Do Egyptian children with beta-thalassemia major have specific cutaneous manifestations? A cross-sectional study

Mostafa M Embaby; Neveen M Farag; Aya Y Badran; El Sayed K Abdel-Karim

doi:10.4103/ejdv.ejdv_32_22

ORIGINAL ARTICLE

Year : 2023 | Volume : 43 | Issue : 2 | Page : 93-101

Do Egyptian children with beta-thalassemia major have specific cutaneous manifestations? A cross-sectional study

Mostafa M Embaby¹, Neveen M Farag¹, Aya Y Badran², El Sayed K Abdel-Karim¹
¹ Pediatrics, Faculty of Medicine, Assiut Univesity, Assiut, Egypt
² Dermatology, Venereology & Andrology, Faculty of Medicine, Assiut Univesity, Assiut, Egypt

Date of Submission	13-Jul-2022
Date of Acceptance	19-Dec-2022
Date of Web Publication	25-Apr-2023

Correspondence Address:
MD Aya Y Badran
Department of Dermatology, Venereology & Andrology, Faculty of Medicine, Assiut University, Assiut 71511
Egypt

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/ejdv.ejdv_32_22

Abstract

Background A wide continuum of cutaneous manifestations might accompany blood diseases and hemoglobinopathies, especially β-thalassemia. In this situation, cutaneous manifestations occur due to both hemoglobin disorder and treatment complications. These manifestations are usually neglected and frequently underdiagnosed among those patients.
Aim To study the cutaneous manifestations in Egyptian children with β-thalassemia to minimize its subsequent complications. Furthermore, we aimed to analyze their relations to duration of disease and frequency of blood transfusions and other disease parameters.
Patients and methods This was a cross-sectional study that included 158 patients with β-thalassemia major. All patients were subjected to detailed history, clinical examination, and laboratory investigations, namely, serum ferritin and hemoglobin level. All patients were subjected to meticulous dermatological examination by an experienced dermatologist to evaluate cutaneous manifestations. The data were analyzed using Student t test, Mann–Whitney U test, χ² test, and Fisher exact test.
Results Xerosis was the commonest encountered cutaneous change (present in 61% of patients), followed by hyperhidrosis (30%), hyperpigmentation (28%), pruritus and pityriasis alba (25%), urticaria (22%), and idiopathic guttate hypomelanosis, scars, ephelides, contact dermatitis, discoid eczema, nail disorders, melasma, tinea, alopecia areata, and warts in descending order. Statistically significant relations were present between the presence of some cutaneous manifestations and disease duration.
Conclusion Cutaneous manifestations are common among Egyptian children with β-thalassemia major. Both xerosis and hyperhidrosis are the commonest cutaneous signs in those patients. Some of those cutaneous manifestations are correlated with disease duration and frequency of blood transfusions.

Keywords: cutaneous manifestations, xerosis, β-thalassemia major

How to cite this article:
Embaby MM, Farag NM, Badran AY, Abdel-Karim EK. Do Egyptian children with beta-thalassemia major have specific cutaneous manifestations? A cross-sectional study. Egypt J Dermatol Venerol 2023;43:93-101

How to cite this URL:
Embaby MM, Farag NM, Badran AY, Abdel-Karim EK. Do Egyptian children with beta-thalassemia major have specific cutaneous manifestations? A cross-sectional study. Egypt J Dermatol Venerol [serial online] 2023 [cited 2023 May 31];43:93-101. Available from: http://www.ejdv.eg.net/text.asp?2023/43/2/93/374463

Introduction

Hemoglobinopathies are among the commonest monogenic diseases worldwide. Up to 5% of the overall population is a carrier for mutation of genetic thalassemia genes [1].

Thalassemia is an autosomal recessive disorder triggered by mutations or deletions of the hemoglobin (Hb) genes, resulting in lack of either alpha or beta chains [2].

β-thalassemia major (BTM) is the most common single-gene disorder, in which Hb β-chain assembly is diminished. The life expectancy of patients with thalassemia has been improved owing to the availability of miscellaneous treatment approaches, though treatment-related complications have also increased [2].

Both anemia and hemosiderosis develop functional and physiologic abnormalities in numerous organs and systems [3].

Iron-overload toxicity arises when ineffective erythropoiesis leads to inappropriately low hepcidin levels and increased iron intestinal absorption. It is considered the primary cause of morbidity and mortality in patients with thalassemia [4].

