Introduction 

Fanconi anaemia (FA), named after the Swiss paediatrician Guido Fanconi who first described the condition in 1927, is a rare genetic disorder that can affect all of our body’s systems. However, it primarily impacts the bone marrow function that is characterised by reduced production of all the lines of blood cells leading to a wide range of haematological (blood-related) disorders with associated structural malformations and an increased risk of developing malignant (cancerous) conditions.¹ 

Understanding and early identification of the clinical manifestation of Fanconi anaemia is crucial for prompt management and intervention to achieve the best possible outcomes. 

Understanding fanconi anaemia (FA)

FA results from a genetic mutation in one of the at least 20 “FANC” genes in our body. It is transmitted from parents to their children and it is more prevalent among individuals with consanguineous parents. FANC gene mutation causes a defect in the DNA repair processes. Therefore, the body is rendered unable to fix any genetic damage in its cells, leading to cell death or dysregulated cell growth. Also, the DNA becomes more susceptible to damage by environmental factors like ultraviolet (UV) light and chemical toxins.  

This accumulation of genetic errors results in bone marrow failure. The production of all lineages of blood cells within the body is compromised, and the uncontrolled growth process leads to an increased likelihood of cancers like leukaemia.² ​  

Presentation 

FA is widely variable in its presentation because not every individual develops all the clinical features. It can be detected as early as during pregnancy checks and prenatal genetic tests especially if there is a family history of the disease. Some are discovered at birth when they manifest certain congenital abnormalities while the majority are diagnosed during infancy and early childhood.² ​

Haematological symptoms

Blood-related disorders are the most prominent feature in FA which typically present at the age of 7 years and primarily result from bone marrow dysfunction, leading to impaired production of the three types of blood cells, red blood cells (RBCs), white blood cells (WBCs) and platelets collectively known as “pancytopenia” and manifest as:  

Anaemia 

Anaemia results from the reduction of the count of red blood cells (RBCs) or haemoglobin level impairing the ability of the blood to deliver oxygen to various body tissues, leading to symptoms such as: 

• Pallor (skin paleness)  
• Tiredness and easy fatigability 
• Shortness of breath especially during physical activities or exerting effort 
• Cool hands and feet 

Leukopenia 

The term leukopenia describes the state of decreased white blood cells (WBCs). WBCs function as the policeman of the body, fighting against microbial invasion and protecting the body from infection; therefore, any impairment in their function leads to increased chances of developing any form of infection like pneumonia, urinary tract infections (UTIs) and even sepsis and they are usually hard to manage. 

Thrombocytopenia 

Thrombocytes or platelets are the cells responsible for blood clotting and wound healing, and in thrombocytopenia, a decrease in the platelets count causes symptoms of increased bleeding tendency, such as: 

• Easy bruising after trauma; however, the person may notice bruises without having any clear reason 
• Epistaxis (nosebleed)  
• Gingival (gum) bleeding during toothbrushing  
• Prolonged bleeding from wounds^3,4 ​

Skeletal manifestations  

Although skeletal features of FA are numerous, an affected individual might present only a few FA skeletal features or none at all. However, when these features are discovered, they are usually apparent from birth and can serve as a good indicator of the presence of the disease. Skeletal defects affect the:

• Thumb: The thumb may be absent, shorter than normal, duplicated or deformed 
• Forearm: The radius is one of the two long bones that make the forearm which may also be absent or short. Additionally, the other bone, the ulna, can also be affected 
• The lower limbs: Such as hip joint dislocation, toe duplication and club foot 
• Head and face: Abnormalities include small head, small jaw, short neck, low hairline and flat head 
• The back: Examples are vertebral anomalies and scoliosis  
• Stature: A child with FA tends to have short stature⁵ ​

Skin abnormalities 

Another common physical characteristic found in patients with FA is skin changes, with over 90% of individuals with FA displaying at least one feature. Examples are: 

• Café au lait spots: These are the most frequently seen skin related feature and appear as light brown skin patches of different sizes 
• Hyper and hypopigmentation: Describes areas of the skin that are darker or lighter than the normal body colour  
• Freckles⁶​    

