Introduction

Most of us think of sunlight as something healthy and life-giving, but for people with De Sanctis-Cacchione syndrome, it can be harmful and dangerous. This rare and severe genetic condition doesn’t just affect the skin and eyes - it also impacts growth, movement, and brain function. Such effects make De Sanctis-Cacchione syndrome one of the most severe forms of xeroderma pigmentosum (XP).

Like many rare disorders, people may spend years visiting different doctors before receiving answers about what is causing their symptoms. The underlying cause of this condition is all to do with the way that the body repairs damage to the DNA caused by sunlight. In De Sanctis-Cacchione syndrome, the nucleotide excision repair (NER) pathway that repairs this damage does not work properly, so DNA damage builds up and causes symptoms throughout the body. 

Currently, there is no cure, and treatment focuses on strict protection from sunlight to reduce complications. In this article, we’ll explore what the syndrome is, what it has to do with the nucleotide excision repair (NER) pathway, and how it affects those living with it.

What is de sanctis-cacchione syndrome?

De Sanctis-Cacchione syndrome is a rare disorder, and it often takes several years to get diagnosed. 

The condition is caused by problems in the body’s DNA repair system. Normally, our cells use the nucleotide excision repair (NER) pathway to fix DNA damage from sunlight. This system acts like a repair crew, spotting and removing damaged sections before replacing them. In De Sanctis-Cacchione syndrome, this pathway does not function properly, resulting in DNA damage buildup and negative effects throughout the body.

De Sanctis-Cacchione syndrome is inherited in an autosomal recessive pattern, meaning a person must receive two faulty copies of the gene, one from each parent, to develop the syndrome. 

The syndrome is closely related to xeroderma pigmentosum (XP) and shares key symptoms such as:¹

• Extreme sensitivity to sunlight
• Changes in skin colour
• Increased risk of eye problems
• Increased chance of skin cancers

Unlike XP, De Sanctis-Cacchione syndrome also affects the nervous system and development, leading to features such as:¹

• Smaller head size
• Learning difficulties
• Poor coordination
• Weak reflexes
• Shorter height
• Underdeveloped sexual organs

Characteristics

• Extra sensitive to light
• Skin discolouration
• Increased chance of eye disorders
• Increased chance of skin cancers
• Mental retardation
• Lower than average intelligence
• Small-sized head
• Weakened reflexes
• Less movement coordination
• Short height
• Underdeveloped ovaries or testes

The first description of the disorder was by scientists De Sanctis and Cacchione in 1932, where they described patients with the characteristics above as having ‘xerodermic idiocy’.²  

How is it inherited?

The syndrome is passed from parents to their child via an autosomal recessive pattern. To break that down, this means that the genetic change, which results in a faulty gene, occurs in one of the 22 non-sex chromosomes.  For a person to develop De Santis-Cacchione syndrome, they must inherit the altered, faulty copy from both of their parents. 

Interestingly, in about 30% of cases of De Sanctis-Cacchione syndrome, the parents of the affected individual are related by blood to each other, which is called being consanguineous. This close relation increases the chances that both parents are carrying the same altered gene, hence the child inherits both and displays the symptoms of the syndrome.

What is the nucleotide excision repair pathway?

Nucleotide excision repair (NER) is a process that is carried out in all types of cells to mend any damage to DNA. DNA might be damaged by a variety of things, one of those being UV light. You might be familiar with the twisty shape of DNA; this is known as the helical structure. When DNA is damaged, this helical structure is changed slightly  - we say it is distorted. There are a few different ways that damaged DNA can be repaired, but we are just going to focus on NER.

In order to understand the NER pathway, you first need a little knowledge of a special group of proteins called enzymes. The main job of enzymes is to speed up all the processes that happen in our bodies. For example, you might have heard of digestive enzymes, which help to break down the food we eat. Enzymes are involved in most bodily processes, one of which is the NER pathway.

The NER pathway involves special proteins which scan the DNA to check for damage, as well as enzymes which unwind the twisted helical shape of the DNA just around that damaged area. This allows other enzymes to access the region to cut the strand of DNA on either side of the damaged portion, meaning a little section is removed. The section that has been removed is called an oligonucleotide. The removal of this oligonucleotide leaves a gap in the DNA which needs to be filled in. An enzyme called DNA polymerase is in charge of filling in this gap.³ Essentially, the NER pathway is a 24/7 maintenance crew, working to scan for damage and repair it, keeping our cells healthy.

