View metadata, citation and similar papers at core.ac.uk brought to you by CORE Review Mendelian Diseases and Conditions in Croatian Island Populations: Historic Records and New Insights Vanja Saftić1, Diana Rudan2, Lina Zgaga3 1Department of Pediatrics, Osijek Among Croatian islands, there are several which are known for University School of Medicine, Croatia unusual autochthonous diseases and specific medical conditions 2Department of Internal Medicine, that result from the reproductive isolation and specific popula- Holy Ghost General Hospital, Zagreb, Croatia tion genetic structure. These populations are characterized by 3Department of Medical Statistics, high degree of genetic isolation, consanguinity, and inbreeding. Epidemiology, and Medical The reported diseases include Mal de Meleda on Mljet island, Informatics, Andrija Štampar School hereditary dwarfism on Krk island, familial learning disability of Public Health, Zagreb University on Susak island, familial ovarian cancer on Lastovo island, and School of Medicine, Croatia several other rare diseases and conditions inherited in Mende- lian fashion. We present a historical perspective on how these conditions were first described, interpreted, and assessed. We reviewed the information obtained through genetic research in the past several years, when the genetic etiology of some of these > Correspondence to: conditions was explained. The disease gene causing Mal de Me- Diana Rudan leda was first localized at 8q chromosome, and mutations in the Department of Internal ARS (component B) gene encoding SLURP-1 (secreted mam- Medicine General Hospital “Holy malian Ly-6/uPAR-related protein 1) protein were identified Ghost” subsequently. The genetic etiology of dwarfism on the island of Ulica Sveti Duh 64 Krk is explained by a mutation in the PROP1 gene, responsible 10000 Zagreb, Croatia for the short stature. The search for mutations underlying other [email protected] monogenic diseases in Croatian islands is under way. > Received: June 23, 2006 > Accepted: July 15, 2006 > Croat Med J. 2006;47:543-52 www.cmj.hr 543 Croat Med J 2006;47:543-552 Unusual autochthonous diseases and specif- The trading routes of the Dubrovnik Repub- ic medical conditions on Croatian islands result lic went toward the Middle East and North- from the reproductive isolation and specific ern Africa, as the Republic of Venice ruled the genetic structure of their populations, charac- Northern Adriatic Sea. This explains the spo- terized by high degree of genetic isolation, con- radic cases of the disease in the Middle East and sanguinity, and inbreeding. In this review, we northern Africa (14). present historical perspective on how these con- An alternative hypothesis is that the mu- ditions were first described, interpreted, and as- tation responsible for Mal de Meleda could be sessed. much older and more widespread. However, other sporadic cases of recessive palmoplantar Mal de Meleda – Mljet D��is��ea�e ���(Is��la�d �of keratoderma were reported in Sweden (15,16), Mljet) Japan (17), and a Chinese family in Taiwan (18), but their clinical presentation was milder than It was named after Croatian island of Mljet, pre- in original Mal de Meleda and some of the usu- viously called Meleda, where the first cases were al signs were absent. This implies possible found- reported by Stulli (1-4). According to Schnyder er mutations in other genes involved in the same et al (5,6), the disease originated on the island of genetic pathway. Recently, two new mutations Mljet between 1397 and 1808, when the island and four ancestral haplotypes were observed in was used by the Dubrovnik Republic for quaran- 69 patients from the countries of the Mediterra- tining people suffering from plague and leprosy nean basin, whereas an additional haplotype was (7). This resulted in reproductive isolation and found in the German and Scottish patients (19), high consanguinity, which increased the frequen- which supports the view that the disease could cy of homozygous genotypes on the island and have a possible etiological complexity and allelic thus increased the incidence of Mal de Meleda heterogeneity. (8). Among the island population, it was histori- cally thought that Mal de Meleda arises as a con- Features of disease tact dermatitis with an unknown endemic plant The first changes in keratinization of the skin on the island (6). become clinically manifest several months after birth, typically affecting palms and soles, with the History and genetic epidemiology of Mal de characteristic skin thickening (Table 1). A dif- Meleda fuse palmoplantar keratosis is the most promi- It was recently revealed that the disease is not ex- nent feature, which at first presents as yellow- clusively found on Mljet island. In the