Xeroderma Pigmentosa Presentation 7/21

A 25-year-old female came with increasingly pigmented spots on her face, arms, hands and feet from 2 years of age. She had taken multiple medications and was advised to avoid sunlight and wear full protective clothing. Despite these measures, her symptoms kept getting worse. She also frequently suffered from dry, red eyes and photophobia. On examination, she had gross signs of actinic damage on exposed parts of the body along with conjunctival pigmentation and corneal opacity. The lips had numerous lentigines and ephelides with no involvement of tongue and oral mucosa. There was suspected consanguinity in her family, although no such manifestations were reported before.

Gautam Srivastava , Govind Srivastava, Xeroderma Pigmentosum, Oxford Medical Case Reports, Volume 2021, Issue 11-12, November-December 2021, omab107, https://doi.org/10.1093/omcr/omab107

Xeroderma Pigmentosm

"parchment skin" -Moriz Kaposi 1874

Overview

• Disease presentation & epidemiology
• Cause
• Diagnostic Testing
• Treatment
• Outcomes

Disease presentation & epidemiology

• autosomal recessive inheritance, faulty NER
• 1/million in the United States (XPC)
• 2.3/million in Western Europe (XPC)
• 45/million in Japan (XPA and XPV)
• 2700/million in India
• XPA+XPC+XPV=75% worldwide cases

Lucero R, Horowitz D. Xeroderma Pigmentosum. [Updated 2022 Sep 22]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK551563/

• exaggerated sunburn reactions w/ minimum sun exposure
• erythema
• swelling
• blister
• erosion

• Keratitis: Chronic inflammation of the cornea

• progressive neuro-degeneration with hearing loss (XPA)

Nishigori, C., Nakano, E., Masaki, T., Ono, R., Takeuchi, S., Tsujimoto, M. and Ueda, T. (2019), Characteristics of Xeroderma Pigmentosum in Japan: Lessons From Two Clinical Surveys and Measures for Patient Care. Photochem Photobiol, 95: 140-153. https://doi.org/10.1111/php.13052

When daylight kills: India's XP children". The Telegraph. 2019-06-26. ISSN 0307-1235. Retrieved 2020-07-05.ishigori

Cause

A Frequent Outcome of UV Radiation Is The Formation of Pyrimidine Dimers

• By far the most likely outcome of UV damage to the DNA is the production of pyrimidine dimers
• UV light can induce adjacent pyrimidine nucleotides (cytosine or thymine) to become covalently joined as a pyrimidine dimer
• This can cause a bulky distortion in the helix, making DNA replication problematic

Weinberg, R. A. (2014). The Biology of Cancer. W.W. Norton & Company.

How do we fix Dimers?

Nucleotide Excision Repair

1. two pathways: transcription-coupled repair (TCR) and global genome repair (GGR).
2. Both involve unwinding DNA helix and removing fragments of damaged DNA, followed by repair through DNA synthesis.
3. Xeroderma pigmentosum (XP) can be classified into seven XP subgroups (XPA to XPG) and XPV based on the specific gene affected.

DiGiovanna, J. J., & Kraemer, K. H. (2012). Shining a Light on Xeroderma Pigmentosum. Journal of Investigative Dermatology, 132(3), 785–796. https://doi.org/10.1038/jid.2011.426

Defective NER Results in Genomic Instability• If NER is inactivated by loss of NER-specific genes (e.g XP family members), the cell is forced to try to replicate over the bulky legions. • This is called bypass synthesis • Bypass synthesis is error prone!! • Cancer loves error prone!

Weinberg, R. A. (2014). The Biology of Cancer. W.W. Norton & Company.

Diagnostic Testing

Unscheduled DNA SynthesisTechniques

Amniocentesis or chorionic vilus sampling (for prenatal diagnosis)

Complementation Analysis (for subtype)

Next Generation Sequencing

TY - JOUR AU - Lehmann, Alan AU - Mcgibbon, David AU - Stefanini, Miria PY - 2011/11/01 SP - 70 T1 - Xeroderma pigmentosum VL - 6 DO - 10.1186/1750-1172-6-70 JO - Orphanet journal of rare diseases ER -

Treatment

No Cure

Prevention is key

1. Sun protection and avoidance
2. UV protecting glasses and lubricating eye drops
3. Systemic retinoids
4. Topical fluorouracil or imiquimod
5. Vitamin D supplementation (why?)

Lambert, W. C., & Lambert, M. W. (2015). Development of Effective Skin Cancer Treatment and Prevention in Xeroderma Pigmentosum. Photochemistry and Photobiology, 91(2), 475–483. https://doi.org/10.1111/php.12385

Treatment of skin lesions and skin cancer - Surgical excision - Cryotherapy - Photodynamic therapy - Topical fluorouracil and imiquimod

Segura, S., Puig, S., Carrera, C., Lecha, M., Borges, V., & Malvehy, J. (2010). Non-invasive management of non-melanoma skin cancer in patients with cancer predisposition genodermatosis: a role for confocal microscopy and photodynamic therapy. Journal of the European Academy of Dermatology and Venereology, 25(7), 819–827. https://doi.org/10.1111/j.1468-3083.2010.03871.x

Outcomes

• 10,000x more likely to develop nonmelanoma skin cancer (median age 9 y/o)
• 2,000x more likely to develop malignant melanoma (median age 22 y/o)
• Also more likely to develop other cancers
• Average life expectancy ~37 yrs

Bradford PT, Goldstein AM, Tamura D, Khan SG, Ueda T, Boyle J, Oh KS, Imoto K, Inui H, Moriwaki S, Emmert S, Pike KM, Raziuddin A, Plona TM, DiGiovanna JJ, Tucker MA, Kraemer KH. Cancer and neurologic degeneration in xeroderma pigmentosum: long term follow-up characterises the role of DNA repair. J Med Genet. 2011 Mar;48(3):168-76. doi: 10.1136/jmg.2010.083022. Epub 2010 Nov 19. PMID: 21097776; PMCID: PMC3235003.

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REVIEW QUESTIONS!

A 2-year-old boy is brought in by his mother to the physician because she is concerned by how easily he gets sunburned. She states that he cannot be outside for barely five minutes without getting a painful, blistering sunburn. Physical examination shows a well-developed child with dry skin, many freckles, multiple actinic keratoses on the dorsum of his hands, and bloodshot eyes. Neither of the child's parents has ever had similar symptoms. This child’s condition is most likely caused by a defect in which of the following cellular processes? A. Base excision repair. B. Homologous recombination. C. Mismatch repair. D. Non-homologous end joining. E. Nucleotide excision repair.

Kaplan USMLE Step 1: Young boy gets blistering sunburn. (2023, January 9). American Medical Association. https://www.ama-assn.org/medical-students/usmle-step-1-2/kaplan-usmle-step-1-young-boy-gets-blistering-sunburn

REVIEW QUESTIONS!

A 4-year-old girl presents with severe sunburn and blistering after minimal sun exposure. Her mother reports a history of similar symptoms in her younger brother who passed away from skin cancer at a young age. Genetic testing reveals a homozygous mutation in the XP gene. Which of the following inheritance patterns is most consistent with this condition? A. Autosomal dominant B. Autosomal recessive C. X-linked recessive D. Mitochondrial E. Multifactorial