Hypophosphatasia (
HPP) is the inborn error of metabolism characterized by low serum
alkaline phosphatase (ALP) activity caused by inactivating mutations within TNSALP, the gene that encodes the "tissue-nonspecific"
isoenzyme of ALP (TNSALP). In
HPP, extracellular accumulation of inorganic
pyrophosphate, a TNSALP substrate, inhibits
hydroxyapatite crystal growth leading to
rickets or
osteomalacia.
Chronic recurrent multifocal osteomyelitis (
CRMO) is the pediatric syndrome of periarticular
pain and radiographic changes resembling infectious
osteomyelitis but without lesional pathogens. Some consider
CRMO to be an autoinflammatory disease. An unrelated boy and girl with the childhood form of
HPP suffered chronic, multifocal, periarticular
pain, and soft tissue swelling. To investigate this unusual complication, we evaluated their cumulative clinical, biochemical, radiological, and histopathological findings and performed mutation analysis of their TNSALP alleles. The earliest radiographic disturbances were typical of childhood
HPP. Subsequently, changes consistent with
CRMO developed at sites where there was
pain, including lucencies,
osteosclerosis, and marked expansion of the underlying metaphyses. Bone marrow
edema was shown by MRI. Biopsies of affected bone showed nonspecific histopathological findings and no pathogens. The boy was heterozygous (c.1133A>T, p.D378V) and the girl compound heterozygous (c.350A>G, p.Y117C, c.400_401AC>CA, p.T134H) for different TNSALP missense mutations. Nonsteroidal anti-inflammatory drugs diminished their
pain, which improved or resolved at maturity.
HPP should be considered when
CRMO is a diagnostic possibility. Metaphyseal radiographic changes and marrow
edema associated with periarticular bone
pain and soft tissue swelling suggestive of
osteomyelitis can complicate childhood
HPP.