Xeroderma Pigmentosum with Cockayne Syndrome Complex

INTRODUCTION

Xeroderma pigmentosum- Cockayne syndrome complex (XP-CS) is a very rare genetic neurodegenerative disorder that combines clinical characteristics of xerodermapigmentosum (XP) with those of Cockayne syndrome (CS). CS is an autosomal recessive multi-system degenerative disorder. There characteristics include by photosensitivity, neurodegeneration, intellectual disability and joint contractures which may be severe enough to cause dislocations, hearing loss, and a range of other complications. Most of the severely affected patients dying are younger and the lifetime expectancy is reduced. In severe, moderate and mildly affected patients, the mean age of death has been approximated at^5,16, and 31 years, respectively.^1,2 CS is usually associated with mutations in the genes CSA/ERCC⁸ or CSB/ ERCC⁶ , which have a major role in DNA repair. Patients with CS do not develop cancer, despite of impairments to DNA repair.

XP is also autosomal recessive and, similar to CS, it impairs DNA repair. Lesions caused by UV light are an important type of damage that cannot be repaired efficiently or at all in both conditions.XP is associated with one of various genes like: XPA, XPB/ERCC³ , XPC, XPD/ERCC² , XPE/DDB² , XPF/ERCC⁴ , XPG/ERCC⁵ , and XPV/ POLH. Based on the gene mutation the patients are classified into complementation groups (XPA, etc.). Patients who have defects in nucleotide excision repair (NER) are grouped in XP-A to XP-G. Patients in XP-V have normal NER, but have a deficiency in the ability to allow DNA replication past unrepaired UV lesions.

In any complementation group, the XP patients who are not been protected from UV light from an early age can develop photo damage that can be severe (e.g., disfiguring solar lentigines and skin atrophy) as well as vision impairment that may include blindness. Damage is permanent. The risk of developing skin cancer in XP patients is very high.

Clinically, there are similarities between these conditions. They include progressive loss of cognitive and motor skills and hearing loss. Differences include hair and nail abnormalities in XP-TTD and progeria in XP-CS.All CS and XP-CS patients have the overall same medical problems,irrespective of disease severity. The primary difference between severitygroups relates to timing and severity. Thus, for example, microcephaly is nearly universal in CS, yet may vary from several standard deviations below the mean for age to roughly two standard deviations below it. In the same way, almost all patients with CS or XP-CS have short stature, but the most severely affected patients are the smallest, and the mildly affected ones are the largest.^3-5

CASE REPORT

An 8-year-old female patient was admitted with hyperpigmentation since the age of 6 months and swaying towards left side since the age of 2 years. On examination, it was found that the hyperpigmentation is insidious in nature, gradually progressive, associated with icterus. The child had a birthweight of 3kg and had a full term normal vaginal delivery. The baby cried immediately after birth. The patient has a younger brother with the same condition. Other symptoms associated are pallor, cyanosis, clubbing, icterus and lymphadenopathy. There was no history of convulsions, fever, trauma, focal deficit, abdominal distension. Head appears to be small in size and shape. Eyelids are normal. Hyperpigmentation is present over the nose and malar area of oral cavity. Ataxic gait is present. Romberg’s test is positive indicating loss of motor coordination. The patient was conscious with a Pulse rate of 88bpm and respiratory rate was 20cpm. ESR was found to be 26mm/hr. liver enzymes was slightly elevated with SGOT of 48.0 U/L and SGPT of 53.4 U/L.

The clinical file reported history of ataxia, developmental delay and pigmented patches in the malar region with brisk reflexes. The patient has a severe hearing loss in the right ear. The MRI of brain revealed abnormal symmetrical T2 hyperintensities seen involving anterior temporal lobe white matter, U fibers along the bilateral frontal white matter, peri trigonal white matter and corona radiate. MRS reveals decreased NAA/ Cr ratio: 1.4 ( normal 2.34+/- 0.37). The child is not able to write. The language was normal till 6yrs of age and started slurry speech from 2 years. Immunizations were given according to National Immunisation Schedule.

The results of patient’s various diagnostic test include:

Gait: Ataxic gait present

Tandem walking test: Abnormal

Kneel Heel Test: Abnormal

Visual Analogue Scale : pain score is 5

The treatment advised to the patient is mainly to avoid direct sun exposure. She was asked to take syrup A to Z, which is combination of minerals and vitamins. They enhance the immune functions and provides strong nerve support. Patient was also on syrup piracetam and Dewmoist cream. Syrup piracetam help increase brain function by promoting communication between the left and right hemispheres of the brain. It also boost cognitive function. Dewmoist cream is used as a moisturizer for dry and dull looking skin. It provides hydration to dry the skin and helps skin fight dryness and dullness. It protects the skin from harmful UV rays.

DISCUSSION

Xeroderma pigmentosum was first described by Moriz Kaposi, a Hungarian dermatologist in 1879, since then some 550 cases have been reported.² The disease has a marked hereditary tendency and is transmitted as an autosomal trait. It is frequent after consanguineous marriage and there is evidence that sex linked transmission also takes place.The disease becomes clinically overt within the first few years of life starting as erythema and development of freckles over the exposed areas of skin.^3,6 Small telangiectasis are common in the early stages. Finally there is the appearance of isolated or coalescent patches of keratosis showing varying amount of pigmentation.^7,8 This may be followed by development of warty growths which may finally ulcerate and convert into squamous or basal cell carcinoma.Hair and nails are usually normal, but they may be defective. The disease is invariably fatal and death occurs within a few years of its onset.Aetiologically it has been suggested that the essential abnormality is increased sensitivity to light, yet the nature of this photosensitivity has not beenunderstood.

It is suggested that DNA damaged by ultraviolet light is not repaired in the affected children. This observation has been made between 280 to 310 nm wavelengths.8 Metabolic defects have been suggested as an aetiological possibility. Gross aminoacidemia has been reported in 25%of cases. Tyrosine excretion has been found to be low in some cases; while in other cases an increase in serum glutamic acid transaminase and high alpha globulinemia have been reported. The central nervous system (CNS) is affected in a significant subset of XP patients The CNS doesnot have direct UV radiation exposure making the mechanism of disease unclear, but unrepaired oxidative damagehas been proposed as a possible cause. Neurodegeneration occurs in an estimated 24%, including loss ofintellectual functioning, deterioration of neurologic status, impaired hearing, abnormal speech, areflexia, ataxia, peripheral neuropathy, and loss of the ability to walk andtalk. These deficiencies correlate with neuronal loss, cortical atrophy and ventricular dilatation without inflammation as seen with imaging studies and pathologicexamination.² The suggested treatment is protection from light, and application of Titanium Oxide in a vanishing cream base to lessen the risk of further epitheliomata. Oral chloroquine has been found to be useful. All tumors should be adequately excised at the earliest opportunity.⁷

CONCLUSION

The following case signifies that affected individuals with xeroderma pigmentosum have dry skin with larger dark spots in which there is decreased ability to repair DNA damage caused by ultraviolet light. Therefore the patient must be aware of not getting exposed to sunlight.

ACKNOWLEDGEMENTS

We would like to thank the staffs of pharmacy practice and postgraduate students of department of paediatrics, SSIMS and RC hospital, Davangere for their guidance.

Conflicts of interest

The authors declare no conflicts of interests.

Abbreviations

CNS- Central nervous system

CS- Cockayne syndrome

NER- Nucleotide excision repair

TTD- Trichothiodystropy

XP- Xeroderma pigmentosum