Gastrointestinal symptoms  

Digestive system abnormalities are less common and affect only 5% of the patients, features include: 

• Imperforated anus: The child is unable to pass the stool
• Tracheoesophageal fistula: It is a condition where there is an abnormal connection between the trachea (windpipe) and the oesophagus (food pipe), leading to choking or coughing during feeding 
• Intestinal atresia: Complete blockage of part of the bowel  
• Megacolon: Abnormally enlarged colon 
• Umbilical hernia: Part of the bowel abnormally protrudes through the umbilicus 

These defects require surgical correction in most of the cases^2,5 ​

Eye and ear defects  

Eye and ear defects are another potential clinical characteristic of FA such as: 

• Epicanthic fold: It describes the presence of a fold of skin that covers the inner corner of the eye 
• Proptosis: Bulging eyes 
• Ptosis: Dropped upper eyelid  
• Cataracts 
• Absent eardrum 
• Ear pinna is smaller or larger than usual 
• Blockage of the ear canal: This can lead to hearing loss^2,5 ​ 

Urinary and reproductive system 

Urinary and genital abnormalities can also occur in patients with FA affecting: 

• Kidneys: The kidneys may be absent, small or have abnormal structure and location 
• Male genitalia: Symptoms might be small testes, small penis, undescended or absent testes and reduced sperm production, affecting the fertility 
• Female genitalia: Almost 50% of people assigned female at birth with FA are infertile, this can be due to structural defects of the ovaries and uterus. Additionally, FA also complicates pregnancy² ​ 

Heart problems  

Congenital heart defects are also seen in FA. These defects affect the structure and therefore the function of the heart and are typically present early, with symptoms such as shortness of breath, cyanosis, heart murmurs and fatigue.⁴ ​

Nervous system  

Developmental delay, intellectual disabilities and seizures can result from structural malformations of the central nervous system such as: 

• Pituitary gland malformations: Structural defects of the pituitary gland – responsible for hormonal regulation 
• Hydrocephalus: The accumulation of fluid within the brain leading to long-term complications
• Small cerebellum: The cerebellum is the structure that controls the balance and regulates the body's movement  

Endocrine manifestations 

Endocrine disorders typically present with features of hormonal dysregulation, these can include: 

• Growth hormone deficiency: It leads to short stature and increased weight 
• Thyroid hormone deficiency: Also known as hypothyroidism 
• Endocrine pancreatic insufficiency: It leads to hyperglycaemia and diabetes  

Cancer risk 

As stated previously, one of the most serious aspects of FA is the increased malignant risk which can sometimes be the first presenting feature of the disease  

• Leukaemia: A type of cancer affecting the white blood cells, with consequences on the blood and bone marrow function 
• Solid tumours: There is an increased susceptibility to most types of solid tumours. However, some are more frequent in FA, such as squamous cell carcinoma of the head and neck, urinary and genital tumours and liver cancer³ ​ 

FAQs 

What is the triad of Fanconi anaemia (FA)?  

There are 3 features which constitute the diagnosis of FA: blood and bone marrow abnormalities, physical malformations and increased risk of cancer. 

How is FA inherited? 

For most individuals with FA, the inheritance pattern is autosomal recessive: for a child to develop the condition, both parents need to pass on a copy of the mutated gene There are also other inheritance patterns of FA but are less frequent. 

How is FA diagnosed?  

If the diagnosis of FA is suspected, the doctor will generally perform blood and genetic testing as well as bone marrow biopsy. Further testing may be required depending on the presenting symptoms. 

What are the available treatment options for FA?  

FA is not yet a curable condition, therefore treatment only focuses on managing the symptoms and reducing complications like frequent blood transfusion, prompt infection treatment and bone marrow transplant. Furthermore, regular follow-up is an essential component of the management process of FA.  

Summary 

Fanconi anaemia is a rare genetic multisystem disorder resulting from a defect in the FANC gene and manifests predominately with physical malformations and an increased risk of cancer. 

FA presents with a wide range of symptoms like short stature, weakness, bruises and skin pigmentation. 

Early recognition and follow-up are important to prevent serious complications.