Introduction 

De Sanctis-Cacchione Syndrome (DSCS) is a rare and severe form of xeroderma pigmentosum (XP), a genetic condition caused by defects in the molecular machinery which is responsible for DNA excision repair.¹ Patients with DSCS experience extreme sensitivity to sunlight, leading to frequent sunburns and an increased risk of skin cancers. DSCS also affects physical development, leading to shorter height, small head size, along with delays in neurological development and intellectual disability. Other neurological symptoms include tight muscles, movement problems, hearing loss, and weakness or pain in the hands or feet.¹ 

It is a genetic condition caused by inheriting autosomal recessive mutations, and some reported cases involve consanguineous marriages.¹ Genetic mutations affecting components of the DNA repair pathway can lead to the development of XP in DSCS. A variety of mutations have been identified in the genes encoding components of the DNA repair pathway in XP, and some of these have been observed in DSCS patients, causing problems with DNA repair in cells following exposure to carcinogens (cancer-causing agents)such as UV radiation. Thus, it is important to identify and characterise the genetics and molecular basis of DSCS for precise diagnosis and accurate treatment strategies. 

Key Points:

• DSCS is a severe form of XP which occurs due to mutations in the nucleic excision repair (NER) machinery
• A variety of different mutations in DSCS have been identified (XP A-G), and they are associated with different onset and clinical symptoms
• Mutations in the NER machinery lead to problems in repairing damaged DNA after exposure to ultraviolet (UV) radiation 
• Genetic and molecular testing is critical for the precise diagnosis and accurate treatment strategies of DSCS 

What is xeroderma pigmentosum? 

XP was first characterised by dryness and pigmentation changes of the skin, along with the early onset of skin cancer. Early research has reported that skin cells from individuals with XP show faulty DNA repair following exposure to UV radiation.² XP is a genetic condition caused by autosomal recessive mutations in genes that encode for proteins of the nucleic excision repair (NER) pathway that are involved in repairing DNA. These mutations lead to malfunctioning of the NER pathway, resulting in an inability to properly repair faulty DNA, which is critical for cellular function.¹

The clinical presentation of XP typically includes the appearance of pigmentation changes on the skin before the age of two, as exposure to sunlight increases. Patches with uneven pigmentation tend to appear on the face, neck and other parts of the body. Along with this, early ageing and increased wrinkling may occur. Skin cancers have also been reported to develop as early as age nine. Other symptoms can include light sensitivity, dry eyes, and changes to the shape of the eyes. In more severe cases, neurological symptoms may arise, such as delays in development, hearing loss, smaller head size (due to poor brain growth), muscle weakness and problems with balance and movement.² 

It has been reported that De Sanctis-Cacchione Syndrome (DSCS), which is an example of XP, has the most serious defects in DNA repair, leading to severe, potentially life-threatening symptoms.¹ The onset and severity of the disease are linked to the extent of damage to the cell’s ability to repair damaged DNA.¹ Importantly, it was reported that patients who have neurological symptoms alongside the usual dermatological symptoms have more severe defects in their DNA repair pathways. This means they have a reduced ability to repair damaged DNA following UV exposure, which increases symptom severity and causes problems with the nervous system as well.² 

DNA repair deficiency in DSCS

The NER pathway is involved in repairing DNA damage caused by agents such as UV radiation (found in sunlight) and chemicals in cigarette smoke.¹ When cells are unable to repair damaged DNA due to defects in the NER machinery, DNA mutations accumulate, leading to a higher risk of skin cancer, and increasing processes that trigger neuronal damage, such as increased levels of reactive oxygen species.¹ When a mutation is present in any component of the NER pathway, the whole DNA repair pathway is affected, preventing it from functioning properly.³ 

