Skeletal Dysplasias

Question 1

What are clinical features of achondroplasia?

Answer 1

Disproportionate short stature
(usually under 4 feet 6 inches)
* Macrocephaly with frontal bossing
(large head, prominent forehead)
* Midface retrusion and depressed
nasal bridge (flat face / nose)
* Rhizomelic (proximal) shortening of
the arms with redundant skin folds
on limbs
* Limited elbow extension
* Brachydactyly

• “Trident” hands
• Genu varum (bowlegs)
• Thoracolumbar kyphosis (excessive
  forward curvature of the spine in the
  upper back) and exaggerated lumbar
  lordosis
• Leads to prominent appearance of
  abdomen and buttocks
• Developmental motor milestones can
  be delayed
• Intelligence and life span are typically
  near normal
• Related complications can may affect
  these

Question 2

What gene is associated with achondroplasia?

Answer 2

FGFR3 mutation
* Gene that makes a protein that is
involved in cell division, cell
maturation, formation of new blood
vessels, wound healing, and bone
growth, development, and
maintenance.

Question 3

What is the MOI for achondroplasia?

Answer 3

AD; 80% de novo, 100% penetrant

Increased risk with APA

Question 4

What is homozygous achondroplasia? (SADDAN)

Answer 4

Biallelic pathogenic variants at nucleotide 1138 of FGFR3
* Severe disorder
* Early death results from respiratory insufficiency because of
the small thoracic cage and neurologic deficit from

Question 5

What medication is often used to treat achondroplasia?

Answer 5

VOXZOGO® (vosoritide) FDA-approved
treatment used to increase linear growth in
pediatric patients with achondroplasia who
are 5 years of age and older with open
epiphyses. Costs about $320,000 per year

Question 6

What are the clinical features of hypochondroplasia?

Answer 6

Clinical Features
* Short stature (adult height 128-165
cm; 2-3 SD below the mean in
children)
* Stocky build
* Shortening of the proximal or
middle segments of the extremities
(rhizomelia or mesomelia)
* Limited elbow extension
* Broad, short hands and feet with
brachydactyly
* Generalized, mild joint laxity
* Macrocephaly with relatively
normal facies

Less common clinical features:
* Scoliosis
* Genu varum (bowlegs; usually
mild)
* Lumbar lordosis with protruding
abdomen
* Mild-to-moderate intellectual
disability
* Learning disabilities
* Adult-onset osteoarthritis
* Acanthosis nigricans
* Temporal lobe epilepsy

Question 7

What gene is associated with hypochondroplasia?

Answer 7

FGFR3

“Majority” of cases are de novo
* Variable penetrance (due to height range
overlap with unaffected populations)

Hypochondroplasia has skeletal and medical issues that are more mild / less frequent than
achondroplasia
* Hypochondroplasia features may present later
in life and not be identified at birth
* ID and epilepsy may be more prevalent in
hypochondroplasia

Question 8

What are features of Cleidocranial dysplasia (CCD)
spectrum disorder?

Answer 8

Ranges from
* Classic presentation (triad of delayed closure of the cranial sutures, hypoplastic or aplastic clavicles, and dental
abnormalities)
* Mild CCD
* Isolated dental anomalies without other skeletal features
Clinical findings
* Abnormally large, wide-open fontanelles at birth
* Broad, flat forehead; cranium is brachycephalic
* Frontal and parietal bossing and mid-face retrusion
* Narrow, sloping shoulders that can be opposed at the midline due to clavicular hypoplasia or
aplasia
* Delayed eruption of secondary dentition, failure to shed the primary teeth, variable numbers
of supernumerary teeth along with dental crowding, and malocclusion
* Hand abnormalities including brachydactyly, tapering fingers, and short, broad thumbs
* Short stature (typically moderate, boys a little shorter than girls)
* Increased risk of recurrent sinus infections, recurrent ear infections leading to conductive
hearing loss, and upper-airway obstruction
* Conductive hearing loss occurs in 39% of affected individuals.
* Normal intellect in individuals with classic CCD spectrum disorder

Question 9

Diagnosis of CCD

Answer 9

Characteristic clinical and
radiographic findings and/or
mutation in RUNX2 (CBFA1).

