Craniosinostoza And Variable Phenotypic Consequences Mutatiiilor Genes Biology Essay


Craniosinostoza is closing fusion premature one or more cranial sutures, resulting in an abnormal shape of the skull. Depending on the merging sutures between them, craniosinostoza is presented in several forms as craniosinostoza sagittal (long and narrow skull), craniosinostoza coronal, craniosinostoza metopes (when sides are convex head and eyes seem closer) and craniosinostoza lambdoida ( bulging the back of the skull) (2).

Craniosinostoza can be divided into four categories, namely: simple itself: a single suture synostosis, together with two or more suture synostosis, Complex dysmorphic skull is included in a complex multi-malformation and accompanying craniosinostoza when dystrophy skull is minor and is an epiphenomenon in other metabolic diseases, hematological (4).

Depending on the symptoms, we identified two types of craniosinostoza: syndromic and non-syndromic. Craniosinostoza syndrome was associated with other diseases linked to mutations in genes: FGFR1 (fibroblast growth factor receptor 1 gene), FGFR2 (fibroblast growth factor receptor 2 gene), FGFR3 (fibroblast growth factor receptor 3 genes), FBN1, TWIST (5) . Craniosinostoza 85% of non-syndromic cases were not associated with genetic mutations so far (4).

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Non-genetic factors that pose a risk in the occurrence craniosinostozei are: smoking during pregnancy, advanced age of the mother at conception, use of certain drugs (nitrofurantoin), fertility treatments, endocrine abnormalities such as hyperthyroidism (3).

Craniosinostoza syndrome cases may be a result of both de novo mutations and of passing of hereditary (autosomal dominant pattern and the autosomal recessive model). In the case of hereditary transmission, most cases of autosomal dominant transmission craniosinostoza are due, so that a parent has affected 50% chance of having children with the disease (8). Mutations in these seven genes: FGFR1, FGFR2, FGFR3, TWIST1, EFNB1, MSX2 and RAB23 were associated unequivocally with Mendelian forms of craniosinostoza syndrome (18).

Depending on the gene affected is developed a syndrome including its features and craniosinostoza shows. Was identified over 60 different mutations correlated with the occurrence of various forms craniosinostoza syndrome. Most of these mutations occur in the gene FGFR2 (fibroblast growth factor receptor 2 gene) (8).

FGFR genes encode for proteins involved in important processes such as cell division, regulation of cell growth and differentiation, blood vessel formation and embryonic development. Mutation in these genes lead to the appearance of abnormal proteins that in turn cause phenotypic traits specific to each syndrome separately (16).

Craniosinostozice syndromes caused by mutations in FGFR genes shows similar phenotypic manifestations in the face, but may or may not be accompanied by limb abnormalities. A significant proportion of mutations that cause these syndromes involve loss or gain of a cysteine ​​residue, affecting disulfide bonds responsible for maintaining the tertiary structure of the Ig-like domain by changing affinity ligand for this area (7). Certain mutations in the FGFR2 gene cause Apert Syndrome, Beare-Stevenson, Crouzon, Jackson-Weiss, Pfeiffer. Pfeiffer syndrome can be caused by mutations that occur in the FGFR1 gene.

All these syndromes appear to be autosomal dominant (Table 1) (11).

Table 1. Correlation between affected genes and different syndromes within which is present craniosinostoza (11).

Syndromes in which affected gene is present craniosinostoza transmission mode

Sdr. Apert FGFR2 AD

Sdr. Beare-Stevenson FGFR2 AD

Sdr. FGFR2 Crouzon AD

Sdr. Muenke FGFR3 AD

Sdr. Jackson-Weiss FGFR2 AD

Sdr. Pfeiffer FGFR1, FGFR2 AD

Sdr. Robinow-Sorauf TWIST AD

Sdr. Saethre-Chotzen TWIST AD

Apert syndrome, also known as the Acrocefalosindactilie type 1 (ACS1) is a genetic disorder characterized by coronal craniosinostoza, syndactyly, simfalagism (fusion of the phalanges of a finger) fusion ulna and radius with varying degrees of mental retardation and cognitive impairment but (4). Less commonly, people with this condition may be additional toes (polydactyly). Other signs and symptoms of Apert syndrome may include hearing loss, hyperhidrosis, oily skin with severe acne (6).

Apert Sindormul has an incidence of 1 in 160,000 newborns. Most cases are sporadic (de novo mutations) and were associated with older age of the mother at conception the fetus (7). Mode of transmission appears to be autosomal dominant.

