Childhood Hypophosphatasia with A Homozygous Mutation of ALPL Gene

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 199-223-Disorders of Bone & Calcium Homeostasis: Case Reports
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-205
Supamit Ukarapong*1, Shankar Srinivas Ganapathy1, Jaime Haidet1, Bradley James Van Sickle1 and Gary David Berkovitz2
1Akron Children's Hospital, Akron, OH, 2Univ of Miami Sch of Med, Miami, FL
Background:  Hypophosphatasia is a condition in which mutation of the tissue nonspecific alkaline phosphatase (ALPL) gene results in subnormal alkaline phosphatase activity and abnormal skeletal development.  Infantile hypophosphatasia is associated with severe skeletal abnormalities.  By contrast childhood hypophosphatasia is a milder condition that may present with premature loss of deciduous teeth, but which is also associated with skeletal deformities and fractures.  In addition to abnormalities of dentition, radiographic signs in childhood hypophosphatasia include osteopenia and rachitic changes with lucent or streak like defects extending to the metaphyses creating "tongues of hypolucency" appearance.  The severe forms of hypophosphatasia usually result from homozygous or compound heterozygous mutations of ALPL.  Childhood forms of hypophosphatasia are typically the result of heterozygous mutations.  We describe a case of childhood hypophosphatasia caused by homozygous mutation in ALPL gene.    

Clinical case:  The subject presented at 13 years of age for evaluation of left knee pain that persisted over several months.  He had a history of loss of four lower incisors in childhood but was not evaluated for skeletal abnormalities.  Parents denied consanguinity.  The patient’s height and linear growth rate were normal.    The left knee had full range of motion and there were no joint deformities.  Radiograph of left knee indicated two oval radiolucent lesions in the femoral metaphysis.  A similar oval radiolucent area was also present in the humerus.  An MRI of lower extremities indicated mild soft tissue swelling of left knee joint and an increased signal in the distal metaphysis and distal diaphysis both femurs.  The ESR was abnormally elevated and serum alkaline phosphatase activity (17 U/L; normal 42-362) was subnormal.  Both thyroid function and serum zinc level were normal.   Serum pyridoxal 5’-phosphate was abnormally elevated (258 mcg/L, normal range 5-50).   Sequence analysis of ALPLgene indicated a homozygous missense mutation, c.1077 C>G (p. Ile359Met).

 Conclusion:  This case adds to information about the broad spectrum of symptoms, radiographic findings, and gene mutation in childhood hypophosphatasia.  Pain, joint swelling and elevated ESR were mostly likely due to inflammation caused by accumulation of inorganic pyrophosphate.  Oval radiolucent skeletal lesions are an unusual radiographic finding in childhood hypophosphatasia, and indeed were initially considered suspicious for malignancy until biochemical analysis indicated the diagnosis.  Another case of homozygous mutations of ALPL was described recently in a child with a mild form of hypophosphatasia (1), but to the best of our knowledge this finding is extremely rare.  The case we report also indicates that the effect of homozygous mutation in ALPL may be modified by other factors and result in a mild form of hypophosphatasia.

(1)  Haliloglu et al., Eur J Pediatrics  2012 October 24; (Epub ahead of print)

Nothing to Disclose: SU, SSG, JH, BJV, GDB

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