eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases
Hypophosphatasia
Updated: May 2, 2008
Introduction
Background
Initially recognized by Rathbun in 1948, hypophosphatasia is a rare inborn error of metabolism caused by low activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP).1 TNSALP is a phosphomonoesterase of 507 residues and is anchored at its carboxyl terminus to the plasma membrane by a phosphatidylinositol-glycan moiety. Alterations in the TNSALP gene lead to rickets, osteomalacia, or both, which characterize this disorder. Incidence has been estimated at 1 per 100,000 births. Clinical presentation widely varies, from death in utero to cases in which pathologic fractures first present only in adulthood.
At least 6 clinical forms of hypophosphatasia have been reported, although form assignment is often challenging. The age when skeletal lesions are discovered determines the type. The types include perinatal (lethal), infantile, childhood, and adult. Two other forms include odontohypophosphatasia (no clinical changes in long bones are present, only biochemical and dental manifestations) and pseudohypophosphatasia. The latter is clinically indistinguishable from infantile hypophosphatasia, because serum alkaline phosphatase (ALP) activity is normal. Pseudohypophosphatasia has been suggested as a possible consequence of a mutant TNSALP gene that still has activity in vitro but not in vivo. Conversely, in these patients, phosphoethanolamine (PEA), inorganic pyrophosphate (PPi), and pyridoxal-5'-phosphate (PLP) levels are elevated in serum and urine despite normal or elevated alkaline phosphatase activity levels.
The different clinical forms have different modes of presentation, history, and inheritance. The most severe forms of the disease have an autosomal recessive mode of inheritance, but the specific pattern of transmission of mild forms is not clear. Analysis of the TNSALP gene aids prenatal diagnosis. In the case of infantile hypophosphatasia, the mutation has been mapped to band 1p36.1-34. Compound heterozygosity in the TNSALP gene may cause childhood and adult hypophosphatasia. No animal model for hypophosphatasia is available.
Pathophysiology
Alkaline phosphatase is present as 4 isomers, each with its own gene locus. Three of these isoforms are tissue specific and are known as germ cell, placental, and intestinal alkaline phosphatase. The fourth isoform, TNSALP, is found in the bone, liver, kidney, and other tissues. The enzyme is physiologically active when in its dimeric form. TNSALP cleaves PLP, PEA, and PPI, which are all extracellular substrates. The TNSALP gene is located on chromosome 1p36.1 and consists of 12 exons distributed over 50 kb. More than 190 distinct mutations have been described for this gene, the vast majority (79%) of which are missense mutations.
Patients with hypophosphatasia have defects in bone mineralization due to TNSALP deficiency. As a consequence, levels of TNSALP substrates (ie, PLP, PPi, PEA) are elevated in serum and urine, and TNSALP activity is reduced.
Frequency
United States
Incidence of the severe form is believed to be approximately 1 case per 100,000 live births.2 In some inbred populations, such as Canadian Mennonites, the frequency is as high as 1 case per 2500 newborns.
International
International incidence is unknown.
Mortality/Morbidity
The perinatal form is considered lethal, whereas the infantile form has a mortality rate of 50%. Individuals with the other forms can reach adulthood, although often with increased morbidity. Patients with the childhood form often have rachitic deformities, and those with the adult type have increased morbidity from poorly healing stress fractures. All patients experience premature loss of dentition.
Race
Hypophosphatasia occurs in all races.
Sex
Males and females are equally affected.
Age
Hypophosphatasia affects all age groups; however, the severity of the disease varies with age.
Clinical
History
The perinatal form is universally lethal. Review of pregnancy history may reveal polyhydramnios.
- Skeletal manifestations of the perinatal form widely vary among patients. Typical radiographic features include lack of ossification in some bones; marked variability in the degree of bone ossification; unusually dense, round, flattened, and butterfly-shaped vertebral bodies; and generalized smaller ossified bones. Bones are affected to different degrees in the same patient; the bones affected differ among patients. Variability in femoral shape is also observed, and osteochondral projections (Bowdler spurs) of the midshaft of the fibula and ulna may be present. Prognosis is poor, but affected newborns may briefly survive. The cause of death is usually severe respiratory compromise, which occurs with fever of unknown origin, anemia, irritability, bradycardia, seizures, and intracranial hemorrhage.
- Initially, patients with the infantile form of hypophosphatasia may appear healthy until the onset of symptoms, which occurs when they are younger than 6 months. These infants have a history of poor feeding and failure to thrive. Hypotonia has also been reported.
- Patients with the childhood form often have a history of delayed walking and early loss of deciduous teeth. Bone pain is a frequent symptom.
- The adult form usually presents during middle age. As with the childhood form, premature loss of deciduous teeth is common. Adults may also have a history of foot pain due to stress fractures and joint pain due to deposition of calcium pyrophosphate dihydrate. Hypophosphatasia often leads to premature loss of deciduous teeth caused by disturbed cementum formation. Mineralization of dentin is less likely to be under the influence of the inhibitory action of pyrophosphate than mineralization of cementum.
- Odontohypophosphatasia presents with a premature loss of adult teeth.
