehabilitation program for both patients and their family members. Since the disease is progressive, it is necessary to help the patient "accept" the diagnosis, adapt to life, and maximize their learning and future independent living capabilities. Due to frequently coexisting neurological pathology, sessions with a clinical psychologist are also necessary to correct potential cognitive deficits in patients. It is also important to include speech therapy sessions to prevent and correct speech disorders. The system of corrective speech therapy work with children involves an early start of ontogenetically sequential speech-language intervention based on preserved functions. The correctional measures are based on the principle of motor-kinesthetic stimulation [57].

5. Prevention and Dispensary Observation

5.1 Prevention

Comment: the examination is performed as part of pregnancy screening; if indications are present, it is performed more frequently, and the frequency is determined individually.

Ultrasound examination in pregnant women may reveal cases of perinatal hypophosphatasia. Characteristic features can be detected on ultrasound starting from the 2nd trimester of pregnancy:

• skeletal changes (shortening, thinning of the ribs; shortening, deformation of the limbs);

• intrauterine growth restriction;

• decreased bone echogenicity;

• soft "membranous" skull, with the brain falx clearly defined;

• polyhydramnios

• It is recommended to provide medical genetic counseling to families with a history of hypophosphatasia (parents, close relatives) during pregnancy planning in order to provide offspring prognosis, explain genetic risks, and discuss prenatal diagnostic options [20].

GCR CLOE 5Grade of Recommendation – C, Level of Evidence – 5

Comments: in families with a positive history it is possible to perform prenatal diagnosis of hypophosphatasia – molecular genetic testing (searching for mutations in the ALPL gene, provided the proband's genotype is known).

Comments: Hypophosphatasia is not a contraindication for routine vaccinations.

If vaccination is necessary in patients on daily asfotase alfa therapy, the drug administration day should be skipped. This recommendation is based on the clinical experience of the expert community.

5.2 Dispensary monitoring

Comment: the frequency of the examination is determined individually, on average once a year. For patients receiving asfotase alfa, according to the schedule (Appendix A3.4)

Comment: the test is performed twice with a 1-week interval at diagnosis and then routinely every 6 months; if enzyme replacement therapy is initiated, every 3 months (Appendix A3.4).

Comments: the frequency of testing is determined individually, on average once every 6 months.

Comments: the frequency of testing is determined individually, on average once every 6 months (Appendix A3.4).

Comments: the frequency is determined individually. For patients receiving asfotase alfa, according to the schedule (Appendix A3.4)

Comments: the study is performed in all patients during diagnosis, and subsequently during follow-up in patients receiving asfotase alfa.

Comments: the frequency of testing is determined individually, on average, once every 6 months (mandatory in the presence of hypercalcemia and/or signs of nephrocalcinosis). For those receiving asfotase alfa – according to the schedule (Appendix A3.4).

Comments: Characteristic radiographic bone changes include deformations and shortening of tubular bones, osteochondral outgrowths of long tubular bones – Bowman's spurs. Widening of growth plates, irregularity of the zone of provisional calcification, and widening of the metaphases with alternating areas of osteoporosis and osteosclerosis can be detected. The so-called "flame-shaped" areas or lucencies projecting from the growth plates into the diaphysis distinguish hypophosphatasia from rickets and/or metaphyseal osteodysplasia. Bone age generally lags behind chronological age. Examination of the skull reveals hypomineralization of bone tissue (membranous skull), craniosynostosis, and the "digital markings" sign—a characteristic feature observed on radiographs when intracranial pressure is elevated. In adult patients, chondrocalcinosis, pseudofractures, and pseudogout may be detected. The frequency of examinations is determined individually, on average, once a year (Appendix A3.4).

Comment: the frequency of the study is determined individually. For those receiving asfotase alfa – (Appendix A3.4).

Comment: the frequency of the study is determined individually, on average, once a year.

Comments: include amplitude-integrated electroencephalography, video-EEG monitoring

The frequency of the study is determined individually at least once a year.

