How is a hypophosphatasis diagnosis

Hypophosphatasia - a clinically and genetically variable disease


Hypophosphatasia (HPP) is a hereditary metabolic multisystem disease, the main clinical characteristics of which are mineralization disorders of bones and teeth as well as muscle and joint pain. The clinical symptoms depend on the age of onset and are very variable both between individuals and within families. Six subforms of the HPP are delineated, whereby the transitions are fluid. They range from the severe perinatal form, which used to be fatal due to a lack of skeletal mineralization, to the adult form with typical symptoms such as fracture healing disorders or stress fractures. Nonspecific symptoms such as muscle pain and weakness, migraines or depression can also be part of the HPP. While severe forms with a prevalence between 1 / 100,000 and 1 / 300,000 are rare, mild forms of HPP are much more common. Perinatal and early childhood forms are usually inherited as an autosomal recessive trait, whereas later forms are inherited as an autosomal recessive or dominant trait. The cause of HPP is a reduced or absent activity of the tissue-unspecific alkaline phosphatase (AP), which is caused by the ALPLGene is encoded. Laboratory chemistry shows an age- and gender-specific reduced AP activity and a consecutive increase in AP substrates, e.g. B. the pyridoxal-5-phosphate (PLP) determine. Since the disease was first described in 1948, the diagnosis and treatment of HPP have improved dramatically. Enzyme replacement therapy with asfotase alfa (Strensiq®) was approved 4 years ago for severely affected HPP patients with onset of the disease before the age of 18. This article provides an overview of the broad clinical spectrum of HPP, the pathophysiological background, the laboratory and molecular genetic diagnostics as well as current therapy options and their treatment indications.


Hypophosphatasia (HPP) is a hereditary metabolic multisystemic disease whose main clinical characteristics are mineralization disorders of bones and teeth as well as muscle and joint pain. The clinical symptoms depend on the age of onset of HPP and are highly variable, both interindividually and within families. Six subtypes of HPP are defined, with fluent transitions. They range from the severe perinatal form, which was previously lethal owing to a lack of skeletal mineralization, to the adult form, with typical symptoms such as fracture healing disorders or stress fractures. Nonspecific symptoms, such as muscle pain and weakness, migraine or depression, can also be part of HPP. Although severe forms, with a prevalence between 1 / 100,000 and 1 / 300,000, are rare, mild forms of HPP are much more common. Perinatal and manifestations in early childhood are mostly inherited in an autosomal-recessive manner, whereas those with later onset are inherited in an autosomal-recessive or autosomal-dominant manner. HPP is caused by reduced or absent activity of the tissue-nonspecific alkaline phosphatase (AP), which is encoded by the ALPL genes. Laboratory testing of serum shows an age- and gender-specific low AP activity and a consecutive increase in AP substrates, e.g., pyridoxal-5-phosphate (PLP). Since the disease was first described in 1948, the diagnosis and treatment of HPP have improved dramatically. Four years ago, enzyme replacement therapy with asfotase alfa (Strensiq®) was approved for severely affected HPP patients with the onset of the disease before the age of 18 years. This article provides an overview of the broad clinical spectrum of HPP, pathophysiological background, laboratory and molecular genetic diagnostics, as well as current therapy options and their treatment indications.


Hypophosphatasia (HPP) is a rare hereditary, metabolic multisystem disease, the main characteristics of which are mineralization disorders of bones and teeth as well as muscle and joint pain. The clinical spectrum of symptoms as well as the age of onset are very variable. Severe forms of HPP have a prevalence between 1 / 100,000 and 1 / 300,000, while mild forms of HPP are significantly more common. The cause of HPP is a reduced or absent activity of the tissue-unspecific alkaline phosphatase (AP), which is caused by the ALPLGene is encoded [1]. Since the disease was first described in 1948 in a 9-week-old infant [2], the diagnosis and treatment of HPP have improved dramatically.


Overall, the clinical spectrum of symptoms depends on the age at the time the disease first appeared and is very heterogeneous. Six sub-forms of HPP are defined, whereby the transitions are fluid and there is more of a clinical continuum (Table 1).

The perinatal form is the most severe form of HPP, which used to lead to intracranial bleeding or thoracic deformities due to a lack of or reduced skeletal mineralization and was usually fatal. Disorders in the vitamin B6 metabolism can lead to epileptic seizures [3].

This is to be distinguished from prenatal benign HPP, in which the fetal ultrasound shows shorter and curved long bones, but no fractures are visible and the physical examination findings are in decline in the third trimester. After birth, the spectrum of prenatally benign HPP can range from clinically asymptomatic to symptoms of an infantile form of HPP, which then appear within the first six months after birth.

