What is Carpenter Syndrome?

Introduction
Causes and Symptoms of Carpenter Syndrome
The RAB23 Gene
The MEFG8 Gene
Epidemiology of Carpenter Syndrome
Diagnosis and Treatment of Carpenter Syndrome
References

Carpenter syndrome is a rare autosomal recessive disorder characterized by several developmental problems. It belongs to a group of disorders known as Acrocephalopolysyndactyly syndromes. A congenital malformation disorder is marked by multisuture craniosynostosis, polysyndactyly of the hands and feet, and many other clinical features. The majority of cases have mutations in RAB23, which codes for a small GTPase that governs vesicular transport.

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Causes and Symptoms of Carpenter Syndrome

Carpenter syndrome is inherited in an autosomal recessive manner and is caused by mutations in the RAB23 or MEGF8 genes. Proteins with little or no function are produced when the RAB23 or MEGF8 genes are mutated. It's unclear how protein malfunctions cause Carpenter syndrome's symptoms, although it's likely that interference with normal body patterning plays a part. People with MEGF8 gene mutations are more likely to suffer dextrocardia, other organ placement abnormalities, and severe craniosynostosis than those with RAB23 gene mutations. The reasons for this are not yet known.

Carpenter syndrome can have a wide range of characteristics and symptoms, even across family members. Premature closure of some skull bones (craniosynostosis), unusual facial characteristics, and/or deformities of the fingers and toes are the prominent characteristics. Carpenter syndrome is associated with an intellectual disability (ranging from mild to severe), but some people with the condition have normal IQ.

Craniosynostosis is a condition that causes the skull to stop growing normally, giving the head a pointed appearance (acrocephaly). The improper fusing of the skull bones causes a deformity known as a cloverleaf skull in seriously affected individuals. Early skull fusion can harm the brain's development, which can result in increased pressure within the skull (intracranial pressure). Carpenter syndrome is characterized by the premature fusing of the skull bones, which can result in various facial traits.

Organs or tissues in the chest and abdomen of a few patients with Carpenter syndrome are in mirror-image reversed locations. This incorrect positioning can impact a variety of internal organs (situs inversus); just the heart (dextrocardia), which causes the heart to be on the right side of the body instead of the left; or only the major (great) arteries of the heart, causing blood flow to be disrupted.

Other characteristics include unusual facial features, brachydactyly with syndactyly in the hands, congenital cardiac abnormalities, growth retardation, mental retardation, hypogenitalism, and obesity. Cerebral deformities, oral and dental abnormalities, genu valgum, hydronephrosis, coxa valga, premature puberty, and hearing loss are also possible.

The RAB23 Gene

The RAB23 gene codes for a protein involved in vesicle trafficking, a process used to transport proteins and other molecules within cells in sac-like structures known as vesicles. Vesicles are transported from the cell membrane to their correct place inside the cell by the RAB23 protein. The transport of components required to initiate signaling during development is made possible via vesicle trafficking.

Jenkins et al. (2007) discovered five distinct mutations in the RAB23 gene in 15 families with Carpenter syndrome (4 truncating and 1 missense). The RAB23 gene codes for a vesicle transport protein belonging to the RAB guanosine triphosphatase (GTPase) family and works as a negative hedgehog (HH) signaling regulator. Alessandri et al. (2010) discovered homozygosity for a 1-bp duplication in the RAB23 gene in four boys with Carpenter syndrome from a consanguineous Comoros Islands lineage.

The MEFG8 Gene

The MEGF8 gene codes for a protein whose function is unknown. The MEFG8 protein, based on its structure, may be involved in cell activities such as cell adhesion and helping proteins interact with one another. According to researchers, the MEFG8 protein may also play a role in correct body patterning. Twigg et al. describe a condition induced by mutations in the MEGF8 gene, which has significant clinical overlap with

Carpenter syndrome is commonly accompanied by aberrant left-right patterning. They concluded that MEGF8 mutations induce a Carpenter syndrome subgroup that is usually associated with abnormal left-right patterning, most likely due to signaling disruption by hedgehog and nodal family members.

Epidemiology of Carpenter Syndrome

Carpenter syndrome is a rare disorder, with about 70 cases reported in the literature.

Diagnosis and Treatment of Carpenter Syndrome

It can be challenging to make a diagnosis for a hereditary or uncommon condition. Healthcare practitioners look at a person's medical history, symptoms, physical exam, and laboratory test findings to determine a diagnosis. Treatment is tailored to each individual's unique characteristics. Most affected children have surgery between 3 and 9 months to open the cranial vault and allow the brain to grow. Life expectancy is reduced, but it varies greatly.

Carpenter and other craniosynostosis syndromes must be diagnosed early to receive the best surgical treatment. The diagnosis of craniosynostosis is based on a combination of physical examination and radiographic investigations, such as computed tomographic scans and conventional radiography.

The identification of faulty genes and associated pathways in explaining various congenital abnormalities is now possible because of advances in molecular genetics. The phenotypic variability of craniofacial disorders like Carpenter necessitates genetic testing, careful clinical observation, and physician observation. Early surgical surgery can thus be indicated to prevent chronic disease's ravages.

References:

• (2021). Carpenter Syndrome. [Online] NIH-GARD. Available at: https://rarediseases.info.nih.gov/diseases/6003/carpenter-syndrome#diseaseOverviewSection
• Güvenç, O., Çimen, D., Arslan, D., & Güler, İ. (2017). Carpenter sendromu ve çift çıkışlı sağ ventrikül birlikteliği [Co-occurrence of Carpenter syndrome and double outlet right ventricle]. Turk Kardiyoloji Dernegi arsivi: Turk Kardiyoloji Derneginin yayin organidir, 45(5), 454–457. https://doi.org/10.5543/tkda.2016.16040
• Twigg, S. R., Lloyd, D., Jenkins, D., Elçioglu, N. E., Cooper, C. D., Al-Sannaa, N., Annagür, A., Gillessen-Kaesbach, G., Hüning, I., Knight, S. J., Goodship, J. A., Keavney, B. D., Beales, P. L., Gileadi, O., McGowan, S. J., & Wilkie, A. O. (2012). Mutations in multidomain protein MEGF8 identify a Carpenter syndrome subtype associated with defective lateralization. American journal of human genetics, 91(5), 897–905. https://doi.org/10.1016/j.ajhg.2012.08.027
• Hidestrand, P., Vasconez, H., & Cottrill, C. (2009). Carpenter syndrome. The Journal of craniofacial surgery, 20(1), 254–256. https://doi.org/10.1097/SCS.0b013e318184357a
• Carpenter Syndrome. [Online] Medline Plus. Available at: https://medlineplus.gov/genetics/condition/carpenter-syndrome/#resources
• Carpenter Syndrome. [Online} OMIM. Available at: https://omim.org/entry/201000#clinicalFeatures

Further Reading

• All Rare Disease Content
• What is a Rare Disease?
• Importance of Research into Rare Disease
• Teaching old drugs new tricks – drug repurposing for rare diseases
• What is Adenomyosis?

Written by

Emily Henderson

During her time at AZoNetwork, Emily has interviewed over 300 leading experts in all areas of science and healthcare including the World Health Organization and the United Nations. She loves being at the forefront of exciting new research and sharing science stories with thought leaders all over the world.