Hypophosphatasia

Laboratory findings and clinical manifestations

The diagnosis of hypophosphatasia is based on a specific biochemical profile. A key sign is a decreased level of serum alkaline phosphatase (both bone and liver isoenzymes are affected). Meanwhile, the concentration of phosphoethanolamine in blood and urine increases compensatorily. It is important to remember that baseline serum calcium and phosphorus levels are not decreased.

In young children (with perinatal and infantile forms), hypercalcemia and hypercalciuria frequently develop. This phenomenon is explained by a marked imbalance: intestinal calcium absorption continues at a normal level, but due to skeletal growth and mineralization defects, this calcium is not utilized by the bone tissue.

Impaired mineralization processes inevitably lead to systemic skeletal lesions:

• Children develop the clinical presentation of rickets (rickets).
• Adult patients develop osteomalacia (osteomalacia).

The disease is characterized by marked variability and a wave-like course. Onset can occur at any age—from the intrauterine period to adulthood. There is a strict pattern: the earlier the disease manifests (in childhood or infancy), the more severe its course.

Treatment of X-linked hypophosphatemic rickets (XLH)

For a long time, the treatment of hereditary hypophosphatemic conditions was purely symptomatic. A breakthrough recently occurred in the therapy of XLH: the US Food and Drug Administration (FDA) officially approved the use of monoclonal antibodies against fibroblast growth factor 23 (Anti-FGF-23 antibody). This drug allows for targeted intervention in the pathogenesis of the disease, improving phosphorus-calcium metabolism.

Differential diagnosis: sclerosing bone diseases

Bone modeling disorders can manifest not only as mineralization defects, but also as an abnormal increase in bone density—osteosclerosis (osteosclerosis). Most of these conditions are not metabolic disorders, but rare congenital and familial dysplasias.

This broad group includes dozens of nosologies that differ in inheritance patterns and radiological appearance. Among them are:

1. Osteopetrosis (osteopetrosis).
2. Pycnodysostosis (pyknodysostosis).
3. Metaphyseal dysplasia (Pyle disease / Pyle disease).
4. Craniometaphyseal and frontometaphyseal dysplasias.
5. Osteodysplasty (Melnick–Needles syndrome / Melnick–Needles syndrome).
6. Progressive diaphyseal dysplasia (Camurati–Engelmann disease / Camurati–Engelmann disease).
7. Hereditary multiple diaphyseal sclerosis (Ribbing disease / Ribbing disease).
8. Endosteal hyperostosis (Worth and Van Buchem types / Worth and Van Buchem types).

Osteopetrosis (Albers-Schönberg disease)

Osteopetrosis was first described by Albers-Schönberg (Albers-Schönberg) in 1904. In literature, it is also known as marble bone disease (marble bone disease) or generalized osteosclerosis fragilis (osteosclerosis fragilis generalisata).

Pathogenesis: The disease arises from a profound defect in osteoclast function. Bone resorption stops, whereas bone formation (osteoblast activity) continues at the same pace. The result is generalized osteosclerosis and severe modeling disruption. Despite high radiological density, bones lack normal trabecular architecture, making them fragile and extremely prone to fractures.

There are two main clinical forms:

• Lethal form: inherited in an autosomal recessive manner, with early manifestations (precocious manifestations).
• Benign form: inherited in an autosomal dominant manner, manifesting at an older age.

Atypical variants also exist: an intermediate form, post-infectious osteopetrosis, and osteopetrosis associated with carbonic anhydrase II deficiency (carbonic anhydrase II deficiency), which is accompanied by renal tubular acidosis and cerebral calcification. Bone marrow transplantation is currently considered an effective treatment method for severe forms, capable of reversing osteosclerosis.

Diagnostic imaging of osteopetrosis

The radiological picture is caused by the failure of normal osteoclastic periosteal resorption. Normally, this process should remodel the distal diaphysis of long tubular bones as they grow in length through endochondral ossification. In osteopetrosis, this mechanism fails.

• Radiography of the hip joint and femur: total increased density of the proximal femur and marked cortical thickening are visualized. Old diaphyseal fractures are frequently detected.
• Radiography of the thoracic spine: in the lateral projection, increased sclerosis along the vertebral endplates is revealed. The central part of the vertebra remains less dense, forming the classic ‘sandwich’ appearance (‘sandwich’ appearance).
• MRI of the femurs: T1-weighted coronal images show partial or complete obliteration of the medullary cavity due to massive proliferation of sclerotic bone tissue.

Class and exam questions

What else to study on this topic

• Craniometaphyseal and frontometaphyseal dysplasias: differential diagnosis
• Osteodysplasty (Melnick-Needles syndrome)
• Carbonic anhydrase II deficiency and renal tubular acidosis in osteopetrosis
• Mechanism of action of FGF-23 antibodies in the treatment of XLH
• Progressive diaphyseal dysplasia (Camurati-Engelmann disease)

Other topics in the "Musculoskeletal System" section

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