Comment: if there is suspicion of elevated intracranial pressure in the patient, it is advisable to perform any available neuroimaging method and consult a neurosurgeon. To date, computed tomography remains the "gold standard" in diagnosing cranial suture involvement. It not only accurately verifies the affected suture but also assesses other signs of developing craniocerebral disproportion (thinning of skull bones, "digital markings" pattern). An informative finding on computed tomography is the calcification of areas of the dura mater, which is also pathognomonic for HPP. A significant drawback of radiological diagnostic methods is radiation exposure. To reduce this, infants may undergo neurosonography with visualization of the cranial sutures and measurement of the diastase between skull bones. If visualization of the cranial suture is impossible or significant asymmetry between paired sutures is detected, a neurosurgery consultation is recommended. Magnetic resonance imaging is the least informative neuroimaging method for craniosynostosis; it does not allow visualization of the affected suture, but it can be used to assess the position of the cerebellar tonsils relative to the foramen magnum, concomitant cerebrospinal fluid dynamics disorders, and deformation of CSF-containing spaces (brain ventricles, basal cisterns, and subarachnoid spaces). An important criterion for assessing the patient's clinical status is neuro-ophthalmological status—detection of papilledema. The frequency of the study is determined individually at least once every 24 months, anesthesia as clinically indicated.

Comments: the study should be performed based on indications, on average, once a year. Pulse oximetry may be performed.

Comment: the frequency of examinations is determined individually, on average, once a year.

Comment: due to the fact that the disease is characterized by multi-organ and multisystem involvement and requires comprehensive therapy, it necessitates the joint management of the patient by specialists in various fields. Initial and follow-up consultations are indicated with a geneticist, neurologist, neurosurgeon, endocrinologist, pediatric endocrinologist, trauma orthopedic surgeon, dentist, nephrologist, pulmonologist, otolaryngologist/otorhinolaryngologist-audiologist, ophthalmologist, pediatrician/neonatologist/general practitioner/family physician, physical and rehabilitation medicine physician, as well as other specialists for HPP patients presenting with dysfunctions in the corresponding organs and systems. The frequency of consultations is determined individually, taking into account the patient's age and disease severity.

Note: the general practitioner (family physician) for pediatric patients should only perform initial routing (referral) to a pediatrician; provide outpatient medical care to children for acute illnesses / "outpatient medical care for children with acute illnesses, dispensary observation of children in their first year of life and children with chronic diseases"; when needed – provide emergency and urgent medical care in the absence of a pediatrician at the primary care level (at the stage of primary health care)

Comment: the frequency of the test is determined individually, on average, at least once a year. For test guidelines, see Appendix A3.4

Comments: performed in accordance with clinical guidelines for gastroesophageal reflux disease

6. Organization of Medical Care

Depending on necessity, patients with hypophosphatasia (HPP) may receive any type, conditions, and form of medical care provided for by the legislation of the Russian Federation.

Management of patients with HPP is usually carried out by a pediatrician, general practitioner, trauma surgeon/orthopedic surgeon, endocrinologist, pediatric endocrinologist, or nephrologist.

Hospitalization is most commonly carried out in a pediatric, therapeutic, surgical, or trauma/orthopedic department; treatment may also be provided in endocrinology, nephrology, pulmonology, neurology, or other departments depending on the dominant symptoms of the disease.

The approximate length of stay in an inpatient hospital is 10–14 days, and in a day hospital for scheduled medical care, 5–7 days (individually, depending on necessity).

When initiating enzyme replacement therapy, it is recommended to start treatment in an inpatient setting with subsequent transfer to an outpatient stage with dynamic monitoring by a pediatrician or general practitioner.

Re-hospitalization in an inpatient setting is carried out to monitor therapy dynamics, treatment side effects, physical therapy, physiotherapy, and the condition of bone tissue and other organs and systems.

Routine vaccination in patients with HPP is carried out in accordance with the National Immunization Schedule.

The required specialist examinations, laboratory and instrumental tests, and their recommended frequency are presented in Section 5.2 and Appendix A3.4.