This is a process which is happening in almost all of our cells all the time! It has been estimated that our DNA is subject to tens of thousands of little bits of damage each day, so our repair systems, like the NER, are incredibly important.

NER in de sanctis-cacchione syndrome

In De Sanctis-Cacchione patients, the NER pathway is dysfunctional; thus, repairs to DNA cannot be made. This is why these individuals are sensitive to UV light. UV light causes damage to the DNA, and the NER pathway is the only way to fix that. If the NER pathway is not working as it should, then the damaged DNA will cause issues throughout the body.^{4, 5}

UV rays can cause damage to our DNA in several ways. For example, they can make two bases (the building blocks of DNA) stick together, creating a bulky bump in the DNA. This makes it tricky for the machinery that reads DNA to do its job properly. UV light can also break one of the DNA strands or cause oxidative damage to the DNA, similar to how metals rust over time.⁶ 

A dysfunctional NER pathway isn’t unique to  De Sanctis-Cacchione syndrome. It also causes other rare disorders, such asCockayne syndrome and trichothiodystrophy. Xeroderma pigmentosum is also caused by a defective NER, and as we discussed earlier, the characteristics are similar. 

There are at least 13 different genes involved in the NER pathway. Mutations in any of these genes can stop the repair system from functioning correctly, leading to the various disorders linked to defective DNA repair in the body.⁷ Clinical presentation of De Sanctis-Cacchione syndrome 

As mentioned earlier, De Sanctis-Cacchione syndrome manifests in several ways, including changes to the skin and eyes. Characteristics involving the skin are known as cutaneous, while those to do with the eyes are termed ocular. It is worth noting that patients are categorised into groups called ‘complementation groups’ depending on which of their genes is mutated. The clinical features may vary between these different complementation groups. 

Cutaneous (skin) clinical presentations are often the most notable and commonly include:

• Increased sensitivity to light
• Potential skin lesions in areas exposed to sunlight 
• Increased risk of skin cancers 
• Sunburn upon minimal sun exposure 
• Generally dry skin 
• Hyperpigmentation freckle freckle-looking skin (called numerous lentigines by medical professionals)⁸ 

Many of these cutaneous presentations occur early in childhood. In fact, it is common for patients to develop sensitivity to sunlight by the age of 2, and develop skin cancer for the first time by the age of 10.⁹

In terms of ocular clinical presentation, those with De Sanctis-Cacchione are likely to experience:

• Redness in the whites of the eyes (conjunctival injection) due to:
  • Widening blood vessels
• Reduction in tears due to:⁸
  • Damage to the tear glands from UV exposure and subsequent inflammation
  • Neurological changes that interfere with the normal tear reflex

Managing clinical features 

Managing any abnormal growths on the skin, like tumours or cancers, can involve many different kinds of medical intervention, such as:

• Burning the growth off with an electric current (electrodissection) 
• Scrapping off ( curettage) 
• Cutting off the growth alongside some surrounding healthy tissue to ensure its removal (surgical excision) 
• Removing the growth a thin layer at a time and checking consistently for abnormal cells under the microscope to remove the smallest amount of normal skin possible (Mohs micrographic surgery)⁹ 

What treatments are available?

Protection from sunlight is key for people with De Sanctis-Cacchione syndrome. The use of suncream, sunglasses and layers of clothing can help facilitate this protection. Otherwise, it is advised that they avoid spending too much time outdoors during daylight hours to decrease how much UV light they are exposed to. 

Unfortunately, due to the syndrome being so rare, there aren’t many treatment options. This is a result of limited funding, and therefore, research for rarer conditions.¹⁰ 

Summary 

De Sanctis-Cacchione syndrome is one of the rarest conditions linked to defects in the nucleotide excision repair (NER) pathway. This condition makes sunlight, a source of life for most, harmful and dangerous for those affected. As the body cannot properly repair DNA damage caused by ultraviolet light, symptoms extend far beyond the skin and eyes to include neurological, developmental, and physical changes. The condition is inherited in an autosomal recessive manner, often leading to delayed diagnosis and complex medical needs. With no cure currently available, management focuses on rigorous protection from sunlight and treatment of complications such as skin cancers or neurological decline. Although research into this syndrome is limited due to its rarity, understanding how it relates to DNA repair highlights the vital role these pathways play in maintaining our health. By raising awareness, we can help improve recognition, care, and support for individuals living with this challenging disorder.