- Affected adults manifest osteomalacia, often with slowly healing metatarsal stress fractures and proximal femur pseudofractures.
Physical
Infants with the lethal perinatal form may be stillborn. Upon examination, infants may have skin-covered spurs that extend from the forearms or legs. These spurs are believed to be diagnostic for hypophosphatasia. Some infants survive a few days but have respiratory complications due to hypoplastic lungs and rachitic deformities of the chest. Other findings include apnea, seizures, and marked shortening of the long bones.
- Patients with the infantile form may appear healthy at birth; however, the clinical signs of hypophosphatasia appear during the first 6 months. This form also has respiratory complications due to rachitic deformities of the chest. Despite the presence of an open fontanelle, premature craniosynostosis is a common finding that may result in increased intracranial pressure. Hypercalcemia is also present, and increased excretion of calcium may lead to renal damage.
- Skeletal deformities (eg, dolichocephalic skull and enlarged joints), a delay in walking, short stature, and waddling gait accompany the childhood form. A history of fractures and bone pain is usually noted. Premature loss of dentition is common; the incisor teeth are often the first affected.
- The adult form presents during middle age. The first symptom may be foot pain, which is due to stress fractures of the metatarsals. Thigh pain, due to pseudofractures of the femur, may also be a presenting symptom. Upon obtaining an in-depth history, many of these patients reveal that they have experienced premature loss of their deciduous teeth.
- The only physical finding in the odontohypophosphatasic form is the premature loss of teeth.
- Chronic bone edema in the adult form and chronic hyperprostaglandinism in the childhood form suggest that, in some patients, bone inflammation is present in conjunction with the metabolic defect. Sterile multifocal osteomyelitis could be demonstrated in 2 cases.3
Causes
A mutation in the gene that codes for tissue-nonspecific alkaline phosphatase is believed to be the cause of hypophosphatasia. The gene has been given the designation ALPL.
- The ALPL gene is located at band 1p36.1-34.
- Perinatal and infantile hypophosphatasia have an autosomal recessive mode of inheritance.
- Both autosomal recessive and autosomal dominant patterns of inheritance have been demonstrated for the childhood, adult, and odontohypophosphatasia forms.
More on Hypophosphatasia |
 Overview: Hypophosphatasia |
| Differential Diagnoses & Workup: Hypophosphatasia |
| Treatment & Medication: Hypophosphatasia |
| Follow-up: Hypophosphatasia |
| References |
| Next Page » |
References
Nishioka T, Tomatsu S, Gutierrez MA, et al. Enhancement of drug delivery to bone: characterization of human tissue-nonspecific alkaline phosphatase tagged with an acidic oligopeptide. Mol Genet Metab. Jul 2006;88(3):244-55. [Medline].
Fraser D. Hypophosphatasia. Am J Med. May 1957;22(5):730-46. [Medline].
Girschick HJ, Mornet E, Beer M, Warmuth-Metz M, Schneider P. Chronic multifocal non-bacterial osteomyelitis in hypophosphatasia mimicking malignancy. BMC Pediatr. Jan 2007;7:[Medline].
Millán JL, Narisawa S, Lemire I, Loisel TP, Boileau G, Leonard P, et al. Enzyme Replacement Therapy for Murine Hypophosphatasia. J Bone Miner Res. Jan 08;23:[Medline].
Whyte MP, Mumm S, Deal C. Adult hypophosphatasia treated with teriparatide. J Clin Endocrinol Metab. Apr 2007;92:1203-8. [Medline].
Cahill RA, Wenkert D, Perlman SA, Steele A, Coburn SP, McAlister WH, et al. Infantile hypophosphatasia: transplantation therapy trial using bone fragments and cultured osteoblasts. J Clin Endocrinol Metab. Aug 2007;92:2923-30. [Medline].
van den Bos T, Handoko G, Niehof A, et al. Cementum and dentin in hypophosphatasia. J Dent Res. Nov 2005;84(11):1021-5. [Medline].
Whyte MP. The metabolic & molecular bases of inherited disease. In: Hypophosphatasia. 8th ed. 2001:5313-29.
Whyte MP. Primer on the metabolic bone diseases and disorders of mineral metabolism. In: Hypophosphatasia. 5th ed. 2003:423-5.
Whyte MP, Kurtzberg J, McAlister WH, et al. Marrow cell transplantation for infantile hypophosphatasia. J Bone Miner Res. Apr 2003;18(4):624-36. [Medline].
Further Reading
Keywords
hypophosphatasia, perinatal hypophosphatasia, infantile hypophosphatasia, childhood hypophosphatasia, adult hypophosphatasia, phosphoethanolaminuria, odontohypophosphatasia, tissue-nonspecific isoenzyme of alkaline phosphatase, TNSALP , rickets, osteomalacia, rachitic deformities, stress fractures, polyhydramnios, Bowdler spurs, severe respiratory compromise, fever of unknown origin, anemia, bradycardia, seizures, intracranial hemorrhage, failure to thrive, hypotonia, hypoplastic lungs, craniosynostosis, hypercalcemia, osteomyelitis, pneumonia
