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Hypophosphatasia Clinical Presentation

  • Author: Horacio B Plotkin, MD, FAAP; Chief Editor: Luis O Rohena, MD  more...
Updated: Dec 11, 2015


The most severe form of hypophosphatasia is universally lethal. Review of pregnancy history may reveal polyhydramnios. Skeletal manifestations of the severe cases vary widely 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 may occur with fever of unknown origin, anemia, irritability, seizures, and dehydration.

Initially, affected infants may appear healthy until the onset of signs, which occurs when they are younger than 6 months. These infants have a history of poor feeding and failure to thrive, developmental delays, and muscle weakness. Hypotonia has also been reported.

Affected children often have a history of delayed walking and early loss of deciduous teeth. Bone pain is a frequent symptom. Both infants and children may present with nephrocalcinosis.

Adults usually present with signs and symptoms during middle age, although careful interrogation often reveals signs during childhood or even infancy. As with the childhood form, premature loss of deciduous teeth due to disturbed cementum formation is common. Mineralization of dentin is less likely to be under the influence of the inhibitory action of pyrophosphate than mineralization of cementum. In most cases, diagnosis is made after a low alkaline phosphatase activity level is detected during routine blood work, or when tested after a direct family member was diagnosed with the condition. Adults may also have a history of foot pain due to stress fractures and joint pain due to deposition of calcium pyrophosphate dihydrate. Affected adults may manifest osteomalacia, with slowly healing or nonunion stress fractures (commonly metatarsal) and proximal femur pseudofractures.

Odontohypophosphatasia presents with a premature loss of adult teeth.



Infants with extremely severe hypophosphatasia may be stillborn. 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, craniosynostosis, and marked shortening of the long bones.

Surviving infants may appear healthy at birth; however, the clinical signs of hypophosphatasia appear during the first 6 months. These patients also have 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 nephrocalcinosis and renal damage. Infants may also present with severe epileptic encephalopathy that results in death. These seizures respond to vitamin B-6 treatment.[3]

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.[4] Premature loss of dentition is common; the incisor teeth are often the first affected.

Adults are often diagnosed during middle age. The condition can be completely asymptomatic and is suspected after a low alkaline phosphatase activity level is found during routine laboratory studies, although careful interrogation often reveals signs and symptoms during childhood or infancy. 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 odontohypophosphatasia 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.[5]



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.

More than 250 mutations have been described to date. 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. Frequently, patients are compound heterozygous.

Contributor Information and Disclosures

Horacio B Plotkin, MD, FAAP Chief Medical Officer, Retrophin, Inc; Adjunct Associate Professor of Pediatrics and Orthopedic Surgery, University of Nebraska College of Medicine

Horacio B Plotkin, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Received salary from Retrophin, Inc for management position.


George A Anadiotis, DO Consulting Staff, Department of Pediatric Rehabilitation and Development, Division of Clinical and Biochemical Genetics, Emmanuel Children's Hospital

George A Anadiotis, DO is a member of the following medical societies: American Medical Association, American Society of Human Genetics

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Luis O Rohena, MD Chief, Medical Genetics, San Antonio Military Medical Center; Assistant Professor of Pediatrics, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Assistant Professor of Pediatrics, University of Texas Health Science Center at San Antonio

Luis O Rohena, MD is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American College of Medical Genetics and Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Additional Contributors

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 for Clinical Pathology, American Society of Human Genetics, Central Society for Clinical and Translational Research, College of American Pathologists

Disclosure: Nothing to disclose.

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