Introduction

Cerebrocostomandibular Syndrome (CCMS) is a rare syndrome characterised by rib gaps (due to abnormal bone formation), mandibular hypoplasia or micrognathia (underdeveloped lower jawbone), other mouth and face anomalies such as cleft palate, and some degree of neurological impairment.

These irregularities can halt the basic body functionality, such as breathing and feeding. Due to its distinctive features, CCMS is sometimes associated with Pierre Robin Syndrome. Moreover, these impairments define how CCMS can affect skeletal, neurological, and facial structures altogether.¹

CCMS was first identified by Smith et al in 1966. In 1991, it was diagnosed in a pair of twin siblings by V Drossou-Agakidou et al. Understanding the developmental mechanism of CCMS is important as it can help us define the complex process of prenatal skeletal formation and how genetic and environmental factors influence it.²

This article describes in detail the unique combination of these inborn defects and provides insights into the biological and other intrinsic pathways involved in CCMS.

Embryological development of ribs and jawbone

The mandible (jawbone) originates from the first pharyngeal arch (bulges on each side of the embryo)  and is primarily formed from neural crest cells. Around the 4th week of fetal development, the mandibular processes begin to form.

The bone formation, formally known as ossification, starts around week 7 of gestation through intramembranous ossification, centres near Meckel’s cartilage, which serves as a cartilaginous template for bone formation. This process creates the mandibular body, ramus (vertical part of the lower jawbone, and coronoid process. 

By week 8, the mandible rapidly grows to form muscle attachment sites for chewing muscles. The mandibular condyle (part of the mandible that joins the skull bone) develops later through bone formation from cartilage. The mandibular condyle becomes evident by about week 14. 

These procedures involved in the early development of the mandible are significant in the precise formation of the head, face, and neck.³

Normal rib and thoracic cage development

The ribs and thoracic cage originate from the paraxial mesoderm, specifically from the sclerotomes, a part of the thoracic somites. These small block–like segments align centrally along the length of the embryo. These somites then differentiate into the spinal bones and the initial structures of the ribs. 

Around week 5-6, these initial structures of ribs start developing into cartilage templates, which will grow into the rib cage by slowly elongating around the chest cavity. 

Rib formation is a complex process that is precisely controlled by genetics and delicate communication between different cellular layers of the embryo (ectoderm, mesoderm, and endoderm).^2,4

Role of neural crest cells in craniofacial and rib formation 

Neural crest cells (NCCs) are specialised cells at the border of the developing nervous system in the ectoderm, the outer layer of an embryo. These cells possess a unique ability to migrate to various parts of the body and grow into distinct body structures. The NCCs help form bones, cartilage, and other connective tissues, including the mandible (jawbone).

If neural crest cells fail to move, grow, and change appropriately, it can lead to neurocristopathies, like birth defects affecting the skull, face, neck, and other parts of the body. 

All in all, when neural crest cells don't work right, it can cause defects in the skeleton and jaws,  just like cerebercostomandibular syndrome.⁵ 

Genetic basis of CCMS

Key gene mutations linked to CCMS 

Cerbercostomandibular syndrome is most frequently associated with mutations in the SNRBP gene. This gene plays a crucial role in the spliceosomal machinery, a mechanism that involves careful synthesis of protein for RNA processing. When this gene does not work properly during pregnancy, it can lead to disruptions in how certain body parts form, in CCMS, these are the mandible and ribs. Most of the alterations in the SNRPB gene are not inherited from parents. However, in some cases, a parent might carry a gene for CCMS and show no signs of the disease; this is called incomplete penetrance.⁶

Inheritance patterns and risk factors

Initially, it was believed that CCMS is caused by an autosomal recessive gene, meaning both parents need to carry the faulty gene for the child to develop the disease. However, new research confirms that the disease is an autosomal dominant. Thus, if one parent carries the CCMS gene, there are 50% chances that the offspring might develop this disease. It is important to note that even if someone carries the faulty gene, the symptoms of this disease vary significantly; they may experience milder or no symptoms at all.⁷ 

How genetic defects are connected to skeletal abnormalities

The SNRPB gene helps in creating specific proteins through the splicing process. Splicing is the process of creating instructions for making particular proteins. When a gene is copied into the mRNA, it includes two types of codes: the introns (the parts that do not encode for protein synthesis) and exons (the part that codes for protein synthesis). Spliceosome molecules carefully cut out introns and stitch exons, creating an effective genetic code that can be used by mRNA for protein synthesis.⁸

How the jaw and ribs are affected in CCMS

The unique combination of jaw and rib malformation is the hallmark feature of cerbercostomandibular syndrome. 

