HPP Registry TM

Disease definition and incidence



Hypophosphatasia (HPP) is a rare inherited metabolic disorder caused by loss-of-function mutations in the alkaline phosphatase liver/bone/kidney (ALPL) gene, which encodes tissue non-specific isoenzyme of alkaline phosphatase.1-4 This results in defective mineralization of bones and teeth, as well as other manifestations of the disease, including respiratory problems and seizures in infants and, in older patients, muscle weakness, musculoskeletal pain, limited mobility, fractures/pseudofractures, and other manifestations.1-3,5

Severe HPP occurs in 1:300,000 births and milder HPP has been reported by some sources to occur in up to 1:6,370 births.4 The overall incidence and prevalence of all forms of HPP is not known.

Diagnosis of HPP


Persistently low age- and sex-adjusted serum alkaline phosphatase (ALP) activity, in addition to clinical manifestations of the disease and in the absence of other factors that may contribute to low ALP activity, is adequate to confirm HPP diagnosis in most cases. Elevated serum pyridoxal 5'-phosphate (PLP) or urinary phosphoethanolamine can confirm the diagnosis. Although PLP (vitamin B6) may not be elevated in all patients, it is the most sensitive ALP substrate marker for HPP.7-9

Although, to date, at least 400 disease-causing mutations in the ALPL gene for both autosomal dominant and recessive inheritance patterns have been identified, genetic confirmation is not required for diagnosis.1,10,11

Integral to the diagnostic evaluation are the considerations listed below, with the key diagnostic indicator being low age- and sex-adjusted serum ALP activity level.3,5
  • Clinical and laboratory findings
  • Skeletal manifestations
  • Systemic complications (neurological, renal, respiratory, muscular, rheumatologic)
  • Dental manifestations
  • Family history of siblings or parents with HPP


It is important to note that normal ranges for serum ALP activity are higher in infants, children, and adolescents than they are in adults.12,13 Laboratories vary in their age- and sex-adjusted reference ranges; therefore, serum or plasma ALP activity must be interpreted based upon laboratory-specific reference ranges.14

ALP reference ranges


The tables below show two examples of age- and sex-adjusted reference ranges.13

Mechanism of disease

HPP Registry Clinical Presentation 

Full reference values depend on the method used and population sampled. The low normal total serum or plasma ALP activity is specific to the laboratory from which measurement of ALP activity is ordered and differs among laboratories. Empiric historical references for the laboratory employed should be preferentially used.19

Clinical manifestations


While HPP is frequently diagnosed during childhood, it may not be diagnosed until adulthood in some patients, even though patients may have had symptoms of the disease for years.6,20,21 The manifestations of HPP are broad, ranging from death in utero or during infancy, with almost no skeletal mineralization, to dental problems in older patients without any apparent bone involvement.22,23 In the literature, mortality has been reported to be 50–100% within the first year of life in the most severely affected patients (neonates and infants with HPP).6,7,24 Data from a noninterventional, retrospective chart review study of 48 neonates and infants with severe HPP estimated 73% mortality at 5 years of age.25

Table 1_ALP reference ranges

Irrespective of the age at onset, HPP has the potential to cause significant morbidity and disability in patients of any age.1,22 The tables below provide a tool to assist in gathering information about the clinical signs and symptoms of HPP, but should not replace professional judgement or clinical decision making.

clinical manifestations

 

Radiographic findings


In children with open growth plates, signs of rickets are visible on plain radiographs. Physeal widening may be seen along with irregularity of the provisional zone of calcification, as well as metaphyseal flaring with areas of radiolucency adjacent to areas of osteosclerosis. In infants and young children with HPP, bone demineralization can progress rapidly. For example, bones that are visible but deformed at birth may show rapid loss of skeletal mineral and severe rachitic changes within the first several months of life. Cupping and fraying of the metaphyses of long bones, widened growth plates, and spotty demineralization of the epiphyses can be seen.1,22 A radiolucent “tongue” shape is commonly seen projecting from the epiphysis into the metaphysis of long bones.1,22 Premature bony fusion of all cranial sutures (craniosynostosis) can occur, and can give the skull a “beaten-copper” appearance on radiographs.3,22 Other radiographic indicators include rachitic ribs and bone fractures.3,22,37,43

In adults, recurrent and/or poorly healing fractures are seen frequently in the metatarsus and femur/hip.8,37,44 Subtrochanteric femoral “stress” fractures might be observed and are actually pseudofractures (Looser’s zone, Milkman fracture) characteristic of the osteomalacia of HPP.7,22 Radiographic chondrocalcinosis and documented pyrophosphate arthropathy have also been observed.8

Differential diagnosis


Misdiagnosis of HPP is common and can lead to ineffective management that can compound the clinical picture and worsen HPP.19,27,43,45

 

Differences in laboratory parameters are important when considering a differential diagnosis. Importantly, a low age- and sex-adjusted ALP activity level can assist in differentiating HPP from other skeletal-related disorders.14,27

Unlike patients with most forms of rickets or osteomalacia, patients with HPP have low ALP activity, not elevated ALP. In addition, patients with HPP do not have low serum calcium level and parathyroid hormone (PTH) levels are typically normal. However, some HPP patients may exhibit hypercalcemia with an accordingly low serum PTH level and low serum PTH levels may be evident when there is only hypercalciuria.22

 

References

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4. Mornet E, Yvard A, Taillandier A et al. A molecular-based estimation of the prevalence of hypophosphatasia in the European population. Ann Hum Genet. 2011; 75: 439-445.
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The information on this page is intended as educational information for healthcare professionals. It does not replace a healthcare professional’s judgement or clinical diagnosis.