Incidence Of Xeroderma Pigmentosum In Larkana, Pakistan ...

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High prevalence and incidence of xeroderma
pigmentosum in Larkana, Pakistan”.
Conference Paper · October 2015
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Shaheed Muhtarma Benazir Bhutto Medical University Larkana
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CASE REPORT DOI 10.1111/J .1365-2133.2004.06311.X
Incidence of xeroderma pigmentosum in Larkana, Pakistan:
a 7-year study
A.M. Bhutto, A. Shaikh* and S. Nonaka
Departments of Dermatology and *Internal Medicine Unit-II, Chandka Medical College Larkana, Pakistan
Department of Dermatology, University of the Ryukyus, Okinawa, Japan
Correspondence
Dr Abdul Manan Bhutto, Doctors’ Colony,
Bunglow no. 14, VIP Road, Larkana (Sindh),
Pakistan.
E-mail: bhutto_manan@hotmail.com
Accepted for publication
16 May 2004
Key words:
clinical observations, Larkana, Pakistan, xeroderma
pigmentosum
Conflicts of interest:
None declared
Summary
Xeroderma pigmentosum (XP) is a rare autosomal recessive inherited disorder
caused by a defect in the normal repair of DNA of various cutaneous cell types
damaged by exposure to ultraviolet radiation. We present our 7-year experience
with 36 XP patients who either visited the Department of Dermatology or were
seen in the medical camps arranged in remote areas for patients’ welfare, from
1995 to 2001. For ease of discussion we classified all cases into the following
subgroups on clinical grounds only: mild, those with light brown freckles on the
face alone; moderate, those with dark brown freckles with burning on the face,
neck, ears, chest, hands and photophobia but without other associated obvious
cutaneous and ocular changes; severe, those with extensive dark brown freckles
with burning on the exposed parts as well as on the unexposed parts of the
body, i.e. the chest, back, abdomen and arms including other associated cutaneous and ocular changes such as ulcers and malignancy. Of 36 patients, three
(8Æ3%) were classified as mild, nine (25%) moderate and 24 (66Æ7%) severe;
there were 18 males and 18 females, age range 2–30 years (mean 8Æ9 years).
Seventeen patients had cutaneous changes: actinic keratosis, keratoacanthoma, fissures and ulcerative nodules on the exposed parts of the body. Four patients had
wide ulcers, along with mass formation and severe pigmentation on the face,
neck and head. Twenty-nine patients developed ocular symptoms: photophobia,
conjunctivitis, corneal keratitis and lid ulcer. One patient had complete loss of
vision. Histopathological findings revealed that six patients had squamous cell
carcinoma (SCC) on the face, head, ear or lip. More than one sibling (two to
four) was affected in four families. The majority of cases (20 ⁄36, 55Æ6%) were
from the Brohi tribe (skin type III), while the remaining cases (16 ⁄36, 44Æ4%)
were from the Sindhi population (skin type IV). The large number of XP patients
seen in those with skin type III (Brohi tribe) compared with skin type IV (Sindhi
population) indicates that the skin type and the race has a considerable value in
the pathogenesis of XP. Furthermore, 24 of 36 patients were in the severe group
and six of these had SCC. Moreover, no neurological abnormalities were observed
in our patients. All patients were treated according to disease severity by prescribing oral antibiotics, local steroids, sunscreens and ⁄or chemotherapy followed by
irradiation in malignant cases. Two patients died because of extensive SCC.
Xeroderma pigmentosum (XP) is a rare autosomal recessive
disease caused by defective DNA repair of various cutaneous
and ocular cell types followed by exposure to sunlight. Hebra
and Kaposi reported the disease initially in 1874.1 It affects
mostly children and is characterized by cutaneous and ocular
pigmentary changes such as freckles, photophobia, conjunctivitis, corneal keratitis and ulcers. If the disease is not controlled at this level, there is a risk of developing malignancy
in the future and most patients die because of malignancy.