The first clinical signs of infantile HPP can be weakness, inadequate food intake, growth disorders, and chest and skull deformities caused by craniosynostosis. Other symptoms include fractures and metaphyseal rachitic bone changes. Hypercalcaemia with increased calcium excretion can lead to nephrocalcinosis. Reduced height in adulthood is common [1].

The child form overlaps in its clinical spectrum with the infant and adult form and is defined by the occurrence of symptoms between 6 months and 18 years. It is characterized by premature loss of milk teeth including intact roots before the age of 5, tooth / jaw misalignments, skeletal deformities such as bent long bones and enlarged joints, as well as muscle weakness and, rarely, short stature [1, 4].

The late-manifest adult form is particularly heterogeneous in its expression, but generally associated with milder symptoms than in child forms. In middle age, stress fractures, bone marrow edema, fracture healing disorders, osteomalacia and dental problems can occur more frequently (Fig. 1; [1]). In many cases, this form shows itself only through unspecific symptoms such as muscle and bone pain, muscle weakness, fatigue, calcification of tendons or joints, migraines and depression [5, 6]. However, the high prevalence of these unspecific symptoms in the general population often makes it difficult to clearly assign the symptoms to HPP, even if there are characteristic laboratory changes and ALPL-Gen mutations are detectable in affected patients.

Odontohypophosphatasia is a special form of HPP and manifests itself exclusively in the teeth. It is the mildest and probably the most common form of HPP [7] and is characterized by the early loss of deciduous and / or permanent teeth. Mineralization disorders of the teeth can lead to severe caries attack and weaken the teeth holding apparatus [3].

Clinical diagnostics

The lack of or reduced activity of the AP leads to an increase in various substrates in the serum or urine, e.g. B. of inorganic pyrophosphate, pyridoxal-5-phosphate (PLP) and phosphoethanolamine. In addition to determining the AP and bone-specific AP, the clinical diagnosis of HPP therefore also includes determining the PLP from the serum, which is considered to be the most informative of the three substrates. In general, a decreased activity of the AP in the serum is the decisive indicator for the presence of a ALPLGene mutation [8]. Patients with severe HPP generally show less age-specific AP activity, while the severity of adult HPP correlates better with the PLP level [5, 9]. For a correct interpretation, it is important that patients have not taken any food supplements with vitamin B6 for at least two weeks before the time of the blood sample, as this can lead to incorrectly increased PLP levels. When accepting PLP, ensure that transport is protected from light and ice-cold. The AP and the bone-specific AP are to be classified in comparison to age- and gender-specific reference values. Other causes of a decrease in AP (hypophosphataemia, Tab. 2) and differential diagnoses of HPP (Tab. 3) should be ruled out clinically or on a laboratory basis. These include, among others. medication with bisphosphonates, denosumab or glucocorticoids, as well as other diseases such as adult bone disease, multiple myeloma, osteogenesis imperfecta, hypothyroidism, celiac disease, vitamin D intoxication or milk-alkali syndrome [5].


The tissue-unspecific AP belongs to the group of alkaline phosphatases and, in contrast to the tissue-specific AP (intestinal AP, placental AP and placenta-like AP), is ubiquitously and strongly expressed in the liver, kidneys and bones. In the tissue, the tissue-unspecific AP is membrane-bound via glycosylphosphatidinositol (GPI) [10]. The tissue-unspecific AP is soluble and lipid-bound in the blood [11]. A homodimerization of two AP monomers is necessary for the catalytic activity, which also explains the allosteric properties of the enzyme [12]. There are various pathophysiological theories on the observed clinical findings: The central role in bone mineralization is explained e.g. B. by the function of the tissue-unspecific AP as a hydrolase of pyrophosphate. Inorganic phosphate that is formed, together with calcium, forms hydroxylapatite crystals, the main component of the bone matrix (Fig. 2). In the nervous tissue, the tissue-unspecific AP hydrolyzes inter alia. PLP, the phosphorylated vitamin B6. The unphosphorylated vitamin B6 can cross the blood-brain barrier, be rephosphorylated and, inter alia, as a coenzyme. act in the synthesis of the neurotransmitter GABA. Furthermore, the tissue-unspecific AP plays a role in brain development and especially in the maturation of neural stem cells, synapse formation and myelination, which is associated with symptoms such as migraines, pain, anxiety disorders and depression in HPP patients [6].

Genetic diagnostics

Perinatal and early childhood forms are usually inherited in an autosomal recessive manner, while benign prenatal, adult HPP and odontohypophosphatasia are inherited in an autosomal recessive or autosomal dominant manner.

