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 Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...

genetic disorder known as a

branchial arch Branchial arches or gill arches are a series of paired bony/ cartilaginous "loops" behind the throat ( pharyngeal cavity) of fish, which support the fish gills. As chordates, all vertebrate embryos develop pharyngeal arches, though the eve ...

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

maxilla In vertebrates, the maxilla (: maxillae ) 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 two maxil ...

and

mandible In jawed vertebrates, the mandible (from the Latin ''mandibula'', 'for chewing'), lower jaw, or jawbone is a bone that makes up the lowerand typically more mobilecomponent of the mouth (the upper jaw being known as the maxilla). The jawbone i ...

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

embryo An embryo ( ) is the initial stage of development for 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 sp ...

, disturbances in their development create lasting and widespread effects. The syndrome is caused by a mutation in a

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

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 134 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the tota ...

that controls the body's production of

fibroblast growth factor receptor 2 Fibroblast growth factor receptor 2 (FGFR-2) 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. FGFR-2 is ...

(''FGFR2''). Crouzon syndrome is named for Octave Crouzon, a French

physician A physician, medical practitioner (British English), medical doctor, or simply doctor is a health professional who practices medicine, which is concerned with promoting, maintaining or restoring health through the Medical education, study, Med ...

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

craniofacial Craniofacial surgery is a surgical subspecialty that deals with congenital and acquired deformities of the head, skull, face, neck, jaws and associated structures. Although craniofacial treatment often involves manipulation of bone, craniofacial ...

" refers to the

skull The skull, or cranium, is typically a bony enclosure around the brain of a vertebrate. In some fish, and amphibians, the skull is of cartilage. The skull is at the head end of the vertebrate. In the human, the skull comprises two prominent ...

and

face The face is the front of the 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 affect th ...

, and " dysostosis" 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. 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,

trigonocephaly Trigonocephaly is a congenital condition due to premature Synostosis, fusion of the metopic suture (), leading to a triangular forehead. The premature 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 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 age, with the two halves of the frontal bone ...

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

(fusion of the coronal suture),

dolichocephaly Dolichocephaly (derived from the Ancient Greek δολιχός 'long' and κεφαλή 'head') is a term used to describe a head that is longer than average relative to its width. In humans, scaphocephaly is a form of dolichocephaly. Dolichoceph ...

(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 caus ...

(unilateral premature closure of lambdoid 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 ...

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 (anatomy), suture, like the Lambdoid suture, lambdoid, or it may be u ...

(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 T ...

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 An eye is a sensory organ that allows an organism to perceive visual information. It detects light and converts it into electro-chemical impulses in neurons (neurones). It is part of an organism's visual system. In higher organisms, the ey ...

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, a ...

(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 an eye disorder in which the eyes do not properly align with each other when looking at an object. The eye that is pointed at 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 is a positional relationship of the Human mandible, mandible or maxilla to the skeletal base where either of the jaws protrudes beyond a predetermined imaginary line in the coronal plane of the skull. In the case of ''mandibular'' ...

(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 cerebrospinal fluid (CSF) builds up within the brain, which can cause pressure to increase in the skull. Symptoms may vary according to age. Headaches and double vision are common. Elderly adults with n ...

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

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 Wisdom tooth, 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 i ...

(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 (1855–1 ...

Causes

The current research indicates fibroblast growth factor receptors (FGFR)

FGFR2 Fibroblast growth factor receptor 2 (FGFR-2) 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. FGFR-2 is ...

and

FGFR3 Fibroblast growth factor receptor 3 (FGFR-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 p16.3, is e ...

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

transmembrane proteins A transmembrane protein 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 frequently un ...

are two of four fibroblast growth factor receptors involved in

osteoblast Osteoblasts (from the Greek combining forms for " bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cells with a single nucleus that synthesize bone. However, in the process of bone formation, osteoblasts fu ...

differentiation during

embryonic development In developmental biology, animal embryonic development, also known as animal embryogenesis, is the developmental stage of an animal embryo. Embryonic development starts with the fertilization of an egg cell (ovum) by a sperm, sperm cell (spermat ...

; 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. Missense mutations change amino acids, which in turn alt ...

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

cysteine Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...

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 sequence ...

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 and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...

, created via

alternative splicing Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative RNA splicing, splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene ma ...

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 ...

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 chemistry, a disulfide (or disulphide in British English) is a compound containing a functional group or the anion. The linkage is also called an SS-bond or sometimes a disulfide bridge and usually derived from two thiol groups. In inor ...

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

frontal bones In the human skull, the frontal bone or sincipital bone is an unpaired bone which 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 ...

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 conditionally essential amino acid with a polar side group. The word "tyrosine" is ...

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 mitochondri ...

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 generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and ...

(MRI) scans,

genetic testing Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...

and CT scans can be used to confirm the diagnosis of Crouzon syndrome.

Treatment

Surgery Surgery is a medical specialty that uses manual and instrumental techniques to diagnose or treat pathological conditions (e.g., trauma, disease, injury, malignancy), to alter bodily functions (e.g., malabsorption created by bariatric surgery s ...

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

blindness Visual or vision impairment (VI or VIP) is the partial or total inability of visual perception. In the absence of treatment such as corrective eyewear, assistive devices, and medical treatment, visual impairment may cause the individual difficul ...

and

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

are typical outcomes. Without treatment, Crouzon syndrome can cause hearing and vision loss, exposure keratitis or conjunctivitis, drying of the cornea, hydrocephalus, sleep apnea, and breathing problems. 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. Additionally, surgery can be performed to relieve pressure inside the skull, fix a cleft lip or palate, correct a malformed jaw, straighten crooked teeth, or correct eye problems. 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 Octave Crouzon 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