Many enzymatic defects are also observed in these patients,2
and some patients also demonstrate neurological abnormalities. XP is classified into eight genetic complementation subgroups from XP-A to XP-G and a variant group XP-V.3 Each
group has different gene alterations. Seven (XP-A to XP-G) are
involved in nucleotide excision repair, and one, the variant
XP-V, is involved in replication of damaged DNA on the
 2005 British Association of Dermatologists • British Journal of Dermatology 2005 152, pp545–551 545
leading strand.4 Its incidence seems to be different from one
region to another. The frequency of this disease in the general
population in the U.S.A. is 1 : 250 000;5 however, it is much
higher in Japan and other countries (1 : 40 000).6,7 Frequent
reports have come from other regions or countries including
Europe,8 Egypt,9 Germany,10 Israel,11 Korea12,13 and China14
that showed a considerable number of XP patients in those
countries. XP is also reported from our neighbouring state,
India, showing both ocular and cutaneous symptoms in their
patients.15 Although this disease is reported from various parts
of the world in all races including whites, blacks and Asians,
detailed studies are still required from the rest of the world.
Here, we present our 7-year experience with XP patients residing in this tropical region. To our knowledge, this is the first
report from Pakistan that provides clinical data on XP patients
from Sindh province that will help to understand the incidence
of the disease in this region, which has hot humid weather with
abundant sunlight for 8 of 12 months during the year.
Materials and methods
A total of 36 cases were seen in either our Department of Dermatology, Chandka Medical College (CMC) Hospital, Larkana
Sindh Province, Pakistan or in the medical camps arranged for
patient welfare purposes in remote areas, from 1995 to 2001.
This institute has been providing medical facilities to
~ 3Æ5 million people. All cases were diagnosed on the basis of
clinical grounds. Fourteen biopsy samples were taken, from
the sites of keratoacanthoma and from those sites suspected of
malignancy. Chemotherapy was given to prevent metastasis
before and after the biopsy. The biopsy material was fixed in
10% formalin for haematoxylin and eosin staining.
Case reports
The details of all the XP patients are summarized in Table 1.
The age distribution of the patients ranged from 2 to 30 years
Table 1 Clinical characteristics of 36 patients with xeroderma pigmentosum (XP) in Larkana, Pakistan
Case
Age
(years) ⁄
sex
Date of
first visit
Cutaneous changes Ocular changes
Burning
of skin Freckles
Actinic
keratosis Malignancy Others Photophobia Conjunctivitis
Corneal
keratisis Others
Neural
changes
Others
in family
1 8 ⁄M 12.8.95 + + (mi) – – – – – – – – –
2 5 ⁄F 3.995 + + (mo) – – – + + – – – –
3 2 ⁄F 28.9.95 + + (mo) – – – + – – – – –
4 3 ⁄F 9.10.95 + + (s) – – Keratoacanthoma + + – – – –
5 6 ⁄M 20.3.96 + + (s) – – Keratoacanthoma + + – Lid ulcer – –
6 12 ⁄M 14.5.96 + + (mo) – – – + – – – – –
7 30 ⁄M 8.4.96 + + (mi) – – – – – – – – –
8 5 ⁄F 11.5.96 + + (s) – – – + – – – – + (f1)
9 6 ⁄M 11.5.96 + + (s) + – – + – – – – + (f1)
10 14 ⁄M 26.2.96 + + (s) + + SCC (lip) Keratoacanthoma + – + – – –
11 20 ⁄F 9.3.97 + + (s) – – – + – – – – –
12 20 ⁄M 7.4.97 + + (mo) – – – – – – – – –
13 8 ⁄F 29.4.97 + + (s) + – Keratoacanthoma + + + – – + (f2)
14 5 ⁄F 15.6.97 + + (s) + – – + + – – – + (f2)
