Xeroderma Pigmentosum Latest Facts: Causes, Symptoms, Diagnosis and Treatments

What is Xeroderma Pigmentosum?

Xeroderma Pigmentosum, also known as DeSanctis-Cacchione syndrome, is a rare autosomal recessive genetic condition affecting the ability of the cells to repair DNA damage caused by UV radiation. It was first described by a Hungarian doctor, Moritz Kaposi. It can be caused by 9 mutations, all affecting the nucleotide excision repair mechanism of the skin cells. Normally, this mechanism repairs DNA damage due to exposure to UVR but in XP, this damage cannot be repaired. This leads to the accumulation of mutated cells that have the potential to become cancerous.

Xeroderma Pigmentosum. Image Courtesy of James Halpern, Bryan Hopping, and Joshua M Brostoff

Affected individuals are referred to as, ‘children of the night’ or ‘moon children’. XP affects men and women equally. However, it does have a geographical preference for India and Japan. It affects every 1 in 370 people in India, 1 in 20,000 people in Japan, and 1 in 100,000 people worldwide.

Causes of xeroderma pigmentosum

Xeroderma Pigmentosum is caused by mutations that reduce the performance of the Nucleotide Excision Repair (NER) mechanism. Due to this, the damage caused by UV rays is not corrected in XP. This further leads to DNA and p53 mutations, the development of pigmented spots, and even cancers. These mutations can be in 9 different genes, leading to 7 different types and one variant of XP, which are as follows:

Mutation in the gene encoding for XPA protein, which normally is responsible for the proper excision of mutated sequences during NER. However, when mutated it causes the classical form of XP, Xeroderma Pigmentosum Group A, Type A
Mutation in the gene encoding for XPB protein, which usually unwinds DNA once damaged and helps in NER. But when mutated, it helps in the development of either XP Type B or XP with Cockayne Syndrome.
Mutation in the gene encoding for XPC protein, which forms the initial damage recognition factor with RAD23B protein. When mutated, it causes XP type C.
Mutation in the gene encoding for XPD and ERCC 6 both of which help in the unwinding of DNA, can lead to many syndromes. XP Type D, trichothiodystrophy, XPD and Cockayne Syndrome combination, and De Sanctis-Cacchione syndrome which is considered as a subtype of XPD are a few of the syndromes these mutations can cause.
Mutation of DDB2 protein encoded by DDB2 gene causes XP Type E
Mutation of ERCC2 protein, which is designated as XP endonuclease F, can cause XP type F
Mutations in RAD2 and ERCC5 (encodes for XPG protein) genes are responsible for the development of XP Type G and COFS syndrome Type III, XP, and infantile lethal Cerebro-oculo-facio-skeletal syndrome combination, or XPG by itself.
Mutation in the POLH gene, which encodes the DNA Polymerase eta protein can cause a variant of XP, called XPV

Clinical Presentation

Patients with Xeroderma Pigmentosum are extremely sensitive to sunlight and UVR. Any source of UV, including halogen bulbs, can cause symptoms in these patients. Symptoms usually appear in the eyes, skin, and nervous system. Signs and symptoms of the disease are as follows:

A. Nervous system Symptoms: Patients may show severe brain atrophy, dilation of brain ventricles, and nerve loss resulting in:

Sensorineural hearing loss
Intellectual disability
Seizures
Poor Coordination

B. Ocular Symptoms:

Photophobia
Corneal ulceration
Clouded, bloodshot, or irritated eyes, with minimal sun exposure
Painful eye irritation with minimal sun exposure
Conjunctival inflammation with sun exposure

C. Skin or Cutaneous Symptoms:

Dryness of skin (parchment-like skin)
Blistering and severe sunburn, even with minimal sun exposure
Freckling at a young age, with minimal sun exposure
Scaly skin, with decreased body hair.
Telangiectasias, or spider veins
Dark, irregular spots and actinic keratoses

The onset of symptoms is around six months of age, with most children showing photophobia, sun-induced conjunctival inflammation, and cutaneous symptoms after exposure to sun or UVR.

Diagnosis of Xeroderma Pigmentosum

Like any other genetic disease, genetic counseling and family psychological support are needed for diagnosis. Diagnosis of XP, however, is clinical initially and then confirmed with genetic testing. Although family history is very beneficial for the diagnosis of genetic disorders, XP might not show a positive family history. Hence, clinical symptoms are used. Molecular testing for mutated genes above can confirm the diagnosis made.

Treatment of Xeroderma Pigmentosum

Unfortunately, there is no cure for Xeroderma Pigmentosum. To prevent symptoms, the best choice is the avoidance of the sun completely. This is the reason for the popularity of XP in pop culture and fiction, and also why patients are called ‘children of the night’. Protection from the sun can be done by using a broad-spectrum sunscreen, covering up as to not expose any part of the body to the sun, and sunglasses. It is also important to protect these patients from UVR, which may be emanating from the halogen bulbs or light sources.

Cryotherapy or Fluorouracil can be used to treat actinic keratosis that may develop in the patients. Retinoid creams and Vitamin D can also be used for the treatment of XP. Routine eye, skin, and neurological exams should be done by dermatologists, ophthalmologists, and neurologists to check for the progression of the disease. It is very important for these exams to be carried out, so as to reduce or diagnose the complication early on.

Complications of Xeroderma Pigmentosum

XP can cause skin cancer, cataracts, and brain cancers. Most patients with XP die due to the progression of cancers, especially if XP or its complications are not diagnosed early on in the progression of the disease.

Prognosis of XP

Patients with XP have an average life expectancy of 37 years, or 29 if neurological symptoms develop. Studies report an average life expectancy of 40 years in 70 % of people diagnosed with Xeroderma Pigmentosum. However, if proper precautions are taken by the patients from the moment of diagnosis, life expectancy can be near normal in some cases.

My Opinion:

XP is a rare disease, and it is often not diagnosed at birth or is misdiagnosed due to its rarity and variation in its types. It is very important for all patients once diagnosed to follow all necessary precautions even though they may be tedious and extremely difficult to follow on a regular basis. Even the UV rays through the window curtains can cause harm, indicating that extreme precautions need to be taken. Also, routine examinations may be life-saving for these patients and should not be skipped.