Osteosarcoma FactFile Part A (Genetic Syndromes)

Risk Factors Of Osteosarcoma Part A

A) Genetic Syndromes

There are many genetic syndromes that increase the risk and is associated with osteosarcoma. Here are some of them

Li Fraumeni Syndrome

It is an autosomal dominant disorder.

Autosomal refers to the 22 pairs of numbered chromosomes in humans that are not involved in determining biological sex. The 23rd pair determines the sex/gender of the subject.

Germline mutation in the TP53 tumour suppressor gene on chromosome 17p13.1 causing loss of function.

Germline –> Sex cells (egg in females) and (sperm in males).

Tumour suppressor –> It stops tumours from growing.

Classical LFS diagnosed before 45 years old who had a relative of first degree before 45 or a second-degree relative with any cancer before age 45 or sarcoma at any age.

What is the difference between autosomal dominant and autosomal recessive?

Table presenting key differences between both types of autosomal disorders.

An illustration on the difference between autosomal dominant and recessive genetic inheritance.

Age at risk of cancer:

50% by 30 years of age and 90% by age 60 years.

5% of osteosarcoma cases are under the age of 30

The metaphysis of long bones most commonly affected area.

It has pleomorphic-shaped tumour cells (different forms) and is subdivided into osteoblastic, chondroblastic, and fibroblastic osteosarcoma depending on the variable amounts of osteoid matrix produced by the tumour.

The potential risk of the genetic syndrome affecting the children. If one parent has the condition, there is a 50% chance the child has the genetic syndrome.

The structure of the chromosome. “p” is the short arm and “q” is the long arm that make one chromatid. The centre is called the centromere that connects two sister chromatids. The ends of the chromosomes are called telomeres.

There are genes found on the chromosome. p53 is found on the short arm “p” at position 13.

Familial Retinoblastoma

It is a rare autosomal dominant disorder.

It is caused by biallelic mutation of the retinoblastoma gene RB1 (70% of cases)

It is present on chromosome 13q14.2.

It affects the retina, especially children under two.

The retina is a light-sensitive area.

What is biallelic?

The difference between homozygous (same) and heterozygous (different) alleles

An illustration on the difference between a healthy eye and a patient with retinoblastoma

The Knudson’s Two-Hit Hypothesis

In 1971, Dr Alfred G. Knudson introduced the two-hit hypothesis, where cancer arises by two mutational events.

There are two types of retinoblastomas: hereditary and sporadic.

At first, the inherited form is where the mutation of the RB gene is inherited from one allele in a germ cell (sex cells) from either the mother or father. This is called hereditary. The second is when the mutation arises in a body cell (somatic cell).

In sporadic retinoblastoma, both mutational events arise in the somatic cells.

Patients with hereditary retinoblastoma have a higher survival rate but they are at risk of developing bone and soft tissue sarcoma especially osteosarcoma.

A combination of genetic factors, exposure to radiation and chemotherapy causes retinoblastoma but highest is related to radiotherapy where there is a 400-fold increase of risk.

The common areas affected areas in 75 patients who were diagnosed with radiotherapy-induced hereditary retinoblastoma:

Skull and face (61%)
Lower limb (29%)
Trunk (7%)
Unknown locations (3.8%)

(Kleinerman et al., 2005; Hameed and Mandelker, 2019).

Werner Syndrome

It is autosomal recessive disorder where the WRN gene is mutated/changed.

The normal role of WRN gene.

The percentage ranges of an autosomal recessive disorder

The WRN gene encodes the Werner protein and is involved in DNA replication and repair.

The WRN maintains the ends of chromosomes (telomeres) which helps to maintain DNA.

DNA undergoes copying before cell division and transfers informed in genes that help make protein (transcription).

It requires the following enzymes:

RecQ helicase: This is located on chromosome 8p11.1 or 8p12. Helicase unwindS and separates the two strands of DNA.
Exonuclease: This enzyme cut the ends to remove DNA building blocks (nucleotides) of damaged DNA.

There are several examples of exonucleases:
Bal31: This removes nucleotides from both strand of the DNA.
The E.coli exonuclease III: This enzyme from the bacteria removed nucleotide from the 3′ end of the DNA molecule.
Lambda exonuclease: This enzyme is from bacteriophage (bacterial viruses) that infects E.coli and it removes nucleotides from the 5′ end of the DNA molecule.

