Inheritance Pattern of Orthopedics Syndrome.pptx

Inheritance Pattern of
Orthopedics Syndrome
Presenter. Dr.Sharew (OSR-1)
Moderator Dr.Theodros (Ass’t Proff.of
Orthopedics & trauma surgery)
5/19/2024 1

Outline
Introduction
Chromosomal structure & function
Single gene inheritance
 Autosomal dominant orthopedics disease
 Autosomal recessive orthopedics disease
 X-linked dominant orthopedics disease
 X-linked recessive orthopedics disease
Multiple inheritance pattern
5/19/2024 2

Introduction
Watson and Crick first deduced the structure of deoxyribonucleic acid
(DNA) in 1953,which greatly advanced the understanding of genetics.
Conditions once grouped by phenotype have been shown to have similar
genotypes.
Knowledge of the genes responsible for specific diseases can lead to
more accurate classifications, prognosis and possibly improved treatment
techniques.
A basic knowledge of disease inheritance and relevant genetic
musculoskeletal disorders is required by the orthopedic surgeon.
5/19/2024 3

Chromosomal structure & function
The karyotype of a normal human somatic cell
is 46 chromosomes (the diploid number).
This includes 22 autosomal pairs and two sex
chromosomes.
Chromosomes are composed of DNA,
ribonucleic acid (RNA),polysaccharides and
histone and non-histone proteins.
Chromosomes are thin thread-like structures
that have a short p arm and a long q arm
separated by a constriction known as the
centromere.
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Cont.
DNA is a polymer of deoxyribonucleotides composed
of a nitrogenous base, a sugar and a phosphate
group.
The bases contain the genetic information and are
derived from purines (adenine and guanine) or
pyrimidines(thymine and cytosine).
DNA sequences are arranged in a specific order to
form genes.
About 100,000 genes make up the human genome.
Genes code for protein synthesis.
Proteins have many different biological functions.
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Single-gene inheritance
Gene defects may be inherited by autosomal chromosomal transmission or
may be linked to X chromosomes.
Defects can be either dominant or recessive. The penetrance of a genetic
disorder relates to the probability that the phenotype will be expressed.
The severity of the phenotypic expression may alter between individuals
with the same genotype; this is known as variable expressivity.
Incomplete penetrance is defined as inheritance of the mutant gene
without expression of the phenotype of the disorder. This is in contrast to
variable expressivity, in which the patient always expresses some of the
symptoms.
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Autosomal dominant inheritance
Affected individuals are heterozygous for the mutation.
Homozygous individuals of the allele usually are more severely
affected and usually do not survive to term
There is a 50% chance of inheritance from one heterozygous parent.
 Males and females are affected equally.
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Examples of Autosomal dominant inheritance
Achondroplasia
Osteogenesis imperfecta (types I-IV)
Hereditary Multiple Exostosis
Osteopetrosis (tarda, mild form)
Syndactyly ,Polydactyly
Marfan's syndrome
Cleidocranial Dysostosis
Metaphyseal chondrodysplasia (Schmid and Jansen types)
Kniest dysplasia
Malignant hyperthermia
Ehlers-Danlos syndrome
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Achondroplasia
Is the most common form of short-limb or disproportionate
rhizomelic dwarfism.
Prevalence approximately 1 in 30,000–50,000.
It is inherited as complete penetrance.
Eighty-seven per cent of cases are as a result of a new mutation.
The mutation affects the gene for fibroblast growth factor receptor 3
(FGFR3).
Increased risk of having a child with achondroplasia is directly
proportional to paternal age after 36 years
5/19/2024 12

Cont.
The primary defect is abnormal endochondral bone formation in the
cartilaginous proliferative zone of the physis.
FGFR3 is a negative regulator of chondrocytic bone growth (through
shortening of the proliferative phase and accelerating terminal
differentiation.
The mutation that results in achondroplasia is a gain of function
mutation, rather than an inactivating mutation.
5/19/2024 13

5/19/2024 14
Clinical presentation
 Normal intelligence
 Short stature
 Delayed motor milestones
 Hearing impairment
 Recurrent ear infections
 Weight gain
 Symptoms of foramen magnum stenosis
 Excessive snoring or apnea
 Difficulty swallowing
 Cranial nerve dysfunction
 Weakness
 Symptoms of spinal stenosis
 Pseudoclaudication and standing
discomfort
 Numbness and paresthesias
 Weakness

