Lipoid proteinosis: a case series from Istanbul

Medical genetics: Report Oxford, UK International IJD Blackwell 1365-4632 45 Publishing Journal Ltd, Ltd of Dermatology 2006

Lipoid proteinosis: a case series from Istanbul Lipoid proteinosis Baykal Report et al.

Can Baykal, MD, Zeynep Topkarci, MD, K. Didem Yazganoglu, MD, Gülsevim Azizlerli, MD, and Betül Baykan, MD

From the Departments of Dermatology and Neurology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey Correspondence Can Baykal, MD Department of Dermatology Istanbul Medical School Istanbul University Millet cad, 34393 Çapa Istanbul Turkey E-mail: [email protected]

Abstract Background Lipoid proteinosis (LP) is a very rare genodermatosis. The literature on LP consists of case reports only. As we have observed 14 LP patients belonging to nine different families in the last 15 years in our practice, we decided to review all reported Turkish LP patients in this 15-year period, and noted 37 diagnosed cases. The reasons for this relatively large number of cases, the clinical features of the patients, and the associations of LP with other clinical conditions are described in this article. Methods Fourteen LP patients followed in our university clinic in Istanbul were scrutinized with regard to their demographic and clinical features. Diagnoses were established using clinical features, with histopathologic confirmation in 13 cases. Results All but one of the patients had a history of consanguinity, or at least a marriage of parents from the same village. Typical cutaneous signs of LP and hoarseness of the voice were observed in all patients. Two patients of the same pedigree had insulin-dependent diabetes mellitus (IDDM), two patients from two different pedigrees had short stature, one patient had multinodular toxic goiter, and one patient had celiac disease. Conclusion LP is not rare in Turkey as consanguineous marriage is still a social problem, especially in some rural areas. The disease is not limited to a particular geographic region in Turkey. Short stature was observed in two cases from two different families, an association not reported previously; the association of LP with IDDM in one pedigree was thought to be coincidental.

Introduction

Materials and Methods

Some genodermatoses, such as neurofibromatosis and tuberous sclerosis, are relatively common diseases in dermatologic practice. Lipoid proteinosis (LP), characterized by the intracellular deposition of an amorphous hyaline material, causing multisystem involvement, is an extremely rare autosomal recessive disease,1 although its actual incidence is not known.2 We have observed 14 LP patients belonging to nine different families in our university clinic since 1990 (five have been reported elsewhere).3–5 In the current study, we reviewed all reported Turkish patients with a diagnosis of LP between 1991 and 2005 from the relevant literature, including national congress reports.6–23 The total number of LP patients reached 37, including our nine newly diagnosed patients. This number is relatively high as reports in the literature consist of only anecdotal case reports or small series. The reasons for this relatively large number of cases are discussed, and the associations of LP with other clinical conditions, such as diabetes, epilepsy, or short stature, are described.

The demographic, epidemiologic, and clinical findings of 14 LP patients followed in our clinic between 1990 and 2005 were

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reviewed. The diagnosis was established clinically, and confirmed by histopathologic examination in 13 cases. Biopsy could not be performed in one case (Case 12) and the diagnosis was established solely on typical clinical findings in this case. Further investigations included ear–nose–throat and neurologic examinations; skull X-rays and computed tomography of the brain were also performed.

Results The clinical features of the 14 patients are summarized in Table 1. The patients came from seven different areas of Turkey. Thirteen of the patients had a history of consanguinity, or at least a marriage of parents from the same small, isolated village. All patients had typical cutaneous signs of LP (Fig. 1a– g) and hoarseness of the voice. Hyaline deposition was shown in eight patients by laryngoscopic examination (Fig. 2a). Four patients had abnormal neurologic findings, International Journal of Dermatology 2007, 46, 1011– 1016

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Table 1 Clinical features of the patients diagnosed with lipoid proteinosis at the Istanbul Medical Faculty between 1991 and 2005 Case

Age (years)

Sex

City of birth

Type of marriage

Neurologic findings

Other findings

1*

35

F*

Sivas

CM

2* (Family 1; sisters) 3* (Family 2) 4 (Family 3) 5 6 (Family 4; sisters) 7† 8† (Family 5; brother/sister) 9 10 (Family 6; sister/brother) 11 12 (Family 7; cousins) 13 (Family 8) 14 (Family 9)

32 43 19 10 12 14 12

F* M* M F F M F

Sivas Corum Amasya Trabzon Trabzon Sivas Sivas

CM SV Unrelated CM CM CM CM

TLE with bilateral mesial temporal lobe calcifications Calcification Normal Normal Normal Normal Normal Normal