6.1 Indications for planned hospitalization

1. provision of diagnosis and treatment requiring prolonged (day or round-the-clock) medical observation and monitoring of clinical and laboratory parameters;

2. the need for various types of expert evaluations or medical examinations in a medical institution when they cannot be performed in an outpatient setting (including issuing a federal consilium or medical commission conclusion);

3. a condition requiring active treatment and round-the-clock medical observation (surgical correction of skeletal deformities, selection of anticonvulsant therapy, etc.);

4. a condition requiring high-tech medical treatment methods (including monitoring the effectiveness of ERT)

5. the inability to provide ERT in outpatient and day-care settings;

6. the need for various expert evaluations or examinations in a medical institution when outpatient performance is not feasible and dynamic observation is required.

6.2 Indications for emergency/urgent hospitalization

1. acute life-threatening conditions and conditions that may develop severe complications requiring emergency treatment, including intensive care, as well as 24-hour medical supervision and special diagnostic and therapeutic procedures.

6.3 Indications for hospital discharge

1. absence of a threat to the patient's life and risk of complications requiring emergency treatment upon completion of diagnostic procedures.

2. stabilization of the patient's condition and main clinical and laboratory parameters of the pathological process, no need for prolonged medical supervision (day or inpatient care);

3. completion of the patient's diagnostic and treatment plan, with recommendations provided for further follow-up and management.

4. need to transfer the patient to another medical facility or social care institution.

7. Additional Information

7.1 Outcomes and prognosis

The perinatal form of HPP without timely provided care is almost always fatal.

In infantile and childhood forms, the prognosis for life is determined by the severity of bone lesions, the presence of seizures and pulmonary hypoplasia, and the need for respiratory support. Without pathogenetic therapy, mortality among patients with the infantile form of HPP is 50% in the first 9 months of life and is primarily due to respiratory failure. In the absence of therapy, the prognosis for disability and quality of life in infantile and childhood forms is unfavorable [47].

In the presence of hypercalcemia complicated by nephrocalcinosis, its progression may lead to the development of renal failure.

In the adult form of HPP, the prognosis for life is favorable, but the natural course of the disease may result in patient disability due to musculoskeletal impairment associated with the development of pseudogout, chondrocalcinosis, arthropathies, and impaired work capacity.

In odontohypophosphatasia, the prognosis for life is also favorable.

Criteria for Evaluating the Quality of Medical Care

Table 2 - Quality criteria for the provision of specialized medical care.

References

Appendix A1. Working Group Composition

Baranov A.A. - Professor, MD, DSc; Honorary President of the Union of Pediatricians of Russia, Advisor to the Head of the Research Institute of Pediatrics and Child Health of the National Medical Research Center No. 2 of the Petrovsky National Research Centre of Surgery, Professor at the Department of Pediatrics and Pediatric Rheumatology of the Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University), Chief freelance pediatric specialist of the Ministry of Health of Russia

Batysheva T.T. - Professor, MD, DSc, President of the Association of Pediatric Rehabilitologists of Russia, Director of the Scientific and Practical Center for Children's Psychoneurology of the Moscow Department of Health, Head of the Department of Neurology, Physical and Rehabilitation Medicine of Childhood of the Faculty of Continuous Medical Education of the Peoples' Friendship University of Russia (RUDN University), Chief freelance pediatric rehabilitologist of the Ministry of Health of Russia, Honored Doctor of Russia.

Bykova O.V. – MD, DSc, Head of the Research Department of the Scientific and Practical Center for Children's Psychoneurology of the Moscow Department of Health, Professor at the Department of Neurology, Physical and Rehabilitation Medicine of Childhood of the Faculty of Continuous Medical Education of RUDN University

Vashakmadze N.D. - MD, DSc, Head of the Department of Orphan Diseases and Prevention of Disabling Diseases at the Research Institute of Pediatrics and Child Health of the National Medical Research Center No. 2 of the Petrovsky National Research Centre of Surgery, Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Ministry of Health of Russia

Vislobokova E.V. - Assistant Professor at the Department of Pediatric Dentistry, Faculty of Dentistry, Yevdokimov Moscow State University of Medicine and Dentistry of the Ministry of Health of the Russian Federation

Vitebskaya A.V. - PhD, Pediatric Endocrinologist, Associate Professor at the Department of Childhood Diseases of the Filatov Institute of Pediatrics, Sechenov First Moscow State Medical University of the Ministry of Health of Russia, Filatov Institute of Children's Health, University Clinical Hospital, Department of Pediatric Endocrinology, Moscow.

