American Journal of Hematology 41 :159-164 (1992)

Pseudoxanthoma elasticumlike Skin Lesions and Angioid Streaks in p-Thalassemia Athanasios Aessopos, Panayotis Savvides, George Stamatelos, loannis Rombos, Thomas Tassiopoulos, Markisia Karagiorga, Phaedon Kaklamanis, and Phaedon Fessas First Department of Internal Medicine, University of Athens (A.A., P.S., G.S., T.T., P.K., P.F.),Thalassemia Unit, Laiko General Hospital (I.R.), and Thalassemia Unit, Aghia Sophia Children’s Hospital, (M.K.), Athens, Greece

One hundred patients with homozygous or doubly heterozygous p-thalassemia (62 with the major form and 38 with p-thalassemia intermedia) were examined for signs of Pseudoxanthomaelasticum (PXE). Diagnostic skin lesions were found in 16 patients with either form of the basic disease. Twenty percent of all patients had angioid streaks (AS); both PXE skin lesions and AS were found in 10% of the patients; in all, 26% had either one or both of these manifestations. A positive correlation was found between the presence of one or both types of lesion and age of the patients (P = 0.032); there were no differences as regards ferritin and hematocrit levels, number of transfused units, chelation therapy, and splenic status between patients with PXEIAS findings and those without. The pathogenesis of these connective tissue manifestations at such a high frequency in p-thalassemia is not clear; the possibilities of it’s being acquired or inherited are discussed, the former being considered to be the more economical interpretation. 0 1992 Why-Liss, Inc.

Key words: connective tissue disorders, Pseudoxanthoma elasticum, angioid streaks, p-thalassemia

INTRODUCTION

Homozygous p-thalassemia is one of the common hereditary diseases which is best understood at the molecular level, genetic and pathophysiological. With more effective supportive therapy, including transfusion regimens and iron chelation, most patients achieve survival over decades; along with this they manifest signs and symptoms which are uncommon or unknown. It is not always easy to discern what is caused by undesirable effects of long-term management and what may be due to the repercussions of a chronic and rather complex diseased state. Recently, following isolated reports [ I ,2,3] we established a high prevalence (20%) of angioid streaks (AS) in the fundi of a series of one hundred patients with thalassemia [4].AS represent breaks in the elastic lamina of Bruch’s membrane; through secondary complications these may lead to loss of vision. AS are a common feature of the skin disorder pseudoxanthoma elasticum (PXE), occurring in 80% of cases; this association has been named the Gronblad-Stranberg syndrome [5,6]. PXE is considered to be a rare (70-160,000) inherited disorder of elastic tissue which has so far defied elucidation [7]. 0 1992 Wiley-Liss, Inc.

In view of this connection between AS and PXE it was natural to extend our. initial observations and to investigate further the relationship of these elastic tissue manifestations to some parameters of the disease or its treatment. A preliminary report of two cases has been presented recently [8]. MATERIAL AND METHODS

One hundred unselected sequential patients with P-thalassemia were regularly followed up in the thalassemia unit at the Laiko General Hospital. All were Caucasians of Greek nationality and residents of various parts of Greece; they were the basis of the previous report [4]. These patients covered the whole spectrum of homozygous or double heterozygous p-thalassemia: sixty-

Received for publication May 3, 1991; accepted February 27, 1992. Address reprint requests to A. Aessopos, First Dept. of Internal Medicine, University of Athens, Laiko General Hospital, 17 Aghiou Thoma, (Goudi), Athens 11527, Greece.

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two of them belonged to the major form, and 38 to the intermedia form of the disease. Their age ranged from 14 to 62 years (mean age: 26 years). Forty-eight were men and 52 women. The patients were examined carefully by two of us (A.A. and S.P.) for the detection of the cutaneous lesions characteristic of PXE. The sites especially inspected were face, neck, axillary folds, lower abdomen, and thighs. Cutaneous lesions compatible with PXE were biopsied. The patients were then divided into two groups. Group A included patients with PXE skin lesions and/or AS (detected previously), while group B included those without. Thirty-one parents and 39 siblings of patients in group A were also examined for PXE. Statistical analysis was performed by x2 test and by discriminant analysis, using the SPSS-PC+ statistical package [S]. The dependent variable was the existence or not of either one or both of the disorders (cutaneous lesions and AS). The independent variables included in the analysis (Table I) were sex, age, type of thalassemia (major or intermediate), transfusion units received, chelating therapy, and hematocrit and ferritin levels. RESULTS