In principle, HPP is a clinical diagnosis that is made on the basis of clinical, laboratory-chemical and radiological findings. A molecular genetic study of the ALPL-Gens is not absolutely necessary for the diagnosis, but is offered for differential diagnostic delimitation and for assessing the likelihood of recurrence in future pregnancies and is necessary when prenatal examinations are used [1, 13].

There are currently almost 400 different disease alleles ALPL-Gens described. The vast majority are missense mutations (~ 70%) followed by smaller deletions (~ 12%), splicesite (~ 6%) and nonsense mutations (~ 4%) or smaller insertions (~ 4%) ). Larger deletions are rarer overall (~ 3%), although a commercial detection method that is easy to use in routine diagnostics (SALSA® MLPA® sample mix) has only been available since the end of 2018, which could lead to a bias in older publications. A hotspot of disease alleles within the ALPL-Gens does not exist [14] and new mutations are rare [15]. Two cases of HPP as a result of a uniparental isodisomy have been described [16, 17]. A founder effect has been described for specific mutations in some populations [18].

Genotype-phenotype correlation and genetic counseling

Depending on the respective disease allele, overexpression analyzes revealed a variability of the residual enzymatic activity, which also allowed a correlation to the clinical findings [19]. In smaller collectives with patients with recurrent genotypes (50 and 105 patients, respectively), similar clinical findings were described for the same genotype [1, 7]. However, intra-family variability can be observed not only in heterozygous mutation carriers, but also within families with autosomal recessive HPP [20, 21]. Also contrary to the above. In studies, the variability seems to be greater for the same genotype [22]. A clear distinction between autosomal dominant and autosomal recessive inheritance does not always seem possible, as heterozygous mutation carriers with a mild clinical phenotype ("dominantly hereditary") can occur alongside patients with biallelic mutations and pronounced clinical symptoms ("recessive hereditary") [1]. Overall, a prognosis of the clinical phenotype based on a genotype does not currently appear possible. To what extent z. B. a quadriallelic model [23] can contribute to the explanation of the phenotypic variability in the future or whether genetic modifiers will be identified remains to be seen.

A particular challenge for genetic counseling and diagnostics is prenatal examinations and the distinction between severe perinatal and benign prenatal HPP. Historically, there was a perinatal manifestation together with a mutation detection in both ALPL-Copy copies are associated with an inferior prognosis (postpartum lethal), but patients with benign prenatal HPP and biallelic mutations have also been described: 1/3 of all patients with benign prenatal HPP become biallelic ALPL-Mutations detected; in 2/3 of the patients with benign prenatal HPP there is a heterozygous one ALPLMutation before [24].

Therapy of hypophosphatasia - a multidisciplinary therapeutic approach

The therapy of HPP requires a multidisciplinary approach and good teamwork in a specialized center. Representatives from the disciplines of paediatrics, osteology, orthopedics, ophthalmology, traumatology, laboratory medicine, human genetics, radiology, neurology, neurosurgery, dentistry, orthodontics, nutritional medicine, psychology and physiotherapy are of central importance for the comprehensive care of HPP patients. Depending on the age of the patient and the severity of the HPP disease, the use of human and equipment resources is coordinated by a specialized center for the individual case and used in a targeted manner in diagnostics and therapy.

Supportive therapy

The non-drug therapy of HPP includes general orthopedic measures for fractures, stress fractures, bone edema or fracture healing disorders, physiotherapeutic use to maintain and improve the function of the musculoskeletal system as well as HPP-specific nutritional advice. The dental preventive measures and regular oral hygiene are just as important for the best possible preservation of the chewing apparatus as the dental-orthodontic therapy for tooth loss and / or misaligned teeth.

There should be an optimal adjustment of the bone metabolism adapted to the HPP. The aim here is to avoid deficiencies in important nutritional factors for the skeletal system (e.g. vitamin D, folic acid, vitamin B 12, magnesium, zinc and others). It should be noted, however, that z. For example, with the vitamin D dosage, the particular pathophysiology of HPP is taken into account and the vitamin D level is not increased too much in order to avoid increased phosphate reabsorption.