• RUNX2 provides instructions for
  making a protein (transcription factor)
  that is involved in the development
  and maintenance of the teeth, bones,
  and cartilage.
• No formal clinical diagnostic criteria for
  CCD spectrum disorder have been
  established.

AD
* High proportion of cases are de novo
* High penetrance and extreme
variability.

Question 10

What is the prevalence of Diastrophic dysplasia?

Answer 10

Prevalence unknown, suspected to be 1 in 100,000
1/33,000 in Finland (founder mutation - approximately 90% of the individuals with DTD in Finland
carry the founder mutation c.-26+2T>C, either in homozygosity or compounded with another
SLC26A2 mutation

Question 11

What are the clinical features of Diastrophic dysplasia?

Answer 11

Clinical Features
* Limb shortening
* Normal-sized head
* Slight trunk shortening
* Hitchhiker thumbs
* Symphalangism (fusion of the joints of the fingers or toes) with missing interphalangeal creases
* Small chest
* Protuberant abdomen
* Normal intelligence
* Contractures of large joints
* Dislocation of the radius
* Cleft palate (in ~1/3 of individuals)
* Cystic ear swelling in the neonatal period (in ~2/3 of infants)
* Ulnar deviation of the fingers, gap between the first and second toes, clubfoot, and flat hemangiomas of the
forehead

Question 12

What is the distinguishing clinical feature of Diastrophic dysplasia?

Answer 12

Hitchhiker thumbs

Question 13

What gene is associated with Diastrophic dysplasia?

Answer 13

SLC26A2
* Protein transports sulfate ions used by
cartilage to build proteoglycans
* Fibroblast and/or chondrocyte testing
may be used if no SLC26A2
pathogenic variants found (rare)
* AR

Question 14

What is Hereditary Multiple Osteochondromas (HMO) Syndrome? What is the prevalence?

Answer 14

Prevalence: 1 in 100 in a small population in Guam; 1 in 50,000 in Washington State*; 1 in
100,000 in European populations

Question 15

What is the gene associated with and molecular mechanism of HMO Syndrome?

Answer 15

EXT1 or EXT2
* EXT1 and EXT2 help produce exostosin-1 and 2
* These two proteins bind together in the Golgi
apparatus, which modifies newly produced
enzymes and other proteins.
* In the Golgi apparatus, the exostosin-1 and
exostosin-2 complex modifies a protein called
heparan sulfate so it can be used by the cell.
* Heparan sulfate is involved in many bodily
processes, it is unclear how the lack of this protein
contributes to the development of
osteochondromas.

Question 16

What is the MOI for HMO Syndrome?

Answer 16

AD
* 10% of cases are de novo
* 96% penetrant in females
* 100% penetrant in males

Question 17

What other risks come with HMO Syndrome?

Answer 17

The risk for malignant degeneration to osteochondrosarcoma increases with age
* Lifetime risk for malignant degeneration is ~2%-5%

Question 18

What is Spondyloepiphyseal Dysplasia congenita (SEDC)? What is the prevalence?

Answer 18

More than 175 cases reported
in the scientific literature
* Present neonatally with severe
disproportionate short stature,
short extremities (<5th
percentile), characteristic
facial features (hypertelorism,
flat profile, PRS), myopia, and
hearing loss, barrel chest
* Radiographs display
delayed/poor ossification of
the vertebrae and the pubic
bones, and the long bones are
short with hypoplastic
epiphyses

Type II Collagen Disorder
- Increased risk for cervical
instability and spinal cord
compression (as seen in Kniest
dysplasia), and individuals with
SEDC are also at greater risk for
tracheolaryngomalacia (collapse of
trachea and laryngeal structures)
* SEDC cannot be distinguished from
Spondyloepimetaphyseal dysplasia
(SEMD), Strudwick type until later
in the first year of life, since
metaphyseal dysplasia in the latter
is not present at birth

Occurs in less than 1 in 100,000 births

Question 19

Diagnosis of SEDC

Answer 19

Based on clinical and radiologic
findings and the identification of a
pathogenic variant in COL2A1, and
involves medical history, physical
examination, x-rays, family history, and
genetic testing.
* No formal clinical diagnostic criteria exist;
specific diagnosis should be confirmed by
genetic testing

Question 20

What gene is associated with SEDC? What is the molecular mechanism?