It is crucial to remove excess iron as there are no physiological mechanisms to eliminate it or to prevent its accumulation. Hence, using a pharmaceutical strategy to limit the serious clinical consequences of iron excess is essential [5].

The development of dermatological diseases in patients with BTM may be related to age, sex, comorbidities, ferritin, Hb, and hematocrit levels [6].

Several literature studies have described various systemic complications of BTM; nonetheless, there is paucity of literature concerning cutaneous manifestations in such patients.

We designed the study with the purpose of studying the cutaneous manifestations in Egyptian children with BTM to minimize its subsequent complications. Furthermore, we aimed to analyze their relations to disease duration and frequency of blood transfusions and other disease parameters.

Patients and methods

Eligible participants

We included all pediatric patients with β-thalassemia of both sexes, aged 2–18 years, attending a children hospital during the study period. The exclusion criteria were patients with other hemolytic anemia, children with any dermatological disease before the diagnosis of thalassemia, and children’s parents (care givers) who refused to participate in the study.

Ethical approval: the study design was approved by Institutional Ethics and Research Committee of Faculty of Medicine Assiut University (N:IRB 17100692).

Enrollment

Written consent was obtained from all parents of eligible participants after explaining the nature of the study. Then, participants who met the inclusion criteria were subjected to detailed history, which included demographic data (age, sex, weight, and duration of illness), age at diagnosis, age of first blood transfusion, frequency of blood transfusion, family history, and residence. For chelation therapy, age of first chelating therapy, type, duration, and dose, as well as compliance were recorded and analyzed for the patients, and full general and systemic examination was done at the time of enrollment. All patients were subjected to meticulous dermatological examination by an experienced dermatologist.

Blood sample was taken from each child to determine the Hb and serum ferritin level.

Statistical analysis

The data were collected and entered into Microsoft Excel Database to be analyzed using the Statistical Package for the Social Sciences (version 22; SPSS Inc., Chicago, Illinois, USA). Quantitative data were statistically described in terms of mean±SD, median, and range, and qualitative data were statistically described in terms of frequencies (number of cases) and relative frequencies (percentages). Comparison of quantitative variables between the study groups was done using Student t test for normal distributed data or Mann–Whitney U test for not normal distributed data. χ² test was used for comparing categorical data. Exact test was used instead of χ² test when the expected frequency was less than 5. P value was always two tailed and set at a significance level of 0.05.

Results

The mean age of the studied cases was 9.33±4.14 years and ranged from 2 years up to 18 years. Of 158 studied BTM cases, 90 (57%) were boys and 68 (43%) were girls. The mean weight was 24.84±9.21 kg and the majority of studied cases had normal weight (63%). The mean height was 121.82±20.19 cm, where more than half (57%) of studied cases were stunted. The median pretransfusion Hb of the studied BTM cases was 6 g/dl and ranged from 3 up to 10, and the median serum ferritin was 1604 ng/ml and ranged from 150 up to 6722 ng/ml. Other demographic and laboratory data are illustrated in [Table 1].

Table 1 Demographic and laboratory data of 158 patients with β-thalassemia major

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Considering cutaneous manifestations, xerosis was the most common dermatological change, being present in 96 (61%) patients, followed by hyperhidrosis in 47 (30%) patients, hyperpigmentation (includes both forehead hyperpigmentation and generalized hyperpigmentation) in 44 (28%) patients, pruritus in 40 (25%) patients, pityriasis alba in 39 (25%) patients, urticaria in 34 (22%) patients, and idiopathic guttate hypomelanosis (IGH), scars, ephelides ([Figure 1]), contact dermatitis, discoid eczema, nail disorders, melasma, tinea, alopecia areata, and warts in descending order ([Table 2]).

Figure 1 An 8-year-old boy with multiple ephelides over both cheeks.

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Table 2 Cutaneous changes among 158 patients with β-thalassemia major

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[Table 3] shows a statistically significant relation between the presence of some cutaneous manifestations and the duration of the disease, namely, hyperpigmentation, xerosis, and ephelides (P=0.002, 0.001, and 0.000, respectively), whereas other correlations were nonsignificant (P>0.05).

Table 3 Relation of different cutaneous manifestations to duration of β-thalassemia major disease and to the frequency of blood transfusion among 158 studied patients

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[Table 3] shows a statistically significant relation between the presence of some cutaneous manifestations and the frequency of blood transfusion, namely, hyperpigmentation, xerosis, and ephelides (P=0.003, 0.000, and 0.004, respectively), whereas other correlations were nonsignificant (P>0.05).