Celiac disease, multinodular toxic goiter – – – – – – –

25 24

F M

Batman Batman

CM CM

Diabetes Diabetes, short stature

12 6

M M

Corum Corum

SV SV

Normal TLE with bilateral mesial temporal lobe calcifications Calcification Not investigated

14 34

F M

Rize Istanbul

SV SV

Normal Calcification

– –

Short stature –

CM, consanguineous marriage; F, female; M, male; SV, marriage from same village; TLE, temporal lobe epilepsy. *Reported previously by us.3,4 †Reported previously by others.5

Figure 1 Cutaneous signs of lipoid proteinosis. (a) Tiny yellow papules. (b) Pearly papules on the eyelids. (c) Diffuse yellow plaques.

(d) Waxy papules and plaques on the axilla. (e) Acneiform scars. (f) Varioliform scars. (g) White infiltrated plaques on the oral mucosa

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Baykal et al.

Lipoid proteinosis Medical genetics: Report

Figure 2 Diagnostic examination of lipoid

proteinosis. (a) Hyaline deposition by laryngoscopic examination. (b) Temporal lobe calcification on direct cranial radiography. (c, d) Typical bilateral mesial temporal lobe calcification was seen on cranial computed tomography, which is a diagnostic sign of lipoid proteinosis

Figure 3 Pedigree of a family with lipoid proteinosis (two patients) associated with insulin-dependent diabetes mellitus (two patients)

and extreme short stature (index patient showing all three manifestations). The parents had a consanguineous marriage (Family 6)

including temporal lobe epilepsy with simple and complex partial seizures in two patients (associated with bilateral mesial temporal lobe calcifications; Fig. 2b–d); the other two patients had the same type of characteristic calcification but did not have any seizures (Table 1). Various endocrinologic problems were also observed: two patients had insulindependent diabetes mellitus (IDDM), and one patient had multinodular toxic goiter. Celiac disease was diagnosed in one patient. IDDM appeared only in one pedigree, shown in Table 1 and Fig. 3. Short stature was found in two © 2007 The International Society of Dermatology

patients from two different pedigrees: Patient 10 (age, 24 years; height, 151 cm) and Patient 11 (age, 12 years; height, 128 cm) in Table 1 are below the third percentile according to Turkish height percentiles.24 There were no other abnormalities associated with short stature. Discussion LP, first described by Urbach and Wiethe2 in 1929, is also known as Urbach–Wiethe disease or hyalinosis cutis et International Journal of Dermatology 2007, 46, 1011– 1016

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No

Reference

Age (years)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

Eksioglu et al.9 Alpan et al.10 Ozgoztaßı et al.11 Cinaz et al.12 Alpay et al.13 Alpay et al.13 Guven Yılmaz et al.14 Guven Yılmaz et al.14 Bozdag et al.15 Ozkan et al.16 Akca et al.17 Sezer et al.18 Kaya et al.19–21 Kaya et al.19–21 Oz et al.7 Oz et al.7 Arca et al.22 Baykır et al.23 Acar et al.6 Acar et al.6 Acar et al.6 Acar et al.6 Parlak et al.8

10 23 11 6 19 20 9 11 21 25 21 32 3 13 9 21 21 12 13 15 8 12 40

Baykal et al.

Sex

Type of marriage

Reporting center

Neurologic findings

M M M F M M F F M F M M F F F F M F F F M M F

CM ? CM ? ? CM CM CM CM ? NM ? ? ? ? ? CM ? ? ? ? ? CM

Ankara Kayseri Gaziantep Ankara Trabzon Trabzon Ankara Ankara Izmir Izmir Ankara Eskisehir Mersin Mersin Istanbul Istanbul Ankara Ankara Ankara Ankara Ankara Ankara Bolu

_ _ Calcification _ _ _ _ _ _ _ Calcification _ _ Calcification _ ? Calcification _ _ _ _ _ _

Table 2 Previously reported lipoid

proteinosis patients from Turkey*

CM, consanguineous marriage; F, female; M, male; NM, nonconsanguineous marriage; ?, not stated. *Our cases are not included in this table.