Answer 20

• AD;AR reported in two families
• Highly penetrant
• COL2A1 (makes pro-α1(I) chains, a
  component of type II collagen

Question 21

What is OI?

Answer 21

There are at least 19 recognized
forms of osteogenesis imperfecta,
however OI is phenotypically divided
into five groups, from OI types 1 to
5*.
* Two classification types: Sillence and
genetically defined types.
* In more than 90% of cases, OI occurs
due to mutations in the COL1A1 or
COL1A2 genes (mostly autosomal
dominant, can be de novo)
* OI can involve other genes and/or
inheritance patterns – See Table 5 in
GeneReviews
https://www.ncbi.nlm.nih.gov/books/NBK12
95/

Question 22

What genes are associated with OI?

Answer 22

• Covered here: OI forms that are
  AD (or de novo) and caused by
  mutations in COL1A1, COL1A2
• Type I collagen is composed of two
  pro-α1(I) chains and one pro-α2(I)
  chain (which is produced from
  the COL1A2 gene).
• Type I collagen is the most
  abundant form of collagen in the
  human body.

Question 23

What are the clinical features of OI 1

Answer 23

Blue sclerae and normal stature (still often shorter than family members)
* Possible femoral bowing at birth
* The first fractures may occur at birth or with diapering or when learning to walk
* Fractures generally occur at a rate of a few to several per year, decrease in
frequency after puberty, can increases again in adulthood, especially in
postmenopausal women and men beyond the fifth decade
* Fractures usually heal normally without deformity
* Joint hypermobility primary clinical concern is early-onset degenerative joint
disease due to malalignment of articular surfaces.
* Sillence et al [1979] designated a subset of classic non-deforming OI with
dentinogenesis imperfecta (DI) (OI type IB).
* Morbidity results not from dental decay but rather from premature wearing
down of the teeth.
* Dental eruption in classic non-deforming OI can sometimes occur early.
* Progressive hearing loss occurs in about 50% of adults with classic non-
deforming OI, beginning as a conductive hearing loss but often with an additional sensorineural hearing loss component in time

Question 24

What is perinatally lethal OI (Type 2)

Answer 24

Evident at birth
* Weight and length are SGA
* Dark blue sclerae
* Connective tissue is extremely fragile
* Large, soft skull
* Callus formation on the ribs
* Extremities are short and bowed; Hips are
usually flexed and in a “frog-leg” position.

• Can result in miscarriage or stillbirth more
  typically infants die in the immediate
  perinatal period.
• Pulmonary insufficiency related to the small
  thorax, rib fractures, or flail chest because of
  unstable ribs. May not be able to ingest
  sufficient calories due to respiratory distress.
• Over 60% die on DOL 1; 80% die within the first
  week; survival beyond one year is exceedingly
  rare and usually involves intensive support

Question 25

What is Progressively Deforming OI (OI Type 3)?

Answer 25

Apparent at birth, fractures are common
right away, even with simple handling.
* The number and severity of rib fractures lead
to death from pulmonary failure in the first
few weeks or months of life. Infants who
survive this period generally do well.
* Most do not walk without assistance
* Usually use a wheelchair or other assistance
for mobility
* Affected individuals have as many as 200
fractures and progressive deformity even in
the absence of obvious fracture.
* Extreme growth delay and very short stature
* Intellect is normal unless there are
complications (intracerebral hemorrhages
[extremely rare] and intracranial
hemorrhage).
* Increased risk for intracranial hemorrhage
(ICH) variants affecting exon 49 of COL1A2

• Considerable heterogeneity and ranges of
  features (normal-appearing teeth and facies
  in some, others have DI, a large head, and
  enlarged ventricles that reflect the soft
  calvarium)
• Relative macrocephaly and barrel chest
  deformity
• Usually sclerae are blue in infancy but lighten
  with age
• Hearing loss generally begins in the teenage
  years
• Basilar impression, an abnormality of the
  craniovertebral junction caused by descent of
  the skull on the cervical spine, is common.
• May progress to brain stem compression,
  obstructive hydrocephalus, or syringomyelia
  (fluid-filled cysts in the spinal cord)
• When swimming, affected individuals may
  perceive that water temperature differs
  below and above the umbilicus

Question 26

What is a distinguishing feature of OI Type 3?

