Introduction

Carpenter’s syndrome is a rare disease typically caused by mutations in the RAB23 or MEGF8 genes that affects approximately 1 in 1 million people. It is part of a group called craniosynostosis syndromes, which describes a collection of craniofacial abnormalities. The main features of Carpenter’s syndrome are premature fusion of skull bones, syndactyly (fused fingers/toes), and polydactyly (extra fingers/toes). Some studies have even linked Carpenter’s syndrome to chronic kidney disease (source). However, the main methods of diagnosis remain recognition of characteristic facial features. But many other diseases belong in the family of craniosynostosis syndromes. So, how best to differentiate Carpenter syndrome from other syndromes with craniosynostosis? Read on to find out!

The word 'craniosynostosis' comes from the Greek kranion (skull) and synostosis (union or fusion) and is used to describe abnormalities in the cranial bone fusion in young children. The cranial sutures are much like pieces of dough connected together to form a big ball, the skull. During development, each dough piece can stretch in different directions without breaking, allowing the skull to develop and change shape. Premature fusion of bone sutures (fusion in the cranium/skull) then leads to deformities in cranial shape. The skull compensates for fused sutures by growing in the direction of open sutures, which can cause abnormal head shapes. This leads to characteristic facial shapes, which give rise to many different syndromes that describe facial abnormalities in children.

Mechanisms responsible for craniosynostosis

The mechanisms behind craniosynostosis syndromes are complex. In the early stages of development, the cranial vault bones of an infant are separated by sutures. This allows the head to pass through during birth and helps support the growth of the skull to fit the developing brain. Sometimes, these sutures may close prematurely due to signals sent by the dura mater. The dura mater is the outer protective membrane that surrounds the meninges and helps protect the brain and spinal cord. During development, it also produces chemicals like growth factors which affect the fusion of sutures.

There are many different theories at the moment that can explain how the dura mater is involved in craniosynostosis. Some authors suggest that there are different areas in the dura mater that control the patency of the sutures, or their ability to stretch and grow new bone to help newborn skull development. Some suggest that craniosynostosis is the result of abnormal osteoprogenitor cells—cells that give rise to bone-forming cells. If cells in the dura mater are abnormal and present different amounts of signalling proteins, for example, this may cause abnormal bone-forming cells to grow and lead to premature fusion of sutures. These studies thus far have been conducted in mice and chick models, so more research is needed to discover the exact mechanisms. 

Syndromes associated with craniosynostosis

Crouzon’s syndrome 

One well-studied syndrome is Crouzon’s syndrome. It was first described in 1912, and it is passed on to offspring if one parent has the faulty allele (autosomal dominant). It is caused by a mutation in the fibroblast growth factor receptor 2 gene (FGFR2) and leads to skull deformities like broad head (brachycephaly), triangular-shaped head (trigonocephaly), or tower skull (oxycephaly).

Attached below is a diagram highlighting the characteristic facial features of Crouzon syndrome.

In most cases, an ophthalmologist (eye doctor) is required to check the eye pressure of a patient with Crouzon. Ophthalmologists often check for papilledema (optic disc swelling) and proptosis (bulging eyes), which may suggest increased intracranial pressure. In rare cases, it can even lead to blindness.

Apert syndrome 

Another well-studied syndrome is Apert syndrome.

The main cause is 1 of 2 FGFR2 mutations involving amino acids (Ser252Trp or Pro253Arg). It is again inherited if one parent has the faulty allele (autosomal dominant) and is characterised by brachycephaly and, frequently, turricephaly (tower-like skull).

In addition to that, patients with Apert syndrome often have fused fingers (complex syndactyly) of the hands and feet. Usually, this happens between the 2nd and 4th fingers and toes. See the image below for reference.

Pfeiffer syndrome 

Finally, another well-studied syndrome is Pfeiffer syndrome.

It is again inherited if one parent has the faulty allele and is caused by a single recurring mutation (Pro252Arg) of the FGFR1 gene, and several mutations involving FGFR2. Patients typically have craniosynostosis, enlarged thumbs and great toes, and a hypoplastic midface (underdeveloped mid-face region).

The condition has been further split into 3 types:

• Type I has the best long-term prognosis.
• Types II and III are more severe and often lead to neurologic compromise and early death.

All the above syndromes, alongside Carpenter’s syndrome, fall in the category of craniosynostosis syndromes and are conditions that affect facial structure and the development of newborns. So, how best to differentiate Carpenter’s syndrome from the other syndromes?

Differentiating carpenter’s syndrome from other syndromes

1. Look for polydactyly: Carpenter’s is one of the few craniosynostosis syndromes with extra fingers or toes in addition to fused ones
2. Check for obesity and intellectual disability: These are more common in Carpenter’s compared to Pfeiffer
3. Inheritance pattern: Carpenter’s syndrome is usually autosomal recessive, meaning both parents must carry the gene, unlike the others, which are mostly autosomal dominant

Treatment for craniosynostosis

Treatment for craniosynostosis is mainly corrective surgery. The main goals are to reduce pressure in the skull, preserve vision and help improve appearance as much as possible.

Many exciting techniques have emerged in plastic surgery in the past 20 years, so the prognosis for patients is improving. The main factors that determine treatment success are the age at diagnosis and the exact location of the fused sutures.

Summary

• Craniosynostosis is a general term used to describe diseases that affect skull development in newborns. It is caused by the fusion of skull bones before they should, which causes the skull to develop an abnormal shape and limits space for the brain to grow.
• Craniosynostosis syndromes are used to describe the specific head shapes and symptoms that result from the early fusion of different cranial bones. Some well-studied examples include: Crouzon syndrome, Apert syndrome, Pfeiffer syndrome and Carpenter syndrome
• Carpenter syndrome is characterised by craniosynostosis, polydactyly, syndactyly, intellectual disability, and obesity, which helps distinguish it from the others.

FAQs

What causes craniosynostosis?

The main cause is the inheritance of mutated copies of genes from parents. The method of inheritance is different depending on the syndrome. For some, only one faulty copy is needed (autosomal dominant), while in others, two faulty copies (one from each parent) are needed.

For Carpenter syndrome, it usually follows an autosomal recessive pattern.

In some cases, the syndromes can occur spontaneously, without the parents having faulty genes, due to random mutations.

How do I know if I have Carpenter’s syndrome?

Doctors look for signs like unusual head shape, extra fingers/toes, and developmental delay, and use genetic testing for diagnosis.

What is the prognosis for Carpenter’s syndrome, and what is the current treatment?

Prognosis depends on how early the condition is detected and treated. With early surgical intervention and support, children can lead longer and more functional lives. Treatment usually involves surgical correction of the skull and hands/feet, monitoring of brain pressure, and developmental support for learning and behaviour.