Stoneman syndrome is an incredibly rare connective tissue disorder. It involves the development of bone in abnormal areas of the body. It presents with autosomal dominant inheritance and no gender predisposition, developing in the first ten years of a person’s life. It is so rare that only 1 person in 2 million is thought to be affected worldwide. Symptoms of the disease include progressive ossification of skeletal muscles and connective tissues, as well as the malformation of great toes and thumbs. This condition is often very painful for sufferers, with no current effective treatment to help.

Characterisation of Stoneman syndrome

The cardinal features of Stoneman syndrome are the progressive osteogenesis and digital abnormalities. The development of bone in abnormal places is typical of this condition. The formation of abnormal bone begins around the age of 3-5 years and presents in almost all patients before the age of 15. The primary place of bone development is the axial musculature, but eventually, bone formation moves to the ligaments, fascia, tendons, and joint capsules. In 79-100% of patients, there are additional abnormalities of the great toes. There are also associations with hand deformities, deafness and baldness, with mental impacts being rare.

The initial symptoms present as pain around the soft tissue masses around the head and neck. This is followed by hard soft tissue swelling and ossification of additional body parts. The impact of this for the patients can be restricted movement, deformities, and pain. As a result of the disease, thoracic volume decreases, as does elastic recoil, meaning the respiratory system is impacted and patients often present thoracic insufficiency syndrome. This is the typical cause of death for patients with Stoneman syndrome. In females with the syndrome, the bone development in the limbs and lower back can make it difficult to conceive, continue a pregnancy and give birth.

The AVR1 gene is a gene found in many tissues of the body, including skeletal muscle and cartilage, and is thought to be responsible for mapping bone morphogenetic protein (BMP) type 1 receptors. BMP is a key mediator of the body’s infrastructure as it helps keep a balance between proliferation and apoptosis, as well as cellular lineage commitment and differentiation. It is also responsible for bone and muscle development and ossification. It is thought that mutations in the ACVR1 gene can disrupt control mechanisms and lead to abnormal activities.

Diagnosis of the syndrome

In 87% of Stoneman syndrome cases there are diagnostic errors. Often, the condition is mistaken for cancer due to the hard swelling in the affected regions. For the syndrome, clinico-radiological diagnosis can be used. Normal radiography can highlight any bony deformities in the patient as well as showing any ectopic ossifications. A better image can be provided by a CT scan. This type of scan shows a better image of anatomical details and can show lesions which can be easily missed using traditional radiographs. Another scan which can be used is an MRI. Whilst is it not always used, it can show the tumour like enlargement of impacted tissues. When assessed histologically, there is an increase in fibroblasts in muscle areas which causes the breakdown of muscle fibres and areas of newly formed bone. The lifespan of patients with Stoneman syndrome being around 40 years of age, with the majority of patients being wheelchair-bound by 30 years of age.

Current treatment/management of Stoneman syndrome

The increasing of ossifications may happen randomly but may also occur in response to trauma. Therefore, doctors avoid taking biopsies and doing surgical procedures when looking at diagnostic and therapeutic options. Management is the main option for patients currently, with non-steroidal anti-inflammatories, leukotriene inhibitors and mast cell stabilisers being used. In the past, surgery has been used for deformities but has been largely unsuccessful. Other things such as overstretching the jaw in dental procedures can cause additional trauma, so many considerations should be taken. There are ongoing studies looking at regulating the overactive signalling pathway (ACVR1/ALK2) which normally blocks heterotopic ossification.