Perinatal - Infantile - Childhood Hypophosphatasia (HPP)

(OMIM phenotype number #241500)

Hypophosphatasia is a rare and heterogeneous inherited disorder characterised by defective bone mineralisation due to the impaired activity of the tissue-non-specific (liver/bone/kidney) iso- enzyme of ALP (TNSALP). TNSALP activity has an essential role for bone and teeth mineralization. Several forms of HPP exist, ranging from lethal to mild. HPP is divided into five types: perinatal, infantile, childhood and adult forms, and odontohypophosphatasia. Recently, a mild prenatal form has been described, as a sixth clinical form. The clinical diagnosis of HPP is based on radiological findings, bone mineral density measurements, and on biochemical assays. The clinical manifestations are highly variable, and depend on the type of mutation, inheritance mechanism, and age of onset. Perinatal, infantile, and childhood HPP are the most severe forms. The main clinical signs are: rickets, osteomalacia, fractures, teeth loss. Other systemic manifestations, in the case of severe forms, include: seizures, respiratory and kidney problems, chronic pain, etc.. The main diagnostic laboratory alterations include: low serum ALP and TNSALP activity and high levels of ALP substrates (inorganic pyrophosphate (PPi), pyridoxal-5’-phosphate (PLP, the active metabolite of vitamin B6), and phosphoethanolamine (PEA).

The treatment of HPP comprise the management of different clinical problems, such as: chronic pain, musculo-articular-skeletal alterations, fractures, renal problems, psychological and neurological problems, and dental problems. There are no established medical treatments for HPP, except treatments to alleviate symptoms and reduce complications. Bisphosphonates or too high doses of vitamin D are contraindicated and potentially dangerous in the case of HPP. In the future, new therapies are being evaluated such as enzyme replacement therapy (ERT) with a recombinant TNSALP for severe infantile forms.


ALPL gene, 1p36.12 (OMIM gene/locus number *171760). HPP is caused by any mutation in the ALPL gene that causes decreased TNSALP activity and increased levels of its substrates (about 275 mutations have been identified). The inheritance mechanism can be autosomal recessive or dominant.



  • Perinatal HPP: Almost always fatal, irritability, periodic apnea with cyanosis, bradycardia, unexplained fever, myelophthisic anemia (due to excess osteoid and unmineralized cartilage), intracranial hemorrhage, profound bone hypomineralization with bone deformities, fractures, craniosynostosis, osteochondral spurs that may pierce the skin and protrude laterally from midshaft of the ulnas and fibulas, and dental abnormalities with deciduous teeth poorly formed.
  • Infantile HPP: Postnatal but before 6 months of age, failure to thrive, hypotonia, bulging of the anterior fontanel, raised intracranial pressure and papilledema, proptosis, mild hypertelorism, brachycephaly, sclera may be blue, vitamin B6-responsive seizures, and rickets.
  • Childhood HPP: After 6 months of age, premature loss of primary teeth (before 5 years) without tooth root resorption, non progressive myopathy, rickets, radiographic focal defect if cartilage that project from the growth plates into the metaphyses (tongues of radiolucency).

Main biochemical alterations


  • Perinatal HPP: Low ALP, high Ca.
  • Infantile HPP: Low ALP, high Ca, high Ur Ca, high Pi (in heterozygotes), high Pi, high Ur Pi.
  • Childhood HPP: Low ALP, high Ca, normal Ca, high Pi due to high TmP/GFR, high Pi, high Ur PPi.
a b

Fig. X-ray abnormalities of a patient affected by HPP (aged 9 years). (a) Distorted trabeculae and irregular osteoporosis with projection of non-ossified tissue (“tongue” of radiolucency, the upper limit shown by the arrows) into the medial metaphysis present in the proband at onset. The tibial curvature was clinically normal, not suggesting soft bone. (b) Fracture of the right femoral neck discovered on X-ray analysis performed because of hip pain in the proband at onset.

Reproduced from Eur J Pediat, Hypophosphatasia may lead to bone fragility: don't miss it, 2009;168:783-8, Moulin P, Vaysse F, Bieth E, et al., with permission of Springer.

Other resources



  1. Whyte MP. Physiological role of alkaline phosphatase explored in hypophosphatasia. Ann N Y Acad Sci. 2010 Mar;1192:190-200.
  2. Bianchi ML, Hypophosphatasia: an overview of the disease and its treatment. Osteoporos Int. 2015 Aug 6. [Epub ahead of print]
  3. Whyte MP, Rockman-Greenberg C, Ozono K et al. Asfotase Alfa Treatment Improves Survival for Perinatal and Infantile Hypophosphatasia. J Clin Endocrinol Metab. 2015 Nov 3:jc20153462.
  4. Weiss MJ, Cole DE, Ray K, et al. First identification of a gene defect for hypophosphatasia: evidence that alkaline phosphatase acts in skeletal mineralization.Connect Tissue Res. 1989;21(1-4):99-104; discussion 104-6.
  5. Moulin P, Vaysse F, Bieth E, et al. Hypophosphatasia may lead to bone fragility: don't miss it. Eur J Pediatr. 2009 Jul;168(7):783-8
  6. Masi L, Agnusdei D, Bilezikian J et al. Taxonomy of rare genetic metabolic bone disorders. Osteoporos Int. 2015 Jun 13.