What is Cerebrocostomandibular Syndrome?

Cerebrocostomandibular Syndrome (CCMS) is an extremely rare genetic disorder characterised by several developmental abnormalities acquired in the womb related to the ribs and jaw. These symptoms include a small chin, cleft palate (opening in the roof of the mouth), gaps between ribs, missing ribs. Additional problems with rib development include a narrow ribcage and ribs disconnected from the spine. Those with this condition can also suffer from difficulties with breathing and feeding, some may further develop scoliosis (about half) though the extent of this depends on how many gaps there are between ribs. Moreover, a quarter are born with a hole in the heart and hearing loss has been found in two thirds of those diagnosed. The extensive range of symptoms can have a significant impact on health from birth so the ability to image and diagnose these issues early on can help support planning for the baby and parents.^1,2

This disease is caused by a genetic mutation and is not inherited in most cases, however, some cases have been inherited from parents who show no symptoms and are only carriers of the disease.¹

Treatment is dependent on each specific case due to the wide variation of issues that can be caused by this disease. For breathing problems, this is often treated by a tracheostomy (the windpipe being cut in order to allow the baby to breathe), specialist feeding tubes or surgery may also need to be considered to ensure the baby can obtain all the nutrients it needs. This can all be discussed with healthcare experts from an early stage if imaging is clear enough making the process of diagnosis and treatment less surprising and reduce complications.¹

Challenges in Prenatal Diagnosis

Many signs of this disease can be detected in prenatal ultrasound imaging, the structure of jaw and ribs can be seen to be deformed in early X-ray and MRI imaging, however there are also many challenges when it comes to diagnosis this early.³

The rarity of the disease itself has led to a lack of awareness of the disease, with less than 100 recorded cases, it is not going to be the most obvious diagnosis.¹ The symptom of micrognathia (an abnormally smaller jaw) which is present in babies and fetuses with cerebrocostomandibular syndrome can be detected through Ultrasound and MRI methods though the rarity of disease and natural variation in the size of developing bones can make these conditions harder to diagnose.⁴ The variety of different symptoms can also pose a major challenge as several parts of the body can be affected and the condition may not manifest identically for all patients with some having less severe symptoms and some being much more affected by the condition.⁵

Other health conditions such as Pierre Robin syndrome share many similar symptoms of abnormal jaw development and so this could be easily confused for cerebrocostomandibular syndrome, preventing the correct diagnosis from being made, particularly if the ribs have not been investigated for signs of the latter condition.⁵

Additionally, to identify different symptoms scans may need to be taken at different times to ensure the most accurate results. For example, micrognathia can be detected from the 12th week of pregnancy, whereas problems with rib development can often only be detected after 18 weeks of pregnancy.³ 2D ultrasounds that are routinely used in prenatal imaging also have a tendency to overlook rib abnormalities, particularly early on, presenting further challenges to diagnosis. 3D ultrasound and MRIs can improve the quality of image which could help to detect this condition but are more expensive, more time consuming and not usually routinely carried out so would probably not be done unless other symptoms were detected.⁶

Advances in Prenatal Imaging

Technological advances have led to more accurate imaging techniques being developed, a higher resolution of ultrasound images can now be produced due to specially modified high-resolution transducers that can be used to determine the number of ribs and size of ribs and jaw⁶. The use of 3D and 4D ultrasound provide more information than 2D images including volumetric measurements which can be used to determine, not only a diagnosis, but also evaluate the extent of the condition.⁶

High quality MRI imaging can also be used alongside ultrasound to image soft tissue such as the tongue, palate and lung volume to build a more detailed and accurate idea of developmental abnormalities. This added detail can help to develop a more precise and effective plan of treatment for the baby once born and provide information on how to best approach the birth process. On the other hand, a major limitation of this technique is that it is the most informative after 18 weeks and even then must be done by fetal MRI experts.⁷

A completely different method of diagnosis can also be approached for this disease as it has been associated with a gene mutation, specifically affecting the splicing factor SNRPB. This means that if cerebrocostomandibular syndrome is suspected, genetic testing can be used to confirm these suspicions. As well as confirming a diagnosis, this information can be used to inform family counseling and evaluate recurrence risks when considering pregnancy.⁸

Clinical Implications of Improved Imaging

When these types of developmental conditions can be detected early on, it gives the family plenty of time to have in depth discussions with fetal medicine specialists and receive counseling from professionals about the best course of action. There are many factors to discuss including the high mortality rate of 35% in the first year after birth and the long-term symptoms affecting those who survive past this point. If a higher quality and dimension of image can be produced, this gives those providing counseling a clearer picture of the extent of the condition and can help them give more specific advice on an individual, case-by-case basis.^1,5

This extra time can also be used to develop multidisciplinary prenatal planning, seeking guidance from experts across genetics, neonatology, surgery/orthopedics and ENT /anesthesia. Professionals in genetics can provide counseling and genetic testing, neonatology specialists can prepare to assess and tackle respiratory issues, surgeons and orthopedics can prepare to combat rib abnormalities and other possible symptoms like scoliosis and ENT and anesthesia specialists can consider plans for if the airways are compromised, particularly during the birth.³ Complications leading to airways becoming compromised is the most pressing concern during delivery and so being able to plan exit procedures in detail can be crucial in ensuring the survival of the baby and this is informed by fetal images taken before the birth.⁶

Future Directions

AI is starting to be used to identify anomalies in ultrasound images, measurements of development, for example of the jaw, can be assessed by deep learning tools and can detect possible cases of micrognathia. Biometric databases can be used to compare fetal images to evaluate symptoms and help inform a diagnosis.⁹ This could be particularly useful for diagnosing this condition as if the scan appears normal a health condition may not be investigated until later on, whereas if AI can take measurements and point out abnormalities it may be able to detect problems that the human eye wouldn’t.

Summary

Cerebrocostomandibular Syndrome is a developmental condition affecting the jaw and ribs from birth. It is an extremely rare disease but has several long term symptoms that can vary in individual cases.

Imaging of this condition is challenged by the time between different symptoms manifesting on ultrasound scans meaning that several scans may be needed to form a diagnosis, this also means that a diagnosis can often not be made very early on. Other challenges include the lack of awareness among physicians due to the rarity of the disease and the similarity in symptoms to diseases such as Pierre Robin syndrome which could easily lead to a misdiagnosis.

Recent advances in the resolution of ultrasound images and the use of 3D techniques has allowed more accurate and helpful information to be provided which can allow an earlier diagnosis to be confirmed. MRI imaging can also be used alongside ultrasound to develop an even more detailed idea of how to support the birth.

Future advances in the use of AI also hope to improve the accuracy of diagnosis and allow earlier detection of Cerebrocostomandibular Syndrome to be made, allowing more time to consider next steps with professionals and specialists.

FAQS

What genetic tests are available?

Whole exome sequencing or targeted gene panels can identify mutations in SNRPB

What advances have improved diagnosis?

• 3D ultrasound and fetal MRI offer better visualization of skeletal and brain anomalies
• AI-assisted imaging analysis is emerging to detect subtle features
• Improved genetic testing allows earlier and more accurate diagnosis

What specialists are involved in prenatal and postnatal care?

• Prenatal: Maternal-fetal medicine, radiology, genetics
• Postnatal: Neonatology, ENT, craniofacial surgery, pulmonology, neurology