Regarding the relations between cutaneous manifestations and sex of included patients, all of them were nonsignificant (P>0.05) ([Table 4]).

Table 4 Relation between cutaneous manifestations and sex of 158 β-thalassemia major patients

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[Table 5] analyzes the relations between the existence of cutaneous manifestations and clinical data (hepatomegaly and splenomegaly) of the included patients. A statistically significant relation was found between the presence of xerosis and urticaria and the existence of hepatomegaly. Moreover, the presence of xerosis and ephelides was significantly related to the presence of splenomegaly (P<0.05 in all).

Table 5 Relation between different dermatological changes and clinical manifestation ‘splenomegaly’ of 158 patients with β-thalassemia major

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Discussion

In Egypt, beta-thalassemia is the most common cause of hemolytic anemia, with a carrier incidence of 9–10%. Patients with BTM typically present with severe anemia within the first 2 years of life [7]. It needs permanent transfusions to maintain Hb level of more than 9.0 g/dl and preserve a healthy growth. This causes iron overload and a diversity of organ dysfunctions, including hepatic impairment, heart failure, gland siderosis, diabetes mellitus, and hyperpigmentation of the skin [8].

Regrettably, cutaneous manifestations are usually neglected and often underdiagnosed among such patients [9]. The current study aimed to identify these manifestations to minimize their subsequent complications. Furthermore, we aimed to analyze their relations to disease duration and frequency of blood transfusions and other disease parameters.

Overall, 37 of our studied cases were underweight, and more than half (57%) were stunted. In line with our study, Nasr et al. [10] showed that 57.6% of patients with BTM were below the fifth centile for age and sex with respect to height and weight. The study by Hashemi et al. [11] shows that 65.71% of patients with thalassemia had height less than five percentile. Likewise, an Indian study by Kumari et al. [12] reported that about 72.9% of studied children were below five percentile for height and 60.8% were below five percentile for weight. In the present study, many of our patients were suboptimally blood transfused. They received blood transfusions, only to raise the Hb level above a critical value of ∼7 g/dl. This was necessitated by economic reasons and explained the significant anemia observed in our patients. Moreover, congestive heart failure, iron overload, the toxic effects of chelators, or the development of endocrinopathies and metabolic disturbances may also be contributory factors. Thus, normal stature is rarely attained, even in well-managed patients.

Overall, 69% of our studied cases had a positive family history of thalassemia. In line with our study, Pektaş et al. [6] reported a positive family history among 66.2%. A high prevalence of consanguinity in Upper Egypt may explain this finding in our study.

The mean serum ferritin level was 2109.9 us/dl, with a range of 150.0–6722.0 us/dl, and the mean pretransfusion Hb was 5.82, with a range of 3.0–9.50. Our results were supported by Fahmey et al. [9], who reported that the mean serum ferritin was 2838 and the mean of Hb was 6.61, and Pektaş et al. [6] reported that the mean serum ferritin was 1337.6 us/dl and the mean of Hb was 9 us/dl. This high level of serum ferritin and number of noncompliant patients on chelating therapy may explain the presence of cutaneous manifestations in our patients.

Xerosis (dry skin) is a crucial psychosocial morbid condition in which skin atrophy, erythema, and pruritus are seen together owing to changes in lipid ratios and a decrease in fluid retention [13]. In tissues affected with thalassemia major, the deterioration of skin hydration, beak down of the barrier function, as well as excessive iron deposition all boost the risk of developing xerosis [14]. In our study, xerosis was the most common cutaneous manifestations recognized in 61% of studied patients; similarly, El‐Dash and Adel [15] found that the most common cutaneous manifestation was xerosis, as seen in 72% of patients.

Pruritus or itching is an unpleasant feeling that causes a desire to scratch; the pathogenesis of pruritus is still unknown. It might be owing to release of histamine from tissue mast cells secondary to stimulation by iron deposits in the skin [16]. Pruritus was documented in 25% of our patients, whereas El‐Dash and Adel [15] reported pruritus in 52% of studied patients. Moreover, our findings were different from the previous Egyptian studies. The studies by Fahmey et al. [9] and Gaber and Galal [17] they found that the most common cutaneous abnormality was pruritus, as documented in 37 and 34.4% of studied patients, respectively. This difference could be due to difference in the type of treatment that was received by the studied participants.