Answer 26

“Popcorn” calcifications in severe OI “popcorn” calcifications, areas of disorganized hyperdense lines in the metaphysis and epiphysis around the growth plate on lower limb radiographs

Question 27

What is Common Variable OI with normal sclerae (Type 4)?

Answer 27

Most variable form of OI
* Mild (diagnosis can be difficult) to
moderately severe
* Mild short stature (variable)
* DI (may be mild)
* Adult-onset hearing loss (in some)
* Normal-to-gray sclerae (can lighten to
near normal)
* Basilar impression can occur

Question 28

Clinical features of COL1A1/2 OI by type

Answer 28

Question 29

What are some differentials for OI?

Answer 29

Question 30

Multidisciplinary management for OI: Testing

Answer 30

Radiographic findings
* Lab tests
* Vitamin D, calcium, phosphorous, and
alkaline phosphatase are typically
normal
* Alkaline phosphatase may be elevated
acutely in response to fracture
* Low alkaline phosphatase levels have
been noted anecdotally in severe OI
* Analysis of type 1 collagen
* Biochemical analysis is essentially
no longer used clinically
* Genetic Testing
* COL1A1, COL1A2
* Mulitgene panel
* Exome/genome sequencing

Question 31

Multidisciplinary management: Management

Answer 31

Physical considerations (avoiding
breaks/fractures, safe physically
activity, joint/bone supports)
* Orthopedic treatments (light casts, PT,
intramedullary rodding)
* Pharmacologic treatment
(Bisphosphonates, including
pamidronate, pain management)
* Surgery
* Dental treatment
* Hearing treatments
* Mental health
* Managing lethal OI

Question 32

What are craniosynostosis syndromes?

Answer 32

Syndromic craniosynostosis is the hereditary form of craniosynostosis, which is associated with extra-
cranial phenotypes such as limb, cardiac, central nervous system and tracheal malformations.
* Syndromic craniosynostosis comprises 15–30% of the total

Question 33

What genes are associated with craniosynostosis?

Answer 33

FGFR1, FGFR2, FGFR3, TWIST1, and EFNB1 genes have been frequently reported to be associated with syndromic
craniosynostosis
* FGFR2 mutations show variable clinical expressivity, and patients with the same FGFR2 mutation can exhibit diverse
clinical manifestations
* are usually named according to the accompanying extra-cranial manifestations (especially the limbs)

Question 34

What is the role of FGFR?

Answer 34

FGFR play central role in growth and differentiation of mesenchymal (a loosely organized, mainly
mesodermal embryonic tissue which develops into connective and skeletal tissues, including blood and
lymph) and neuroectodermal cells by binding of FGFR and initiation of signal transduction; FGFR also
regulates cranial suture fusion
* Mutations in the FGFR2 gene are thought to result in production of an FGFR2 protein with overactive
signaling, which causes the bones of the skull to fuse prematurely.
* The sagittal suture (40–55%) is the most commonly affected, followed by the coronal (20–25%), metopic
(5–15%), and lambdoid (<5%) sutures

Question 35

What is craniosynostosis? Prevalence?

Answer 35

Craniosynostosis describes partial or
complete premature fusion of cranial
sutures

The prevalence of craniosynostosis is
estimated to be 1 in 2100 to 2500 live
births

Question 36

What facial features are seen with craniosynostosis?

Answer 36

Ocular hypertelorism, proptosis (eye-
bulging), beaking of the nose and
midface hypoplasia are the common
facial features of the craniosynostosis

Question 37

What is Cloverleaf skull (Kleeblattschädel)?

Answer 37

More commonly associated
with thanatophoric dwarfism,
achondrogensis, camtomelic
dysplasia
* Also seen in Carpenter
syndrome and Apert, Pfeiffer,
and Crouzon Syndromes

Trilobed skull resulting associated with intra-uterine synostosis of the
coronal and lambdoidal sutures
* Hydrocephalus and ID
* Increased intracranial pressure is manifested as bulging in the areas of
the sagittal suture and squamosal sutures with a downward
displacement of the ears, severe proptosis or exophthalmos (out of the
orbit), and facial deformities similar to those of craniofacial dysostosis

Question 38

Common Genetic Syndromes
Associated with Craniosynostosis

Answer 38

Question 39

What is Apert Syndrome? Prevalence? Gene?