Drug therapy for HPP

The drug therapy of HPP serves on the one hand for targeted analgesia and the suppression of inflammatory activity in the organism. Here, Whyte et al. shown that z. B. Naproxen can relieve the pain associated with bone marrow edema and contribute to reducing the inflammatory status [25]. The pain caused by hydroxyapatite and / or calcium pyrophosphate crystal deposits in joints also seem to respond to the administration of non-steroidal anti-inflammatory drugs [26, 27]. On the other hand, the improvement of the bone quality and the therapy of the osteomalacic component of HPP are an essential goal of drug therapy. Attempts have been made in the past to replace the defective AP in HPP patients with soluble alkaline phosphatase in patients with Paget's disease or human placental alkaline phosphatase [28]. A temporary increase in the AP in the serum could be achieved, but no clinical or radiological improvement of the HPP findings. Antiresorptive drugs such as B. Bisphosphonates are contraindicated in HPP because, as PPI analogues in HPP, they directly inhibit mineralization or can further suppress the residual function of the AP by binding zinc or magnesium. In contrast to anti-resorptive drugs, in individual cases osteoanabolic drugs (e.g.Teriparatide), which increase the activity of AP, have shown some positive effects such as fracture healing or suppression of bone marrow edema [29]. Furthermore, a sclerostin antibody (BPS804) was used as an osteoanabolic drug in an open label phase 2 A single-center study, which led to an increase in bone formation parameters and an improvement in bone density in HPP patients [30].

Enzyme replacement therapy for HPP

Targeted enzyme replacement therapy has been available for 4 years and is now a relevant drug option for patients severely affected by HPP. Asfotase alfa (AA) is a "first-in-class" drug that is administered via a deca-aspartate Anchor adheres to the hydroxyapatite of the mineralized bone surface and takes over the catalytic activity of the AP with the half-life extended by the Fc fragment of IgG1 [31]. It is a human recombinant, tissue-unspecific alkaline phosphatase-Fc-deca-aspartate fusion protein, which comprises two identical polypeptide chains with a length of 726 amino acids each and from the catalytic domain of the human tissue-unspecific AP, the human immunoglobulin G1-Fc domain and a deca-aspartate peptide domain [32].

In the first clinical open-label phase 2 study, 11 severely affected patients with perinatal and infantile HPP received asfotase alfa. The evaluation of the 9 patients who completed the study showed that there had been a significant improvement in bone mineralization, muscle strength and respiratory function [31]. The analysis of the 7-year results of the above-mentioned study confirms a prolonged improvement in skeletal mineralization, respiratory function, growth and motor development with overall good tolerability [33]. In the meantime, study results have also been published that show efficacy in adult HPP patients. Kishnani et al. have shown in a study with 19 adult HPP patients, in which 14 HPP patients completed the study, that a significant improvement in the 6-min walk test (6MWT) and an improved mineralization time of the bone could be achieved [4 ]. In a multiscale analysis of bone quality under enzyme replacement therapy, an improvement in bone mineralization and other bone quality parameters was also observed histologically in a case study [34]. In addition, there are individual case reports that even after pseudarthroses that have existed for years, e.g. B. of the femur with an inserted intramedullary nail, the healing of the pseudarthrosis can still be achieved with enzyme replacement therapy [35]. In Germany, enzyme replacement therapy is approved for long-term enzyme replacement therapy in patients who developed hypophosphatasia in childhood and adolescence in order to treat the bone manifestations of the disease.

Against the background of the rarity of the disease and the limited number of patients who received enzyme replacement therapy in studies, and taking into account the side effect profile (injection reactions of the skin and subcutaneous adipose tissue, allergic reactions, etc.), the indication must be checked very carefully in the individual case. The clinical benefits and risks as well as the lack of experience with long-term use must be carefully weighed up. Shapiro and Lewiecki recommend, due to the limited experience, the costs of the therapy and the manageable data situation, especially for adult HPP patients, that the use should only be considered in very severely affected patients with a well-documented medical history [36].

Overall, the therapeutic options have expanded sufficiently, not least and above all through enzyme replacement therapy, so that the care of patients affected by hypophosphatasia is better than it was a few years ago. Nevertheless, there is a great deal of clinical and scientific potential to further improve treatment options for HPP.

conclusion for practice

  • Hypophosphatasia is an inherited, multisystem metabolic disease with a wide clinical spectrum of symptoms.

  • A lack of or reduced activity of alkaline phosphatase (AP) is the cause of mineralization disorders of bones and teeth as well as muscle and joint pain.

  • The diagnosis of HPP can be made on the basis of clinical symptoms and typical laboratory changes (AP decrease, PLP increase).

  • The molecular genetic investigation of the ALPL-Gens is offered for confirmation of the diagnosis and differential diagnostic delimitation, for assessing the likelihood of recurrence in future pregnancies and for prenatal diagnosis in familial severe HPP.

  • There is a certain geno-phenotype correlation, but an individual prediction of the phenotype based on genetic findings is not possible.

  • Interdisciplinary clinical care of the patient with representatives from a. the disciplines of paediatrics, osteology, orthopedics / trauma surgery, neurology, psychology and dentistry / orthodontics is of central importance.

  • Enzyme replacement therapy should be considered after careful individual indication in severe cases with proven bone manifestation and the onset of the disease before the age of 18.


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