15 3Æ5 ⁄M 9.10Æ97 + + (s) + + SCC (neck) – + + + Lid ulcer – –
16 11 ⁄M 18.8.97 + + (s) + + SCC (ears) Ulcerative nodules + + + Lid ulcer – + (f3)
17 9 ⁄F 18.8.97 + + (s) + – Face ulcer + + + Loss of vision – + (f3)
18 7 ⁄F 18.8.97 + + (s) + – Face ulcer + + + Lid ulcer – + (f3)
19 8 ⁄M 24.12.97 + + (mo) – + SCC (face) – + + + – – –
20 8 ⁄M 8.3.98 + + (mo) – – – – – – – – –
21 14 ⁄F 22.8.98 + + (s) + – Keratoacanthoma + + + – – + (f4)
22 11 ⁄F 22.8.98 + + (s) + – Face ulcer + + + – – + (f4)
23 9 ⁄F 22.8.98 + + (s) – – – + + – – – + (f4)
24 5 ⁄F 22.8.98 + + (s) – – Keratoacanthoma + + – – – + (f4)
25 4 ⁄M 5.10.98 + + (mo) – – – + + – – – –
26 6 ⁄M 4.7.99 + + (mo) – – – + + – – – –
27 12 ⁄M 28.5.99 + + (s) + – Keratoacanthoma + + – – – –
28 6 ⁄M 6.6.99 + + (s) – – – + + + – – –
29 4 ⁄F 10.7.99 + + (s) – – – + + – – – –
30 10 ⁄M 4.9.99 + + (s) + – Lip ulcer + + – – – –
31 7 ⁄F 14.11.99 + + (s) – – – + + – – – –
32 5 ⁄M 8.8.00 + + (s) + – Keratoacanthoma + + – – – –
33 4 ⁄F 16.9.00 + + (mo) – – – + + – – – –
34 6 ⁄F 20.4.00 + + (s) + + SCC (head) Multiple ulcers + + + Lid ulcer – –
35 6 ⁄M 3.1.01 + + (s) + + SCC (nose) Nose cartilage
damage
+ + + – – –
36 14 ⁄F 25.6.01 + + (mi) – – – – – – – – –
–, Absent; +, present; (mi), mild; (mo), moderate; (s), severe; (f), family.
 2005 British Association of Dermatologists • British Journal of Dermatology 2005 152, pp545–551
546 Incidence of XP in Larkana, Pakistan, A.M. Bhutto et al.
(mean ¼ 8Æ9 years). There were 18 males and 18 females.
The majority of cases (20) were from the Brohi tribe while
the remaining 16 patients were from the Sindhi population.
The patients had first shown freckles and pigmentation on the
face at about 6–24 months of age and simultaneously developed sensitivity to sunlight (Fig. 1). The majority of the
patients had a history of sunburn at the time of first visit. For
ease of discussion, we divided the patients in three groups
and propose the following classification on clinical grounds
only: mild, those patients with light brown freckles limited to
the face alone; moderate, those patients with dark brown
freckles with burning on the face, neck, ears, chest and extensor surface of the hands, and photophobia but without other
associated obvious cutaneous or ocular changes; severe, those
patients who had extensive dark brown freckles with burning
on the face, neck, ears, chest, extending to the other parts of
the body, i.e. back, abdomen, arms, hands; they also had
other ocular and cutaneous complications including malignancy. The mild group comprised three of 36 (8Æ3%) patients,
the moderate group, nine of 36 (25%), and the severe group,
24 of 36 (66Æ7%) patients. Twenty-four patients were severely
affected and had developed extensive freckles associated with
other cutaneous and ocular lesions. Fifteen patients had
additional cutaneous lesions such as keratoacanthoma, ulcer
on various parts, ulcerative nodules, fissures and damage to
the cartilage of the nose. Six patients had developed squamous
cell carcinoma (SCC) on the lip, neck, ear, face, head and
nose (Figs 2a,b and 3a,b). Ocular changes were frequently
seen in the majority of cases. Twenty-nine patients developed
photophobia, 21 had conjunctivitis, 12 had corneal keratitis
and five patients had lid ulcers. One patient presented with
Fig 1. Clinical picture of a 7-year-old girl with moderate type of
xeroderma pigmentosum.