Osteogenesis imperfecta
This is a generalized disease of connective tissue due to a
quantitative or qualitative defect of type I collagen.
Type I collagen is the major extracellular protein in bone, skin and
tendons, made of two α1 chains (tropocollagen) and one α2 chain in
a triple helix structure.
The pro-α1 chain is encoded by the COL1A1 gene on chrom 17 and
the pro-α2 chain is encoded by the COL1A2 gene on chrom 7.
Mutations in the COL1A1 and COL1A2 genes cause approximately 90
percent of all cases.
The estimated incidence is approximately 1 per 20,000 live births
5/19/2024 15

A defect in the structure of type I collagen weakens connective
tissues, particularly bone
The clinical features can be broadly classified into skeletal and
extraskeletal
5/19/2024 16

Orthopaedic manifestations
Bone fragility and fractures
 Fractures heal in normal fashion
initially but does not remodel can
lead to progressive bowing
Ligamentous laxity
Short stature
Scoliosis
Codfish vertebrae (compression #)
Basilar invagination
Olecranon apophyseal avulsion #
Most common first presenting sign
Coxa vara (10%)
Congenital anterolateral radial head
dislocations
5/19/2024 17

Non-Orthopaedic manifestations
Blue sclera
Dysmorphic, triangle shaped facies
Hearing loss
 50% of adults with OI May be conductive,
sensorial and mixed
Brownish opalescent teeth
(dentinogenesis imperfecta)
Wormian skull bones (puzzle piece intrasutural
skull bones)
Hypermetabolism
Thin skin prone to subcutaneous hemorrhage
Cardiovascular
Mitral valve prolapse
Aortic regurgitation
19

Classification of OI
5/19/2024 20

Hereditary Multiple Exostosis (HME)
Also called hereditary multiple osteochondromas,
Characterized by multiple osteochondromas that grow near the growth
plates of bones especially long bones.
HME is mainly caused by mutations and functional loss of the ext1 and
ext2 genes which encode glycosyltransferases, which involved in heparan
sulfate synthesis
The penetrance is estimated to be 96% in females and 100% in males
Individuals with the EXT1 mutation have a more severe presentation
compared to patients with the EXT2 mutation
5%-10% malignant transformation to chondrosarcoma
Proximal lesions more likely to undergo malignant transformation than
distal lesions
5/19/2024 21

Appearance of a palpable mass near the joints.
Limb deformities most common sites of include the knee, forearm, and
ankle
 Femoral shortening and limb-length discrepancy
 Coxa valga
 Knee valgus (because of shortened fibula) and patellar dislocation
 Ankle valgus (because of shortened fibula)
The effects of HME depend largely on the number and shape of the
exostoses.
With early onset, the lesion tends to be bigger and causes more problems.
Upper extremity deformities are well tolerated and lead to little loss of
function
5/19/2024 22

Osteopetrosis
Osteopetrosis is a heterogeneous group of heritable conditions in
which there is a defect in bone resorption by osteoclasts.
Bone is in a dynamic state and is dependent upon a healthy balance
between osteoclast-mediated resorption and osteoblast-mediated
deposition.
In osteopetrosis, defective osteoclast development or function leads
to a disruption in normal bone homeostasis.
Osteoclasts that have defective proton pumps, chloride channels, or
carbonic anhydrase II proteins are unable to resorb bone effectively.
Consequently, the unorganized, overly dense bone that is prone to
fracture develops unchecked.
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Classification of Osteopetrosis
5/19/2024 26

Clinical Presentation of Autosomal dominant Osteopetrosis
Usually asymptomatic
Low energy pathologic fracture (lower extremity >upper
extremity>axial skeleton)
Anemia (fatigue)
Joint pain
Lower back pain
Early hip osteoarthritis
5/19/2024 27

Autosomal recessive inheritance
Affected individuals are homozygous for the genetic mutation
Heterozygous individuals are known as carriers.
There is a 25% chance of producing an affected individual from two
parental carriers.
Males and females are affected equally.
Most autosomal recessive conditions produce errors of metabolism
due to the deficiency of specific enzymes.
This can result in an accumulation of substrate or product, or both.
5/19/2024 29

Examples of Autosomal Recessive inheritance
Diastrophic Dysplasia
Hypophosphatasia
Spinal muscular atrophy
Osteopetrosis (infantile, malignant form)
Friedreich's Ataxia
Gaucher disease
Sickle cell anemia
5/19/2024 31

Clinical presentation of Infantile Osteopetrosis
Requent fractures
Progressive deafness and blindness
Severe anemia beginning in early infancy or in utero
Bleeding risk
Frequent infections
Macrocephaly
Hepatosplenomegaly (caused by compensatory extramedullary
hematopoiesis)
Dental abscesses and osteomyelitis of the mandible
5/19/2024 32