Vishnyova E.A. - MD, DSc, Professor of the Russian Academy of Sciences, Deputy Head for Scientific Work at the Research Institute of Pediatrics and Child Health of the National Medical Research Center No. 2 of the Petrovsky National Research Centre of Surgery, Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Ministry of Health of Russia, Member of the Union of Pediatricians of Russia

Voinova V. Yu. - MD, DSc, Chief Researcher at the Veltischev Research and Clinical Institute of Pediatrics of the Pirogov Russian National Research Medical University

Zhurkova N.V. - PhD, Leading Researcher at the Research Institute of Pediatrics and Child Health of the National Medical Research Center No. 2 of the Petrovsky National Research Centre of Surgery, Member of the Union of Pediatricians of Russia, Member of the Association of Medical Geneticists (AMG)

Zakharova E.Yu. – MD, DSc, Head of the Laboratory of Hereditary Metabolic Diseases at the Bochkov Research Centre for Medical Genetics, Member of the Russian Society of Medical Geneticists, Member of the Society for the Study of Inborn Errors of Metabolism (SSIEM).

Kiselnikova L.P. - Head of the Department of Pediatric Dentistry, Faculty of Dentistry, Federal State Budgetary Educational Institution of Higher Education «A.I. Evdokimov Moscow State University of Medicine and Dentistry» of the Ministry of Health of the Russian Federation, Department of Pediatric Dentistry, Faculty of Dentistry, Head of the Department

Kostik M.M. - Doctor of Medical Sciences, Professor of the Department of Hospital Pediatrics, Saint Petersburg State Pediatric Medical University (SPbGPMU); Almazov National Medical Research Centre

Kutsev S.I. - Academician of the Russian Academy of Sciences, Professor, Doctor of Medical Sciences, President of the Association of Medical Geneticists (AMG), Director of the Federal State Budgetary Scientific Institution «Research Centre for Medical Genetics named after Academician N.P. Bochkov» of the Ministry of Science and Higher Education of Russia, Chief freelance specialist in medical genetics of the Ministry of Health of Russia

Margieva T.V. – Candidate of Medical Sciences, Chief Physician of the State Budgetary Healthcare Institution of the Moscow Region «Research Clinical Institute of Pediatrics of the Ministry of Health of the Moscow Region», Chief Specialist of the Methodological Center for Accreditation of Specialists of the Federal State Autonomous Educational Institution of Higher Education «I.M. Sechenov First Moscow State Medical University» of the Ministry of Health of Russia (Sechenov University), Nephrologist, Member of the Union of Pediatricians of Russia

Mikhailova S.V. - Doctor of Medical Sciences, Federal State Budgetary Educational Institution of Higher Education «Pirogov Russian National Research Medical University» of the Ministry of Health of Russia, Russian Children's Clinical Hospital, Head of Department

Moiseev S.V., - Doctor of Medical Sciences, Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University (Sechenov University) of the Ministry of Health of Russia

Namazova-Baranova L.S. - Academician of the Russian Academy of Sciences, Professor, Doctor of Medical Sciences, President of the Union of Pediatricians of Russia; Past-President of EPA/UNEPSA; Head of the Research Institute of Pediatrics and Child Health of the Scientific and Clinical Center No. 2 of the Federal State Budgetary Scientific Institution «Petrovsky National Research Centre of Surgery», Head of the Department of Faculty Pediatrics, Pediatric Faculty, Federal State Budgetary Educational Institution of Higher Education «Pirogov Russian National Research Medical University» of the Ministry of Health of Russia, Chief freelance pediatric specialist in preventive medicine of the Ministry of Health of Russia