Fig 2. (a) Clinical picture of a 6-year-old girl with severe xeroderma
pigmentosum. She developed the lesions at the age of 2 years. Almost
the whole of the face is ulcerated and many keratoacanthomas and
ulcerative masses are visible. The cartilage of the tip of the nose is
completely destroyed, and a huge mass (tumour) is visible on the
centre of the head. (b) High magnification of the hypertrophic and
ulcerative mass (tumour) of head. It was histopathologically diagnosed
as squamous cell carcinoma.
 2005 British Association of Dermatologists • British Journal of Dermatology 2005 152, pp545–551
Incidence of XP in Larkana, Pakistan, A.M. Bhutto et al. 547
complete loss of vision. No patient presented with neurological signs and symptoms, hence we could not detect any
remarkable neurological abnormality in our patients. Two
patients, cases 15 and 34 (Figs 2a,b and 3a,b) had extensive
and wide tumours on the head and neck and were noted to
have mentally deteriorated. With regard to the history of mental deterioration, their parents said that both had been active
and well orientated since birth, but deteriorated after the
growth of the huge mass (tumours) on the infected sites.
They looked ill. More than one sibling (two to four) had
developed XP in four different families. All patients were treated accordingly and we advised them to avoid sunlight for the
rest of their life. Topical steroids and sunscreens were prescribed to each patient, while oral and topical antibiotics were
given to the secondarily infected patients. Keratoacanthomas
were surgically removed. Cases 15 and 34 died of extensive
SCC.
Histopathological findings
Histopathologically, eight cases were diagnosed as keratoacanthoma. In most of the specimens the tumour centre showed
an irregularly shaped crater filled with keratin. At the base of
the crater irregular epidermal proliferations extended upwards
and downwards into the dermis. There was extensive keratinization along with numerous islands.
The findings in six cases (nos 10, 15, 16, 21, 34 and 35)
were consistent with SCC. All tumours had well-differentiated
characteristics of SCC. The irregular masses of epidermal cells
were invaded from the upper to the lower dermis (Fig. 4a).
Horn pearls were frequently seen in the dermis showing the
Fig 3. (a) Clinical picture of a 3Æ5-year-old boy with severe type of
xeroderma pigmentosum. Various ulcerative nodules are present on
the face. A wide ulcer is visible on the left side of neck.
(b) High magnification of the ulcerative mass (tumour) of neck of
above patient; it was diagnosed as squamous cell carcinoma.
Fig 4. (a) Section from the ulcerative mass (tumour) of a xeroderma
pigmentosum patient showing the characteristics of squamous cell
carcinoma. The irregular masses from the epidermal cells are invaded
from the upper to the lower dermis. Horn pearls are also visible in
the dermis and showing keratinization (haematoxylin and eosin,
original magnification · 10). (b) Tumour cells and mitosis are visible
(haematoxylin and eosin, original magnification · 50).
 2005 British Association of Dermatologists • British Journal of Dermatology 2005 152, pp545–551
548 Incidence of XP in Larkana, Pakistan, A.M. Bhutto et al.
keratinization. Mitosis was often visible in the specimens
(Fig. 4b). There was an infiltration of chronic inflammatory
cells and plasma cells were also visible in infected sites.
Discussion
Pakistan is a tropical country and its climate varies from one
region to another. XP symptoms are thought to have a close
relationship with the latitude and weather;16,17 however,
defective repair of DNA damaged by ultraviolet (UV) radiation
plays a key role in the pathogenesis of XP. Nonmelanoma skin
cancer is clearly linked to sun exposure, as it is found in
greatest frequency in regions nearest to the equator. In order
to understand the symptoms of XP in Pakistan it is important
to consider the latitude and weather of the country. Pakistan is
located between latitudes 23Æ45N and 36Æ75N and longitudes 61E and 75Æ5E. The north of the country is a high
mountainous region and the area is extremely cold; in winter
the temperature falls below freezing point. In contrast, in the
south of the country, where this study was performed, it is
flat and the climate is extremely hot; in summer the temperature goes up to 53 C. The contribution of frequency of UV
radiation around the country has not yet been determined.
