Osteopetrosis: a clinical perspective by Ansgar Schulz and Despina Mohous

Osteopetrosis (OP) encompasses a heterogenous group of rare monogenetic bone diseases with the common features of reduced osteoclast activity, increased bone mass and high bone fragility. The spectrum of clinical presentations is large, ranging from asymptomatic benign courses and intermediate forms to infantile, malignant OP with high lethality in early childhood. Since Hematopoietic stem cell transplantation (HSCT) is a curative treatment option for most of severe OP forms, the awareness of this rare disease is increasingly important.

The most common form with a prevalence of 1:20,000 is the autosomal dominant Albers-Schönberg disease (ADO). This disease is causes by monoallelic mutations in the CLCN7 gene. Most of the other forms show an autosomal recessive inheritance (ARO). Their incidence is estimated at 1:200,000 live births. In summary 13 genetically distinct forms of OP have been identified since 2000 including one with autosomal dominant and one with X-chromosomal recessive inheritance.

The pathophysiological basis of all OP forms including pycnodysostosis is a quantitative or qualitative defect of osteoclast function denominated osteoclast poor or osteoclast rich forms of OP. In the process of enchondral ossification osteoclasts have the important job to remove the mineralized cartilage in the growth plate. The consequence of the defective enostal resorption in OP is a defective bone modelling resulting in an overflowing installation of bone and a poor bone quality. All other clinical and radiological symptoms of the disease are derived from this defective bone modelling.

The diagnostic hallmark of OP seen in X-ray is characterized by increased cortical thickening, increased overall bone density and loss of medullary canal diameter with so called bone-in-bone appearance. Impaired bone modelling leads to the various manifestations of Osteopetrosis: Disturbance of the calcium homeostasis gives rise to hypocalcemia leading to tetany and (neonatal)  seizures. Progressive blindness is caused by compression of the optical nerves. Enchroachment of bone on marrow leads to severe anemia, commonly associated with thrombocytopenia and bleeding risk and hepatosplenomegaly with extramedullary hematopoiesis.  Macrocephaly, frequent fractures, dental abscesses and osteomyelitis of the mandible are frequently present. Since symptoms may appear at different time points, the sequence of appearance is heterogenous, and different organ systems are involved with a broad spectrum of differential diagnosis (of more common diseases), the diagnosis of OP is rather challenging particular in patients with incomplete presentations.

Early molecular diagnosis is essential to guide management decisions, as most, but not all, genetic forms of Osteopetrosis can be cured by allogeneic stem cell transplantation from a healthy donor.  The engraftment of hematopoietic stem cell allows the generation of functional osteoclasts in all known genetic forms (see table) besides deficiency in RANK-Ligand, as this defect is not intrinsic to the hematopoietic osteoclast lineage but rather to the mesenchymal one. For this very rare form, pharmacological RANKL-based therapy may be efficient to cure the disease. In some instances OP is associated to progressive neurodegeneration that may evolve independently of successful HSCT. OSTM1 has a primary and autonomous role in neuronal homeostasis resulting in severe and rapid neurodegeneration. Therefore HSCT is clearly contraindicated in these patients. Also, some, but not all, patients with biallelic CLCN7 mutations may develop neurodegeneration. A careful and complete neurological evaluation including brain MRI and EEG is necessary to confirm the HSCT indication in patients with CLCN7 variants that have not been described yet.

Extensive progress has been achieved in the survival rates upon allogeneic HSCT, independently of the availability of an HLA matched donor, as also haploidentical parental HSCT lead to excellent results. Patients should thus be scheduled for HSCT as soon as possible in order to prevent the progression of visual impairment. It is recommended to refer patients to centers with expertise in treating OP patients, as specific comorbidities during the transplant procedure require a multidisciplinary approach in an experienced center.

Allogeneic HSCT remains the standard of care so far, but intensive research is carried out in order to develop gene therapy.

Table : Classification, genetics and clinical manifestations of human ARO