Molecular Genetics and Principles in Craniosynostosis

Question 1

how common is craniosynostosis?

Answer 1

Craniosynostosis, or the premature fusion of calvarial sutures, occurs in approximately 1 in 2500 live births1 and has traditionally been classified as being syndromic or nonsyndromic based on phenotypic descriptions.

Question 2

are genetic changes involved with syndromic craniosynostosis only?

Answer 2

it is clear that there are genetic underpinnings to most, and possibly all, types of craniosynostosis, and thus the genetic distinction between the two categories has eroded. Thus, the phenotypic classification, which had been considered the “gold standard,” has increasingly given way to a genetically based classification system for craniosynostosis.

Question 3

where do calvarial bones come from, in terms of lineage?

Answer 3

using a transgenic mouse model, Jiang and associates were able to show that there is a heterogeneous origin for the calvarial bones—the frontal bone was found to be of neural crest origin, whereas the parietal bone was of mesodermal lineage.

Question 4

What are the 6 most common forms of craniosynostosis?

Answer 4

Muenke’s, Saethre-Chotzen, Crouzon’s, Pfeiffer’s, and Apert’s syndromes and Crouzon’s syndrome with acanthosis nigricans

Question 5

what is the inheritance pattern for syndromic craniosynostosis?

Answer 5

Many of the syndromic conditions follow a familial inheritance pattern, although spontaneous mutations are possible. The inheritance pattern in familial cases tends to be autosomal dominant, with only a few exceptions. Therefore, there is a 50% transmission rate to offspring, with variable penetrance. There is increasing evidence that in sporadic cases, there is an association with advanced paternal age, suggesting that older men may be more susceptible to a variety of germline mutations.

Question 6

sporadic cases of craniosynostosis is associated with what?

Answer 6

here is increasing evidence that in sporadic cases, there is an association with advanced paternal age, suggesting that older men may be more susceptible to a variety of germline mutations.

Question 7

what are the most common implicated genes in syndromic craniosynostosis?

Answer 7

most commonly implicated genes in syndromic craniosynostosis are those of the fibroblast growth factor (FGF) and its receptors (FGFRs) and TWIST.

Question 8

Muenke’s syndrome

Answer 8

Unicoronal or bicoronal craniosynostosis with brachydactyly, thimble-like middle phalanges, coned epiphyses, carpal and tarsal fusions, sensorineural hearing loss, and developmental delay

Question 9

Saethre-Chotzen syndrome

Answer 9

Coronal craniosynostosis with limb abnormalities (syndactyly of the second and third digits, bifid hallux) and facial abnormalities (facial asymmetry, low frontal hairline, ptosis, and small ears with prominent ear crura)

Question 10

Crouzon’s syndrome

Answer 10

Classical triad: coronal synostosis, midfacial hypoplasia, and exophthalmos; may also include involvement of other calvarial sutures, brachycephaly, hypertelorism, Chiari I malformation, hydrocephalus, and mental retardation

Question 11

Pfeiffer’s syndrome

Answer 11

Type I classical Pfeiffer’s syndrome is a mild entity.
Types II and III are more severe, with early death.
Features include coronal synostosis with or without premature fusion of other calvarial sutures, broad fingers and toes, and partial syndactyly of the fingers and toes; they may also include maxillary hypoplasia, small nose with a low nasal bridge, hypertelorism, shallow orbits, proptosis, strabismus, limb malformation, and radiohumeral synostosis

Question 12

Apert’s syndrome

Answer 12

Coronal synostosis with severe syndactyly in the fingers and toes, symphalangism, radiohumeral fusion, and mental retardation

Question 13

Jackson-Weiss syndrome

Answer 13

Craniosynostosis, with broad toes and a medially deviated great toe, second and third toe syndactyly, tarsal-metatarsal fusion, broad and short metatarsals and proximal phalanges, midfacial hypoplasia, hypertelorism, proptosis, and normal intelligence

Question 14

what is this?

