Hypophosphatasia

Hypophosphatasia (HPP) is an inherited metabolic disease caused by loss-of-function mutations in the tissue non-specific alkaline phosphatase (TNAP) gene. Reduced activity of TNAP leads to the accumulation of its substrates, mainly inorganic pyrophosphate and pyridoxal-5΄-phosphate, metabolic aberrations that largely explain the musculoskeletal and systemic features of the disease. More than 400 ALPL mutations, mostly missense, are reported to date, transmitted by either autosomal dominant or recessive mode. Severe disease is rare, with incidence ranging from 1:100,000 to 1:300,000 live births, while the estimated prevalence of the less severe adult form is estimated to be between 1:3100 to 1:508, in different countries in Europe. Presentation largely varies, ranging from death in utero to asymptomatic adults. In infants and children, clinical features include skeletal, respiratory and neurologic complications, while recurrent, poorly healing fractures, muscle weakness and arthropathy are common in adults. Persistently low serum alkaline phosphatase is the cardinal biochemical feature of the disease. Management requires a dedicated multidisciplinary team. In mild cases, treatment is usually symptomatic. Severe cases, with life-threating or debilitating complications, can be successfully treated with enzyme replacement therapy with asfotase alfa.

Altered Thyroid Function Tests Observed in Hypophosphatasia Patients Treated with Asfotase Alfa

Background. Asfotase alfa is the only approved treatment that can normalize mineralization in patients with hypophosphatasia (HPP). Its interference in alkaline phosphatase (ALP) dependent immunoassays has been reported. Objective. To describe thyroid function tests interfered with by asfotase alfa and elucidate the underlying mechanism. Patients and Methods. Three patients with HPP treated with asfotase alfa were included. Thyroid hormone levels measured using five different immunoassays with or without ALP as a labeling enzyme during asfotase alfa treatment were evaluated. Results. After the initiation of asfotase alfa, three HPP patients showed low free triiodothyronine (FT3) and free thyroxine (FT4) measured with AIA-2000 (Tosoh, Tokyo, Japan), an enzyme immunoassay system that uses ALP as a labeling enzyme, but their thyroid-stimulating hormone (TSH) levels were within the normal range. The other CLEIA system using ALP as a label, AIA-CL2400 (Tosoh, Tokyo, Japan), and ALP-independent immunoassay systems demonstrated normal FT3 and FT4 levels. These data suggested that although the thyroid function of these three patients was normal, asfotase alfa interfered with the thyroid hormone measurements made with AIA-2000. AIA-2000 and AIA-CL2400 adopted one-step and delayed one-step measurements, respectively, and the same antibody was used for both immunoassays. However, asfotase alfa may be absorbed on the magnetic beads used in the AIA reagent with the AIA-2000 system but not absorbed on the microparticles used in AIA-CL2400. Conclusion. Clinicians should be aware of the possible interference in thyroid function measurements by adopting specific types of immunoassays in asfotase alfa-treated HPP patients.

Bilateral atypical femoral fractures during denosumab therapy in a patient with adult-onset hypophosphatasia

Summary Hypophosphatasia (HPP) is a rare and under-recognised genetic defect in bone mineralisation. Patients presenting with fragility fractures may be mistakenly diagnosed as having osteoporosis and prescribed antiresorptive therapy, a treatment which may increase fracture risk. Adult-onset HPPhypophosphatasia was identified in a 40-year-old woman who presented with bilateral atypical femoral fractures after 4 years of denosumab therapy. A low serum alkaline phosphatase (ALP) and increased serum vitamin B6 level signalled the diagnosis, which was later confirmed by identification of two recessive mutations of the ALPL gene. The patient was treated with teriparatide given the unavailability of ALP enzyme-replacement therapy (asfotase alfa). Fracture healing occurred, but impaired mobility persisted. HPP predisposes to atypical femoral fracture (AFF) during antiresorptive therapy; hence, bisphosphonates and denosumab are contraindicated in this condition. Screening patients with fracture or ‘osteoporosis’ to identify a low ALP level is recommended. Learning points Hypophosphatasia (HPP) is a rare and under-recognised cause of bone fragility produced by impaired matrix mineralisation that can be misdiagnosed as a fragility fracture due to age-related bone loss. Antiresorptive therapy is contraindicated in HPP. Low serum alkaline phosphatase (ALP) provides a clue to the diagnosis. Elevated serum vitamin B6 (an ALP substrate) is indicative of HPP, while identification of a mutation in the ALPL gene is confirmatory. Enzyme therapy with recombinant ALP (asfotase alfa) is currently prohibitively costly. Treatment with anabolic bone agents such as teriparatide has been reported, but whether normally mineralized bone is formed requires further study.

A Rare Case of Perinatal Hypophosphatasia Treated With Asfotase Alfa

Background: Perinatal Hypophosphatasia (HPP) is a rare and lethal disorder associated with a 50–100% mortality rate, usually due to respiratory complications. HPP occurs due to a loss-of-function mutation in the ALPL gene, responsible for the function of tissue-nonspecific alkaline phosphatase (TNSALP). Clinically, HPP presents as a severe lack of bone mineralization leading to a rickets-like presentation. Clinical Case: A 4-month-old female presented from an outside hospital for the ongoing care of perinatal HPP. Prenatal scans with long-bone fractures raised concern for Osteogenesis imperfecta. However, alkaline phosphatase (ALP) at birth was <11 U/L, and vitamin B6 was elevated >250 ng/mL. Calcium, 25-OH vitamin D, and urine phosphoethanolamine were normal. A genetics panel for HPP confirmed two pathogenic autosomal recessive mutations on the ALPL gene. Treatment with asfotase alfa 3 mg/kg three times weekly was started on day two of life. The clinical course has been complicated by the need for mechanical ventilator support, seizure-event shortly after birth, recent EEG demonstrating epileptogenic potential in the bitemporal cortical regions now on treatment with Keppra, possible craniosynostosis with mild-to-moderate ventriculomegaly, and minimal grade 1 medullary nephrocalcinosis. Bone mineralization is monitored via skeletal surveys, and changes are measured using the Radiographic Global Impression of Change (RGI-C) and the Rickets Scoring Scale (RSS). After four months of asfotase alfa treatment, substantial progress in bone mineralization per RGI-C scoring has been noted, but RSS scoring still indicates severely low bone mineralization. ALP remains >3,000 U/L. Calcium, 25-OH vitamin D, and vitamin B6 are normal. Careful monitoring with weekly biochemical and urine profiles and monthly skeletal surveys, neuro assessments, and renal ultrasounds are ongoing. Conclusions: This clinical case demonstrates the improvement in bone mineralization with asfotase alfa, but the clinical course is slow and arduous. Despite the early initiation of asfotase alfa the patient’s bone mineralization remains severely low and is not in a safe range to proceed with G-tube, broviac, or tracheostomy placement. The current management goal is to maximize bone mineralization in preparation for the life-sustaining procedures mentioned above. With only a handful of surviving cases in the world, current long-term survival and outcomes for patients with perinatal HPP are unclear.