X-linked dominant inheritance
Either sex can be affected.
The phenotype is dominant when a heterozygous female expresses
the phenotype.
All daughters will inherit the affected gene from an affected
male, but no sons will be affected.
50% of sons and 50% of daughters risk inheriting the mutated
gene from an affected mother.
5/19/2024 33

Examples of X-linked dominant inheritance
Hypophosphatemic rickets
Leri-Weill dyschondrosteosis (bilateral Madelung's deformity)
5/19/2024 35

Hypophosphatemic rickets
It is the most common cause of heritable rickets, with an
incidence of 1:20,000live births.
It accounts for more than 80% of familial hypophosphatemic rickets.
Presents at 1-2 years of age
Caused by inability of renal tubules to absorb phosphate
Results from mutation in PHEX gene
leads to increased levels of FGF23, which decreases renal phosphate
absorption and suppresses renal 25-(OH)-1α-hydroxylase activity
Males express the disease fully, but females have variable
expressivity in the heterozygous genotype.
5/19/2024 36

X-linked recessive inheritance
The phenotype is recessive when expressed by a homozygous female.
All males are affected, as they possess only one X chromosome.
Heterozygous females are carriers.
5/19/2024 39

Examples of X-linked recessive inheritance
Duchenne muscular dystrophy
Becker's muscular dystrophy
 Hunter's syndrome
 Hemophilia
 SED tarda
 Lesch-Nyhan
5/19/2024 41

Duchenne muscular dystrophy
Duchenne muscular dystrophy is a common congenital condition caused by
an x-linked recessive mutation leading to the absence of dystrophin protein
that affects young males.
Its prevalence is 2-3/10,000 with age of onset is between 2-6 years of age
Xp21.2 dystrophin gene defect due to point deletion and nonsense
mutation
One third of cases result from spontaneous mutations
Dystrophin absence leads to
 Poor muscle fiber regeneration
 Progressive replacement of muscle tissue with fibrous and fatty
tissue
 Skeletal and cardiac muscle lose elasticity and strength
Diagnosis is made with DNA testing showing an absence of
the dystrophin protein.
5/19/2024 42

Orthopaedicmanifestations
 Calf pseudohypertrophy
 Scoliosis
 Equinovarus foot deformity
 Joint contractures
Nonorthopaedic conditions
 Cardiomyopathy
 Static encephalopathy
5/19/2024 43

Becker's muscular dystrophy
Similar to Duchenne's despite that in Becher’s
 Dystrophin protein is decreased instead of absent
 Later onset with slower progression and longer life expectancy
(average diagnosis occurs at age 8 compared to 2 years of age with
duchenne's)
 More prone to cardiomyopathy
5/19/2024 45

Hemophilia
Haemophilia is the oldest known hereditary bleeding disorder with
an X-linked recessive inheritance.
Haemophilia A has abnormal factor VIII and haemophilia B (Christmas
disease) has abnormal factor IX.
Patients present with abnormal bleeding spontaneously or following
trauma.
Typically, bleeds occur deep within muscles and in joints.
The iliacus is the most commonly involved muscle, presenting with
abdominal or hip pain, flexion deformity and swelling
(pseudotumour) of the hip.
Ultrasonography is very helpful in delineating the cause.
5/19/2024 47

Cont.
Haemarthrosis presents with pain,
swelling and restricted motion (most
commonly in the knee).
Recurrent bleeds cause deposition of
haemosiderin in the synovium and the
articular cartilage, leading to early
destruction of joints and causing
chronic haemophilic arthropathy.
5/19/2024 48

Multiple Inheritance pattern
Many orthopaedic conditions are derived from multiple gene defects
and environmental factors.
Examples include developmental dysplasia of the hip, talipes
equinovarus and neural tube defects.
These conditions demonstrate familial inheritance but do not behave
like single-gene disorders.
The risk of the condition being inherited in subsequent relatives
increases compared with the population but decreases in
subsequent-degree relatives
5/19/2024 49

Examples of multiple inheritance
Charcot-Marie-Tooth (AD, AR, X-link)
Osteopetrosis (AD, AR)
Osteogenesis Imperfecta (AR, AD)
Neurofibromatosis (AD, AR)
5/19/2024 50

Summary
oMany diseases commonly treated by orthopaedists have a genetic
basis.
oAs a result basic knowledge of disease inheritance and relevant
genetic musculoskeletal disorders is required by the orthopedic
surgeon.
oBecause it is not possible for a practicing orthopaedist to be familiar
with so many genetic disorders, it is important for orthopaedists to
have a framework for understanding the disorders and have resources
readily available.
5/19/2024 52

Reference
 Basic orthopedic science 2nd edition
 Orthopedic Basic science foundation of clinical practice 4th edition
 Orthobullet
 Related Articles
5/19/2024 53

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