Please enable JavaScript.
Coggle requires JavaScript to display documents.
Craniosynostoses (Other Syndromes (Trigonocephaly from Metopic Suture…
Craniosynostoses
FGFR-related Craniosynostoses
- Possibility for bilateral coronal synostosis, aka turribrachycephaly, aka Clover Leaf Skull
- cloverleaf skull: trilobar skull from multiple suture synostoses and protrusion of the brain through the fontanelles
- Characteristic Facial Features
- hypertelorism
- midface hypoplasia with proptosis
- small beaked nose
- prognathism
- high arched palate
- Variable hand and feet abnormalities
GenesFGFR1
FGFR2
- Apert (100%)
- Crouzon (100%)
- Pfieffer (95%)
FGFR3
- Muenke (P250R - 100%)
- Achondroplasia
- Thanatophoric Dysplasia
- Crouzon w. Acanthosis Nigricans (A391E - 100%)
TWIST
- Saethre-Chotzen (Mutations and Deletions - 46-80%)
MSX2
Other Genes
Mutations
- Autosomal Dominant
- aberrant splicing
- different isoforms exist in different tissues
- mutations affect binding to the receptor
- FGFR2 mutations arise exclusively in sperm
- Advanced paternal age implicated in Crouzon, Apert
- New mutations [are being discovered?] in severe forms
- Idnetical mutations seen in Crouzon, Pfieffer, and Jackson-Weiss
Pathology
- FGFR mutations create or destroy cysteine residues
- gains or losses that result in odd numbers of cysteine in the IgIII domain leads to increased activity of tyrosine kinase
- [Different degrees of ligand independent signaling]
- Tissue-specificity of mutations is secondary to differences in glycosylation
SYNDROMES
- Apert, Crouzon, Pfieffer
- FGFR3-related Muenke
- Crouzon with Acanthosis Nigricans
- FGFR2-related Isolated Coronal Synostosis
- Beare-Stevenson
- Jackson-Weiss
Muenke
- FGFR3 P250R: highest transversion rate
- Coronal synostosis or Macrocephaly
- Facial Features
- high forehead
- hypertelorism
- midface hypoplasic
- high-arched palate
- downturned palpebral fissures
- Hearing loss
- Developmental Delays
- Carpal and Tarsal fusions
- Phenotypic variability
- FEMALES: bilateral coronal synostosis more common
- MALES: bilateral and unilateral coronal synostosis is about equal
Pfieffer
- Autosomal Dominant
- Incidence of all types is 1 in 100000
- broad thumbs
- broad great toes
- variable soft tissue syndactyly of the hands
- Complete penetrance with variable expressivity
- [Paternal mutations]
- in 65% of cases, mutations are identified
- FGFR1, P252R
- [FGFR2 leadings to changes in IgIII; some overlap with Crouzon]
Pfieffer Subtypes
Type 1
- Normal intellect
- Best prognosis
- Moderate to severe midface hypoplasia
- Broad and medially deviated thumbs and toes
- 5% FGFR1, P252R
- 95% FGFR2
Type 2
- Developmental delay
- Intellectual Disability is common
- Extreme proptosis
- Cloverleaf skull
- Hydrocephalus
- Broad toes and thumbs
- Brachydactyly
- Ankylosis of the elbows and knees
- 100% are due to FGFR2
Type 3
- Similar to type 2
- Turribrachycephaly aka cloverleaf skull
- Laryngotracheal abnormalities
- Hydrocephalus
- High mortality
Apert
- Incidence is 1 in 100,000
- Make up 4-5% of all craniosynostoses
- Usually sporadic
- Autosomal Dominant
- 100% due to mutations in FGFR2
- 98% are due to either S252W or P253R
- Rarely due to 3 other mutations
S252W
- cleft palate
- humeroradial synostosis in 2/3 of cases
- less severe syndactyly
P253R
- syndactyly
- mental impairment common
- better cosmetic response to surgery in 1/3 of cases
CLINICAL FINDINGS
- moderate to severe midface hypoplasia
- soft tissue and bone syndactyly of fingers and toes
- fused cervical vertebrae (C5 and C6) in 68%
- cleft palate and bifid uvula in 30%
- rhizomelic shortening of the limbs
- generalized body dysplasia in some, with limited motion of the shoulders and elbows
- hydrocephalus seen in 2%
MRI FINDINGS
- absent or abnormal corpus callosum
- defects of limb structure
- megalencephaly
- gyral abnormalities
COGNITION
- reported highest rates of impairment
- mean IQ ~70
- no one above 100
Crouzon
- Incidence is 1.6 in 100000
- Make up 4.8% of all craniosynostosis cases
- Variable Expression!