mucosae. The exact pathogenesis of this genodermatosis is currently unknown, but it has been found to be associated with a disturbance of collagen metabolism, with a decrease in type 1 collagen and an increase in type 4 collagen, resulting in deposits in the dermis and around the blood vessels and appendages.25 The gene for LP was mapped by Hamada26,27 in 2002 to the 1q21 locus, and the responsible gene is the extracellular matrix protein 1 gene (ECM1). ECM1 presumably has important physiologic and biologic roles in aspects of epidermal differentiation, binding of dermal collagens and proteoglycans, and in the regulation of angiogenesis.28 The exact biologic function of ECM1 and its initiating role in the pathomechanisms of LP are still unknown. Despite these important developments in genetic understanding, epidemiologic data on the disease are limited. Although LP is seen worldwide, there have been no reports of large series. Approximately 250 patients from different countries have been described in the English literature.7 Most of the relevant reports are from European countries; however, a few patients have been reported from India,29,30 Sri Lanka,31 USA,32,33 Brazil,34 Argentina,35 Japan,36 China,37 Pakistan,38 and Saudi Arabia.39 Findlay et al.,40 in 1966, noted that large pedigrees of LP had been reported in South Africa, and that most of these cases were descendants of German immigrants. In 1971, Heyl41 also emphasized that LP was most prevalent International Journal of Dermatology 2007, 46, 1011–1016

amongst descendants of German or Dutch immigrants in South Africa. Our university clinic, which is an important dermatology referral center in Turkey, receives 20,000 patients per year. As 14 LP patients have been observed in the last 15 years, we reviewed all reports from Turkey. In our literature search, we found reports concerning 23 further patients from different clinics (excluding the cases reported in our clinic) throughout Turkey (Table 2). Of these reported cases, 12 were published in the English literature6–8,12,15,17,19–21, six were published in the Turkish literature,9–11,13,22 and five patients were presented in national congresses only.5,14,16,18,23 The reports originated from medical centers in 10 different cities in Turkey, but the places of birth of the patients were not stated in most cases. The fourteen patients seen in our clinic were from nine different families and seven different cities in various geographic regions of Turkey (Table 1). Three of our patients have been described by us previously in the German literature,3,4 and two patients by another clinic as a national congress report.5 Including our nine newly diagnosed patients, the total number of reported LP patients from Turkey reaches 37, suggesting that LP is not that rare in Turkey. The different places of birth of our patients and the various reporting centers of other LP patients summarized in Table 2 demonstrate that the disease is not limited to a particular geographic region of Turkey. © 2007 The International Society of Dermatology

Baykal et al.

Unfortunately, consanguineous marriages are still common in Turkey,42 and, for this reason, autosomal recessive diseases are more commonly seen, which is also the case for LP. Studies indicate that the frequency of consanguineous marriages is in the range 11.5–46% in the eastern part of the country, decreasing to 11.7% in the west.42,43 All but one of our patients had either a family history of a consanguineous marriage or a marriage of parents from the same village. LP mainly involves the skin and mucous membranes of the upper aerodigestive tract, as well as the central nervous system, lung, lymph nodes, and striated muscles.44 Infantile hoarseness of the voice is a common presenting feature of the disease as a result of infiltration of the larynx.44 In most cases, the first manifestation involves voice changes in early infancy.44 All of our patients with LP had various types of skin lesion (Fig. 1a–g) and hoarseness. Two of our patients had temporal lobe epilepsy presenting with simple and complex partial seizures without generalized tonic–clonic convulsions, and four had typical symmetrical mesial temporal lobe calcifications observed on cranial computed tomography. Two of our patients also had prominent short stature, an interesting association that has not been reported previously. Two patients of the same consanguineous pedigree, shown in Fig. 3, had IDDM, which has been reported as a rare association of LP. The reported incidence of diabetes mellitus in LP patients or their relatives is 20%.45 An individual in this pedigree had IDDM, but not LP, suggesting that this relationship might be coincidental or a result of closely related but different genetic defects. The disease usually runs a benign, but slowly progressive course. Although death from respiratory obstruction has been reported in the literature, it can be avoided by early recognition of the disease and appropriate management of respiratory tract disorders.46 Although various agents have been used, no effective therapy is available for LP. Limited success has been claimed with dimethyl sulfoxide,4,37 oral corticosteroids,21 etretinate,47 and d-penicillamine.20 Facial lesions have been treated successfully by dermabrasion, chemical peeling, blepharoplasty, and CO2 laser.48–50 In conclusion, LP is not that rare in Turkey. Consanguineous marriages, still existing as a social problem, especially in some rural areas, may be the cause of this observation. Short stature was also observed in two patients from two different families, an association not reported previously. Moreover, one of the pedigrees showed that the association of LP with IDDM may be coincidental or a result of closely related but different genetic defects. Acknowledgments The authors thank Professor Dr Nesimi Buyukbabani for performing the histopathologic examinations and Professor Dr Tuncay Ulug (Ear–Nose–Throat Department) for performing © 2007 The International Society of Dermatology

Lipoid proteinosis Medical genetics: Report

the laryngoscopic examination and photographic documentation of the patients.