Nagornova T.S. - Medical Geneticist, Federal State Budgetary Scientific Institution «Research Centre for Medical Genetics named after Academician N.P. Bochkov»

Selimzyanova L.R. - Candidate of Medical Sciences, Leading Researcher at the Research Institute of Pediatrics and Child Health of the Scientific and Clinical Center No. 2 of the Federal State Budgetary Scientific Institution «Petrovsky National Research Centre of Surgery», Associate Professor of the Department of Pediatrics and Pediatric Rheumatology, Federal State Autonomous Educational Institution «I.M. Sechenov First Moscow State Medical University» of the Ministry of Health of Russia (Sechenov University), Associate Professor of the Department of Faculty Pediatrics, Pediatric Faculty, Federal State Budgetary Educational Institution of Higher Education «Pirogov Russian National Research Medical University» of the Ministry of Health of Russia, Member of the Union of Pediatricians of Russia

Semyachkina A.N. - Doctor of Medical Sciences, Chief Researcher at the Department of Clinical Genetics, Federal State Budgetary Institution «Moscow Research Institute of Pediatrics and Pediatric Surgery of the Ministry of Health of Russia

Smirnova O.Ya. – Medical Geneticist, Senior Researcher at the Department of Standardization and Study of Evidence-Based Medicine Foundations, Research Institute of Pediatrics and Child Health, Scientific and Clinical Center No. 2 of the Federal State Budgetary Scientific Institution «Petrovsky National Research Centre of Surgery», Member of the Union of Pediatricians of Russia, Member of the Association of Medical Geneticists

Fedoseenko M.V. - Candidate of Medical Sciences, Head of the Department for the Development of Scientific Approaches to Immunization of Patients with Health Deviations and Chronic Diseases, Leading Researcher, Pediatrician at the Research Institute of Pediatrics and Child Health, Scientific and Clinical Center No. 2 (Central Clinical Hospital of the RAS) of the Federal State Budgetary Scientific Institution «Petrovsky National Research Centre of Surgery», Associate Professor of the Department of Faculty Pediatrics, Pediatric Faculty, Federal State Budgetary Educational Institution of Higher Education «Pirogov Russian National Research Medical University» of the Ministry of Health of Russia, Member of the Union of Pediatricians of Russia

Pishchalnikova S.V. – Representative of the All-Russian Organization for Rare Diseases

The authors declare no financial support or conflicts of interest that need to be disclosed.

Appendix A2. Methodology for Developing Clinical Guidelines

These guidelines are intended for use by medical organizations and institutions of federal, territorial, and municipal healthcare management systems, compulsory and voluntary medical insurance systems, and other medical organizations of various legal forms engaged in the provision of medical care.

Clinical guidelines are based on a literature review and current international clinical guidelines for the diagnosis, treatment, and management of patients with metabolic disorders.

Hypophosphatasia is a rare hereditary disease, which precludes large-scale cohort and randomized controlled trials; therefore, clinical diagnostic and therapeutic protocols are developed solely on the basis of expert case studies published over the past two decades.

The evaluation of the quality of evidence and the strength of recommendations for the use of medical technologies was carried out in accordance with the standardized grading scale presented in Tables 3–5.

Target audience for these clinical guidelines:

1. General practitioners (family physicians);

2. Pediatricians;

3. General practitioners;

4. Medical geneticists;

5. Laboratory geneticists;

6. Neurologists;

7. Neurosurgeons

8. Orthopedic trauma surgeons

9. Surgeons

10. Pediatric surgeons

11. Cardiologists;

12. Pediatric cardiologists

13. Nephrologists;

14. Radiologists;

15. Ophthalmologists;

16. Functional diagnostics physicians;

17. Physical and rehabilitation medicine physicians

18. Psychiatrists;

19. Otorhinolaryngologists;

20. Otorhinolaryngologists-Audiologists

21. Anesthesiologists-intensivists

22. Rheumatologists

23. Neonatologists

24. Pulmonologists

25. Endocrinologists

26. Pediatric endocrinologists;

27. Dentists

28. Pediatric dentists

29. Medical psychologists;

30. Medical students;

31. Residents and postgraduate students.

Table 3. Scale for assessing the levels of evidence reliability (LER) for diagnostic methods (diagnostic interventions)