FGFR2 mutation in the gene responsible for the occurrence of this syndrome. FGFR2 gene encodes the receptor 2, fibroblast growth factor. This protein interferes with cell differentiation in immature bone cells during embryonic development. A mutation in a particular region of FGFR2 gene causes an abnormal protein that causes premature fusion of the bones of the skull, hands and feet (6).

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Almost all cases of Apert syndrome are caused by one of 2 mutations in the FGFR2 gene. One of the tryptophan mutations induce serine substitution at position 252 (Ser252Trp). The other mutation cause proline to arginine substitution at position 253 (Pro253Arg) (9).

Syndrome Beare - Stevenson is a rare genetic disorder characterized by skin abnormalities and craniosinostoza. This condition affects the normal shape of the head and face. Premature fusion of skull bones affects normal brain development, leading to disabilities.

Among the phenotypic features of this syndrome is found cutis gyrate, represented by lined and wrinkled appearance of the skin especially on the face, close your ears, palms and foot plant.

Other symptoms of Beare-Stevenson syndrome: blockage of the nasal passages, overgrowth of abnormal umbilical cord and genitals and the anus (10).

Generally, this syndrome can be caused by mutations in the gene FGFR2 other 2. In most cases, the amino acid tyrosine is replaced with the amino acid cysteine ​​in position 375 (Tyr375Cys). With a lower frequency, identify serine substitution in position 372 of the amino acid cysteine ​​(Ser372Cys). These mutations in the FGFR2 gene cause the formation of abnormal proteins that cause premature fusion of the skull bones (9). The transmission seems to be autosomal dominant (11).

Crouzon syndrome is a genetic disorder characterized by coronal suture synostosis, brachycephalism, protruding forehead (prominent), exophthalmos, hypertelorism, maxillary hypoplasia, prognathism, external auditory canal atresia, premature calcification of the styloid ligament, hydrocephalus and mental retardation (4). Skull shape varies according to the order of the merger, but is most common brachycephalism by coronal suture closure and basal (12).

Also among phenotypic features of Crouzon syndrome and strabismus are serious and dentition. Varying severity of affected persons (13).

Were identified more than 35 gene mutations in FGFR2 associated with the occurrence of this syndrome. These mutations are located predominantly in the IgIII and adjacent linker region of the extracellular domain.

Most of these entail replacing a nucleotide sequence with another. Replacement of nucleotide sequences with each other leading to the formation of an abnormal protein that causes premature fusion of skull bones (9).

Pfeiffer syndrome known as the Acrocefalosindactilie type 5 (ACS5) is a rare autosomal dominant pattern transmitted on that is associated with premature fusion of skull bones. Patients may experience a premature fusion of the coronal suture and the sagittal lambdoide and occasionally, abnormal development of the skull affects the shape of the head and face.

As with Apert syndrome are affected and bones in the hands and feet. May be present partial syndactyly of the hands and feet. Premature fusion of skull bones determines a phenotype characterized by bulging eyes (bulging-eye proptoza) hipopalzia middle floor face with exaggerated widening its high forehead, underdeveloped upper jaw but the beaked nose.

Another Characteristic of the syndrome can be represented by mental retardation, ears inserted into the bottom of the head, thumb and toe short and wide. More than half of all children with Pfeiffer syndrome have hearing loss and dental problems (14) (15).

This condition can be caused by mutations in FGFR1 and FGFR2 genes. Pfeiffer syndrome is divided based on phenotypic severity in three clinical categories: type 1, type 2 and type 3.

Pfeiffer syndrome Type 1 or class includes individuals who have mild manifestations such as brachycephalism (15) (premature fusion of coronal sutures both the biparietal diameter increases, the skull is short antero-posterior diameter, orbits are elliptical and supraorbital ridge may not be normal) (12), middle floor hipopalzia face and limb abnormalities. This type is associated with a normal intellectual and neurological development (15).

Type 2 includes individuals who have clover-shaped deformities of the skull, proptoza, developmental delay, abnormalities of the fingers and legs and neurological complications. Clover-shaped skull can cause limited growth of the brain and can cause serious deficiencies proptoza view.

Type 3 is similar to type 2, except clover shaped skull. The absence of this malformation of the skull is difficult to establish the diagnosis. Types 2 and 3 are sporadic cases with an increased risk of early death due to severe neurological compromise and respiratory problems (15).

Pfeiffer syndrome type 1 is caused by a mutation in the FGFR1 gene that causes the replacement of proline in position 252 with arginine (Pro252Arg) (16).