References 1 Gordon H, Gordon W, Botha V. Lipoid proteinosis in an inbred Namaqualand community. Lancet 1969; 1: 1032–1035. 2 Urbach E, Wiethe C. Lipoidosis cutis et mucosae. Virchows Arch Pathol Anat 1929; 273: 285– 319. 3 Ozarmagan G, Baykal C, Ozkaya E, et al. Lipoidproteinose bei zwei Schwestern. Hautarzt 1993; 44: 315 – 318. 4 Ozkaya E, Ozarmagan G, Baykal C, et al. Orale DMSO Therapie bei 3 Patienten mit Lipoidproteinose. Hautarzt 1997; 48: 477 – 481. 5 Yilmaz F, Yerebakan Ö, Ozcaglar H, et al. Iki kardeste lipoid proteinozis. In: 19 Ulusal Dermatoloji Kongresi (National Congress), Özet kitabı (Abstract Book). Nevsehir, 2002: 44. 6 Acar A, Eryılmaz A, Gocer C, et al. Lipoid proteinosis of larynx: review of four cases. Int J Pediatr Otorhinolaryngol 2004; 68: 1557–1561. 7 Oz F, Kalekoglu N, Karakullukcu B, et al. Lipoid proteinosis of the larynx. J Laryngol Otol 2002; 116: 736– 739. 8 Parlak AH, Koybası S, Boran C, et al. Lipoid proteinosis: an usual presentation with verruca vulgaris. J Dermatol 2005; 32: 751– 755. 9 Eksioglu M, Can G, Akbay G. Lipoid proteinosis. Lepra Mecmuası 1991; 22: 201– 207. 10 Alpan O, Can S, Soyuer U, et al. Lipoid proteinosis. Turkderm 1992; 26: 105–107. 11 Ozgozta$ı O, Bayraktaroglu Z, Ozsarac C, et al. Lipoid proteinosis. Turk J Dermatopathol 1993; 2: 211–213. 12 Cinaz P, Guvenir T, Gonlusen G. Lipoid proteinosis: Urbach–Wiethe disease. Acta Paediatr 1993; 82: 892–893. 13 Alpay K, Turgutalp H, Bahadır S, et al. Lipoid proteinosis. Turk J Dermatopathol 1995; 4: 119–121. 14 Guven Yılmaz B, Eskioglu F, Kasım P. Lipoid proteinosis: Urbach–Wiethe hastalı%ı. In: 17 Ulusal Dermatoloji Kongresi (National Congress), Özet Kitabı (Abstract Book). Aydin, 1998: 236. 15 Bozdag KE, Gul Y, Karaman A. Lipoid proteinosis. Int J Dermatol 2000; 39: 203–204. 16 Ozkan S, Fetil E, Erdem Y, et al. Urbach–Wiethe sayrılı%ı. In: 18 Ulusal Dermatoloji Kongresi (National Congress), Özet Kitabı (Abstract Book). Antalya, 2000: 47. 17 Akca AE, Ucok O, Akar A, et al. The role of lipoid proteinosis in gingival hypertrophy. Quintessence Int 2004; 35: 584–586. 18 Sezer E, Saracoglu Z, Urer S, et al. Lipoid proteinosis: Urbach–Wiethe disease. 3rd Congress of the Mediterranean Association of Dermatology. Abstract Book. Antalya, 2001: 32. 19 Kaya TI, Gunduz O, Kokturk A, et al. A life threatening exacerbation of lipoid proteinosis. J Eur Acad Dermatol Venereol 2002; 16: 284–301. 20 Kaya TI, Gunduz O, Kokturk A, et al. d-Penicillamine treatment for lipoid proteinosis. Pediatr Dermatol 2002; 194: 359–362. International Journal of Dermatology 2007, 46, 1011– 1016