Table 4. Scale for assessing the levels of evidence reliability (LER) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitation interventions)

Table 5. Scale for assessing the levels of confidence of recommendations (LCR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitation interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

1. Order of the Ministry of Health and Social Development of the Russian Federation No. 185 dated March 22, 2006 "On mass screening of newborns for hereditary diseases",

2. Order of the Ministry of Health and Social Development of the Russian Federation dated April 16, 2012, No. 366n, "On approval of the Procedure for Pediatric Care Delivery"

3. Order of the Ministry of Health of the Russian Federation dated April 21, 2022, No. 274n, "On approval of the Procedure for Medical Care Delivery to Patients with Congenital and/or Hereditary Diseases"

4. Decree of the Government of the Russian Federation dated April 9, 2015, No. 333, "On approval of the Rules for the Formation of the List of Specialized Medical Nutrition Products for Disabled Children"

5. Order of the Ministry of Health of the Russian Federation No. 1094n dated November 24, 2021 "On approval of the Procedure for prescribing medicinal products, prescription forms for medicinal products, the Procedure for issuing said forms, their accounting and storage, forms of prescriptions containing appointments of narcotic drugs or psychotropic substances, the Procedure for their manufacture, distribution, registration, accounting and storage, as well as the Rules for issuing prescription forms, including in the form of electronic documents"

6. Order of the Government of the Russian Federation dated December 31, 2018, No. 3053-r, "On approval of the lists of medical devices implantable into the human body during the provision of medical care within the framework of the state guarantee program for free medical care to citizens and dispensed by prescription for medical devices upon the provision of a set of social services"

7. International Statistical Classification of Diseases and Related Health Problems (ICD-10);

8. Order of the Ministry of Health of the Russian Federation No. 1183n dated December 20, 2012 "On approval of the nomenclature of positions of medical and pharmaceutical workers".

9. Order of the Ministry of Health of the Russian Federation No. 541n dated July 23, 2010. "Unified Qualification Handbook of Positions of Managers, Specialists, and Employees, Section: Qualification Characteristics of Positions of Healthcare Workers."

10. Federal Law No. 489-FZ dated December 25, 2018, «On Amendments to Article 40 of the Federal Law „On Compulsory Medical Insurance in the Russian Federation“ and the Federal Law „The Fundamentals of Protecting Citizens' Health in the Russian Federation“ Regarding Clinical Guidelines».

11. Order of the Ministry of Health of the Russian Federation No. 103n dated February 28, 2019, "On Approval of the Procedure and Timeframes for the Development and Revision of Clinical Guidelines, Their Template Form, and Requirements for Their Structure, Composition, and Scientific Validity of Information Included in Clinical Guidelines".

12. Order of the Ministry of Health of Russia No. 804n dated October 13, 2017, «On Approval of the Nomenclature of Medical Services».

13. Order of the Ministry of Labor and Social Protection of the Russian Federation No. 585n dated August 27, 2019, «On Classifications and Criteria Used in Medical and Social Expert Evaluation of Citizens by Federal State Institutions of Medical and Social Expert Evaluation»;

14. Order of the Ministry of Health and Social Development of the Russian Federation dated August 9, 2005, No. 494, "On the procedure for the use of medicinal products in patients for vital indications"

15. Information letter of the Russian Ministry of Health on the possibility of procuring a medicinal product by its trade name (https://www.rosminzdrav.ru/news/2019/12/18/13043-minzdrav-podgotovil-informatsionnoe-pismo-po-vozmozhnosti-zakupki-lekarstvennogo-preparata-po-torgovomu-naimenovaniyu);

Drug information: https://grls.rosminzdrav.ru/

Main regulatory and legal acts governing the provision of

palliative medical care

1. Federal Law No. 18-FZ dated March 6, 2019, "On Amendments to the Federal Law 'On the Basics of Protecting the Health of Citizens in the Russian Federation' Regarding the Provision of Palliative Medical Care."

