Skeletal Dysplasia Flashcards
Achrondoplasia
Inheritance: Autosomal dominant
Gene: FGFR3
**98% of cases due to transition pt mutation, c.1138G?A (p.G380R)
***80% de novo–> associated w/ APA
Antley-Bixler syndrome
Inheritance:Autosomal recessive
Gene: FGFR2, POR
Cleidocranial Dysplasia
Inheritance:Autosomal dominant
Gene: RUNX2 (CBFA1)
Diastrophic Dysplasia
Inheritance: Autosomal dominant
Gene: SLC26A2
FGFR2-Related Disorders
Inheritance:Autosomal dominant
Gene: FGFR2 (FGFR1 may cause Pfeiffer, FGFR3 may cause Crouzon)
Apert, Pfeiffer, Crouzon syndromes
FGFR2= Apples, pepper, croutons!
Crouzon syndrome
May be caused by FGFR3
Features:
Hypochondroplasia
Inheritance: Autosomal dominant
Gene: FGFR3
**70% due to transversion pt mutation @ c.1620C>A
**30% due to transversion pt mutation @ c.1620C>G
McCUne Albright syndrome
Inheritance: Somatic post-zygotic mutation, typically results in mosaicism
Gene: GNAS1
Muenke syndrome
Inheritance: Autosomal dominant
Gene: FGFR3
Multiple exotoses
Inheritance:Autosomal dominant
Gene: EXT1, EXT2
**Slightly reduced penetrance in women (96%), fully in men
Saethre-Chotzen syndrome
Inheritance:Autosomal dominant
Gene: TWIST
Thanatophoric Dysplasia
Inheritance:Autosomal dominant
Gene: FGFR3
Achrondoplasia: Features
- Normal intellect
- Rhizomelic shortening
- Trident hands
- Brachydactyly
- Frontal bossing
- Kyphosis or lordosis
- Bow-leg or knock knee leg deformities
- Sleep apnea
- Higher risk for obesity
- Hydrocephalus
- Delayed motor milestones
- Normal life span
Antley-Bixler syndrome: Features
- Brachycephaly
- Bulging eye (Proptotic exophthalmos)
- Arachnodactyly
- Craniosynostosis
- Facial hypoplasia
- Bowed ulna and femur
- Radial, humeral, and trapezoidal stenosis
Cleidocranial Dysplasia: Features
- Partial or complete absence of the clavicles
- Prognathia, micrognathia
- Failure or late closure of the fontanelle
- Failure of cranial stutures to close
- Underdeveloped joints
- Supernumerary teeth/delayed tooth eruption
- Frontal bossing
- Hypertelorism
- Delayed ossification
- Cox vara hip deformity
- Vertebral anomalies
- Scoliosis
- Spina bifida
- Brachydactyly
- Shorter stature when compared to unaffected sibs
- Mild motor delay
Antley-Bixler syndrome: Other Features
- ID
- Hydrocephalus
- Upper airway obstruction
- Early death primarily due to respiratory concerns
- Camptodactyly
- Nasal, anal, and vaginal atresia
- Cryptorchidism
- Renal malformations
Diastrophic Dysplasia
Major features: ●Respiratory insufficiency in newborns ●“Unusual” Clubfoot-->Inward and upward-turning foot ●Scoliosis ●“Hitchhiker thumbs” ●Cleft palate ●Restricted joint mobility ●Severe lumbar lordosis ●Valgus deformities ●Toe walking/standing due to severe club foot and shortened tendons ●Brachydactyly ●Phalangeal synostosis with disability ●Broad forehead with high anterior hairline ●Cystic ear swelling ●Short stature ●Spinal cord compression ●Normal intellect
Apert syndrome
●Craniosynostosis
●Radially deviated short thumb
●Syndactyly
●Omphalocele
Pfeiffer syndrome
●Craniosynostosis–>May exhibit cloverleaf skull (also seen in thanatophoric dysplasia)
●Bulging eyes
●High, prominent forehead
●Hearing loss
●Dental malocclusion
●Wide thumbs/large toes which bend outward from other digits
●Brachydactyly and/or syndactyly
●Type 1 is associated with FGFR2/AD inheritance and normal lifespan/intelligence
●Types 2 and 3 are sporadic and severe and often result in early death
Crouzon syndrome
“Branchial arch syndrome”
●Craniosynostosis ●Brachycephaly ●Bulging eyes ●“Beak-like” nose ●Strabismus ●Prognathic profile ●CHDs – PDA and aortic coarctation
If treated for cranial vault symptoms, lifespan is normal
Hypochondroplasia
● “Normal” appearance at birth ●Decreased growth velocity in childhood ●Disproportionately short limbs ●Broad, short hands and feet ●Mild joint laxity ●Macrocephaly ●Usually normal intelligence ●Scoliosis ●Shortening of the long bones with metaphyseal flare ●Similar but milder skeletal features as in achondroplasia
McCune-Albright syndrome
●Coast of Maine café au lait macule
oDistribution of macules along the midline
●Fibrous dysplasia
oCan involve any part/combination of craniofacial, axial, and/or appendicular skeleton
●Endocrine dysfunction
oUbiquitous overexpression of hormones
oHyperthyroidism
oCushing syndrome
oPrecocious puberty
oOvarian cysts
oTesticular lesions
oExcess growth hormone
oExcess cortisolMuenke syndrome
●Craniosynostosis ●Abnormally shaped head (even if craniosynostosis is not present as other parts of the skull may be malformed) ●Hypertelorism ●Hearing loss ●Developmental delay ●Some may have learning disabilities ●Slightly reduced penetrance (93-94%)
Multiple exotoses
●Multiple osteochondromas (cartilage-capped bone tumors)
oLow malignant potential to develop into osteochondrosarcoma (increases with age but lifetime risk is ~1%)
oTypically develop in areas of active bone growth (growth plate)
oCan lead to shortening or bowing of bones/short stature
oCan decrease range of motion
Saethre-Chotzen Syndrome
●Craniosynostosis ●Acrocephaly (cone-shaped head) ●Lop-sided face ●Syndactyly, brachydactyly ●Valgus deformity ●Optic atrophy ●Vision problems ●Small, low-set ears ●Cleft palate/high-arched palate ●Malocclusion, peg teeth ●Ptosis, strabismus, down-slanting palpebral fissures ●Short stature ●CHDs
Thanatophoric dysplasia
●Short-limb dwarfism
●Micromelia
●Short ribs
●Macrocephaly
●Brachydactyly
●Redundant skin folds on arms
●Dysmorphic facies
●Most die of respiratory insufficiency shortly after birth
Type I can be distinguished by bowed femurs
TYPE II CAN BE DISTINGUISHED BY CLOVERLEAF SKULL DEFORMITY
Thanatophoric means “death bearing”