Hyperhidrosis was recognized in 29.7% patients. In agreement with our study, Alatas et al. [18] reported that hyperhidrosis was among the most common skin findings, whereas Fahmey et al. [9] reported that hyperhidrosis was documented in only three (5.6%) cases of individuals with thalassemia.

In our study, hyperpigmentation was documented in 27.8% of patients. Closely, Fahmey et al. [9] documented hyperpigmentation in 31.5% of the studied cases. This was in accordance to other studies, such as Alatas et al. [18], who observed pigmentation disease in 20.8% of the studied cases, and also, Gaber and Galal [17] reported pigmentary disorders in 23.9% of individuals with thalassemia. Patients with thalassemia patients also appear darker owing to hemosiderosis.

Pityriasis alba is a relatively common skin disorder characterized by the presence of asymptomatic, superficial, hypopigmented macules with slight overlying scaling, located usually on the face, neck, and shoulders [19]. Copper is required to activate the tyrosinase enzyme in melanocytes, which is required for the formation of melanin. Pityriasis alba occurred owing to low levels of serum copper [20]. Several studies reported reduced serum copper in patients with thalassemia [21].

In our study, pityriasis alba was reported in 25% of patients. Similar result was obtained by Alatas et al. [18], who observed pityriasis alba in 25% of studied patients, whereas Fahmey et al. [9] reported pityriasis alba in 18.5% of individuals with thalassemia, and Gaber and Galal [17] reported it in 10.5% of individuals with thalassemia.

The presence of plentiful immunologic defects in patients with thalassemia explains the urticaria that was detected in 22% of our patients. This finding was consistent with Fahmey et al. [9] and Gaber and Galal [17], who reported urticaria in 16.7 and 21.1% of individuals with thalassemia, respectively. However, Dogramaci et al. [3] documented urticaria in only 3.8% of the studied patients.

IGH was among the most commonly detected dermatologic diseases. Even though its cause is still unidentified, genetic tendency and solar exposure have been assumed as causative factors [3]. IGH was documented in 17.7% of our patients. Similarly, El‐Dash and Adel [15] reported IGH in 22%. Meanwhile, Fahmey et al. [9] and Alatas et al. [18] reported IDH in only two (3.7%) cases and one (4.2%) case of patients with thalassemia, respectively.

Presence of scars indicates the extent of cell proliferation and extracellular matrix production and deposition [22]. Their occurrence was among the most commonly encountered cutaneous manifestations in our patients (present in 13.3% of our studied patients). The dark skin of individuals with thalassemia, due to severe hemosiderosis, could explain their existence [3]. In consistent with our finding, El‐Dash and Adel [15] and Gaber and Galal [17] documented scars in 13 and 10.5% of the studied cases, respectively.

On the contrary, Dogramaci et al. [3] and Fahmey et al. [9] reported scars in 24.4 and 33.3% of individuals with thalassemia, respectively.

Ephelides are physiologic areas of increased pigment production. We observed ephelides in 11.4% of our patients. Dogramaci et al. [3], Fahmey et al. [9], and Alatas et al. [18] reported ephelides in 23.1, 148, and 20.8% of patients with thalassemia, respectively. Iron deposition in the skin might explain ephelides in individuals with thalassemia [17].

Contact dermatitis was present in 7% of our patients, whereas Fahmey et al. [9] reported contact dermatitis in 13% of studied patients.

Melasma is an acquired skin disease characterized by symmetric hyperpigmentation on sun-exposed areas, particularly on the face [23]. In the current study, melasma was found in 1.9% of studied patients. This finding was in harmony with the result obtained by Dogramaci et al. [3], as melasma was present in 1.3% of patients.

The perceived difference in the frequency of cutaneous manifestations between the aforementioned studies could be ascribed to the differences in genetic, racial, or ethnic parameters among the included patients. Furthermore, there were differences in the number of included patients, method of treatment, or difference in transfusion criteria.

Conclusion

Cutaneous manifestations are common among Egyptian children with BTM. Both xerosis and hyperhidrosis are the commonest cutaneous signs in those patients. Some of those cutaneous manifestations are correlated with the duration of the disease and the frequency of blood transfusions.