Telomeres in normal and cancer cells. Normally, every round of DNA replication, the telomeres shorten. However, in cancer cells, telomeres remains the same/continuous growth of cancer cells.

Alternative presentation on how telomeres work

The normal role of helicase during transcription.

The distinctive roles of endonuclease and exonuclease work in cutting nucleotides.

The role of exonuclease extracted from *Escherichia coli (E.coli)*

Mutation in the WRN gene

A number of symptoms may appear:

Premature ageing (progeria) that starts at teenage years e.g. 14
Loss of bone density leading to osteoporosis
Muscle wasting (atrophy)
Hair loss
Disease progression: vision (bilateral cataracts), skin changes (scleroderma due to abnormal production of collagen caused by abnormal immune system), diabetes and heart issues.

The link between osteosarcoma and Werner’s syndrome

Osteosarcomas occur at a later age in Werner syndrome patients (ages ranging from 35-57).

They tend to present at atypical sites such as foot, ankle and patella (kneecap) to more common sites such as long bones (Langer, Cunniff and Kucine, 2023).

Rothmund -Thomson syndrome type 2

RTS is an autosomal recessive disorder that commonly affects babies.

There are two types:

Type 1 is caused by a mutation in ANAPC1 gene

Type 2 caused by a biallelic mutation in chromosome 8q24.3 of the RECQLA gene. There can also be mutation in APC/C gene. Type 2 is associated with osteosarcoma.

The effects of mutation in RECQLA gene

Cell cycle delays.

RECQLA recruits cTIP to cause double-strand breaks.

The effects of mutation in APC/C gene

Mutation in APC/C degrades ctIP (CtBP-interacting protein) steadily to prevent hyper double-stranded break and maintain genomic instability.

There are several signs and symptoms of RTS

Rash (usually on the cheeks)
Changes to the bones, hair and teeth.
Frontal bossing – enlarged forehead
Short stature
Radial defects
Hypoplastic patellae – underdeveloped or abnormal kneecap.
Oesophageal or pyloric atresia – Oesophageal atresia is a rare birth defect where the oesophagus does not connect to the stomach, preventing food from reaching the stomach.
Poikiloderma congenital or poikiloderma of Rothmund-Thomson
Small saddle nose
Protruding jaw

(Langer, Cunniff and Kucine, 2023)

Rash presented on the cheeks, hands and upper legs (not shown)

There are different types of frontal bossing. Plagiocephaly is when there is lack of symmetry in shape of the head because there is irregular closure of the sutures in the bones. There are different type ipsilateral on the left side of the forehead and contralateral on the right side of the forehead. Synostosis is the joing of the two adjacent bones e.g. sutures via ossification. Scaphocephaly and is where there is a sagittal suture caused by the premature closure between the two parietal bones. This creates a abnormally long and narrow skull compared to the other types of bossing. Trigonocephaly fused metopic suture where there is a triangular shape of the skull because the skull is sharply angled by the ears.

The effect of the other parts of the skull when part of the front of the head enlarges (bossing), it affects the back and side of the head where the occipatal and parietal lobes are respectively. It can also affect the ear.

Example of a Displacement of the kneecap

Bloom’s syndrome

It is an autosomal recessive disorder.

There is a Biallelic mutations on Chromosome 15 (15q26.1) in the BLM gene.

BLM gene encodes for a RecQ helicase.

If both parents are heterozygous (carriers) of the BLM gene but are not affected, there is a 25% chance of having a child with BLM pathogenic gene and affected. 50% being a carrier and 25% no BLM pathogenic neither carrier nor affected. Prenatal and preimplantation genetic testing are affected.

Signs and symptoms

Repeated infections due to immune abnormalities
Blistering hands and lips
short stature
Sun-sensitive erythematous rash on face with a butterfly shape.
Sparse subcutaneous fat
Growth deficiency affects height, weight and head circumference throughout life. However, body proportions are normal.
Resistant to insulin (type 2 diabetes)
Normal intellectual ability.
Fertile but early menopause
Men tend to be infertile.
Chronic obstructive pulmonary disease (COPD). Acondition where the lungs are intoxicated with smoking or airborne pollution and cause difficulty breathing and obstructs the lungs.
Hypothyroidism (underactive thyroid gland /low production of thyroxine hormone) affecting metabolism

(Langer, Cunniff and Kucine, 2023)

Some of the signs and symptoms of Bloom syndrom

RAPADILINO syndrome

This is another genetic syndrome caused by the mutation of the RECQL4 gene.

