Slov Pediatr, letnik 19, 2012/ 4. Uvodnik P. Kotnik. Kemoprofilaksa perinatalne okužbe s človeškim virusom imunske pomanjkljivosti M. Arnež, L.L.

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1 Slov Pediatr, letnik 19, 2012/ 4 Uvodnik P. Kotnik Kemoprofilaksa perinatalne okužbe s človeškim virusom imunske pomanjkljivosti M. Arnež, L.L. Lah Blaschkove linije T. Bregant, V. Dragoš Izvlečki 18. srečanja Srednjeevropskega združenja za pediatrično endokrinologijo indeksira: biomedicina slovenica in COBISS ISSN

2 320 Slov Pediatr 2012; 19 VSEBINA Uvodnik P. Kotnik Kemoprofilaksa perinatalne okužbe s človeškim virusom imunske pomanjkljivosti M. Arnež, L.L. Lah Blaschkove linije T. Bregant, V. Dragoš Povzetki 18. srečanja Srednjeevropskega združenja za pediatrično endokrinologijo

3 Slov Pediatr 2012; CONTENTS Editorial P. Kotnik Chemoprophylaxis of perinatal infection with human immunodeficiency virus M. Arnež, L.L. Lah Blaschko s lines T. Bregant, V. Dragoš Abstracts from the 18 th meeting of the Middle-European Society for Paediatric Endocrinology

4 322 Slov Pediatr 2012; 19: 322 Uvodnik / Editorial ON OCCASION OF THE 18 TH MEETING OF MIDDLE-EUROPEAN PEDIATRIC ENDOCRINOLOGISTS Endocrinopathies in children are relatively rare. Accordingly, there are also relatively small numbers of pediatric endocrinologists. Therefore it makes sense for several relatively small countries, with a similar historic background, to join their resources and to cooperate in research and exchange of valuable clinical experiences in this field. Scientific collaboration in the field of pediatric endocrinology and diabetology has a long standing tradition in the Central-European and Adriatic regions. Several groups of interest were formed in this region already in the eighties, however due to several different reasons they disintegrated by the beginning of the nineties. In 1993 three esteemed pediatric endocrinologists from the region, Prof. Herwig Frisch from Vienna, Prof. Jan Lebl from Prague, and Prof. Ciril Kržišnik from Ljubljana embarked on the projects to start a workshop of Middle- European Countries on Pediatric Endocrinology. One of the main reasons for staring this workshop was to make possible for pediatric endocrinologist from Czech Republic, Slovakia, Hungary and Slovenia, countries that have not joined EU at that time, to participate in EU funded projects. First meeting was organized in St. Ozwald in 1994 and thereafter annually in a different member country. Several successful collaborative projects were started. The one on congenital adrenal hyperplasia was especially successful, culminating in several excellent publications. Following this success workgroup, was transformed into a society. This year the 18 th meeting of the Society will take place in Gozd Martuljek, Slovenia. This place was selected due to its position in the idle Alpine landscape reminiscent of the one from the first meeting in St. Ozwald. By this the organizers wanted the participant to relive the excitement from the first meeting and hopefully carry this energy forward to the future. In the last couple of years the Society has namely lost its momentum. All of the participating countries are presently members of the EU and participating centers are collaborating with centers of excellence all over the world. Regional collaborations are at the moment rare. Future of the Society is therefore at stake. At the moment the baton is being past forward, from the experienced and establishes colleagues to the younger generation, for whom this Society could be the first step to the international establishment and success. In this spirit I and my colleagues from the Department of Endocrinology, Diabetes and Metabolism, University Children s Hospital Ljubljana welcome MESPE participants to Slovenia for the fourth time. Doc. dr. Primož Kotnik, MESPE Vice-President