Answer 14

Pfeiffer’s Syndrome

Question 15

Pfeiffer’s Syndrome

Answer 15

Pfeiffer’s syndrome is characterized by bilateral coronal synostosis with or without premature fusion of other calvarial sutures, broad fingers and toes, and partial syndactyly of the fingers and toes. Patients may also have maxillary hypoplasia, a small nose with a low nasal ridge, hypertelorism, shallow orbits, proptosis, strabismus, limb malformation, and radiohumeral synostosis.31 At the most severe end of the spectrum, children often have pan-sutural synostosis at birth, with significant hydrocephalus and brain malformations (Fig. 192-1). In 1993, Cohen suggested categorizing Pfeiffer’s syndrome into three different types based on the severity of deformities, ranging from type 1 (classical Pfeiffer’s syndrome, a mild entity with autosomal dominant inheritance) to types 2 and 3 (more severe, with early death and sporadic inheritance).

Question 16

Crouzon’s Syndrome

Answer 16

Crouzon’s syndrome is an autosomal dominant disorder characterized by the classic triad of bilateral coronal synostosis, midfacial hypoplasia, and exopthalmos.13 Other manifestations may include involvement of other calvarial sutures, brachycephaly, hypertelorism, Chiari I malformation, hydrocephalus, and impaired cognition (Fig. 192-2). Numerous missense mutations in the Ig III domain of the FGFR2 gene

Question 17

Jackson-Weiss Syndrome

Answer 17

Jackson-Weiss syndrome is characterized by a highly variable range of phenotypes, including craniosynostosis, broad and short metatarsals, and proximal phalanges with a medially deviated great toe, second and third toe syndactyly, tarsal-metatarsal fusion, midfacial hypoplasia, hypertelorism, proptosis, and normal intelligence.

Question 18

Saethre-Chotzen Syndrome

Answer 18

Saethre-Chotzen syndrome have bilateral coronal craniosynostosis with highly variable clinical findings; the most distinguishing features include limb abnormalities (syndactyly of the second and third digits, bifid hallux) and facial abnormalities (facial asymmetry, low frontal hairline, ptosis, small ears with prominent aural crura) (Fig. 192-3).47 It is inherited in an autosomal dominant fashion with complete penetrance and variable expressivity

Question 19

define genetics behind sagittal craniosynostosis

Answer 19

Sagittal craniosynostosis (also known as scaphocephaly or dolichocephaly) is the most common form of craniosynostosis and occurs at a rate of 1 in 5000 children, with a male-to-female ratio of 3.5 : 1. Missense mutations (S188L and S201Y) in the TWIST box have been identified in patients with isolated sagittal craniosynostosis. Interestingly, unaffected parents were also found to have the same mutations, which confirms the reduced penetrance and high expressive variability of TWIST1 mutations

Question 20

genetics behind coronal synostosis

Answer 20

Coronal craniosynostosis is the second most common sutural fusion and occurs at a rate of 1 in 10,000 children, with a male-to-female ratio of 1 : 2. Because many cases of syndromic craniosynostosis, especially Muenke’s syndrome, may be associated with unicoronal synostosis, it is recommended that one should test for these mutations before diagnosing nonsyndromic coronal synostosis.65 In our clinical practice, we have found an association of genetically proven Muenke’s syndrome in children with unilateral coronal synostosis whose contralateral side does not exhibit significant compensatory bossing, thus establishing an association of the phenotype with the genotype.

Question 21

genetics of metopic non sydrnomal craniosynositis

Answer 21

Metopic craniosynostosis, which causes trigonocephaly, is the third most common single-suture nonsyndromic craniosynostosis, occurring in 1 out of 10,000 to 15,000 live births with a male-to-female ratio of 3.3 : 1.60 There is evidence that the incidence of metopic craniosynostosis may be increasing in the Northeastern United States and Europe, for unclear reasons.66,67 The etiology of this phenotype is considered heterogeneous, with both genetic and environmental factors, such as prenatal head constraints playing a role.68 A recent study implicated RUNX2 in the etiology of metopic craniosynostosis, but it is unclear what the prevalence of this mutation is.