- significant proptosis
- shallow orbits
- external strabismus
- mandibular prognathism
- various suture involvement
- multiple suture involvement
- cervical spine abnormalities; fusion of C2-C3
- normal extremities
- stiffness of the elbows
- Normal Intellect
Genetics
- Autosomal Dominant
- Can be de novo, or inherited from a mildly affected parent
- 100% are FGFR2 mutations
- de novo mutations are of paternal origin
- Some of the mutations are seen in Pfieffer syndrome
Crouzon with Acanthosis Nigricans
- 100% are due to FGFR3
- Bilateral coronal and often saggital synostosis
- Normal extremities
- Acanthosis Nigricans
Beare-Stevenson
- Intellectual Disability
- Midface hypoplasia
- Abnormal ears
- Cutis gyrata
- Acanthosis Nigricans
- Skin tags
- Bifid scrotum
Jackson-Weiss
- Broad, medially-deviated toes
- Hands normal
- Abnormal tarsals
- 2,3 toe syndactyly
FGF and FGFR = Fibroblast Growth Factors and ReceptorsFIBROBLAST GROWTH FACTORS
- 19 different FGFs
- Signaling molecules involved in regulating:
- cell proliferation
- cell migration
- cell differentiation
- acts as a mitogen for ectodermal, neuroectodermal, and endodermal derivative cells
- Important in:
- angiogenesis
- wound healing
- limb development
- mesoderm induction
- neuronal differentiation
FIBROBLAST GROWTH FACTOR RECEPTORS
- FGFs interact with any of the four receptors
- Expressed in embryogenesis
- in the craniofacial and apical skeleton
- FGFR2 crucial regulator of bone formation
- There is a GOF for FGFR in Pfieffer, Apert, Muenki, and Beare-Stevenson syndromes; the mutant receptor works more vigorously than the wildtype receptor
Sutures
Saggital
- make up 50% of cases
- unknown etiology
- male to female ratio is 3 to 1
Coronal
- make up 20-30% of cases
- male to female ratio is 1 to 2
- unilateral fusion is 2x more frequent than bilateral fusions
- these cases are often due to Muenke syndrome
Metopic
- make up 4-10% of cases
- ~30% have Chiari I malformation
- ~8% of these cases are familial
- can be due to cytogenetic abnormalities
Lamboidal
- make up 1% of cases
- very rarely are familial
Multiple Sutures
- make up 5% of cases
- fusion of 2 sutures = higher rate of re-operation vs single suture (25% vs 5%)
- Complex, 2+ sutures leads to increased intracranial pressure, developmental delay, and a 37% chance for re-operation
Nonsyndromic FGFR Craniosynostoses
- variable expression in identical mutations
- isolated craniosynostosis
- FGFR2 and FGFR3, TWIST in unilateral coronal synostosis
- Intrafamilial variability
- bilateral or unilateral coronal synostosis (even in same family)
- Unilateral coronal craniosynostosis
- asymmetric brachycephaly and hypertelorism
- mutations in FGFR2, FGFR3, and TWIST
Nonsyndromic Sagittal Craniosynostosis
- 80% of total cases of craniosynostosis
- Higher rate of concordance in monozygotic vs dizygotic twins
- recurrence within families
- affects males more often, 3:1
- ALX4: role in calvarial development, repressed by TWIST1
- loss of function: enlarged parietal foramina
- gain of function variants (also seen in unaffected parents)
GWAS studies of BMP2 and BBS9
- association downstream of BMP2
- BMP2 has a role in skeletal development
- variant in BMP2 leads to osteoporosis
- mutation in limb-specific regulatory element downstream of BMP2 seen in brachydactyly type 2A
- ? skull-specific BMP2 regulatory element located within the area of association
- association within region of BBS9
- role in intraflagellar transport and moving molecules in and out of cilia
- loss of function mutations: Bardet Biedl (have skeletal features
- ? Effect on suture fusion
OTHER GENES
ERF
- lambdoid, metopic, saggital, coronal, multisuture, delayed pansynostosis
- facies resemble Crouzon
- Learning disabilities
TCF12
- decreased penetrance
- coronal, saggital, multisuture
- low hairline
- brachydactyly
- hallux valgus
- learning disability
- strabismus
Other Syndromes
Shprintzen-Goldberg Syndrome
- Craniosynostosis
- Developmental delay
- Intellectual disability
- Maxillary hypoplasia
- Micrognathia
- Proptosis
- Downslanting palpebral fissures
- High palate
- Marfanoid features
- arachnodactyly
- hernias
- mitral valve prolapse
- aortic root dilatation
- Pectus
- joint laxity
- C1-C2 abnormalities
- mutations in SKI
