eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Hypophosphatasia

Horacio Plotkin, MD, FAAP, Adjunct Associate Professor of Pediatrics and Orthopedic Surgery, University of Nebraska School of Medicine
George A Anadiotis, DO, Consulting Staff, Division of Clinical and Biochemical Genetics, Department of Pediatric Rehabilitation and Development, Emmanuel Children's Hospital

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.

Differential Diagnoses

Achondrogenesis
Osteogenesis Imperfecta
Rickets
Thanatophoric Dysplasia

Other Problems to Be Considered

Osteoglophonic dwarfism
Camptomelic dysplasia
Craniosynostosis

Workup

Laboratory Studies

• Assess the alkaline phosphatase levels. The levels are low in all types of hypophosphatasia. Do not use ethylenediaminetetraacetic acid (EDTA) tubes because these cause erroneous test results. The reference range should be appropriate for the age group undergoing testing, and results vary among laboratories.
• Laboratory testing must be performed on fasting individuals. Laboratory evaluations should include levels of calcium, phosphorus, magnesium, alkaline phosphatase, creatinine, parathyroid hormone (PTH), 25(OH) vitamin D, and 1,25(OH)2 vitamin D. Levels of PLP, PPi, and PEA in serum and urine determine the diagnosis. Measurement of ALP in amniotic fluid yields variable results, which are of value in the prenatal diagnosis of this entity. ALP in cultured amniotic cells may be quantified, but interpretation of the results is difficult. Monoclonal antibodies against TNSALP may serve to reveal a deficiency in chorionic villous tissue. The test for PPi in urine is typically performed only in research laboratories.
• PEA levels can be obtained from urine to help support the diagnosis. Elevated levels of PEA may also characterize other forms of bone disease.
• An elevation of PLP is also present. This test must be done carefully, as the patient's intake of vitamins (particularly vitamin B-6) may affect results.
• Liver function test results tend to be normal.
• Whenever possible, measure alkaline phosphatase activity levels in all members of the direct family.

Imaging Studies

• Perform a radiologic skeletal survey on patients in whom the diagnosis of hypophosphatasia is being considered.
• The lethal perinatal form is associated with a near absence of skeletal mineralization. Fractures and rachitic changes are often present. Skin-covered spurs that extend from the medial and lateral aspects of the knee and elbow joints may also be present.
• Deficient skeletal mineralization is also evident in the infantile form, although it tends to be less severe than in the perinatal form. Premature cranial synostosis often occurs despite an open fontanelle.
• Rachitic deformities characterize the childhood form. Upon radiologic examination of the metaphysis, evidence of radiolucent projections from the epiphyseal plate into the metaphysis is present. This is not found in other types of rickets.
• Pseudofractures are one of the hallmarks of the adult form of hypophosphatasia, often occurring in the lateral aspect of the proximal femur. An increased incidence of poorly healing stress fractures, especially of the metatarsals, also occurs.
• Radiography findings are normal for patients with odontohypophosphatasia, except for osteopenic appearance of the maxilla.

Procedures

• Bone biopsy findings are normal for patients with odontohypophosphatasia.

Histologic Findings

• Histologic examination of the skeleton reveals rachitic abnormalities of the growth plates, such as failure of cartilage calcification.
• Both osteoclasts and osteoblasts appear morphologically normal, but the latter lack membrane-associated ALP activity on histochemical testing. This disrupts incorporation of calcium into the matrix.
• Histologic examination of the teeth reveals a decrease in cementum, which varies with the severity of the disease. The pulp chamber also appears to be enlarged. The incisors tend to be the most affected.

Treatment

Medical Care

The effects of bone marrow transplant in hypophosphatasia are transient, and bone lesions may recur approximately 6 months after the transplant. Nonsteroidal anti-inflammatory drugs have been used in patients with childhood hypophosphatasia with some clinical improvement, although more experience is warranted before this therapy can be recommended. Enzyme replacement therapy with partially purified plasma enzyme was attempted, but with little clinical improvement. Some success has been achieved in delivering functional TNSALP enzyme to bone.

Supportive care is necessary to decrease the morbidity associated with hypophosphatasia. Regularly examine infants and children to check for evidence of increased intracranial pressure. Observe fractures closely. Adult pseudofractures may require orthopedic care to heal properly. A dentist should closely monitor all individuals with hypophosphatasia.

Surgical Care

Orthopedic surgical involvement may be necessary in patients with hypophosphatasia. Rachitic deformities and gait abnormalities require orthopedic evaluation. For them to heal completely, pseudofractures of the adult type may require rod placement. Patients may need neurosurgery for craniosynostosis.