2. Order of the Russian Ministry of Health No. 345n, Russian Ministry of Labor No. 372n dated May 31, 2019, "On approval of the Regulations on the organization of palliative medical care, including the procedure for interaction between medical organizations, social service organizations, and public associations, and other non-profit organizations operating in the field of health protection."

3. Order of the Russian Ministry of Health No. 348n dated May 31, 2019, "On approval of the list of medical devices intended to maintain human organs and body systems, provided for home use."

4. Order of the Russian Ministry of Health No. 505n dated July 10, 2019, "On approval of the Procedure for the transfer by a medical organization to a patient (their legal representative) of medical devices intended to maintain the functions of human organs and body systems for home use in the provision of palliative medical care."

Appendix A3.1 6-Minute Walk Test (6MWT) [48]

6MWT – 6-minute walk test (6 minutes walking test, 6MWT)

The 6-minute walk test is one of the simplest and most accessible methods in global clinical practice for assessing exercise tolerance and functional capacity in patients with cardiac and pulmonary conditions, as well as for screening purposes, including in children. Before and after the 6-minute test, the specialist evaluates the distance covered to the nearest meter, as well as exertion tolerance using the Borg scale, blood pressure, heart rate, respiratory rate, and blood oxygen saturation. The patient's blood pressure, heart rate, and respiratory rate must be measured, and pulse oximetry must be performed. The child must walk the maximum possible distance for them over 6 minutes at a comfortable pace. The distance covered in 6 minutes (6MWT) is measured in meters, evaluated dynamically once every 6 months, and compared with previous test results.

It should be noted that the absolute contraindications for this test include acute chest pain, decompensated heart and respiratory failure, acute illness, fever, and musculoskeletal disorders that prevent the test from being performed.

Relative contraindications include marked bradyarrhythmia/tachyarrhythmia, severe hypertension, and the child's age. Young children find it difficult to understand and follow all the rules of the test; therefore, it is recommended for children aged 5 years and older.

If the patient is on continuous oxygen support, the oxygen flow rate during the test must be maintained in accordance with the prescription of the physician who prescribed and monitors the therapy.

The test must be stopped immediately if the patient experiences chest pain, severe shortness of breath, leg cramps, dizziness, loss of balance, increasing weakness, or marked pallor.

The 6MWT is performed in an indoor environment familiar to the patient, featuring a sufficiently long, hard-surface corridor. The walking track must be at least 30 meters long, with markings every 5–10 meters and turnaround points. Chairs for patient preparation and rest should be placed at both ends of the track. Additionally, an oxygen source and a defibrillator must be available.

You will also need a sphygmomanometer, a stopwatch with a sweep second hand, a pulse oximeter, and a phone for the test. The test is recommended to be performed in the morning hours after a light breakfast. The patient should wear comfortable clothing and appropriate walking shoes. Vigorous physical exertion is prohibited less than two hours before the test. The patient's treatment continues as usual. If the child routinely uses a cane, crutches, or a walker for walking, these should also be used during the test.

Appendix A3.2 Adverse events of asfotase alfa therapy

Table 6. Adverse events during asfotase alfa therapy and management principles according to [18].

Appendix A3.3. Concomitant and symptomatic therapy for HPP

Table 7 Concomitant and symptomatic therapy for HPP

Appendix A3.4. Monitoring parameters for patients with HPP receiving ERT with asfotase alfa

Table 8. Monitored laboratory parameters in patients with HPP [18].

Table 6. Recommendations for monitoring patients with perinatal/infantile-onset hypophosphatasia receiving asfotase alfa therapy.

Notes:

1 - Radiography of the wrist (left) in the anteroposterior projection can be used to monitor the state of the epiphyses and assess bone age in children with HPP up to adolescence and can be performed annually.

Skeletal radiography includes anteroposterior projections of the feet (metatarsals), tibia and fibula (including the femoral head), chest, spine (+lateral projection), and skull (skull base, including lateral projection).

