Introduction

Carpenter syndrome (CS) is a rare genetic condition that falls under the category of craniosynostosis syndromes. These describe a genetic abnormality where an infant’s skull bones fuse prematurely, causing growth abnormalities and deformity of the skull. CS is the rarest of these syndromes and is characterised by two additional features: musculoskeletal abnormalities and midface hypoplasia (a condition where the bones of the middle face, including the upper jaw, eye sockets and cheekbones, fail to grow sufficiently in comparison to the rest of the face).

People with CS may also have other associated clinical features such as foetal developmental defects, including polydactyly and hypogenitalism, heart disease, and intellectual developmental disorders. Because of the varied scope of organ systems that may be affected in CS, the functioning of the child’s vital organs must be monitored as they grow and develop to prevent associated complications, risk of mortality, and improve their quality of life. This article will discuss the potential complications associated with CS and the type of monitoring that may be necessary.^1,2 

Common organ and heart-related issues in carpenter syndrome

Cardiac abnormalities

Mutation of the MEGF8 gene is one of the genetic causes of CS. The function of this gene is essential for early organ development of the foetus, particularly the regulation of a signalling pathway that is responsible for left-right axis formation. In short, this refers to the formation of the asymmetry of the body’s internal organs, one example being the heart. The absence of axis formation can result in various congenital heart defects, such as right aortic arch and dextrocardia (when the heart is positioned on the right side instead of the left).^3,4

The RAB23 gene also contributes to the cause of CS. It is an important regulator of the hedgehog signalling pathway, a well-preserved system of cellular communication that is essential for both embryonic development and the maintenance of tissue integrity. It is important for cell growth, differentiation, and the organisation of tissue structures, including heart, brain and muscle development. Dysregulation of this pathway in CS patients can cause cardiac defects such as heart murmurs, atrial septal defects and Tetralogy of Fallot.^5,6

Respiratory complications

CS is characterised by craniosynostosis, which leads to the delayed growth of the midface bones of the skull, causing the narrowing of the upper respiratory tract. This narrowing makes it difficult for individuals to breathe in and out, and can even cause periods of halted breathing during sleep. This is known as obstructive sleep apnea (OSA).⁷

Brain abnormalities

Upper respiratory tract obstruction in CS has been linked to raised intracranial pressure (pressure within the skull) due to craniosynostosis. This occurs due to:

• Hydrocephalus: when cerebrospinal fluid builds up in the brain, usually due to an underlying obstruction, preventing it from being drained
• Craniocerebral disproportion: disproportion between the size of the brain and the space available in the skull
• Disrupted intracranial venous blood drainage: causing venous blood to accumulate in the skull, resulting in a rise in pressure

Raised intracranial pressure has multiple associated risks, such as brain damage and, in extreme cases, increased risk of mortality. In children, brain damage is also linked to intellectual impairment and reduced intelligence quotient (IQ).^7,8,9

Recommended monitoring and diagnostic tools

If CS is suspected, formal diagnosis and investigations should include a multi-organ review. Because the mutations can vary between individuals with CS, organ function and severity of the condition can also vary. Early and frequent monitoring must be carried out for early detection of organ abnormalities and prevention of serious and life-threatening associated complications.

Cardiac function

The initial assessment of the heart begins shortly after birth, involving the use of a stethoscope to listen to heart sounds. During this assessment, a clinician can identify heart murmurs, irregular heartbeats and additional sounds that may be present in infants with CS. If a cardiac abnormality is suspected, the next step is to perform an echocardiogram, a type of ultrasound used to assess the structure, function and blood flow of the heart. A definitive diagnosis of conditions such as Tetralogy of Fallot, right aortic arch and atrial septal defects can be made using this diagnostic tool.^10,11

Computed tomography (CT) and magnetic resonance imaging (MRI) scans can be considered if needed. Both of these scans produce high-resolution, three-dimensional scans of a section of the body that can be assessed in greater detail. However, these do not go without risks:^12,13,14,15

• During CT scans, children are exposed to high doses of radiation. When compared to adults, children have a higher risk of developing radiation-related cancer, which is why CT scans should only be used when echocardiography is not sufficient to visualise the underlying cardiac abnormalities
• MRI Scans do not use any radiation to produce an image; however, some children may find the machines uncomfortable due to the enclosed space, noise and the time spent staying still. Some children may need to be sedated to avoid distress and to remain still during the scan, but sedation has additional risks, such as adverse reactions and breathing complications 

Respiratory monitoring

The gold standard screening for obstructive sleep apnea is polysomnography. This is used to monitor sleep patterns and disruption through the evaluation of brain waves using a test known as an electroencephalogram (EEG). Eye movements, breathing patterns, heart rate and muscle activity are also monitored.

Lung function tests such as spirometry and peak flow can also be carried out to determine any underlying breathing difficulties or diminishment in lung function. These tests also help rule out any other underlying respiratory conditions, such as asthma, and determine the severity of the craniosynostosis, how it affects the individual's breathing and if it warrants any interventions such as reconstructive surgery.^16,17

General investigations

• Blood tests: many markers in the blood can be measured through blood tests to determine the function of many organ systems, such as liver and kidney function¹⁸
• Scans: ultrasound, MRI, and CT scans can be carried out to investigate organ systems, including the brain and heart 
• Pulse oximetry: a device commonly used by health professionals to measure the percentage of oxygen saturation, which helps to indicate reduced oxygenation of the blood. In the case of CS, this may be due to an underlying respiratory issue. Pulse oximetry can be used to determine its severity¹⁹
• Regular measurement of height, weight and head circumference to monitor normal growth and development of the child 

Summary

• CS is a rare genetic disorder caused by the mutation of genes involved in the regulation of signalling pathways in normal organ development
• Multiple organs can be affected in individuals with CS; however, all are characterised by craniosynostosis, musculoskeletal abnormalities and midface hypoplasia
• Congenital heart defects are associated with mutations of the RAB23 and MEGF8 genes, which can cause varying outcomes depending on the types of mutations 
• Respiratory issues, raised intracranial pressure, and organ asymmetry are examples of other complications that may arise in individuals with CS
• Early investigations and monitoring, such as imaging techniques and blood tests, should be carried out to allow for early diagnosis and intervention to prevent further complications