Answer 39

1/65,000
* Mutation in FGFR2
* AD, mostly sporadic; some association with paternal
age
* Severe symmetrical syndactyly – distinguishes it from
other FGFR2-relaterd syndromes (often 2nd,3rd and 4th
digits)

Question 40

What are clinical features of Apert Syndrome?

Answer 40

Craniosynostosis (coronal synostosis)
* Flat forehead
* Retracted midface, airway obstruction
* Proptosis, hypertelorism
* Skeletal anomalies such as poor joint mobility, cleft palate,
orthodontic problems, short stature
* GI such as malrotation, esophageal anomalies
* Learning disabilities

Question 41

What are clinical features of Crouzon syndrome?

Answer 41

1/61,000 (differing numbers out there)
* Midface hypoplasia
* Prominent nasal bridge
* Proptosis, strabismus
* Underdeveloped upper jaw, protrusion of lower jaw,
overcrowded teeth
* Hearing loss
* Most have normal intelligence
* Airway blockages leading to breathing and respiratory
difficulties
* Usually no intellectual impairment or effects of the arms, legs
or hands

Question 42

What is the MOI and gene for Crouzon?

Answer 42

AD, usually mutations in FGFR2
* Mutations in ERF (19q13.2) gene encoding the ETS2 repressor,
resulting in anosteogenic stimulation, have been associated to a
Crouzon-like syndrome.

Question 43

Crouzon with Acanthosis Nigricans
(CWAN):

Answer 43

Very similar to Crouzon
syndrome
* Differences
* CWAN has acanthosis nigricans
(pigmentary changes in the skin
fold regions)
* In CWAN hearing loss is less
common
* CWAN has normal hands and feet
* “Typically” normal in Crouzon
* Vertebral fusions in 25% (often
C2-C3) seen in Crouzon

Question 44

What is Antley Bixler Syndrome?

Answer 44

Less than 1 in 1,000,000
* AD (FGFR2); mostly de novo; without genital anomalies and
disordered steroidogenesis
* AR (POR); with genital anomalies and disordered steroidogenesis
* Both coronal sutures fuse before birth, rarely lambdoid and metopic
sutures are also fused

Question 45

What are the clinical features of Antley Bixler Syndrome?

Answer 45

Clinical features:
* Midface hypoplasia
* Choanal atresia or stenosis
* Multiple joint contractures, arachnodactyly
* High mortality due to airway compromise
* Phenotypic overlap between ABS caused by POR mutations and
those caused by FGFR2 mutations
* With POR mutations, also see genital anomalies and abnormal
steroidogenesis
* May be at risk for adrenal insufficiency and Addisonian crisis with illness
or surgery
* High doses of fluconazole can cause similar features

Question 46

What are the clinical features of Beare-Stevenson cutis gyrata syndrome?

Answer 46

Multisuture craniosynostosis with cloverleaf skull
* Most common skull configuration
* Moderate-to-severe midface retrusion, proptosis, abnormal
ears, cleft palate, conductive hearing loss, natal teeth, and
relative prognathism (protruding jaw)
* Multilevel airway obstruction includes choanal stenosis,
tongue-based airway obstruction, and tracheal anomalies,
with survivors requiring endotracheal intubation with
mechanical ventilation and/or tracheostomy
* Neonatal mortality is common
* Hands and feet are normal aside from cutis gyrata
* Intellectual disability is present in all affected individuals
* Widespread cutis gyrata and acanthosis nigricans are
usually evident at birth
* Hirsutism, skin tags, prominent umbilicus with
redundant tissue, and accessory nipples are also seen.
* Genitourinary anomalies (e.g., bifid scrotum, prominent
labial raphe, rugated labia majora, pyloric stenosis, and anterior anus)

Question 47

Craniofrontonasal syndrome

Answer 47

Extremely rare (115 cases in the literature)
* Primarily early fusion of coronal sutures
* Intelligence usually unaffected
* XLD; EFNB1 gene
* Heterozygous females show a greater severity than
hemizygous males (suspected to be at least partly related to
X-inactivation)
* Females have frontonasal dysplasia, craniofacial
asymmetry, craniosynostosis, bifid nasal tip, grooved
nails, wiry hair, and abnormalities of the skeleton
(narrow sloping shoulders, scoliosis, malformation of
the sternum or clavicle), whereas males typically show
only hypertelorism
* Males often have hypertelorism and rarely a cleft lip
* Males mosaic for this condition may have more severe
features

Question 48

What is FGFR2-related Isolated
Coronal Synostosis?