5 323 Slov Pediatr 2012; 19: Pregledni članek / Review article KEMOPROFILAKSA PERINATALNE OKUŽBE S ČLOVEŠKIM VIRUSOM IMUNSKE POMANJKLJIVOSTI CHEMOPROPHYLAXIS OF PERINATAL INFECTION WITH HUMAN IMMUNODEFICIENCY VIRUS M. Arnež, L.L. Lah Klinika za infekcijske bolezni in vročinska stanja, Univerzitetni klinični center Ljubljana, Ljubljana, Slovenija IZVLEČEK V prispevku predstavljamo nova priporočila za kemoprofilakso perinatalne okužbe s človeškim virusom imunske pomanjkljivosti. Ključne besede: HIV, novorojenček, perinatalna kemoprofilaksa. ABSTRACT The article presents new guidelines for chemoprophylaxis of perinatal infection with the human immunodeficiency virus. Keywords: HIV, newborn, perinatal chemoprophylaxis. UVOD Sindrom pridobljene imunske pomanjkljivosti ali AIDS (angl. Acquired immunodeficiency syndrome) je neozdravljiva infekcijska bolezen, ki jo povzroča človeški virus imunske pomanjkljivosti ali HIV (angl. human immunodeficiency virus). Bolezen lahko dobro obvladamo s protiretrovirusnimi zdravili (1). Med ljudmi se HIV prenaša horizontalno (s krvjo in s spolnimi odnosi) ter vertikalno (z okužene matere na otroka med nosečnostjo ali med porodom in z dojenjem). Incidenca, da se bo okužil otrok matere, ki ne doji, je do 25 %, otrok matere, ki doji, pa do 45 %. (2). Pri vertikalnemu prenosu okužbe traja povprečna inkubacijska doba bolezni pet mesecev. Posledica okužbe je napredujoča tkivna imunska pomanjkljivost. Resnost okužbe pri otroku opredeljujemo na podlagi kliničnih meril (simptomi in znaki) in imunoloških meril (absolutno število in odstotek celic CD4 ). Kdaj začnemo zdraviti s proti-

6 324 Slov Pediatr 2012; 19 retrovirusnimi zdravili, je odvisno od starosti otroka ob diagnosticiranju bolezni, od kliničnih in imunoloških meril ter virusnega bremena (2). V Sloveniji moramo vsako okužbo s HIV po Zakonu o nalezljivih boleznih obvezno prijaviti (3). Po podatkih Inštituta za varovanje zdravja Republike Slovenije število oseb, okuženih s HIV, po letu 2003 narašča (4). V obdobju smo v Sloveniji zabeležili skupaj 315 primerov novih okužb s HIV, in sicer 278 pri moških in 37 pri ženskah. Letna incidenca novih primerov HIV se je dvignila s 7,0/ prebivalcev na 23,5/ prebivalcev (4). O možnostih preprečevanja okužbe s HIV pri novorojenčku smo v slovenski strokovni literaturi že pisali (1, 5). V obdobju nismo zasledili nove prijave okuženega otroka, ki bi se rodil materi, okuženi s HIV (4). To je verjetno posledica nizke incidence okužbe s HIV v nosečnosti in izvajanja ukrepov za preprečevanje okužbe s HIV pri novorojenčku. V tem obdobju je kemoprofilakso ob rojstvu prejel en otrok matere z znano okužbo. Učinkovite imunoprofilakse za preprečevanje okužbe s HIV še nimamo (6). Prav tako v Sloveniji nimamo obveznega presejalnega testiranja na okužbo s HIV med nosečnostjo. Perinatalne kemoprofilakse so zato deležne nosečnice (in novorojenčki) z znano okužbo in nosečnice, pri katerih okužbo s HIV odkrijemo slučajno ob porodu. V prispevku želimo predstaviti nova priporočila za kemoprofilakso perinatalne okužbe s HIV. KEMOPROFILAKSA PERINATALNE OKUŽBE S HIV PRI NOVOROJENČKU Z MAJHNIM TVEGANJEM ZA OKUŽBO Novorojenčki, katerih matere so med nosečnostjo prejemale učinkovita protiretrovirusna zdravila, imajo majhno tveganje za okužbo s HIV. Priporočila za kemoprofilakso pri novorojenčkih z majhnim tveganjem za okužbo s HIV prikazujemo v Tabeli 1 (7). Tabela 1. Kemoprofilaksa perinatalne okužbe s človeškim virusom imunske pomanjkljivosti pri novorojenčku z majhnim tveganjem za okužbo (7). Table 1. Chemoprophylaxis of perinatal infection with the human immunodeficiency virus in newborns with low risk of infection (7). Porodnica Odmerek Trajanje** ZDV novorojenček ZDV intravensko 2 mg/kg TT v eni uri, nato 1 mg/kg TT/uro v trajni infuziji 35 GT: oralno* 4 mg/kg TT/12 ur (intravensko 1,5 mg/kg TT/6 ur) <35 30 GT: oralno* 2 mg/ kg TT/12 ur (intravensko 1,5 mg/kg TT/12 ur); v starosti 2 tedna povečamo na 2 mg/ kg TT/8 ur <30 GT: oralno* 2 mg/kg TT/12 ur (intravensko 1,5 mg/kg TT/12 ur); v starosti 4 tedni povečamo na 2 mg/ kg TT/8 ur od začetka do konca poroda šest tednov šest tednov šest tednov ZDV: zidovudin (Retrovir ); TT: telesna teža; GT: gestacijski teden; * sirup 10 mg/1 ml; ** prvi odmerek čim prej po rojstvu, priporočljivo v 6 12 urah po rojstvu. ZDV zidovudine (Retrovir ); TT body weight; GT gestation weeks; * syrup 10 mg/1 ml; ** first dose as soon as possible, preferably within 6 12 hours of delivery. KEMOPROFILAKSA PERINATALNE OKUŽBE S HIV PRI NOVOROJENČKU Z VELIKIM TVEGANJEM ZA OKUŽBO Novorojenčki z velikim tveganjem za okužbo s HIV so: novorojenčki, katerih matere so prejemale protiretrovirusna zdravila med nosečnostjo in med porodom, vendar ta niso bila učinkovita (HIV RNA PCR >400 kopij/ml krvi); novorojenčki, katerih matere so prejemale protiretrovirusna zdravila med porodom, ne pa tudi med nosečnostjo; novorojenčki, katerih matere niso prejemale protiretrovirusnih zdravil med nosečnostjo niti med porodom; novorojenčki, katerih matere so okužene s HIV, ki je odporen na protiretrovirusna zdravila.

