Skeletal Dysplasias and Short Stature

Thanatophoric dysplasia

the most common lethal skeletal dysplasia characterized by a cloverleaf skull with frontal bossing and hydrocephalus. Caused by mutations in FGFR3

SADDAN

Severe achondroplasia with developmental delay and acanthosis nigricans. Caused by heterozygosity for the K650M mutation in the FGFR3 gene

Achondroplasia most common mutation

Gly380Arg

Achondroplasia de novo rate

80%

achondroplasia dwarfism type

Average height: 4'4" for males, 4'1" for females. shortened proximal limbs, average size trunk

achondroplasia dysmorphism

macrocephaly, prominent forehead, frontal bossing, foramen magnum stenosis, midface hypoplasia

Trident hand

Hand finding associated with achondroplasia. A wide separation between the middle and ring finger, which gives the hand a 3-pronged appearance

Voxzogo

FDA approved CNP C-type Natriuretic Peptide, which bypasses FGFR3 in its pathway, increasing chondrocyte proliferation and differentiation in those with achondroplasia. Requirements: 5 years of age or older, open growth plates

achondroplasia complications

lordosis, kyphosis, apnea, obesity, spinal stenosis, joint pain, delayed motor milestones

achondroplasia prenatal ultrasound

frontal bossing, shortened long bones, sometimes increased NT. Usually not diagnosed until the 3rd trimester

FGFR3 gene function

Cell proliferation and differentiation, blood vessel formation, wound healing, ossification (cartilage --> bone)

Achondroplasia testing considerations

can be diagnosed on x-ray alone, 99% of all cases associated with Gly380Arg

hypochondroplasia mutation

TK1 region of FGFR3

most significant genes mutated in APA

FGFR2, FGFR3, RET

hypochondroplasia distinctive feature

although stature is increased over classic achondroplasia, ID/DD and CNS problems are more common in hypochondroplasia

osteogenesis imperfecta genetics

AD, defects in type 1 collagen (COL1A1, COL1A2)

wormian bones

extra irregularly shaped bone pieces that occur within a suture in the cranium. Can occur in OI.

OI prenatal ultrasound

Shortened long bones, increased NT, evidence of fetal fractures and healing, growth restriction. All most likely only going to be seen in OI2

biphosphinates in OI

slow bone turnover by retaining more calcium in the bones during growth. Does not work for type 1. Side effect: hypocalcemia

dentinogenesis imperfecta

Disorder of dentin formation in which the odontoblasts lay down an abnormal matrix. Associated with OI Type 2 & 4, and can occur as its own disorder associated with the DSPP gene

OI clinical features (all types)

recurrent fractures, relatively short stature, risk of hearing loss, leg bowing, possible wormian / sutural bones

OI Type 1 unique features

light blue sclera, triangular face, unresponsive to bicarbonate therapy

OI Type 2 unique features

congenital fractures, neonatal respiratory failure, dark blue sclera, bone deformities, IUGR, muscle weakness, barrel chest, dentinogenesis imperfecta

Basilar invagination

bones of spine intersect with brain, can occur in OI 3 & 4

telescope rod bone support

surgically implanted rod into long bones in those with OI. Can provide additional stability for walking without fractures, can grow with patient

Spondyloepiphyseal Dysplasia (SED) dwarfism type

short trunk / spine, average limbs

Diastrophic Dysplasia

AR at SLC26A2. Progressive skeletal features such as hip dysplasia and scoliosis (diastrophy = destroyed over time). Constant hitchhiker thumb, flat nasal bridge, prominent cheeks, cleft palate, cystic pinnae, cleft palate, abnormal cartilage in trachea, cervical spine instability, cervical scoliosis / kyphosis, contractures, subluxations, clubfeet, sandal gap, arthritis, short stature

Campomelic Dysplasia

AD (de novo) at SOX9. Campomelic = bent limbs. Bowing of the legs, dislocated hips, small lungs and chest, undervirilization of XY infants, Pierre Robin Sequence, prominent eyes, flat face, large head, congenital heart defects, laryngotracheomalacia, 11 pairs of ribs instead of 12. Death typically occurs in early infancy due to trouble breathing.

