Crouzon syndrome is an

autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

genetic disorder known as a

branchial arch Branchial arches, or gill arches, are a series of bony "loops" present in fish, which support the gills. As gills are the primitive condition of vertebrates, all vertebrate embryos develop pharyngeal arches, though the eventual fate of these arc ...

syndrome. Specifically, this syndrome affects the first branchial (or pharyngeal) arch, which is the precursor of the

maxilla The maxilla (plural: ''maxillae'' ) in vertebrates is the upper fixed (not fixed in Neopterygii) bone of the jaw formed from the fusion of two maxillary bones. In humans, the upper jaw includes the hard palate in the front of the mouth. The t ...

and

mandible In anatomy, the mandible, lower jaw or jawbone is the largest, strongest and lowest bone in the human facial skeleton. It forms the lower jaw and holds the lower tooth, teeth in place. The mandible sits beneath the maxilla. It is the only movabl ...

. Since the branchial arches are important developmental features in a growing

embryo An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...

, disturbances in their development create lasting and widespread effects. This syndrome is named after

Octave Crouzon Louis Édouard Octave Crouzon (1874–1938) was a French neurologist born in Paris. He received his doctorate from the University of Paris, where he studied under Paul Georges Dieulafoy (1839–1911), Joseph Babinski (1857–1932) and ...

, a

French French (french: français(e), link=no) may refer to: * Something of, from, or related to France ** French language, which originated in France, and its various dialects and accents ** French people, a nation and ethnic group identified with Franc ...

physician A physician (American English), medical practitioner (Commonwealth English), medical doctor, or simply doctor, is a health professional who practices medicine, which is concerned with promoting, maintaining or restoring health through th ...

who first described this disorder. First called "craniofacial dysostosis" ("

craniofacial Craniofacial (''cranio-'' combining form meaning head or skull + ''-facial'' combining form referring to the facial structures grossly) is an adjective referring to the parts of the head enclosing the brain and the face. The term is typically used ...

" refers to the

skull The skull is a bone protective cavity for the brain. The skull is composed of four types of bone i.e., cranial bones, facial bones, ear ossicles and hyoid bone. However two parts are more prominent: the cranium and the mandible. In humans, the ...

and

face The face is the front of an animal's head that features the eyes, nose and mouth, and through which animals express many of their emotions. The face is crucial for human identity, and damage such as scarring or developmental deformities may aff ...

, and "

dysostosis A dysostosis is a disorder of the development of bone, in particular affecting ossification. Examples include craniofacial dysostosis, Klippel–Feil syndrome, and Rubinstein–Taybi syndrome. It is one of the two categories of constitutional dis ...

" refers to malformation of bone), the disorder was characterized by a number of clinical features which can be described by the rudimentary meanings of its former name. This syndrome is caused by a mutation in the

fibroblast growth factor receptor 2 Fibroblast growth factor receptor 2 (FGFR2) also known as CD332 (cluster of differentiation 332) is a protein that in humans is encoded by the ''FGFR2'' gene residing on chromosome 10. FGFR2 is a receptor for fibroblast growth factor. The protein ...

(''FGFR2''), located on

chromosome 10 Chromosome 10 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 10 spans about 133 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the tota ...

. The developing fetus's skull and facial bones fuse early or are unable to expand. Thus, normal bone growth cannot occur. Fusion of different sutures leads to abnormal patterns of growth of the skull.

Signs and symptoms

A defining characteristic of Crouzon syndrome is

craniosynostosis Craniosynostosis is a condition in which one or more of the fibrous sutures in a young infant's skull prematurely fuses by turning into bone (ossification), thereby changing the growth pattern of the skull. Because the skull cannot expand perpe ...

, which results in an abnormal head shape. This is present in combinations of:

frontal bossing Skull bossing is a descriptive term in medical physical examination indicating a protuberance of the skull, most often in the frontal bones of the forehead ("frontal bossing"). Although prominence of the skull bones may be normal, skull bossing m ...

trigonocephaly Trigonocephaly is a congenital condition of premature fusion of the metopic suture (from the Greek , "forehead"), leading to a triangular forehead. The merging of the two frontal bones leads to transverse growth restriction and parallel growth ex ...

(fusion of the

metopic suture The frontal suture is a fibrous connective tissue, fibrous suture (joint), joint that divides the two halves of the frontal bone of the human skull, skull in infants and children. Typically, it completely fuses between three and nine months of ag ...

brachycephaly Brachycephaly (derived from the Ancient Greek '' βραχύς'', 'short' and '' κεφαλή'', 'head') is the shape of a skull shorter than typical for its species. It is perceived as a desirable trait in some domesticated dog and cat breeds, ...