Skin type plays a considerable role in the induction of
symptoms of this disease. The nonwhite population, whose
skin is black or brown due to a high amount of epidermal
melanin, has a very low incidence of developing sun-induced
cutaneous complications such as sunburn, keratosis, freckles,
wrinkles and rarely skin cancer. On the other hand, the fairskinned (white) population, whose skin is white due to the
low amount of melanin in the epidermis, are at high risk of
developing the acute and chronic problems associated with
frequent exposure to sunlight such as sunburn, keratosis,
freckles, wrinkles, skin cancer, etc. In general, the susceptibility of human skin to sun-induced acute and chronic damage
is directly related to the intensity of UV radiation and duration
and frequency of sun exposure. In order to identify the population at high risk for developing sun-induced skin changes
including cutaneous malignancy, a simple classification of skin
types (six types) has been proposed. More than one skin type
is recognized in the Pakistani population and these people
reside in different provinces with different weather conditions.
Those who reside in the central and south part of the country
are of skin types III and IV; those who reside in the northern
part of the country generally have fair-coloured skin with
blond hair and blue eyes and have skin type II.
As well as four nations, there are several tribes residing in
the various regions of the country. They have their own particular cultures and different languages, and have considerable
populations. The Brohi tribe is among those residing in the
south part of the country together with the Sindhi people in
Sindh province. They have fair skin colour with dark hair and
brown eyes and all have skin type III.
This study was conducted in the south part of the country
in Sindh province. The majority of the population residing
there are Sindhi people with skin type IV. The majority of our
cases (20 of 36, 55Æ6%) were from the Brohi tribe with skin
type III and the remaining 16 of 36 cases (44Æ4%) were
Sindhi people with skin type IV. Here it should be noted that
the ratio of the Brohi tribe to the general population of Sindh
province is less than 1 : 4. In our series of patients the data
showed that the symptoms of our XP patients were more
highly induced in the skin type III Brohi tribe people than in
the skin type IV Sindhi people. Although the incidence of XP
is determined by genetic factors and the higher incidence in
the Brohi tribe is likely to be the result of factors such as
founder effects and consanguinity, it is the symptoms of the
disorder that are affected by skin type, weather and latitude.
There are variations described in the frequency of XP in different countries. XP occurs with an estimated frequency of
1 : 250 000 in the U.S.A.; however, it is much higher in Japan,
at 1 : 40 000.18,19 On the basis of the number of our XP
patients in the general population, our estimation for the average frequency of XP in the southern region of Pakistan is about
1 : 100 000. This ratio is still higher than in the U.S.A. reports
but lower than in the Japanese studies. At present we do not
have data regarding the frequency of XP in the other provinces
of the country, especially the northern areas and Kashmir,
where the majority of people have white skin, blue eyes and
skin type II. Further studies are required in this regard.
It is reported that sunlight exposure is responsible for the
induction of malignant melanoma as well as nonmelanoma
[basal cell carcinoma (BCC) and SCC] skin cancer in patients
with XP.20 These patients are more at risk of developing cutaneous malignancy when they are severely affected in early
childhood. XP patients younger than 20 years of age have a
higher than 1000-fold risk of developing cutaneous malignancy.20,21 In our series of patients, those who developed
cutaneous malignancy were young, between the ages of 3Æ5
and 14 years (mean 9Æ8 years) at the time of examination,
which is consistent with earlier reports. The white people in
the world are the population at risk for sun-induced malignant
melanoma and nonmelanoma skin cancers. Kraemer et al.