7 Slov Pediatr 2012; Priporočila za kemoprofilakso pri novorojenčkih z velikim tveganjem za okužbo s HIV prikazujemo v Tabeli 2 (7). Kemoprofilakso mora pred porodom odobriti infektolog. Nosečnici, ki ima neposredno pred porodom viremijo >1000 kopij/ml, svetujemo elektivni carski rez v 38. tednu nosečnosti. Kemoprofilaksa kasneje kot 48 ur po rojstvu ni več učinkovita in je zato ne priporočamo. Tabela 2. Kemoprofilaksa perinatalne okužbe s človeškim virusom imunske pomanjkljivosti pri novorojenčku z velikim tveganjem za okužbo (7). Table 2. Chemoprophylaxis of perinatal infection with the human immunodeficiency virus in newborns with high risk of infection (7). Porodnica Odmerek Trajanje ZDV intravensko 2 mg/ kg TT v eni uri, nato 1 mg/kg TT/uro v trajni infuziji od začetka do konca poroda novorojenček ZDV in NVP ZDV enako kot v Tabeli 1 enako kot v Tabeli 1 NVP PT g: oralno* 8 mg/ odmerek PT >2000 g: oralno* 12 mg/odmerek tri odmerke v sedmih dneh: prvi odmerek v 48 urah po rojstvu drugi odmerek 48 ur po prvem odmerku tretji odmerek 96 ur po drugem odmerku ZDV: zidovudin (Retrovir ); TT: telesna teža; NVP: nevirapin (Viramune ) ni na voljo v Sloveniji; PT: porodna teža; * suspenzija 50 mg/5 ml. ZDV zidovudine (Retrovir ); TT body weight; NVP nevirapine (Viramune )-not available in Slovenia; PT birth weight; * suspension 50 mg/5 ml SLEDENJE OTROKA S TVEGANJEM ZA OKUŽBO S HIV, KI PREJEMA KEMOPROFILAKSO Do dokončnega diagnosticiranja okužbe pri otroku materi odsvetujemo dojenje (5, 7). Pri otroku z majhnim tveganjem za okužbo s HIV opravimo pregled krvi za krvno sliko in PCR HIV DNA v prvih dneh življenja. PCR HIV DNA v krvi ponovimo pri 1 2 mesecih in pri 4 6 mesecih življenja. Pri otroku z velikim tveganjem za okužbo s HIV opravimo pregled krvi za krvno sliko, jonogram in hepatogram ter PCR HIV DNA takoj po rojstvu. Okužba s HIV lahko z veliko verjetnostjo izključimo, če je rezultat PCR HIV DNA v krvi otroka dvakrat zapored negativen (prvič v starosti 14 dni in drugič v starosti 1 mesec). Okužba s HIV je izključena, če je rezultat PCR HIV DNA v krvi dvakrat zapored negativen (prvič v starosti 1 mesec in drugič v starosti 4 mesece) in je rezultat serumskih specifičnih protiteles pri otroku v starosti 18 mesecev negativen. Okužbo s HIV potrdimo, če je rezultat PCR HIV DNA v krvi dvakrat pozitiven. Pri otrocih s potrjeno okužbo svetujemo genotipizacijo in/ali fenotipizacijo HIV, odpornost virusa na protiretrovirusna zdravila ter serološko testiranje na druge povzročitelje infekcijskih bolezni (človeški citomegalovirus, virus herpes simpleks, virus hepatitisa C, Treponema pallidum, Toxoplasma gondii) in Mycobacterium tuberculosis (7). Takoj uvedemo protiretrovirusno zdravljenje, in sicer ne glede na klinična, imunološka in virološka merila (2). V starosti 4 6 tednov začnemo s preventivnim zdravljenjem proti pljučnici, povzročeni s Pneumocystis jirovecii (5, 7). Kemoprofilaksa perinatalne okužbe s HIV ni povsem brez nevarnosti. Pri % otrok na kemoprofilaksi se pojavi anemija. Zidovudin (nukleozidni inhibitor revezne transkriptaze) sam ali v kombinaciji z nevirapinom (nenukleozidni inhibitor revezne transkriptaze) povzroči pri 15 % otrok na kemoprofilaksi srednje hudo do hudo nevtropenijo. Nevirapin lahko povzroči tudi kožno alergijo in okvaro jeter. Vse otroke, pri katerih se med kemoprofilakso pojavi nepojasnjena huda okvara osrednjega živčevja ali srca, moramo pregledati na prirojene mitohondrijske bolezni (7). Vse otroke, ki so bili v maternici in/ali po rojstvu izpostavljeni protiretrovirusnim zdravilom, moramo zaradi morebitnih poznih neugodnih učinkov zdravil (kancerogenost) spremljati do odraslosti.