Skin lesions compatible with PXE were detected in 16 patients (16%). They consisted of small cutaneous yellowish papules or larger coalescent plaques, with or without thickened, leathery, lax, and/or inelastic skin (Fig. 1). In all 16 patients lesions were observed on the back and the lateral aspects of the neck and were bilateral. Similar lesions were found in the axillary folds of three of the patients, and on the interior surface of the elbows in two of them. Skin biopsies of the neck lesions were performed in these 16 cases. On staining with orcein the elastic fibers were increased and displayed clumping, abnormal arrangement and fragmentation. With routine hematoxylin-eosin stain the fibers were evident because of a bluish tinge. The histological findings were compatible with PXE in all (Fig. 2). As stated above, angioid streaks had been detected in this group of patients at a frequency of 20% [4].Both angioid streaks and skin lesions were found in ten patients (10%). Twenty-six patients (26%)had either one or both of these abnormalities. The occurrence of both types of lesion in ten patients greatly exceeds the expected simultaneous presence of the lesions if they were due to independent mechanisms: the probability of finding 10 patients with both lesions is less than 0.001. Accordingly, we treat the two manifestations as one, due to a similar mechanism, in keeping with what was observed long ago in the PXE syndrome. Among 70 family members of group A patients, none was found to have Pseudoxanthoma elasticum skin lesions or AS.

I-

m"

Pseudoxanthoma-LikeSyndrome in p-Thalassemia

Fig. 1. Typical cutaneous manifestations of Pseudoxanfhoma elasticum on the dorsal aspect of the cervical area.

Data concerning the hematological history of our 100 patients with P-thalassemia are summarized in Table I. It is worth noting that of the 26 group A patients, six had never been transfused and 12 had never received chelation therapy. There is, moreover, an equal distribution of splenectomy between groups A and B. The age distribution of all patients is presented separately for the two clinical forms of P-thalassemia in Table 11. Clearly, the younger age groups predominate and, as expected, patients with thalassemia major were younger than those with intermediate thalassemia. As seen in this Table, an increasing number of patients in the older age groups had one or both of the PXE/AS manifestations. The results of our statistical analysis are summarized in Table 111. The existence of either one or both of the disorders is positively correlated with age (P = 0.032). We found no correlation with the number of transfusion units, the hematocrit and the ferritin levels. The x2 test indicated that patients with thalassemia intermedia are more frequently affected, while patients under chelation are less so; these correlations disappear when the con-

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Fig. 2. Degeneration of elastic fibers, abnormal arrangement, swelling, and fragmentation are obvious (orcein, X 125).

founding effect of age is taken into account using the multivariate analysis. The reason is that older patients usually belong to the (3-thalassemia intermedia group, receiving less chelation therapy, while younger patients mainly have the major form and receive intensive therapy. Finally, while we found no overall correlation with the sex of the patients, we did observe a higher frequency of AS in males than in females ( 12 vs. 8), and conversely more PXE skin lesions in females than in males (12 vs. 4). This difference is statistically significant (x2= 4.41; P = 0.036). DISCUSSION

Considering the evidence cited above, it is, we believe, legitimate to treat PXE and AS as manifestations of a common basic mechanism affecting elastic tissue. In the present study of 100 P-thalassemic patients, a total of 26 have ocular or skin findings or both (20 patients had AS, 16 showed cutaneous lesions of PXE and 10 had

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Aessopos et al. TABLE II. Distribution of Patients by Age and Lesions Age groups Disease P-Th major WithPXE skin lesions and/or AS Without any lesions P-Th intermedia With PXE skin lesions and/or AS Without any lesions Total

+

Total

-

-

13 49

2 1 3

2 I 3

13 25 I00

11-20

21-30

3140

41-50

4 30

7 17

2 2

-

-

5 13 42

4 5 13

5 39

51

TABLE 111. Discriminant Analysis: Distribution of Coefficient (b), t-Value (t), and Level of Significance (P)* Independent variables Sex ( I = male, 2 = female) Age Type of thalassemia ( I = major, 2 = intermedia) Transfusion units Chelating therapy (1 = yes, 2 = no) Hematocrit Ferritin levels

b

t

P

- 0.092 0.157 0.037

1.05 2. I5 0.85

0.30 0.032 0.60

0.030 0.097 0.005 0.05 I

0.75 I .22 0.44 0.99

0.54 0.22 0.67 0.68

*Dependent variable: existence (1) or not (0) of PXE and/or AS.

both). The occurrence of the findings is age-related. In 19 patients aged over 30 years the prevalence is as high as 50% (10/19, Table 11); in contrast, no patient under the age of 19 showed any lesions. The findings occur in both major and intermediate types of P-thalassemia with no clear correlation when the effects of age are controlled for. Women appear to present skin lesions more frequently than men (12 vs. 4), while the opposite is true for AS (8 females vs. 12 males). This difference disappears when both ocular and skin findings are considered together. Somewhat similar differences in sex ratios are quoted by McKusick [lo] for genuine PXE, although he considered that such differences might be factitious, owing to the increased attention of women to cosmetic problems of the skin. Before discussing the pathogenetic aspect, a brief mention should be made of the possible relationship of our findings in thalassemia to the genetically determined PXE syndrome which may be inherited as a dominant or as a recessive determinant [7]. In our series the dominant form of PXE can be easily excluded, since not a single affected parent was found. As for the recessive form, the lack of a test for heterozygotism for the PXE gene leaves much room for speculation. Since the appearance of the PXE signs in our group is age-dependent, the estimation of frequency is probably more accurate in patients aged over 30 years (50%). Assuming that the PXE-like syndrome is genetically determined as a recessive, one must admit that the abnormal gene is extremely frequent and