1015

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21 Kaya TI, Gunduz O, Kokturk A, et al. The early erosive vesicular stage of lipoid proteinosis: clinical and histopathological features. Br J Dermatol 2003; 148: 363–384. 22 Arca E, Acıkgoz G, Kose O, et al. Bir lipoid proteinozis olgusu ve Türk dermatoloji literatüründe retrospektif bir çalı$ma. Turkderm 2004; 38: 62– 66. 23 Baykır M, Gungor E, Yavuzer K, et al. Lipoid proteinozis: olgu sunumu. In: 20 Ulusal Dermatoloji Kongresi (National Congress), Özet kitabı (Abstract Book). Izmir, 2004: 121. 24 Neyzi O, Ertugrul T. Büyüme–Gelisme Bozuklukları. In: Neyzi O, Günöz H, eds. Pediatri, Vol. 1. Istanbul: Nobel, 2002: 98 – 99. 25 Newton JA, Rasbridge S, Temple A, et al. Lipoid proteinosis – new immunopathological observations. Clin Exp Dermatol 1991; 16: 350–354. 26 Hamada T. Lipoid proteinosis. Clin Exp Dermatol 2002; 27: 624– 629. 27 Hamada T, McLean WH, Ramsay M, et al. Lipoid proteinosis maps to 1q21 and is caused by mutations in the extracellular matrix protein 1 gene (ECM). Hum Mol Genet 2002; 11: 833– 840. 28 Chan I, El-Zurghany A, Zendah B, et al. Molecular basis of lipoid proteinosis in a Libyan family. Clin Exp Dermatol 2003; 28: 545– 548. 29 Shivaswamy KN, Thappa DM, Laxmisha C, et al. Lipoid proteinosis in two siblings: a report from south India. Dermatol Online J 2003; 9: 12. 30 Ramanan C, Nandi BN, Iqbal MS. Lipoid proteinosis: a case report. Indian J Dermatol 1983; 28: 183– 188. 31 Chularatna W, Harendra de Silva DG, Ruberu R, et al. A Sri Lankan family with lipoid proteinosis. Ceylon Med J 1995; 40: 50 – 51. 32 Ko C, Barr RJ. Vesicular lesions in a patient with lipoid proteinosis: a probable acantholytic dermatosis. Am J Dermatopathology 2003; 25: 335– 337. 33 Cote DN. Head and neck manifestations of lipoid proteinosis. Otolaryngol Head Neck Surg 1998; 119: 144–145. 34 Staut CC, Naidich TP. Urbach–Wiethe disease (lipoid proteinosis). Pediatr Neurosurg 1998; 28: 212– 214. 35 Caccamo D, Jaen A, Telenta M, et al. Lipoid proteinosis of the small bowel. Arch Pathol Lab Med 1994; 118: 572 – 574. 36 Nagasaka T, Tanaka M, Ito D, et al. Protean manifestations

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Baykal et al.

37

38 39

40

41 42

43

44

45

46

47

48

49

50

of lipoid proteinosis in a 16-year-old boy. Clin Exp Dermatol 2000; 25: 30 – 32. Wong CK, Lin CS. Remarkable response of lipoid proteinosis to oral dimethyl sulphoxide. Br J Dermatol 1988; 119: 541– 544. Hafeez ZH, Hussain T. Lipoid proteinosis in a family. J Pak Med Assoc 1996; 46: 204– 206. Al-Bitar Y, Samdani AJ. Lipoid proteinosis in two brothers with multiple organ involvement from Saudi Arabia. Int J Dermatol 2004; 43: 360 – 361. Findlay GH, Scott FP, Cripps DJ. Porphyria and lipoid proteinosis: a clinical, histological and biochemical comparison of 19 South African cases. Br J Dermatol 1966; 78: 69– 80. Heyl T. Lipoid proteinosis in South Africa. Dermatologica 1971; 142: 129 – 132. Basaran N, Saylı BS, Basaran A, et al. Consanguineous marriages in the Turkish population. Clin Genet 1998; 4: 339– 341. Ulusoy M, Tuncbilek E. Consanguineous marriages in Turkey and their effects on child death. Nufus Bil Derg 1987; 9: 7– 26. Desmet S, Devos SA, Chan I et al. Clinical and molecular abnormalities in lipoid proteinosis. Eur J Dermatol 2005; 15: 344–346. Navarro C, Fachal C, Rodriguez C et al. Lipoid proteinosis: a biochemical and ultrastructural investigation of two new cases. Br J Dermatol 1999; 141: 326 – 331. Savage MM, Crockett DM, McCabe BF. Lipoid proteinosis of larynx: a cause of voice change in the infant and young child. Int J Pediatr Otorhinolaryngol 1998; 15: 33– 38. Gruber F, Manestar D, Stasic A, et al. Treatment of lipoid proteinosis with etretinate. Acta Derm Venereol (Stockh) 1996; 76: 154– 174. Bannerot H, Aubin F, Tropet Y, et al. Lipoid proteinosis: importance of dermabrasion. Apropos of a case. Ann Chir Plast Esthet 1998; 43: 78– 81. Buchan NG, Kemble JVH. Successful surgical treatment of lipoid proteinosis. Br J Dermatol 1974; 91: 561 – 566. Rosenthal G, Lifshitz T, Monos T, et al. Carbon dioxide laser treatment for lipoid proteinosis (Urbach–Wiethe syndrome) involving the eyelids. Br J Ophthalmol 1997; 81: 253.

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