Consultations

The skeletal involvement of hypophosphatasia requires consultation with an orthopedist. Patients with the infantile and childhood form should have regular follow-up appointments with their orthopedist. Evaluate adults for pseudofractures of the femur or stress fractures of the metatarsals. Refer all patients with any form of hypophosphatasia to a dental specialist. Construction of dentures may be necessary if the permanent teeth cannot be preserved. Patients may need to see a metabolic bone diseases specialist.

Diet

No special diet for hypophosphatasia is followed. Avoid vitamin and mineral supplements for rickets. The traditional defects of vitamin D metabolism are not present in hypophosphatasia, and excessive vitamin D can cause hypercalcemia and other side effects.

Activity

Gait difficulties may hamper activity in children. Although no distinct guidelines have been established, avoidance of contact sports and adequate protection of the teeth are advisable.

Medication

Drug therapy is currently not a component of the standard of care for this disease. See Treatment.

Follow-up

Complications

• Complications of the more severe forms of hypophosphatasia usually involve the respiratory system. Skeletal deformities can predispose an infant to respiratory compromise or pneumonia.
• In the infantile form, craniosynostosis can lead to increased intracranial pressure.

Prognosis

• The perinatal form is considered lethal.
• The infantile form is believed to be fatal in approximately 50% of patients.
• Longevity studies have not been conducted for the infantile and childhood forms. Individuals with the adult and odontohypophosphatasic forms are believed to have normal lifespans.

Patient Education

• Genetic counseling is important for all families who have affected children.
• A pedigree is essential, especially for the childhood, adult, or odontohypophosphatasic forms, which can have either autosomal dominant or recessive forms.
• Options for future pregnancies, such as prenatal testing for the perinatal form, should be discussed with parents.

Miscellaneous

Medicolegal Pitfalls

• Failure to discuss recurrence risks with parents of an affected child
• Failure to refer patient to appropriate specialist for care of skeletal or dentition complications

Special Concerns

• Prenatal diagnosis is available only for the perinatal form.
• Chorionic villus sampling (CVS) is used during the first trimester.
• A monoclonal antibody assay for TNSALP activity is available, as are DNA testing methods.
• By the second trimester, many of the skeletal abnormalities can be noted on ultrasound.
• Currently, protocol involves the use of CVS followed by serial ultrasonography.

References

1. 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].

2. Fraser D. Hypophosphatasia. Am J Med. May 1957;22(5):730-46. [Medline].

3. 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].

4. 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].

5. Whyte MP, Mumm S, Deal C. Adult hypophosphatasia treated with teriparatide. J Clin Endocrinol Metab. Apr 2007;92:1203-8. [Medline].

6. 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].

7. 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].

8. Whyte MP. The metabolic & molecular bases of inherited disease. In: Hypophosphatasia. 8^th ed. 2001:5313-29.

9. Whyte MP. Primer on the metabolic bone diseases and disorders of mineral metabolism. In: Hypophosphatasia. 5^th ed. 2003:423-5.

10. 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].

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

Contributor Information and Disclosures

Author

Horacio Plotkin, MD, FAAP, Adjunct Associate Professor of Pediatrics and Orthopedic Surgery, University of Nebraska School of Medicine
Horacio Plotkin, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics
Disclosure: Genzyme Corporation Salary Management position

Coauthor(s)

George A Anadiotis, DO, Consulting Staff, Division of Clinical and Biochemical Genetics, Department of Pediatric Rehabilitation and Development, Emmanuel Children's Hospital
George A Anadiotis, DO is a member of the following medical societies: American Medical Association and American Society of Human Genetics
Disclosure: Nothing to disclose.

Medical Editor

James Bowman, MD, Senior Scholar of Maclean Center for Clinical Medical Ethics, Professor Emeritus, Department of Pathology, University of Chicago
James Bowman, MD is a member of the following medical societies: Alpha Omega Alpha, American Society of Clinical Pathologists, American Society of Human Genetics, Central Society for Clinical Research, and College of American Pathologists
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

Leonard G Feld, MD, PhD, MMM, Chairman of Pediatrics, Carolinas Medical Center; Chief Medical Officer, Levine Children's Hospital, Carolinas Healthcare System
Leonard G Feld, MD, PhD, MMM is a member of the following medical societies: American Academy of Pediatrics, American College of Physician Executives, American Heart Association, American Physiological Society, American Society of Nephrology, American Society of Pediatric Nephrology, American Society of Transplant Surgeons, Eastern Society for Pediatric Research, International Society of Nephrology, Juvenile Diabetes Foundation International, National Kidney Foundation, Society for Experimental Biology and Medicine, and Society for Pediatric Research
Disclosure: Nothing to disclose.

CME Editor

Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine
Daniel Rauch, MD, FAAP is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, and Society of Hospital Medicine
Disclosure: Baxter Honoraria Consulting; Pfizer Honoraria Consulting

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

© 1994- by Medscape.
All Rights Reserved
(http://www.medscape.com/public/copyright)