Basic Science for the FRCSOrth

Courtesy: Rishi Dhir, FRCS Orth, Consultant Upper Limb Surgeon, Princess Alexandra Hospital, Harlow, UK

Genetics

Chromosome Structure

• Chromosomes are structures in the nucleus containing genetic material
• Components include:
  • DNA
  • RNA
  • Histone proteins
  • Non-histone proteins

Human Karyotype

• Normal somatic cell contains 46 chromosomes
  • 22 pairs of autosomes
  • 1 pair of sex chromosomes
• Sex chromosomes:
  • XX ? Female
  • XY ? Male

Chromosome Anatomy

• Chromosome has:
  • Short arm (p arm)
  • Long arm (q arm)
• Arms separated by centromere

Chromosome Types (based on centromere location)

• Metacentric
  • Centromere near middle
  • p and q arms equal length
• Submetacentric
  • Arms unequal
• Acrocentric
  • Centromere near one end
  • Very short p arm
• Telocentric
  • Centromere at terminal end

DNA Structure

DNA Composition

DNA consists of:

• Nitrogenous base
• Sugar (deoxyribose)
• Phosphate backbone

Nitrogenous Bases

Purines

• Adenine (A)
• Guanine (G)

Pyrimidines

• Cytosine (C)
• Thymine (T)

Base Pairing

• Adenine pairs with Thymine
• Guanine pairs with Cytosine

Structure

• DNA forms a double helix
• Bases linked by hydrogen bonds

Cell Division

Mitosis

• Produces two identical daughter cells
• DNA replication occurs before division
• Replication is semi-conservative
  • Each daughter strand contains one original strand

Steps:

• DNA replication
• Chromosomes align in cell center
• Chromatids separate
• Two identical cells formed

RNA and Protein Synthesis

Transcription

• DNA ? mRNA
• Enzyme: RNA polymerase

Translation

• mRNA moves to cytoplasm
• Combines with:
  • Ribosomal RNA
  • Transfer RNA
• Produces proteins

Key Definitions

• Replication: DNA ? DNA (DNA polymerase)
• Transcription: DNA ? RNA
• Translation: RNA ? Protein

Chromosomal Abnormalities

Numerical Abnormalities (Aneuploidy)

Monosomy

• Loss of one chromosome
• Example:
  • Turner syndrome (XO)

Features of Turner syndrome:

• Short stature
• Webbed neck
• Cubitus valgus
• Coarctation of aorta
• Broad chest with widely spaced nipples
• Amenorrhea and infertility

Trisomy

• Gain of one chromosome

Examples:

Down syndrome (Trisomy 21)

• Intellectual disability
• Characteristic facial features
• Congenital heart disease
• Wide gap between first and second toes

Klinefelter syndrome (XXY)

• Male with extra X chromosome
• Features:
  • Gynecomastia
  • Female body habitus
  • Sparse body hair
  • Testicular atrophy
  • Infertility

Structural Chromosome Abnormalities

Definitions

Genotype

• Genetic constitution of an individual

Phenotype

• Clinical expression of genotype

Allele

• Alternative form of a gene at same locus

Homozygous

• Two identical alleles

Heterozygous

• Two different alleles

Mutation Types

Point mutation

• Single nucleotide change

Deletion

• Loss of chromosome segment

Inversion

• Segment rotated 180°

Translocation

• Genetic material transferred between chromosomes

Modes of Inheritance

Meiosis

• Specialized cell division producing gametes
• Results in haploid cells (23 chromosomes)

Key Features

• Crossing over occurs at chiasma
• Produces genetic variation

Sources of variation:

• Crossing over
• Independent segregation

Mendelian Inheritance

Autosomal Dominant

Characteristics:

• Only one abnormal allele required
• Affected parent ? 50% chance of affected child
• Male : Female ratio 1:1

Examples:

• Achondroplasia
• Marfan syndrome
• Neurofibromatosis type 1
• Osteogenesis imperfecta

Autosomal Recessive

Characteristics:

• Two abnormal alleles required
• Parents usually carriers

If both parents are carriers:

• 25% affected
• 50% carriers
• 25% normal

Example:

• Sickle cell disease

X-Linked Recessive

• More common in males
• Males have only one X chromosome

Examples:

• Hemophilia
• Duchenne muscular dystrophy

Inheritance patterns:

Mother carrier + father normal

• 50% sons affected
• 50% daughters carriers
• No daughters affected

Father affected + mother normal

• All daughters carriers
• All sons unaffected

X-Linked Dominant

Example:

• Hypophosphatemic rickets

Inheritance:

Mother affected:

• 50% sons affected
• 50% daughters affected

Father affected:

• All daughters affected
• No sons affected

Penetrance and Expressivity

Penetrance

• Probability that genotype will express phenotype

Incomplete penetrance

• Gene present but no clinical expression

Variable Expressivity

• Same genotype
• Different severity of symptoms

Example:

• Marfan syndrome

Polygenic Inheritance

• Multiple genes influence phenotype
• Environmental factors may contribute

Examples:

• Developmental dysplasia of hip (DDH)
• Clubfoot (Talipes equinovarus)

Key feature:

• Risk decreases in subsequent generations

Embryology of the Limb

Limb Bud Development

• Occurs 4–8 weeks gestation

Rule of Threes

• Three zones
• Three genes
• Three directions

Zones

Apical Ectodermal Ridge (AER)

• Controls limb growth

Progress Zone

• Cells undergo proliferation

Zone of Polarizing Activity (ZPA)

• Controls anterior-posterior development

Growth Directions

Proximal ? Distal

Controlled by:

• HOX (homeobox) genes

Posterior ? Anterior

Controlled by:

• Sonic hedgehog gene

Associated abnormalities:

• Radial club hand
• Thumb hypoplasia
• Fibular hemimelia

Dorsal ? Ventral

Controlled by:

• WNT (wingless type) gene

Limb Bud Associations

Congenital anomalies often associated with VACTERL association

VACTERL stands for:

• Vertebral anomalies
• Anal atresia
• Cardiac defects
• Tracheoesophageal fistula
• Renal anomalies
• Limb abnormalities

Important exam principle:

• Associated anomalies may be life-threatening, not limb deformity.

Embryology of the Spine

Gastrulation

Occurs during week 3

Three germ layers form:

• Ectoderm
• Mesoderm
• Endoderm

Germ Layer Derivatives

Ectoderm

• Nervous system
• Skin epidermis

Mesoderm

• Muscle
• Bone
• Connective tissue

Endoderm

• Gastrointestinal lining
• Respiratory tract lining

Vertebral Development

Key structures:

• Notochord
• Somites

Notochord

• Releases sonic hedgehog signals
• Forms nucleus pulposus

Somites

Differentiate into:

• Dermatome ? Skin
• Myotome ? Muscle
• Sclerotome ? Vertebrae and annulus fibrosus

Neural Tube Development

Process called neurulation

Steps:

• Neural plate formation
• Neural folds develop
• Fusion ? neural tube

Neural Tube

Forms:

• Brain
• Spinal cord

Neural Crest

Forms:

• Peripheral nervous system

Spina Bifida

Failure of neural tube closure

Types:

• Spina bifida occulta
• Meningocele
• Myelomeningocele

Clinical sign:

• Hair tuft over spine

Physis (Growth Plate)

Growth Plate Zones

Resting (Germinal) Zone

• Storage zone
• Contains glycogen, lipids

Associated disorders:

• Storage diseases
• Pseudoachondroplasia
• Diastrophic dysplasia

Proliferative Zone

• Chondrocyte multiplication

Associated disorders:

• Gigantism
• Achondroplasia

Hypertrophic Zone

• Cells enlarge
• Site of physeal fractures

Subdivisions:

• Zone of maturation
• Zone of degeneration
• Zone of provisional calcification

Metaphysis

Contains:

• Primary spongiosa
• Secondary spongiosa

Common site of:

• Osteomyelitis

Reason:

• Hairpin vascular loops
• Slow blood flow
• Bacterial deposition

Salter–Harris Fractures

Salter–Harris II

• Through physis + metaphysis
• Germinal layer preserved
• Better prognosis

Salter–Harris III

• Through physis + epiphysis
• Involves germinal layer
• Worse prognosis

Complications of Physeal Injuries

Complete Physeal Arrest

• Limb shortening

Partial Physeal Arrest

• Angular deformity

Management of Physeal Bar

Evaluation:

• MRI
• CT scan

Treatment depends on:

• Patient age
• Size of physeal bar
• Remaining growth

Options:

• Bar excision + interposition graft
• Completion epiphysiodesis
• Contralateral epiphysiodesis
• Corrective osteotomy