With growth and epiphyseal closure, radiography is performed mainly in characteristic problem areas with an individualized approach, which is more useful than a full skeletal survey. Screening tests to assess disease progression or major complications (kyphoscoliosis, chondrocalcinosis, decreased bone mineral density) or complications typical of different age groups (e.g., craniosynostosis in children, metatarsal stress fracture in adults) should be performed depending on age.

Table 9 Recommendations for monitoring pediatric patients aged 6 months to 18 years with HPP receiving asfotase alfa, per [18]

Table 10. Monitoring recommendations for adult patients (≥ 18 years) with HPP receiving asfotase alfa, according to [18]

Notes

1 - Pseudofractures are a type of pathological fractures that appear on radiographs as narrow radiolucent bands consisting of poorly mineralized excess osteoid in the cortical bone.

2 - Pathological fractures occur in altered bones under normal load.

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Hypophosphatasia (HPP) is a rare inherited (genetic) progressive disease whose symptoms can appear at any age. The prevalence of HPP is extremely low, estimated in various countries from 1 patient per 100,000 population to 1 in 300,000. The cause of HPP is a mutation in the ALPL gene, which significantly reduces the activity of alkaline phosphatase in the body—an enzyme that plays a crucial role in the formation and mineralization of bones and teeth. With alkaline phosphatase deficiency, the absorption of minerals (calcium and phosphorus) in bones is impaired, making them insufficiently strong and easily prone to deformations and fractures. In children, characteristic manifestations of HPP include rachitic skeletal deformations, growth and developmental delay, and premature tooth loss, while in adults they include bone pain, frequent fractures, severe muscle weakness, and even the need for a wheelchair. However, besides the skeletal system, HPP also affects other organs and systems: low alkaline phosphatase levels can impair lung, kidney, and nervous system function, and affect overall development. The severity of the disease generally depends on when HPP manifests—it poses the greatest danger to newborns, infants, and children, but in adults too, HPP can lead to severe, disabling consequences that negatively affect the overall condition, working capacity, and lifestyle of patients.

Inheritance.

Hypophosphatasia is inherited in one of two ways:

1. Autosomal recessive inheritance: the patient inherits 2 mutated genes, one altered gene from each parent.

2. Autosomal dominant inheritance: 1 mutated gene is inherited (from one parent). With this type, just a single mutation is enough for the disease to manifest. Not every mutation can have this effect; these are specific mutations. Most carriers of the disease have no clinical manifestations.

How the diagnosis is made.

Doctors may suspect the disease based on clinical symptoms. In this case, laboratory tests and X-ray examination of the bones are performed. One of the most important indicators is the activity of the enzyme alkaline phosphatase; this indicator will be reduced in the blood test of all patients. The levels of minerals (calcium, phosphorus), vitamin D, and hormones responsible for their metabolism are also measured. When clinical signs, abnormal laboratory parameters, and characteristic changes on radiographs are combined, a diagnosis of hypophosphatasia is established. For additional confirmation of the diagnosis, the doctor may order genetic testing to identify a mutation in the ALPL gene.

Treatment.

Hypophosphatasia is one of the hereditary diseases for which treatment exists. A special enzyme replacement therapy has recently been developed. The essence of the therapy is that the patient is regularly administered the missing enzyme via subcutaneous injections. The procedure is so simple that patients can receive treatment at home. The effectiveness of the therapy largely depends on when treatment is started. With early initiation of enzyme replacement therapy, there is a higher chance of achieving the expected effect, giving the child the opportunity to grow and develop close to age norms.

Public organizations in Russia

Patients diagnosed with hypophosphatasia have the opportunity to receive treatment in Russia. Public organizations can help patients access treatment, raise public awareness about rare diseases, and promote legislative initiatives in the field of orphan diseases.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1 Subjective Exercise Scale (Borg scale)

Source: [49, 50, 51].

Type: rating scale

Purpose: subjective assessment of exercise tolerance

Assessment tool: scale

Content and scoring:

The patient is instructed to rate shortness of breath during physical exertion: from 0 points—calm breathing, no sensation of shortness of breath—up to 10 points, when shortness of breath is maximal. Rate your current sensations.