Craniofacial development 

The SNRPB gene plays a critical role in neural crest cells’ function due to its splicing mechanism. By carefully splicing the mRNA, the SNRPB can affect NCC survival, growth, migration, and differentiation during embryonic development. The NCCs are major contributors to the development of the jaw and facial structure. This is how mutations in SNRPB are related to mandibular hypoplasia.⁹

Skeletal development

Both bones and cartilage are derived from the middle cell layer of the embryo, called the mesenchymal cells. These cells are responsible for successful osteogenesis and chondrogenesis, which means bone and cartilage formation, respectively. SNRBP gene abnormalities can affect progenitor cells in the mesenchymal cell layer. It also negatively affects the cells that form bones and cartilage through abnormal protein synthesis and gene expression.¹⁰

Wider genetic networks and malformations

In addition to the SNRBP gene, other broader irregularities can contribute to CCMS.

Faulty migration of neural crest cells

Neural crest cells are vital for normal embryonic development. Normally, NCCs migrate from the border of the neural tube to various regions where they help form the facial bones. If these cells do not migrate properly, this can lead to craniofacial differences such as micrognathia. Other conditions related to faulty NCC migration include Treacher Collins and Pierre Robin sequence.^11,12

Defects in ribosome assembly

Ribosomes act as protein-forming factories in the cell. Ribosomes are made up of several subunits, including the ribosomal RNA (rRNA) and its many protein subunits. These must assemble properly to function well. If ribosomes fail to assemble properly, it results in reduced protein synthesis, which can affect the multiplication and formation of essential cells, such as neural crest and mesenchymal cells. These two cell types are progenitors of bone-forming cells, impacting rib growth and craniofacial development. These mechanisms can appear as bone marrow failure syndromes with distinct facial structures, like in  Diamond-Blackfan anaemia, which could be broadly linked to CCMS.^11,13

Patterning defects in embryonic development

The early development of the embryo relies on a specific set of instructions called the body plan. It participates in the spatial organisation of body tissues, organs, and structures such as bones, muscles. It is associated with anatomical axes that define which structure goes in front, back, right, left, up, and down. Based on this planning, organs are carefully formed in their designated position.

The body plan is executed, controlled, and regulated by several tools, such as:

• Morphogen gradients.
• Hox gene expression¹⁴

Morphogen gradients

Morphogen gradients are made up of morphogen chemicals that diffuse across the body, forming a gradient detected by progenitor cells. It helps in organ development in a specific manner; for example, bone morphogenic protein (BMP) is concentrated in areas marked for specific bones like ribs, spine, and mandible. The presence of BMP signals multiplication, assembly, and differentiation of bone-forming cells in this area, resulting in the accurate formation of bones in their specific positions.^15,16

Hox gene expression

The Hox genes are crucial transcription factors that help define the positional identity of anatomical structures embryo. For example, they guide where features such as the nose should be in an anterior position of the face. Specific Hox genes are active only in their specific regions; Hox genes for the jawbone are only active in the lower face area. 

If the Hox genes are disturbed, it can result in the complete disappearance of a structure or formation in a position where they do not normally exist. This can result in conditions such as syndactyly (missing finger), polydactyly (extra finger), or later in life myeloid leukaemia.^17,18

Summary

The cerberocostomandibular syndrome (CCMS) is a developmental disorder characterised by a small jawbone (micrognathia) and wider rib gaps. CCMS develops when the jawbone and ribs fail to form properly from neural crest cells and the mesoderm, respectively. The developmental anomalies can be broadly associated with mutations in the SNRBP gene as well as irregularities in the body pattern formation, through inconsistencies in signalling pathways and Hox gene expression. CCMS is an autosomal dominant disorder with incomplete penetrance characteristic as parents may carry a gene and never show any signs or symptoms of the disease. In conclusion, CCMS is a classical example of how complex embryological development is and how intricate genetic factors can affect craniofacial and skeletal formation. 

FAQs

What is an embryo?

Answer - The developing structure that lasts from a fertilised egg until major body parts are formed is called an embryo.

What are ectoderm, mesoderm, and endoderm? 

Answer - An embryo is divided into three layers of cells; the outer layer is called ectoderm, the middle layer is called mesoderm, and the inner layer is called endoderm.