It is an autosomal recessive condition.

The structure of the RECQL4 gene and the genetic syndromes associated with its mutation

The association with RAPADILINO and Osteosarcoma

This can be seen on the signs how it affects the growth of the bone and soft tissue of the human skeleton.

The RAPADILINO is mneumonic for its signs

RA Radial dysplasia

Dysplasia – abnormal development of lining (epithelium)

PA Patella aplasia or hypoplasia/ left high arched palate

Hypoplasia – underdevelopment of cells and tissues and organs.

Aplasia –
Aplasia refers to the incomplete or absent development of an organ, tissue, or body part, often evident at birth. This is different from agenesis. Agenesis is the complete absence of an organ where there is no structure at all.

DI Diarrhoea and dislocated joints

LI little size and limb malformations

NO long, slender Nose and Normal intelligence.

Diamond-Blackfan anaemia (DBA syndrome)

It is an autosomal dominant disorder.
45% of cases have been passed down through heredity (parents).
Other cases may occur randomly (sporadic) when cells are dividing.
Other causes of genetic mutations of DBA are:
Viruses

UV radiation from sunlight

Other environmental factors.

What are the effects of DBA?

The bone marrow unable to produce red blood cells.

This is partially caused by inefficient or disrupted metabolism.

Metabolism is a series of chemicals to make energy and remove toxins.

Each chemical reaction are maintained by hormones and enzymes.

The production of blood cells (haematopoiesis) occurs in the red bone marrow (spongy bone) through the differentiation of the haematopoietic stem cell to make platelets, white blood cells, and red blood cells.

What are the genes affected by Diamond Black fan anaemia?

The ribosomal subunit

The ribosomes produce proteins.

They are structurally divided into two subunits: large and small

The size of proteins in plants, animals and fungi (eukaryotic) is different compared to bacteria (prokaryotes)

The large ribosomal subunit in eukaryotes is 60S. This is referred to as RPL.

The small ribosomal subunit in eukaryotes is 40S. This is referred to as RPS.

Deficiency in maturation of 60S causes the buildup and rapid maturation of 40S.

GATA1

It encodes the GATA1 protein.

GATA is needed for the development of many cells (blood, heart, and skin).

GATA 1, 2, and 3 are specifically needed for normal production of blood cells (haematopoiesis).

GATA1 is an X-linked gene that encodes a DNA-binding protein needed for the growth and development of erythroid cells and immune cells (megakaryocytes, mast cells, eosinophils, and basophils).

The differentiation of the early progenitor cell (Multipotential hematopoietic stem cell) differentiates and divides into specialised blood cells and platelets.

TSR2 ribosomal maturation factor

The TSR2 gene encodes a protein that represses or stops the transcription of NF-kappaB (NF-κB), which is important for transcription, inflammation, cell cycle control, cell death (apoptosis), survival, and production of cytokine proteins involved in the immune system.

HEATR3 Gene – HEAT Repeat Containing 3

The gene encodes a protein that is involved in the transport of the 60S ribosomal protein subunit RPL5.

It helps in the production of ribosomes. Ribosomes are organelles that produce proteins.

It also helped to assemble the 5S ribonucleoprotein particle (5S RNP).

It is involved in the NOD2-mediated NF-kappaB signaling for inflammation.

It helps to mature red blood cells (erythrocytes).

ADA2 (Adenosine deaminase)

The ADA2 gene encodes a protein enzyme called adenosine deaminase 2.

This gene is needed for the growth and development of many immune cells involved in inflammation, where to increase or decrease.

For instance, macrophages promote inflammation.