11 pairs of ribs

highly associated with campomelic dysplasia. Remember: musicals are campy and your favorite musical is about [sox]9/11[ribs]

hitchhiker placement of thumb

highly associated with diastrophic dysplasia. Remember: if you hitchhike you'll be destroyed over time

Cleidocranial dysplasia

AD at CBFA. Hypertelorism, failed /delayed closure of the anterior fontanelle / cranial sutures, hypoplasia or aplasia of the clavicles, short stature, supernumerary teeth, dental anomalies, skeletal anomalies, smooshed together shoulders (could touch elbows together behind the back)

Cartilage-hair hypoplasia

AR at RMRP, an untranslated mitochondrial processing gene. Features: short stature, fine and sparse blond hair, defective T-cell immunity (cannot receive live vaccines), severe combined immunodeficiency, anemia, Hirchsprung, aganglionic megacolon, increased risk of basal cell carcinoma + non-Hodgkin lymphoma.

Spondyloepiphyseal Dysplasia

AD at COL2A1. Short trunk, average trunk, pectus carinatum, flattened vertebrae resulting in scoliosis / lordosis / kyphosis, decreased joint mobility, conductive hearing loss, myopia, retinal detachment. Gives short & stiff Marfan vibes.

Robinow

AR at ROR2, AD at FZD2, WNT5A, DVL1, and DVL3. Shortened long bones, brachydactyly, wedge-shaped hemivertibrae resutling in kyphoscoliosis, fused / missing ribs, short stature, "fetal facies", overgrowth of gums, crowded teeth

mulibrey nanism

AR at TRIM37. MUscle-LIver-BRain-EY Nanism (Dwarfism). Growth restriction, short-broad neck, misshapen sternum, small thorax, square shoulders, enlarged liver, and yellowish dots in the ocular fundi. Individuals with Mulibrey nanism have also been reported to have intellectual disability, tumors, and infertility. Almost all cases are in Finnish population

Johanson-Blizzard

AR at UBR1. Malabsorption of fats and other nutrients due to pancreatic insufficiency, failure to thrive, short stature, small "beak-shaped" nose, varying degrees of intellectual disability, sparse light hair, aplasia cutis. Pancreatic features / failure to thrive give the vibe of CF. Remember: Blizzard "Beak" like the Disney park Blizzard Beach

Seckel Syndrome

AR at ATR. Primordial dwarfism, microcephaly, IUGR, ID/DD, sloping forehead, beak-like nose, micrognathia, hip dysplasia, radial dyslocation, *bird head dwarfism*

Hallermann-Streiff Syndrome

AD, unknown genes. Distinctive craniofacial malformations (brachycephaly, prominent forehead, hypoplastic mandible, high arched palate, pinched / tapering nose), sparse hair, eye abnormalities, dental defects, scalp and nasal atrophy, proportionate short stature, ongenital cataracts, corneal stromal opacities, microphthalmia, glaucoma, retinal detachments, delayed tooth eruption, enamel hypoplasia, absent permanent teeth (hypodontia or partial adontia), abnormal tooth development resulting in short roots and early loss of teeth, and/or improper alignment of teeth.

fibrous bone dysplasia

An uncommon bone disorder in which scar-like (fibrous) tissue develops in place of normal bone. Associated with McCune Albright

delayed closure of the cranial sutures

Buzzword for Cleidocranial dysplasia

Madelung deformity

Shortened distal radius with abnormal ulnar tilt of its distal articular surface. Think of Leri Weill Dyschondrogenesis

Leri Weill Dyschondrogenesis

pseudoautosomal at SHOX (X chromosome, pseudoautosomal region). Mesomelia (resultant short stature). Most people with the condition also have an abnormality of the wrist and forearm bones called Madelung deformity, which may cause pain and limit wrist movement.

Meier-Gorlin Syndrome

AR at ORC1, ORC4, ORC6, CDT1, and CDC6. Primary dwarfism which begins with IUGR, microcephaly, *absent kneecaps*, underdevelop of sex organs / secondary sex characteristics

bird-head dwarfism

think of Seckel Syndrome (even though there are definitely other beak-nosed skeletal dysplasias)

Geleophysic Dysplasia

AR at ADAMTSL2. Geleophysic literally means "good natured", named after the good natured facial appearance of affected individuals. Think of this syndrome when you see short stature, contractures, and "good natured" facial appearance

Albright hereditary osteodystrophy

AD / imprinted at GNAS1. Pseudohypoparathyroidism Type 1 (body does not respond to parathyroid hormone). Results in brachydactyly, hypogonadism, choroid plexus calcification, full / round face, short stature.