(fusion of the coronal suture),

dolichocephaly Dolichocephaly (derived from the Ancient Greek δολιχός 'long' and κεφαλή 'head') is a condition where the head is longer than would be expected, relative to its width. In humans, scaphocephaly is a form of dolichocephaly. Dolichocep ...

(fusion of the

sagittal suture The sagittal suture, also known as the interparietal suture and the ''sutura interparietalis'', is a dense, fibrous connective tissue joint between the two parietal bones of the skull. The term is derived from the Latin word ''sagitta'', meaning ...

plagiocephaly Plagiocephaly, also known as flat head syndrome, is a condition characterized by an asymmetrical distortion (flattening of one side) of the skull. A mild and widespread form is characterized by a flat spot on the back or one side of the head cause ...

(unilateral premature closure of

lambdoid The lambdoid suture (or lambdoidal suture) is a dense, fibrous connective tissue joint on the posterior aspect of the skull that connects the parietal bones with the occipital bone. It is continuous with the occipitomastoid suture. Structure Th ...

and

coronal suture The coronal suture is a dense, fibrous connective tissue joint that separates the two parietal bones from the frontal bone of the skull. Structure The coronal suture lies between the paired parietal bones and the frontal bone of the skull. It r ...

s),

oxycephaly Turricephaly is a type of cephalic disorder where the head appears tall with a small length and width. It is due to premature closure of the coronal suture plus any other suture, like the lambdoid, or it may be used to describe the premature fusi ...

(fusion of coronal and

lambdoidal suture The lambdoid suture (or lambdoidal suture) is a dense, fibrous connective tissue joint on the posterior aspect of the skull that connects the parietal bones with the occipital bone. It is continuous with the occipitomastoid suture. Structure Th ...

s), and complex

(premature closure of some or all sutures).

Exophthalmos Exophthalmos (also called exophthalmus, exophthalmia, proptosis, or exorbitism) is a bulging of the eye anteriorly out of the orbit. Exophthalmos can be either bilateral (as is often seen in Graves' disease) or unilateral (as is often seen in ...

(bulging

eye Eyes are organs of the visual system. They provide living organisms with vision, the ability to receive and process visual detail, as well as enabling several photo response functions that are independent of vision. Eyes detect light and conv ...

s due to shallow eye sockets after early fusion of surrounding bones),

hypertelorism Hypertelorism is an abnormally increased distance between two organs or bodily parts, usually referring to an increased distance between the orbits (eyes), or orbital hypertelorism. In this condition the distance between the inner eye corners as ...

(greater than normal distance between the eyes), and psittichorhina (beak-like nose) are also very common features. Other facial characteristics that are present in many cases include external

strabismus Strabismus is a vision disorder in which the eyes do not properly align with each other when looking at an object. The eye that is focused on an object can alternate. The condition may be present occasionally or constantly. If present during a ...

and hypoplastic maxilla (insufficient growth of the midface), which results in relative

mandibular prognathism Prognathism, also called Habsburg jaw or Habsburgs' jaw primarily in the context of its prevalence amongst members of the House of Habsburg, is a positional relationship of the mandible or maxilla to the skeletal base where either of the jaws pr ...

(protruding chin) and gives the effect of the patient having a concave face. Most symptoms are secondary to the abnormal skull structure. Approximately 30% of people with Crouzon syndrome develop

hydrocephalus Hydrocephalus is a condition in which an accumulation of cerebrospinal fluid (CSF) occurs within the brain. This typically causes increased intracranial pressure, pressure inside the skull. Older people may have headaches, double vision, poor ...

Sensorineural hearing loss Sensorineural hearing loss (SNHL) is a type of hearing loss in which the root cause lies in the inner ear or sensory organ (cochlea and associated structures) or the vestibulocochlear nerve (cranial nerve VIII). SNHL accounts for about 90% of rep ...

is present in some cases. The abnormalities in the manner in which the eyes fit in the eye sockets can cause vision problems, the most common of which is corneal exposure that can lead to visual impairment. Some people with the condition have a restricted airway and can experience severe problems breathing. Common features are a narrow/high-arched palate, posterior bilateral crossbite,

hypodontia Hypodontia is defined as the developmental absence of one or more teeth excluding the third molars. It is one of the most common dental anomalies, and can have a negative impact on function, and also appearance. It rarely occurs in primary teet ...

(missing some teeth), and crowding of teeth. Due to maxillary hypoplasia, people with Crouzon syndrome generally have a considerable permanent

underbite In orthodontics, a malocclusion is a misalignment or incorrect relation between the teeth of the upper and lower dental arches when they approach each other as the jaws close. The English-language term dates from 1864; Edward Angle (1855-1930), ...

