Crouzon Syndrome


Article Author:
Christopher Conrady


Article Editor:
Bhupendra Patel


Editors In Chief:
Eric Flake


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Frank Smeeks
Kristina Soman-Faulkner
Radia Jamil
Patrick Le
Sobhan Daneshfar
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
4/10/2019 11:53:06 AM

Introduction

Crouzon syndrome is a genetically inherited syndrome characterized by craniosynostosis (premature fusion of coronal sutures) resulting in the skull and facial deformities. The syndrome was first described in 1912 by French physician Octave Crouzon when he identified both a mother and daughter with what was originally called “craniofacial dysostosis.” He described a triad of skull deformities, facial anomalies, and proptosis. This triad of findings was then re-labeled “Crouzon syndrome.” The syndrome’s genetic and molecular basis has since been identified and will be discussed in more detail below. The syndrome is one of many craniosynostosis syndromes and is considered to be the mildest form of them.

Etiology

Crouzon syndrome is inherited in an autosomal dominant pattern and is caused by a mutation in the fibroblast growth factor receptor (FGFR)-2 and -3 on chromosome 10 [1][2].  The syndrome has complete penetrance but variable expressivity resulting in phenotypically unaffected to severe deformities within the same family. In approximately 50% of cases, the mutation is the result of de novo mutations [3].

Epidemiology

Crouzon syndrome is a fairly rare entity and is estimated to occur in 1 in 60,000 newborns; however, it is the second most common craniosynostosis syndrome behind only the more recently described Muenke syndrome [4][5].

Pathophysiology

FGFR-2 and FGFR-3 are two of the four transmembrane protein receptors responsible for osteoblast differentiation during embryological development. Missense mutations in these two receptors result in gain-of-function signaling and subsequent acceleration in the differentiation of osteoblasts [6][7]. Detailed discussion of these receptors and their downstream signaling can be found in Azoury et al., 2017 [8]. This process results in premature fusion of sutures. The complexity of which and why a specific suture is involved is not currently known. Depending on the sutures involved, different, abnormal patterns of growth of the skull can occur. In Crouzon syndrome brachycephaly (widened and shortened) is the most common presentation due to bi-coronal suture fusion. However, trigonocephaly (triangular) and scaphocephaly (long and narrow) are not uncommon. In the most severe cases, a “cloverleaf” skull known as a Kleeblattschadel deformity can be seen due to the closure of multiple sutures.

History and Physical

Due to the autosomal inheritance pattern, family history is an important component of the history and physical. The clinical course of worsening of facial deformities over the first 1 to 2 years of life helps make the clinical diagnosis. Additional testing is usually not needed to make the diagnosis. As a genetic disease, the rest of the history of the newborn infant is unlikely to contribute much more to identifying the underlying diagnosis. 

Crouzon syndrome is usually suspected at birth due to specific facial and cranial deformities and positive family history. There are several characteristic features of patients with Crouzon syndrome that can be seen on physical examination. The most commonly seen include brachycephaly, wide-set (hypertelorism), bulging eyes (proptosis), a flattened forehead, a beaked nose, and underdeveloped upper jaw (maxillary/midface hypoplasia) that defines the Crouzonoid face. These patients can also suffer from a cleft lip and/or palate, hearing loss, and dental problems. The incidence of strabismus (misaligned eyes) is very high. An important detail to note is the normal hands and feet found in a Crouzon patient in contrast to those with Apert syndrome, a similar but more severe craniosynostosis syndrome, where there is pronounced syndactyly of the extremities. Pfeiffer syndrome, another craniosynostosis, is also epitomized by short, broad big toes and thumbs in contrast to the previously mentioned normal digits of those with Crouzon syndrome [4].

Evaluation

The evaluation for Crouzon syndrome is relatively straightforward in the setting of known family history as the characteristic physical examination findings confirm the diagnosis. However, in cases where there is a spontaneous mutation, and the clinical presentation is not clear initially, these patients may require genetic testing for diagnosis. Additional tests in these situations may include imaging techniques such as magnetic resonance imaging (MRI) and computed tomographic (CT) imaging of the brain to detect craniosynostosis or other skeletal abnormalities. The most common imaging findings on x-ray-based techniques are perisutural sclerosis, reduced serration, and bony bridging and/or the absence of the suture altogether [9]. A beaten bronze appearance of the skull is also a common finding on CT in this syndrome due to multiple radiolucencies of the skull bones. These imaging modalities can also help identify sequelae of the syndrome such as radiographic findings suggestive of increased intracranial pressure that may be otherwise difficult to detect in uncooperative children.