past two ish, smooth skin on palms and soles. Eventually, decades, several sporadic cases have also been re- painful fissures develop, which do not necessari- ported in Italy (9), Tunisia (10), western region of Saudi-Arabia (11), and United Arab Emirates Table 1. Features of the Mal de Meleda* (12). A recent analysis showed that Croatian and Autosomal recessive inheritance Onset at birth or in early infancy Algerian families with the disease share the com- Characteristic glove-like and sock-like hyperkeratosis with sharp margination mon haplotype that presents the same mutation Occasional hyperkeratotic plaques on elbows, knees. or corner of the in both populations (13). This is consistent with mouth Marked hyperhidrosis, maceration, and malodor a genetic epidemiological view that a causal mu- Slow progression without remissions Ortohyperkeratosis, hypergranulosis, and acanthosis on histological tation originated on Mljet at least 800 years ago, examination, with no signs of epidermal or spongiotic atypia Increased amount of tonofibrils and keratohyalin granules on electron and was then spread by sailors through trade microscopy routes of the medieval Dubrovnik Republic. *Source: references ���and ��11. 544 Saftić et al: Mendelian Diseases on Croatian Islands ly correspond to creases of the skin. Hyperkera- ed individuals, localized a disease gene to chro- tosis extends to the sides and the dorsa of the feet mosome 8qter (24). The maximum two-point and hands, and interdigital spaces are macerated, lod score for D8S1751 was found in this study, with a sharp delineation from healthy skin. An and it amounted to 8.21, which was the first po- intense hyperhidrosis produces unpleasant fetid sitional cloning of the gene region. An analysis of smell which is present only in the affected areas 5 affected individuals originating from the island of the skin (8). of Mljet confirmed the segment of homozygosi- Contractures of variable severity due to hy- ty in the same region, implying a founder effect perkeratosis are usually present on the fifth (25). A subsequent study on 12 individuals from finger, and they are associated with bilater- Mljet further confirmed the findings (8). al brachytelephalangia in the majority of cases. Subsequent pooled genetic analysis of 12 Al- Other symptoms and signs are less common and gerian kindred and 7 Croatian families with a they may involve papulous keratoses, hyperkera- denser set of genetic markers identified the mu- totic changes similar to lichenification, perioral tations in the ARS (component B) gene encod- erythema, and a cystic osteolysis and acroosteol- ing a protein SLURP-1 (secreted mammalian ysis of the wrist and tarsal bones and phalanges Ly-6/uPAR-related protein 1) (26). SLURP-1 (20). Typically, orthohyperkeratosis, hypergran- belongs to the Ly-6/uPAR receptor superfamily ulosis, and acanthosis are observed on histologi- and secreted proteins, which are known to par- cal examination, with no signs of epidermal or ticipate in signal transduction, immune cell acti- spongiotic atypia (5,20). Electron microscopy vation, and cellular adhesion. SLURP-1 shows a shows increased amount of tonofibrils and kera- high degree of structural similarity with the three tohyalin granules (20). Symptoms progress very fingers motif of snake neurotoxins, which sug- slowly and there are no indications that life ex- gests its interaction with the neuronal acetylcho- pectancy among the affected is reduced (21,22). line receptors. SLURP-1 potentiates human al- pha 7 nicotinic acetylcholine receptors present in New insights into genetic etiology keratinocytes (27). Therefore, SLURP-1 is likely The first attempt to understand the possible -ge to be a secreted epidermal neuromodulator that netic etiology of the disease was undertaken by influences both epidermal homeostasis and in- Šalamon et al (23), who analyzed MN, Ss, and hibition of tumor necrosis factor (TNF)-alpha Kk erythrocyte antigen polymorphisms in 9 pa- release by macrophages during wound healing. tients with Mal de Meleda on the island of Mljet. Such roles would explain hyperproliferative and They merely attempted to demonstrate the in- inflammatory clinical phenotype in Mal de Me- creased homozygosity in the patients in compar- leda (27). ison with control population, to show that the There is a number of clinically similar pheno- disease may be caused in some way by increased types, which can now all be easily distinguished consanguinity. However, their results were in- from Mal de Meleda based on genetic muta- conclusive due to a very small sample and a small tions involved. Papillon-Lefevre syndrom, also number of analyzed genetic markers. recessive palmoplantar keratosis, has a candi- An analysis of the pedigrees of 12 cases living