Pfeiffer syndrome type 2, 3 is caused by mutations in the FGFR2 gene. Was identified over 25 mutations associated with Pfeiffer syndrome. Many of these mutations alter the number of cysteine ​​in the IgIII (FGFR2 protein critical region) (9).

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Some of the 25 mutations were identified in patients with Crouzon syndrome and also in patients with Jackson-Weiss syndrome. Pfeiffer syndrome patients with mutations in FGFR1 gene generally exhibit milder phenotype than those with mutations in the FGFR2 gene (7).

Jackson syndrome - Weiss is a rare genetic disorder characterized by abnormalities in the legs and craniosinostoza. Cause premature fusion of skull bones as if set forth above syndromes, characteristic facial features such as misshapen skull, eyes wide apart, prominent forehead.

Defining features of this syndrome are abnormalities of the feet. Within these toe abnormalities are short, wide and far away from the other toes; remaining fingers may or may have other congenital syndactyly. In most cases, Hand constitution is generally normal, people with syndrome Jackson - Weiss can have a normal life span (17).

In general, people with this syndrome do not have mental retardation or cognitive impairment, and has a normal intelligence. Patients may develop strabismus, hypertelorism (excessive removal of the eyes). Individuals most severely affected require amputation of thumb when it deviates about 90 degrees from the rest of the fingers.

Genetically speaking, Jackson-Weiss syndrome is transmitted in an autosomal dominant pattern. So far this syndrome was associated with a mutation in the FGFR2 gene that resulted in the replacement of arginine in position 344 with glycine. This led to the replacement of an abnormal protein that led to the craniosinostozei and leg abnormalities characteristic of this syndrome (7).

Molecular Basis of most types of craniosinostoze are today known genetic tests allow an accurate diagnosis. Most are autosomal dominant craniosinostozelor. Because of expressiveness variable identifying mutations in affected individuals must be found through genetic testing of parents. In the most severe types of craniosinostoze, novo mutation rate is high. When craniosinostozei mode of transmission is autosomal dominant mutation carriers have a 50% risk of transmitting the gene affected offspring. (4)

Craniosinostoza is found relatively frequently, with a prevalence of 1/3000 newborns. More than 100 craniosinostozice syndromes have been described, but the most common are Apert, Pfeiffer, Crouzon, Muenke and Saethre-Chotzen.

Table 2. Craniosinostozice main syndromes and genes involved [19]

Apert syndrome, Crouzon syndrome Pfeiffer syndrome Saethre-Chotzen syndrome Muenke Syndrome

Synostosis, skull malformations Bicoronale, irregular ossification defects Bicoronala rarely pansinostoza Bicoronala, clover-shaped skull in type III or bicoronala unilateral synostosis, macrocephaly Uni-or only rarely bicoronala

Facies hypertelorism, palpebral fissures, hypertelorism cleft palate,

Sharp nose (beak-shaped) hypertelorism, palpebral fissures Facies affected moderately small ears palpebral fissures, facial asymmetry

Severe limb abnormalities syndactyly - thumbs and great toe are wide and deflected median Brahidactilie moderate hallux valgus, hallux partially duplicators, easy sindactile

Other mental retardation, cardiac tests 10% - multiple malformations in types II and III Possible learning difficulties mental retardation with microdeletions

Ser252Trp FGFR2 gene mutations or gene mutations in FGFR2 Multiple Pro253Arg Pro252Arg FGFR1, FGFR2 FGFR3 mutations Pro250Arg multiple mutations in the gene TWIST, rarely complete deletion of the gene

It was found that mutations in FGFR3 gene cause two syndromes craniosinostozice: Muenke syndrome (originally called type craniosinostoza Adelaide) and Crouzon syndrome with acanthosis nigricans (AN).

FGFR3 is located on 4p16.3 and has a size of 15KB. Presents several isoforme, which isoforma 1 contains a total of 18 exons (17 are coded) and produce the largest amount of mRNA. Coronal Sinostozele associated with FGFR mutations are usually autosomal dominant and shows reduced penetrance. Apert syndrome and Pfeiffer shows complete penetrance and Crouzon syndrome shows complete penetrance provided that the mutation does not appear to be inherited and de novo. [20]

Muenke syndrome is associated with a mutation in the gene structure Pro250Arg FGFR3 (Muenke et al., 1997). Mutation Pro250Arg is homoloaga with FGFR2 gene mutation Pro252Arg of structure and mutation causing Pro253Arg Pfeiffer syndrome that occurs in Apert syndrome [21]. Like other mutations in FGFR genes, this mutation acts through a gain of function mechanism type. Muenke syndrome is an autosomal dominant phenotype can be gentle and as careful evaluation is recommended first-degree relatives to identify affected members of a family. [22]

Muenke syndrome patients with unilateral or bicoronala shows synostosis, but about 20% of those who wear craniosinostoza mutation shows no clinical relevance. Unicoronala synostosis is more common in male patients. Facies varies from normal to a dysmorphism can be confused Saethre-Chotzen syndrome. Patients have significant ocular hypertelorism and hypoplastic.