If the history, physical, and imaging are still not conclusive, molecular testing can be pursued. Unfortunately, multiple craniosynostosis syndromes have a defect in one of the FGFRs; therefore, there is some overlap even in their molecular pathophysiology [8]. For those patients that have a family history of Crouzon or one of the other craniosynostosis syndromes, prenatal genetic testing and 2-dimensional and 3-dimensional ultrasounds can be utilized to confirm the diagnosis before the birth of the child [8]. In high-risk pregnancies, amniocentesis and/or chorionic villus sampling can be performed, but a detailed dialogue of risks and benefits must be discussed with the parents before proceeding.  

While not all required, the combination of detailed family history, specific physical examination findings, the use of various imaging modalities, and genetic testing help differentiate the spectrum of craniosynostosis syndromes (Pfeiffer, Apert, Saethre-Chotzen, Carpenter, and Jackson-Weiss syndromes) in which signs and symptoms can have significant overlap.

Treatment / Management

The management of any patient with craniosynostosis is complex and requires a team of subspecialists including pediatricians, oral maxillofacial surgeons, plastic surgeons, neurosurgeons, otorhinolaryngology (ENT) specialists, and ophthalmologists (pediatric and oculoplastics).  Other specialists may be required depending on the specific issues at hand. Surgical management is the treatment modality of choice to correct the maldevelopment of the midface and orbits to prevent blindness and intellectual disability related to restriction of the brain and orbital development. A detailed review of surgical techniques including the timing of repair can be seen in a recent review of the topic [10]. Most craniofacial surgeons currently feel that single suture craniosynostosis can be repaired with only one surgery, while multiple suture craniosynostoses require a staged approach to coincide with facial growth patterns. If the cranial vault abnormalities are corrected, patients with Crouzon syndrome will have normal cognitive function, vision, hearing, and lifespans. Fortunately, not all patients will require surgery, so a team-based approach to monitoring for the development of complications related to the syndrome is necessary that would warrant intervention. The overall prognosis depends on the severity of malformations and when they were corrected. Earlier correction (prior to 1 year of age) anecdotally minimizes cognitive disabilities, airway obstructions, and decreased visual acuity and results in better outcomes [11].

It requires long-term followup to monitor ocular development due to the propensity to develop strabismic amblyopia and the need for strabismus surgery. These examinations should also monitor for optic nerve edema that would raise concerns for elevated intracranial pressure. Due to airway changes, sleep apnea is also of concern. The previously mentioned team-based approach helps monitor for these vision and life-threatening complications.

There is some ongoing work investigating the role of tyrosine kinase inhibitors in mutated FGFR-related craniosynostosis conditions [12]. Unfortunately, these studies have not been tested in humans, and are likely years away from clinical use.

Differential Diagnosis

  • Apert syndrome
  • Muenke syndrome
  • Pfeiffer syndrome
  • Nonsyndromic craniosynostosis

Consultations

  • Pediatricians
  • Ophthalmologists (pediatric and oculoplastics)
  • Maxillofacial surgeons
  • Neurosurgeons
  • Plastic surgeons
  • ENT specialists

Enhancing Healthcare Team Outcomes

eam Management of craniosynostosis is complex and difficult and requires a team of subspecialists including pediatricians, oral maxillofacial surgeons, plastic surgeons, neurosurgeons, otorhinolaryngology (ENT) specialists, and ophthalmologists (pediatric and oculoplastics). The nurses involved need to be specialty trained to assist in recognizing complications and educating the families. A multidisciplinary team approach appraoch will provide the best patient outcomes. [Leve V] 


  • Image 6959 Not availableImage 6959 Not available
    By Octave Crouzon - Octave Crouzon: Dysostose cranio-faciale héréditaire. Bulletins et mémoires de la Société médicale des hôpitaux de Paris Vol. 33, 545-55 (1912) (http://web2.bium.univ-paris5.fr/livanc/?cote=epo0192&do=chapitre), Public Domain, https://commons.wikimedia.org/w/index.php?curid=2049832
Attributed To: By Octave Crouzon - Octave Crouzon: Dysostose cranio-faciale héréditaire. Bulletins et mémoires de la Société médicale des hôpitaux de Paris Vol. 33, 545-55 (1912) (http://web2.bium.univ-paris5.fr/livanc/?cote=epo0192&do=chapitre), Public Domain, https://commons.wikimedia.org/w/index.php?curid=2049832

Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Crouzon Syndrome - Questions

Take a quiz of the questions on this article.