reported on the malignant skin neoplasms in 45% of XP
patients.21 In other studies, Goyal et al. observed these malignant changes in 60% of their patients.15 In our cases, six
patients (16Æ7%) had developed SCC on the exposed parts of
the body, i.e. head, neck, face and ears. We could not find
other types of cutaneous malignancies, such as BCC and
malignant melanomas, which have been reported frequently
in XP patients.22 The incidence of internal neoplasms is said
to be 10–20 times higher in XP patients than in the normal
population.23 None of our patients had any internal malignancy. The mortality occurs in XP patients due to either neurological complications24 or actinic-induced tumours. In our
series, six patients had developed actinic-induced malignancy
but none of the patients had neurologically complicated malignancy. Two patients (5Æ5%) died due to extensive spreading of
multiple tumours. Our deceased patients were aged 3Æ5 and
6 years, which is in contrast to previous reports that showed
the mortality in their patients in the second and third
decades.8,25,26
 2005 British Association of Dermatologists • British Journal of Dermatology 2005 152, pp545–551
Incidence of XP in Larkana, Pakistan, A.M. Bhutto et al. 549
Eyes are the second most common organs involved in XP
because of direct exposure to UV radiation from sunlight.
Ocular neoplasms and other abnormalities are usually limited
to the conjunctiva, cornea and eyelids. Sparing of the iris, lens
and posterior segment was attributed to shielding of these
structures from UV radiation by the eyelids, cornea and lens.
Photophobia is the earliest ocular symptom and it is more
commonly seen in younger patients than in adults.5 In early
studies Kraemer et al. reported it in 21% of cases.21 In another
study photophobia was seen in 50% of cases. We observed
photophobia in 80% of our cases.15 The prominent conjunctival changes such as conjunctivitis including telangiectasia, xerosis, chronic conjunctival congestion and pigmentation are
most prominently seen in the sun-exposed interpalpebral fissure, and have been reported by Kraemer et al. in 18% of
cases.21 A single study from India has shown these problems
in 40% of cases;15 however, in our cases the conjunctival
abnormalities were seen in 29 of 36 (80Æ6%) cases. Corneal
abnormalities have generally consisted of exposure keratitis
leading to haziness, scarring, ulceration and even perforation
resulting in corneal opacities and vascularization. Kraemer
et al. reported corneal abnormalities in 17% of cases,21 while
another study shows it in 40% of their cases.15 Among our
cases, we saw corneal complications in 12 of 36 (33Æ3%)
cases. Both lower lids displayed cutaneous pigmentation, irregular margins, partial loss of lashes and lid ulcers. The
involvement of lids was seen in more than 80% in early
reported cases.21 In our series, five of 36 (13Æ9%) cases
showed ulceration of the lower lid. The upper lid changes
were either absent or less prominent compared with the
lower lid.
Ocular neoplasms like SCC, BCC and malignant melanoma
are frequently reported from the conjunctiva, cornea and eyelids. A single rare case of malignant melanoma developed
from the iris is reported by Johnson et al.27 We could not find
any malignancy from ocular complications in our patients.
Kraemer et al. have reported 11% of cases as having ocular
malignancies,21 while Goyal et al. have reported 20% of cases
having ocular malignancies.15 We observed an unusually
complicated case of XP whose vision was completely lost.
This 14-year-old female patient, belonging to the Brohi tribe,
had lost her vision because of extensive involvement of XP
and she had been unable to see for the last 3–4 years. She
developed XP at age 1 year. We saw this patient in a medical
camp arranged in Shahdadkot. We could not arrange for her
complete eye examination because of the unavailability of an
eye specialist. To our knowledge this is the first case of XP
with this unusual complication ever reported. Carcinoma of
the tongue, which is thought to be due to a significant
amount of UV radiation from sunlight reaching the tip of the
tongue, has been reported in 13 of 830 (1Æ6%) cases.21 In
other studies, it was reported in two of 10 cases.15 None of
our patients had carcinoma of the tongue except for ulceration of the tip of tongue in a few cases. At present, because
of the lack of facilities, we could not confirm or classify the
complementation groups of our XP patients. Although the
number of patients in our study is not very high, it is of special importance that none of these Pakistani patients have neurological symptoms and are predominantly from two tribal
groups. In this regard, further studies will be carried out in
future.
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