closely linked to the ey GP-globin cluster. However, the corresponding genes for collagen I and elastin are located on chromosomes 17 and 7, respectively [ 11,121, while those for (3-globin are located on chromosome 1 1 [ 131, This alone would render impossible a genetic lesion concerning the structural genes for elastin or collagen I; alternatively, one must assume the existence of other genetic determinants involved in elastic tissue structure or function close to the (3-globin cluster. Since the P-thalassemia genes in the Greek population are very heterogeneous [ 141, it is not very likely that the assumed PXE-like gene has become associated with most of these P-thal genes. In view of the high prevalence of the PXE-like syndrome in (3-thalassemia and the rarity of PXE in the general population, it is more economical at the moment to accept that some of the pathological mechanisms of the basic disease mimic the PXE syndrome. The probability that this predisposition is due to another genetic determinant interacting with the thalassemic background must also be considered; such an additional genetic factor must be assumed to be very frequent. PXE or PXE-like skin lesions and AS may occur in association with other diseases [ 151. Among these, sickle cell disease, Marfan’s syndrome, the Ehlers Danlos syndrome, and Paget’s disease are of particular interest; no uniform or clear explanations for these combinations have been offered. Since sickle cell disease is not only frequent but also well understood, it offers itself best for comparison with thalassemia.

Pseudoxanthoma-Like Syndrome in p-Thalassemia

In sickle cell anemia the prevalence of AS has been reported to vary between 1.4 and 21%, older patients being more frequently affected [ 16,171. Furthermore, the PXE syndrome has been observed in at least seven patients with sickle cell anemia [18]. Although the exact prevalence of PXE in sickling disorders cannot be deduced, the data suggest frequent association of these two diseased states. Indeed, an early American case of PXE also had sickle cell anemia [ 101. While routine skin biopsies in sickle cell anemia were negative, the recent application of more sophisticated techniques revealed disorders of elastic fibers analogous to those of PXE [19]. Common features of both thalassemic and sickling disorders are the chronic anemia and/or a varying degree of hemolysis . Vascular occlusion has been incriminated for the occurrence of PXE in sickling disorders; however, this is not a constant and prominent feature of thalassemia and seems unlikely to be the common etiological factor. Tissue iron deposition is a prominent feature of thalassemia and increases with advancing age; in our patients no correlation was observed between ferritin levels and PXE manifestations, but these were high in the entire series; also, with high tissue iron deposition the ferritin levels lose their accuracy as a measure of iron stored. In sickle cell anemia, iron overload is not as frequent or as severe as in thalassemia. However, the available data are insufficient for an effect of iron to be excluded as the causation of PXE/AS. In this connection it is interesting to note that two instances of AS have been reported in primary hemochromatosis [20]; the coexistence of two very rare conditions may not be fortuitous, but no other relevant studies are known to us. Penicillamine, a chelating substance, has been reported [ 151 and held to be responsible for the induction of skin lesions similar to those of PXE in a few patients (who had neither AS nor a family history of PXE). As stated earlier, in our study statistical analysis showed that chelation therapy with desferrioxamine did not seem either to protect against or to induce the development of these manifestations; 12 patients with PXE/AS had, in fact, never received chelation therapy. Although the sickling and thalassemic disorders have a different underlying pathogenesis, they share the component of causing oxidative damage through production of oxygen free radicals; one could speculate that this is the common denominator for the causation of the PXE-like lesions. One should add that the exact molecular defect in the structure and/or metabolism of elastin in cases of genetic or otherwise acquired PXE has still not been identified [ 191. In the light of the present report, further manifestations may be seen: in fact, an ongoing study in our patients reveals that another frequent component of the genuine PXE syndrome, namely, vascular calcifica-

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tion, can also be observed. As a corollary, heart valvular calcifications have already been reported [21]. More comparative and extensive data are needed, which should include other iron storage disorders as well as other hemoglobinopathies such as a-thalassemia intermedia; interestingly, AS have been reported in a single case of hemoglobinopathy H [22]. Such studies would provide useful information not only for thalassemia and allied conditions, but also for the primary PXE syndrome. ACKNOWLEDGMENTS

Thanks are due to Professor I. Nicolis of the Dermatology Department, University of Athens, for his help in carrying out the histological examination. REFERENCES 1 Gibson JM, Roychauduri P, Raenthal AR: Angioid streaks in a case of

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