Endocrine Abstracts

A previously well 27-year old female presented with atraumatic foot pain to the orthopaedic service and was identified to have a healing subacute metatarsal stress fracture in the right foot. In view of the unusual presentation, the patient was referred to the metabolic bone clinic for further evaluation.

On initial evaluation the patient reported no prior skeletal, joint or dental problems. However at the time of review she reported pain in her right thigh and clinical examination revealed a myopathic gait. Unexpectedly, plain x-rays revealed a stress fracture of right femoral shaft. Simultaneous biochemical analysis demonstrated undetectable serum alkaline phosphatase (ALP) activity consistent with a diagnosis of hypophosphatasia. Subsequent genetic analysis revealed a compound heterozygous ALPL mutation (p.Tyr101*;Ala176Thr). The patient required intra-medullary nailing of the right femoral fracture and subsequent physiotherapy. Future treatment options are limited but potential therapies include teriparatide or enzyme replacement with asfotase alfa.

Hypophosphatasia is a condition characterised by low ALP activity due to loss-of-function mutation of the ALPL gene, which encodes tissue non-specific ALP (TNSALP). Consequently inorganic pyrophosphate accumulates extracellularly and impairs skeletal mineralisation. It may be inherited in an autosomal dominant or recessive manner with wide ranging clinical expressivity.

Adult hypophosphatasia typically presents during middle age with loss of adult dentition, or with recurrent non-healing metatarsal fractures. The diagnosis may be made clinically on the basis of radiographic fractures coupled with low serum ALP. Genetic analysis of the ALPL gene can confirm the diagnosis. The treatment of adult hypophosphatasia is challenging. Teriparatide has been reported to stimulate osteoblast synthesis of TNSALP resulting in reduced pain and potential fracture healing, although benefits of such treatment appear increased if a wild type ALPL allele is present. Enzyme replacement therapy with asfotase alfa has been approved for paediatric onset hypophosphatasia but with limited evidence for adult use.