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Skeletal dysplasias: Disorders of growing bones

By Dr. Dineshani Hettiarachchi Sirisena 

Dwarfism is the colloquial term used to describe what is medically known as skeletal dysplasia. This group of disorders, which primarily affect growing bones and cartilage, encompass an array of many different conditions. As the physical appearance of those affected digress from the norm, they can face many challenges. To shed some light to this age-old condition, we spoke to Sabaragamuwa University Faculty of Medicine Department of Anatomy Lecturer Dr. Yasas Kolambage. He is currently conducting research on skeletal dysplasias among Sri Lankans.  

What are skeletal dysplasias?  

Skeletal dysplasias (SDs) are a group of rare disorders with generalised developmental defects in bone and cartilage. There are more than 450 disorders that fall under SDs and the list is expanding each year due to the remarkable discovery rate of genes and variants. They occur in approximately 1 in 5,000 births and their severity ranges from mild short stature to severe lethal forms of SDs. Non-lethal SDs usually present with disfiguring skeletal abnormalities leading to a varying degree of deformity and disability. Frequently seen skeletal dysplasias include achondroplasia, osteogenesis imperfecta, thanatophoric dysplasia, achondrogenesis, and campomelic dysplasia.

How do you identify them?

It is important to note that we can identify SDs even before birth using routine ultrasound scans. These ultrasound scan findings (i.e. abnormalities in femur length, chest, abdominal circumference, etc.) are useful not only to suspect SDs but also to predict the lethality of the condition. When ultrasound features are suggestive, parents are benefited from prenatal counselling and anticipatory guidance. However, accuracy of prenatal diagnosis is approximately 40% and the diagnosis can be missed due to delayed onset of the disease. Misdiagnosis of SDs often lead to suboptimal management of the patients. 

Soon after the birth of a child, paediatricians play the main role in identifying SDs. Short stature is one of the most common presentations that we encounter in clinical practice. According to the current practice, the majority of SDs are diagnosed based on clinical and radiological features alone. As these disease entities have very similar features, coming to a definitive diagnosis is never an easy task. Just like treasure hunting, sometimes it takes years to narrow down the correct diagnosis, out of all the possible diagnoses. But utilising molecular genetic studies can cut down a great deal of time spent on the diagnostic process, stated Dr. Kolambage.

What is the workup?

The diagnostic workup of SDs begins with medical history and careful physical examination followed by radiological imaging and genetic studies (Figure 1). Firstly, we look at the family history over multiple generations to detect the pattern of inheritance by identifying any similar conditions running in the family. The risk of having a child with SDs grows with consanguinity and increased age of parents. Birth history and developmental history are essential to identify any complications that occur during prenatal, postnatal, and early childhood. 

Physical examination aims at recognising main abnormalities such as short stature, and further analysis is needed to differentiate proportionate from disproportionate shortening. Obtaining serial anthropometric measurements like sitting and standing height, upper/lower segment ratio, arms span and head circumference, etc. and plotting them in relevant charts are essential steps for early detection of these skeletal disorders. Specific growth charts are available for specific conditions such as achondroplasia (commonest non-lethal SD). The systemic examination is carried out focusing on syndromic features.

Thereafter, radiological imaging of the whole skeleton is done to identify the affected bones. We call this series of radiographs a skeletal survey. If clinical and radiological features cannot pinpoint a definitive diagnosis, genetic testing of the affected individual as well as family members will be offered after pre-test counselling. 

The most appropriate genetic test should be determined based on clinical suspicion and in collaboration with a geneticist. Whole exome sequencing is often performed to locate the causative gene/variant and it is considered more cost-effective than the other sequencing techniques. 

The inheritance and genetics of SDs

As SDs are genetically heterogeneous, they can be inherited as autosomal dominant, autosomal recessive, x-linked recessive, x-linked dominant, and y-linked disorders. The nosology and classification of genetic skeletal disorders, which had its last revision in 2019, contains 461 disease entities that have pathogenic variants in 437 different genes. The discovery of novel genes associated with SDs provides insights for understanding the pathogenesis of rare genetic skeletal disorders, which is important to predict the progression of the disease over a lifetime and the recurrent risk for future pregnancies.

Table 1 shows some of the common genes associated with SDs.

Table 1: Some common genes associated with SDs

GeneDisorder
Fibroblast growth factor Receptor-3 gene (FGFR3)Achondroplasia
Thanatophoric dysplasia
Hypochondroplasia
Collagen genes
(COL1A1, COL1A2, etc.)
Osteogenesis imperfecta
Ehlers-Danlos syndrome
SOX9Campomelic dysplasia

Some disorders have only a single known causative gene, e.g. achondroplasia (Figure 2); whereas others have several known causative genes, e.g. osteogenesis imperfecta. Although the genetic basis of a large majority of skeletal disorders is now well known, still we tend to see patients with no significant known variant. 

Astonishingly, we have very limited knowledge about the genetic basis of SDs in the Sri Lankan population. Therefore, we are conducting a study at the Human Genetics Unit of the Faculty of Medicine at the University of Colombo to identify families with rare SDs that do not have a definitive diagnosis based on clinical and radiological findings. The best way to detect causative mutations is to perform exome sequencing. In sporadic cases, we analyse trios (index patient and the parents) that may reveal de-novo mutations. In familial cases, we may include other affected family members as well.  

Are they treatable? Are there any alternative therapies on the horizon?

It depends on the type of dysplasia and its severity. Patients with skeletal dysplasia should be followed by a multidisciplinary team composed of paediatricians, geneticists, and endocrinologists, as well as surgical subspecialists. The current treatment approach is generally palliative in nature for the majority of non-lethal disorders. There are a variety of non-surgical treatment modes that may include growth hormone treatment, bisphosphonate therapy, physiotherapy, and psychological support through counselling. Surgical interventions focus on understanding unique orthopaedic and neurological challenges to improve the patient’s quality of life and comfort. Bone marrow transplantation and stem cell transplantation may benefit patients with some types of SDs.

The good news is that there are alternative therapies that have been introduced recently. Enzyme replacement therapy is already available to treat certain conditions. Advancement in molecular genetic technologies to understand the pathogenic pathways has enabled the emergence of these enzyme replacement therapies. Furthermore, with the identification of suitable biomarkers, a new door is opened for gene therapy that targets specific mutations. This will allow us to provide more personalised treatment to cure skeletal dysplasias stated Dr. Kolambage.

Take-home message 

Although individual skeletal dysplasia types are relatively rare, as a group they significantly contribute to the health burden of the country. Usually, it takes a long time to arrive at a definitive diagnosis, which prevents the optimum management of the disease using therapies specific to the underlying diagnosis. Advances in molecular genetic testing allow an early diagnosis to end the diagnosis odyssey experienced by the families suffering from SDs. We foresee that enzyme replacement therapy and targeted gene therapy will be developed as personalised treatment modalities to treat and cure skeletal dysplasias in the future.