Take Quiz
A 4-year-old girl presents with a wide face, loss of spinal curvature, and acanthosis nigricans around the lips and in the axillae. These findings suggest the presence of which syndrome?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
An 18-year-old man with Crouzon syndrome presents with severe residual midfacial deformity despite several prior surgical attempts at midfacial advancement using conventional techniques. Diagnostic imaging demonstrates extensive bony loss and fragmentation across the orbitomaxillary region of the facial skeleton. Which of the following is a reasonable reconstructive surgical plan for this person?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 6-year-old child presents for evaluation of severe sleep apnea. Her past medical history is significant for conductive hearing loss, underdevelopment of the midface, and fused coronal sutures. The patients' parents are also extremely concerned about her facial features. What is the best approach to definitively treating both the sleep apnea and the maldeveloped midface?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
What is a characteristic feature of Crouzon syndrome?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following craniosynostosis syndromes is characterized by a tall, flattened forehead?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following types of hearing loss is commonly seen in patients with Crouzon syndrome?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
What is the underlying mutation responsible for Crouzon syndrome?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Crouzon Syndrome - References

References

Reardon W,Winter RM,Rutland P,Pulleyn LJ,Jones BM,Malcolm S, Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome. Nature genetics. 1994 Sep     [PubMed]
Meyers GA,Orlow SJ,Munro IR,Przylepa KA,Jabs EW, Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with acanthosis nigricans. Nature genetics. 1995 Dec     [PubMed]
Pal US,Gupta C,Chellappa AA, Crouzon syndrome with primary optic nerve atrophy and normal brain functions: A case report. Journal of oral biology and craniofacial research. 2012 May-Aug     [PubMed]
Mathijssen IM, Guideline for Care of Patients With the Diagnoses of Craniosynostosis: Working Group on Craniosynostosis. The Journal of craniofacial surgery. 2015 Sep     [PubMed]
Rannan-Eliya SV,Taylor IB,De Heer IM,Van Den Ouweland AM,Wall SA,Wilkie AO, Paternal origin of FGFR3 mutations in Muenke-type craniosynostosis. Human genetics. 2004 Aug     [PubMed]
Di Rocco F,Biosse Duplan M,Heuzé Y,Kaci N,Komla-Ebri D,Munnich A,Mugniery E,Benoist-Lasselin C,Legeai-Mallet L, FGFR3 mutation causes abnormal membranous ossification in achondroplasia. Human molecular genetics. 2014 Jun 1     [PubMed]
Snyder-Warwick AK,Perlyn CA,Pan J,Yu K,Zhang L,Ornitz DM, Analysis of a gain-of-function FGFR2 Crouzon mutation provides evidence of loss of function activity in the etiology of cleft palate. Proceedings of the National Academy of Sciences of the United States of America. 2010 Feb 9     [PubMed]
Azoury SC,Reddy S,Shukla V,Deng CX, Fibroblast Growth Factor Receptor 2 ({i}FGFR2{/i}) Mutation Related Syndromic Craniosynostosis. International journal of biological sciences. 2017     [PubMed]
Kim HJ,Roh HG,Lee IW, Craniosynostosis : Updates in Radiologic Diagnosis. Journal of Korean Neurosurgical Society. 2016 May     [PubMed]
Taylor JA,Bartlett SP, What's New in Syndromic Craniosynostosis Surgery? Plastic and reconstructive surgery. 2017 Jul     [PubMed]
Warren SM,Proctor MR,Bartlett SP,Blount JP,Buchman SR,Burnett W,Fearon JA,Keating R,Muraszko KM,Rogers GF,Rubin MS,McCarthy JG, Parameters of care for craniosynostosis: craniofacial and neurologic surgery perspectives. Plastic and reconstructive surgery. 2012 Mar     [PubMed]
Carter EP,Fearon AE,Grose RP, Careless talk costs lives: fibroblast growth factor receptor signalling and the consequences of pathway malfunction. Trends in cell biology. 2015 Apr     [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of Pediatric-Developmental. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for Pediatric-Developmental, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in Pediatric-Developmental, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of Pediatric-Developmental. When it is time for the Pediatric-Developmental board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study Pediatric-Developmental.