Trigonocephaly from Metopic Suture Synostosis
- Interfrontal suture closes 6-24 months
- syndromic vs nonsyndromic
- many chromosome anomalies
- Opitz C syndrome
Opitz C Syndrome
? Autosomal Dominant
Recurrence risk ~10%
- Short stature
- Failure to thrive
- Micrognathia
- upslanting eyes
- oral frenula
- thick alveolar ridges
- macrostomia
- CHD: VSD, PDA
- Anomalous ribs
- short limbs
- polydactyly
- transverse limb reductions
- hypotonia
- seizures
- intellectual disability
- Skin laxity
- CD96 gene at 3q13.13, IG superfamily, ?interference with cell adhesion and growth
- Translocation and missense mutations in a heterozygous state
Craniofrontonasal Syndrome
- females with frontonasal dysplasia
- craniofacial asymmetry
- craniosynostosis
- bifid nasal tip
- grooved nails
- wiry hair
- thoracic abnormalites
- hypertelorism in males
- inheritance X linked dominant: Ephrin B
Saethre-Chotzen
- Autosomal dominant
- Variable expressivity
- Incidence 1 in 25000 to 50000
- Craniosynostosis
- Blepharoptosis
- Facial assymetry
- Small ears
- Low frontal hairline
- Brachydactyly
- Syndactyly
- Hallux Valgus (Bunion)
- Duplicated Hallus
Rare Features
- vertebral fusion
- short stature
- tear duct stenosis
- cleft palate
Genetics of Saethre-Chotzen Syndrome
TWIST1 GENE (7p21)
- Insertions
- Deletions
- Nonsense
- Missense
- Complete deletion (as maybe due to a microdeletion disorder) leads to intellectual disability
TWIST GENE
- Transcription factor that induces the expression of many genes
Mice studies:
- expression in mesenchyme of developing head
- first aortic arches
- somites
- lateral mesoderm
- progressively in branchial arches and limb buds
- newborn mouse calvaria
Breast Cancer and Saethre-Chotzen Syndrome
Sahlin et al, 2007
- 65 pts from 15 families
- Of 29 women over 25y, 15 were diagnosed with breast cancer (52%)
- 4 with an onset < 40y
- 5 with an onset between 40-50 y
- TWIST plays a role in mice and human mammary cell tumors
*Another study did not confirm this finding
Carpenter
- Autosomal recessive
- Coronal, saggital and/or lamboid synostosis (cloverleaf)
- Short stature
- Obesity
- Intellectual disability to normal intelligence
- Polydactyly
- Syndactyly
- CHD
- Low set ears
- Downslanting eyes
- Small mandible
- Hypogonadism
- RAB23 gene
(vesicle transport protein, negative Hedgehog signalling)
MSX-2 Craniosynostosis aka Boston Syndrome
- Autosomal dominant
- Myopia
- Seizure disorder
- Normal intelligence
Variable Features
- Forehead retrustion
- Turribrachycephal
- Cloverleaf Skull
- Not a common cause of craniosynostosis
- Responsible for enlarged parietal foramina (defects in parietal bone) due to haploinsufficiency
- Plays a role in the differentiation of the calvarial osteogenic inductive tissue interactions (homeobox gene)
Antley-Bixler Syndrome
- Midface hypoplasia
- Proptosis
- Choanal stenosis/atresia
- Frontal bossing
- Dysplastic ears
- Urogenital abnormalities
- Joint contractures
- Synostosis of elbow
- Long bone fractures
GENETICS of ABS
- Autosomal recessive
- FGFR2 mutations
- on basis of elbow ankylosis (probably Pfieffer)
- ? Those with normal steroidogenesis
- POR deficiency (cyto P450 reductase)
- those with ambiguous genitalia and disordered steroidgenesis
ReQL DisodersBALLER-GEROLD SYNDROME
- Autosomal recessive
- Craniosynostosis with radial defects
- other reported abnormalities such as anal abnormalities may indicate another condition
- Poikiloderma
- RECQL gene
- DNA helicase, unwinds double stranded DNA into single stranded DNA
- Part of spectrum including Rothmund-Thomson syndrome and Rapdilino syndrome
ROTHMUND THOMSON
- Cataracts
- Saddle nose
- poor hair growth
- poikiloderma
- hypogonadism
RAPDILINO
- short stature
- radial ray defect
- infantile diarrhea
- poikiloderma
Genetic Counseling
- The de novo rate is high
- dominant FGFR2 mutations from the male chromosome
- paternal age effect in de novo mutations has been conclusively demonstrated at the molecular level in Apert syndrome
- Apert mutation may convey an advantage in sperm, as the FGF/FGFR pathway is known to be important in maintaining and initiating spermatogenesis
- germline mosaicism has been observed
- If gene mutation is known, then there is the possibility of preimplantation genetic diagnosis
-