ADA2 is an enzyme encoded by the gene Cat Eye Syndrome Chromosome Region 1 (CECR1) mapped to chromosome 22q11.1. It is produced by early progenitor blood cells (myeloid). It is adapted to low pH or high temperature. It can also function during low levels of oxygen (hypoxia), oncogenesis, and inflammation, where the activity levels are higher. ADA2 promotes the proliferation of monocytes (a type of immune cell), and this in turn, increases the differentiation of macrophages, especially M2 anti-inflammatory macrophages. Low levels of ADA2 cause less production of M2. In another type of immune cell, such as neutrophils, ADA2 promotes inflammation by increasing the expression of myeloperoxidase and activating cytokine proteins. Low levels of ADA2 can increase the expression of neutrophil-expressed genes and cytokine proteins that promote an inflammatory response. ADA2 can also indirectly function as a growth factor in endothelial cells (Caorsi *et al*., 2016).

What are the pathogenic variants affected by Diamond-Blackfan anaemia?

There are three forms:

Autosomal recessive
Autosomal dominant
X-linked

A closer depth

Autosomal recessive DBA

Example: HEATR

There is a biallelic pathogenic variant.

There is a 25% chance that each sibling of an affected patient is at risk of being affected. 50% a carrier without symptoms, and 25% are neither carriers nor affected.

Hemizygous – a gene on a single copy that is normally an X-linked gene in males. Males have an XY chromosome. X from the mother and Y from the father.

Genetic testing can be done to identify any at-risk relatives for the HEATR3 gene.

Autosomal dominant DBA

It represents 40 to 45% of cases of all DBA syndromes.

55 to 60% of the autosomal dominant DBA cases are de novo.

De novo refers to having the condition for the first time in a family member.

X-linked DBA

Example: GATA1 or TSR2 gene.

For example:

The mother has a GATA1 or TSR2 mutation.

There is a 50% chance the offspring will have it.

Males have an XY chromosome.

Females have an XX chromosome.

The condition is on an X chromosome.

Therefore, females could have the condition or could be a carrier (heterozygote).

Males who have the mother’s X chromosome will have the condition because men carry only one X chromosome.

The affected male can transmit the mutation to their daughters but not to his sons.

The make-up of the chromosomes for females and males

Signs and symptoms of DBA syndrome

Symptoms arise from birth.
Congenital malformations in up to 50% of affected individuals.

(Genetic and Rare Diseases Information Center, 2026; Cheng et al., 2019; Crispino and Horwitz, 2017‌‌; MedlinePlus, 2018; Gene Cards, 2026a; Gene Cards,2026b; Sieff, 2025)

An illustration presenting the difference in size of microcytic and macrocytic anaemia.

The muscles that affect the movement of thumb “pollicis” Adductor (moving towards the small finger – index). Abductor (moving away from the index finger/extensor).
**Abductor pollicis brevis:** “brevis” means short or limited. The origin of abductor pollicis brevis is situated at the flexor retinaculum and the tubercles of the scaphoid and trapezium (carpals). The retinaculum is a band of dense fibrous connective tissue containing collagen and it provides tensile strength for the tendons and nerves as they cross the joints to ensure smooth efficient movement whilst withstanding pressure. This prevents displacement.
The insertion of the abductor pollicis brevis is the lateral side of the base and proximal phalange of the thumb. It abducts (moves away) the thumbs and helps opposes it.
The flexor pollicis brevis has the same origin and insertion of abductor pollicus brevis but has an opposing action of flexing the thumb. Flexor movement is bending towards.
**Adductor pollicis:** Oblique head: bases of 2nd and 3rd metacarpals, capitate, adjacent carpals. tranvese head. Anterior surface body and 3rd metacarpals. Insertion is the medial side of the base of the proximal phalange of the thumb. Thumb is Adducted (brings towards) thumb toward the middle digit.
**Opponens pollicis**: The origin is the Flexor retinaculum and tubercles of scaphoid and trapezium. Insertion involves the lateral side of the 1st metacarpal. The action involves draws the first metacarpal bone laterally to oppose thumb towards the center of palm and rotates medially.

The retinaculum of the hand and how it supports the nerves, ligaments and tendons

The retinaculum of the hand and how it supports the nerves, muscles and tendons

Differences between the Septal defect of the atrium (top chambers of the heart) and the ventricles (bottom chambers of the heart) affecting the cardiac cycle.

An alternative presentation of the ventricular septal defect.

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Updated July 2026 Next Review July 2028