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

Hypophosphatasia: Differential Diagnoses & Workup

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

Updated: May 2, 2008

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.

More on Hypophosphatasia

Overview: Hypophosphatasia
Differential Diagnoses & Workup: Hypophosphatasia
Treatment & Medication: Hypophosphatasia
Follow-up: Hypophosphatasia
References
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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. 8th ed. 2001:5313-29.

  9. Whyte MP. Primer on the metabolic bone diseases and disorders of mineral metabolism. In: Hypophosphatasia. 5th 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].

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Further Reading

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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

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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.

 
 
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