Causes

The current research indicates

fibroblast growth factor receptors A fibroblast is a type of cell (biology), biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and plays a critical role in wound ...

(FGFR)

FGFR2 Fibroblast growth factor receptor 2 (FGFR2) also known as CD332 (cluster of differentiation 332) is a protein that in humans is encoded by the ''FGFR2'' gene residing on chromosome 10. FGFR2 is a receptor for fibroblast growth factor. The protein ...

and

FGFR3 Fibroblast growth factor receptor 3 is a protein that in humans is encoded by the ''FGFR3'' gene. FGFR3 has also been designated as CD333 (cluster of differentiation 333). The gene, which is located on chromosome 4, location q16.3, is expressed in ...

as the leading factors in causing the autosomal dominant Crouzon syndrome. These two

transmembrane proteins A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...

are two of four fibroblast growth factor receptors involved in

osteoblast Osteoblasts (from the Greek language, Greek combining forms for "bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cell (biology), cells with a single Cell nucleus, nucleus that synthesize bone. However, in the p ...

differentiation during

embryonic development An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm ...

; mutations amongst these receptors are involved in several genetic disorders. There are 40 known mutations, most of which are caused by a

missense mutation In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Substitution of protein from DNA mutations Missense m ...

. FGFR2 is the most commonly mutated gene, a missense at

cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, sometime ...

342 in

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...

9, which creates a gain-of-function. The FGFR2lllc

isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...

, created via

alternative splicing Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be ...

of exon 3 of the FGFR2 gene, uses exon 9 and is used in

mesenchymal stem cells Mesenchymal stem cells (MSCs) also known as mesenchymal stromal cells or medicinal signaling cells are multipotent stromal cells that can differentiate into a variety of cell types, including osteoblasts (bone cells), chondrocytes (cartilage ce ...

to control

ossification Ossification (also called osteogenesis or bone mineralization) in bone remodeling is the process of laying down new bone material by cells named osteoblasts. It is synonymous with bone tissue formation. There are two processes resulting in t ...

. However, the mutation constitutively activates the transmembrane protein via a

disulfide bond In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...

formed incorrectly due to the loss of cysteine 342. FGFR3 is expressed more in the

frontal bones The frontal bone is a bone in the human skull. The bone consists of two portions.''Gray's Anatomy'' (1918) These are the vertically oriented squamous part, and the horizontally oriented orbital part, making up the bony part of the forehead, part ...

during embryonic development, guiding cranial bone development. A point mutation causes constitutive activation of

tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...

in the activation loop, located in the

cytosolic The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrio ...

region of the protein, leading to accelerated differentiation of frontal osteoblasts, resulting in premature fusion of frontal cranial bones.

Diagnosis

Diagnosis of Crouzon syndrome usually can occur at birth by assessing the physical appearance of the infant. Further analysis, including radiographs,

magnetic resonance imaging Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio wave ...

(MRI) scans, genetic testing and CT scans can be used to confirm the diagnosis of Crouzon syndrome.

Treatment

Surgery Surgery ''cheirourgikē'' (composed of χείρ, "hand", and ἔργον, "work"), via la, chirurgiae, meaning "hand work". is a medical specialty that uses operative manual and instrumental techniques on a person to investigate or treat a pat ...

is typically used to prevent the closure of sutures of the skull from damaging the brain's development. Without surgery,

blindness Visual impairment, also known as vision impairment, is a medical definition primarily measured based on an individual's better eye visual acuity; in the absence of treatment such as correctable eyewear, assistive devices, and medical treatment� ...

and

intellectual disability Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation,Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signifi ...

are typical outcomes. To move the orbits forward, surgeons expose the skull and orbits and reshape the bone. To treat the midface deficiency, surgeons can move the lower orbit and midface bones forward. People with Crouzon syndrome tend to have multiple sutures involved, most specifically bilateral coronal craniosynostoses, and either open vault surgery or strip craniectomy (if the child is under 6 months) can be performed. In the latter scenario, a helmet is worn for several months following surgery. Once treated for the cranial vault abnormalities, Crouzon patients generally go on to live a normal lifespan.

Epidemiology

Incidence of Crouzon syndrome is currently estimated at 1.6 out of every 100,000 people. It is the most common craniostenosis syndrome.

History

Crouzon syndrome was first described by

in 1912. He noted the affected patients were a mother and her daughter, implying a genetic basis.

References

External links

Crouzon syndrome
on Genetics Home Reference from U.S. National Library of Medicine & National Institutes of Health
GeneReviews/NIH/NCBI/UW entry on FGFR-Related Craniosynostosis Syndromes
{{Authority control Genodermatoses Hearing loss with craniofacial syndromes Congenital disorders of musculoskeletal system Cell surface receptor deficiencies Rare syndromes Congenital oral disorders