Recommendations

We do recommend regular and meticulous skin examination of children with BTM to offer early diagnosis and better management with healthier quality of life.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Modell B, Darlison M. Global epidemiology of haemoglobin disorders and derived service indicators. Bull World Health Organ 2008; 86:480–487.
2.	Saki N, Abroun S, Salari F, Rahim F, Shahjahani M, Javad MA. Molecular aspects of bone resorption in β-thalassemia major. Cell J 2015; 17:193.
3.	Dogramaci AC, Savas N, Ozer B, Duran N. Skin diseases in patients with β‐thalassemia major. Int J Dermatol 2009; 48:1057–1061.
4.	Huang Y, Lei Y, Liu R, liu G, Yang X, Xiang Y, Liang Lai Y. Imbalance of erythropoiesis and iron metabolism in patients with thalassemia. Int J Med Sci 2019; 16:302.
5.	Daher R, Karim Z. Iron metabolism: state of the art. Transfus Clin Biol 2017; 24:115–119.
6.	Pektaş SD, Alataş ET, Pektas G, Karakuş V, Azik FM, Dogan G. Analysis of Skin, Hair and Nail Diseases in the Adults with Beta Thalassemia Major. Gazi Medical Journal 2018; 28:29.
7.	Sherief LM, Dawood A, Ali HS, Sherbiny NM, Elshanshory KM, Alazez OA, Alhady MA, Nour M, Mokhtar WA. Premature atherosclerosis in children with beta-thalassemia major: new diagnostic marker. BMC Pediatr 2017; 17:1–8.
8.	Vetsiou E, Mpouras V, Nikolaidou C, Klonizakis P, Mandala E, Vamvakis K, Psarras K, Vlachaki E. Necrobiosis lipoidica in a patient with β-thalassemia major: a case report and review of the literature. Hemoglobin 2020; 44:221–223.
9.	Fahmey SS, Taha G, EL-Refaey A, Adly S. Skin disorders in Egyptian children with β-thalassemia major. J Trop Pediatr 2018; 64:104–109.
10.	Nasr MR, Ebrahim NA, Salahedin O. Growth pattern in children with beta-thalassemia major and its relation with serum ferritin, IGF1 and IGFBP3. J Clin Exp Investig 2012; 3:157–163.
11.	Hashemi A, Ghilian R, Golestan M, Akhavan GM, Zare Z, Dehghani MA. The study of growth in thalassemic patients and its correlation with serum ferritin level. Iranian Journal of Pediatric Hematology Oncology 2011; 1:4.
12.	Kumari V, Upadhyay S, Gupta V, Piplani KS, Bhatia B. Growth retardation and malnutrition in children with thalassemia major. Indian J Prev Soc Med 2012; 43:149–151.
13.	Farage MA, Miller KW, Berardesca E, Maibach HI. Clinical implications of aging skin. Am J Clin Dermatol 2009; 10:73–86.
14.	Noureldine MHA, Taher AT, Haydar AA, Berjawi A, Khamashta MA, Uthman I. Rheumatological complications of beta-thalassaemia: an overview. Rheumatology 2018; 57:19–27.
15.	El‐Dash H, Adel S. Cutaneous manifestations in Egyptian children with beta‐thalassemia major: relationship with serum ferritin, thyroid profile, and treatment modalities. Pediatr Dermatol 2018; 35:639–643.
16.	Lavery MJ, Kinney MO, Mochizuki H, Craig J, Yosipovitch G. Pruritus: an overview. What drives people to scratch an itch? Ulster Med J 2016; 85:164.
17.	Gaber MA, Galal M. Cutaneous manifestation of β-thalassemic patients. Menouf Med J 2020; 33:267.
18.	Alatas ET, Pektas SD, Dogan G, Azik MF. Skin, hair and nail findings in children with beta-thalassemia. Medicine 2019; 8:578–580.
19.	Vinod S et al. Clinico epidemiological study of pityriasis alba. Indian J Dermatol Venereol Leprol 2002; 68:338–340.
20.	Miazek N et al. Pityriasis alba—common disease, enigmatic entity: up‐to‐date review of the literature. Pediatr Dermatol 2015; 32:786–791.
21.	Sherief LM, El-Salam A, Sanaa M, Kamal NM, Almalky MA, Azab S, Morsy H, Amal G. Nutritional biomarkers in children and adolescents with beta-thalassemia-major: an Egyptian center experience. Biomed Res Int 2014; 2014:261761.
22.	Yang Y, Wu X, Liu W. Scar symptom: erythema and thickness. In textbook on scar management. Cham: Springer; 2020. 103–108.
23.	Austin E, Nguyen JK, Jagdeo J. Topical treatments for melasma: a systematic review of randomized controlled trials. J Drugs Dermatol 2019; 18:11.