Answer 48

Unilateral or bilateral
coronal synostosis,
asymmetric brachycephaly
and/or orbital
hypertelorism
* Normal Intellect and
extremities

Question 49

What is Jackson-Weiss syndrome?

Answer 49

• Prevalence unknown, rare
• AD, FGFR2
• Multisuture craniosynostosis with proptosis and prognathism
• Foot abnormalities are most consistent feature
• Broad and medially deviated great toes, with 2/3 toe syndactyly, and normal
  hands
• Hearing loss (68%) is usually conductive
• Ranges from no airway issues to multilevel airway obstruction
  (choanal stenosis, tongue-based airway obstruction, and tracheal
  anomalies)
• Short first metatarsal, calcaneocuboid fusion, and abnormally formed
  tarsals; genu valgum
• Intellect is typically normal

Question 50

What is Muenke syndrome?
Inheritance? Gene?

Answer 50

Premature fusion of skull bones
* Often the coronal suture
* AD; FGFR3 gene
* Features
* Abnormally shaped head
* Wide-set eyes
* Flattened cheekbones
* Macrocephaly (5%)
* May also have mild abnormalities of the hands or
feet
* Hearing loss (MAJORITY SENSORINEURAL)
* Usually normal intellect
* Developmental delay and learning problems possible
* Phenotypic variability and penetrance
* Some have no features

“Conductive hearing loss
is more common than
sensorineural for all FGFR
craniosynostosis
syndromes except Muenke
syndrome.”

Question 51

Pfeiffer Syndrome:

Answer 51

Pfeiffer syndrome shares significant phenotypic
overlap with Crouzon syndrome
* People with the same pathogenic variant have been
diagnosed with either Pfeiffer or Crouzon syndrome
* Some FGFR pathogenic variants have been reported only
in individuals with Pfeiffer syndrome.
* Multisuture craniosynostosis in most individuals
* Range from normal to cloverleaf skull (depends on the
sutures involved and the timing of premature fusion)
* Severe craniosynostosis can lead to shallow orbits, eyes
are very prominent, risk of for subluxation of the globe
* Midface retrusion is moderate to severe
* Greater vertical impaction of the midface than Crouzon
syndrome
* Hearing loss occurs in 92%
* Most often conductive
* Some have cleft palate
* Multilevel airway obstruction
* Choanal stenosis/atresia, laryngotracheal abnormalities
including tracheal cartilaginous sleeve, and tongue-based
airway obstruction.

Question 52

What are the clinical features of Pfeiffer syndrome?

Answer 52

Thumbs and great toes are broad and
medially deviated, variable brachydactyly.
* Synostosis of the radius and humerus occurs in
some individuals particularly those
with FGFR2 pathogenic variant p.Trp290Cys.
* Intelligence - from normal to severe intellectual
disability.
* Seizures and an increased risk for early death are
reported.
* Early surgery to prevent cephalocranial
disproportion and intervention to manage sleep
apnea may promote improved cognitive outcomes
in children with severe presentations
* Approximately 28% of children require surgical
intervention for hydrocephalus
* Approximately 50% of individuals with
cloverleaf skull have Chiari I malformation
(brain tissue extends into the spinal canal)
* Prune belly has been reported in two infants
* Deficient abdominal muscles, undescended testes, urinary tract abnormalities

Question 53

What is Saethre-Chotzen syndrome? MOI/Gene?

Answer 53

• Craniosynostosis leading to asymmetrical skull
• AD, mutations in TWIST1

Question 54

What are clinical features of Saethre-Chotzen syndrome?

Answer 54

• Underdeveloped eye sockets, cheekbones and
  lower jaw
• Low-set hairline
• Ptosis (drooping upper eye-lid)
• Cleft palate, dental problems
• Syndactyly (often 2nd and 3rd fingers)
• Short digits and broad great toes
• Short stature, scoliosis
• Intelligence normal