An earlier research study focused on a Palestinian family with three siblings affected by DSCS and investigated the ability of skin cells taken from these patients to repair UV-induced DNA damage.⁴ Their results revealed that these patients had almost no DNA repair activity in their skin cells. Previous studies had found that some DSCS patients retained limited DNA repair activity, highlighting that the DNA repair activity of skin cells is not always identical at the molecular level across different DSCS patients. Also, it was reported that DSCS differs from classic XP at both the molecular and genetic levels, highlighting the presence of different mutations in DSCS.⁴ 

The genetic basis of XP in DSCS

The NER pathway is responsible for removing DNA damage. This usually includes removing the pyrimidine dimers that form upon exposure to UV radiation.² When this damage is not repaired, it contributes to the development of XP. To date, eight different mutations in the NER machinery have been identified as responsible for the incidence of XP. These mutations are characterised as XP-A through X-PG, and they affect different components of the NER machinery.² 

Below is a summary of these mutations: 

• XPA: affects DNA damage binding protein 1, which is responsible for sensing damaged DNA and facilitating DNA unwinding and resulting in both skin problems and neurological symptoms
• XPB: affects the excision-repair cross-complementing 3 component of a protein complex
• XPC: affects an endonuclease, which is responsible for sensing DNA damage and results in skin problems, but not neurological symptoms 
• XPD: affects the excision-repair cross-complementing 2 component of a protein complex
• XPE: affects a DNA damage binding protein 2
• XPF: affects the excision-repair cross-complementing 4 component of a protein complex 
• XPG: affects the excision-repair cross-complementing 5 component of a protein complex² 

As an example, a case report has been filed against a mutation in the XPC gene causing DSCS in a 12-year-old male.³ It was reported that he had approximately 15 skin cancers by age twelve and exhibited neurological symptoms. The mutation was identified as a homozygous c.547A>T mutation in the XPC gene, which led to the production of a non-functional XPC protein. This has been the first reported case of DSCS linked to the XPC mutation. This boy was the child of first-cousin parents, highlighting the role of consanguinity in increasing the risk of inheriting rare recessive genetic conditions. DSCS represents the severe end of the XP spectrum, with the onset of disease in infancy, fast progression, neurological decline and high cancer risk.³ 

Another case has reported a 55-year-old woman with learning difficulties, progressive loss of coordination and neurological decline.⁵ She was diagnosed with DSCS due to having the severe neurological form of XP. This case demonstrates that DSCS can also be present in adulthood with neurological degeneration and movement disorders, highlighting the importance of genetic counselling and how different genotypes can relate to varied clinical onset and symptoms.⁵ 

Another similar disorder, Cockayne syndrome (CS), also results in an increased sensitivity to UV radiation due to defects in DNA repair; however, the clinical symptoms and underlying genetics are believed to be different.⁶ Notably, a study of two siblings diagnosed with DSCS reported that their cells behaved similarly to CS cells.⁶ The mutation was in the gene encoding the CSB protein, and the same mutation was also identified in another patient having CS. Therefore, the same CSB mutation led to the development of CS in one patient but DSCS in the three siblings. This means that clinical symptoms cannot be strictly associated with one type of mutation, and that there is no simple link between disease severity and mutation.⁶ 

This highlights the complex genotype-phenotype relationships and shows that other factors, such as the inheritance of different mutations in other genes or environmental factors, can affect disease severity, clinical symptoms, and cancer risk. Overall, this underlines the importance of genetic and molecular testing in patients, besides clinical evaluation.⁶ 

Summary

De Sanctis-Cacchione Syndrome is a severe form of xeroderma pigmentosum, caused by mutations in components of the DNA repair machinery, leading to defects in repairing damaged DNA upon exposure to ultraviolet (UV) radiation. Clinical symptoms include increased skin sensitivity, areas of hyperpigmentation and hypopigmentation, increased risk of skin cancers, and neurological symptoms in more severe cases associated with De Sanctis-Cacchione Syndrome. Different mutations have been identified and it is essential to understand the genotype-phenotype correlations to properly diagnose and treat this potentially life-threatening disorder.