Members often have the carpienelor mergers and tarsienelor and brahidactilie. Radiographic examination showed that the median phalanges were looking for thimble, epiphyses are tapered. Of intellectually normal, but may show a slight mental retardation.

Some carriers of the mutation may have a sensorineural loss, bilateral hearing loss and delayed development. [23]

Crouzon syndrome with acanthosis nigricans (AN) is characterized by replacement Ala391Glu. Acanthosis nigricans is a skin disease that causes skin thickening a black pigmentation in skin creases.

In terms of cranio-facial patients have significant ptosis, external strabismus and mandibular prognathism. Their extremities appear normal radiographic although the fingers may appear shortened. Of intellectually normal, do not have mental retardation or growth. Crouzon syndrome with AN children should be evaluated for hydrocephalus is associated neurological disease. [24]

TWIST FBN1 gene and gene - implications Craniosinostoza

Craniosinostoza is a heterogeneous group of disorders. Mutations in these genes: FGFR1, FGFR2, FGFR3, TWIST1, EFNB1, MSX2, RAB23, FBN1, ROP, TGFBR1 and TGFBR2 are associated with craniosinostoza, last 4 genes appear to have a minor impact on phenotype due to low penetrantei [18].

General aspects

TWIST gene (also called TWIST1) belongs to a class of transcriptional regulators of basic helix-loop-helix (bHLH) that recognize a consensus DNA element called box E. This gene is located on chromosome 7p21.1 and type I craniosinostoza determine if mutations occur in its structure [25].

Studies by Shishido et al. (1993) have shown that in Drosophila gene transcription TWIST affect receptor fibroblast growth factor (FGFRs), a family of genes involved in craniosinostoza [26].

Connerney et al. (2006) showed that TWIST1 gene activity in human cell lines is dependent dimer partner. TWIST1 form so homodimeri (T / T) and heterodimers with E2A proteins E (T / E).

Based on the patterns of expression of TWIST1 in the cranial sutures from mice Connerney et al. (2006) hypothesized that TWIST1 homodimeri formed by T / T in frontal sutures and heterodimers of T / E in median sutures. In support of this hypothesis, it was found that genes regulated by homodimeri T / T, such as FGFR2 and periostin were expressed in frontal sutures, and the genes regulated by heterodimers T / O, such as thrombospondin-1, s- expressed in median sutures. Homodimeri ratio of T / T and heterodimers T / E was modified sutures in mice TWIST1 + / -, favoring the growth and expansion of homodimerilor frontal sutures. In addition, the ratio of T / T and T / E was higher than the sagittal coronal sutures, so the authors suggested that coronal sutures are more susceptible to fusion due haploinsuficientei TWIST1 gene. It was concluded that the dimer partner selection is critical for TWIST1 gene function [27].

Genetic Structure

He Ghouzzi et al. (1997) indicated that TWIST gene contains 2 exons and one intron of 538 bp, and the only coding exon, exon 1, has 772 bp [28].

Wang et al. (1997) identified two alleged TATA boxes near the promoter region of the gene TWIST1, but it seems that the proximal location appeared to be functional. They also identified several potential binding sites for transcription factors in the promoter region of the gene TWIST1 [29].

Mapping. Bourgeois et al. (1996) used isotopic in situ hybridization to chromosome 7p21.1 charter TWIST1 gene [30].

Some mutations in the TWIST gene are associated with Robinow syndrome-Sorauf Saethre-Chotzen syndrome and.

Saethre-Chotzen syndrome has an incidence of 1/25000, 1/50000 newborns. TWIST gene encodes a protein that plays an important role in early development. TWISTT protein is active in cells that give rise bones muscles and other tissues in the head and face. It also is involved in limb development. Mutations in this gene cause a truncated protein. This protein affects development and differentiation truncata correct cells from the skull, face and limbs. These abnormalities causing including craniosinostoza. Craniosinostoza alongside other phenotypic manifestations are facial asymmetry and partial syndactyly. Intelligence is usually normal [7].

Allelic variants

To date have been identified 14 allelic variants of gene TWIST1.