8 326 Slov Pediatr 2012; 19 LITERATURA 1. Matičič M, Gregorčič S, Vovko T, Tomažič J. Pogoste indikacije za protivirusno kemoprofilakso. V: Beović B, Strle F, Tomažič J editors. Novosti v infektologiji. Preprečevanje okužb: imunoprofilaksa in kemoprofilaksa. Infektološki simpozij 2012, 2012 mar; Ljubljana. Ljubljana: Slovensko zdravniško društvo, Sekcija za protimikrobno zdravljenje, 2012; Smith S. Infectious diseases. HIV and AIDS. V: Marcdante KJ, Kliegman RM, Jenson HB, Behrman RE, eds. Nelson essentials of pediatrics. 6th ed. Philadelphia: Saunders, 2011; Zakon o nalezljivih boleznih /ZNB/. Ur. l. RS, št. 69/ Klaus I, Kustec T, Kastelic Z. Okužba s HIV v Sloveniji v letu Ljubljana: Inštitut za varovanje zdravja, Dostopno na: Arnež M. Novosti v pediatrični infektologiji. V: Beović B, Strle F, Čižman M editors. Okužbe pri transplantirancih. Novosti v infektologiji. Infektološki simpozij 2005; 2005 mar; Ljubljana. Ljubljana: Slovensko zdravniško društvo, Sekcija za kemoterapijo, 2005; Tomažič J, Poljak M. Cepivo proti HIV. V: Beović B, Strle F, Tomažič J editors. Novosti v infektologiji. Preprečevanje okužb: imunoprofilaksa in kemoprofilaksa. Infektološki simpozij 2012, 2012 mar; Ljubljana. Ljubljana: Slovensko zdravniško društvo, Sekcija za protimikrobno zdravljenje, 2012; CDC. Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States Dostopno na: guidelines Kontaktna oseba / Contact person: Izr. prof. dr. Maja Arnež, dr. med., specialistka pediatrije in infektologije Klinika za infekcijske bolezni in vročinska stanja Univerzitetni klinični center Ljubljana Japljeva Ljubljana Tel.: Fax: Elektronski naslov: maja.arnez@kclj.si Prispelo / Received: Sprejeto / Accepted:

9 327 Slov Pediatr 2012; 19: Pregledni članek / Review article BLASCHKOVE LINIJE BLASCHKO S LINES T. Bregant 1, V. Dragoš 2 (1) Klinični oddelek za otroško, mladostniško in razvojno nevrologijo, Pediatrična klinika, Univerzitetni klinični center Ljubljana, Ljubljana, Slovenija (2) Klinični oddelek za otroško dermatologijo, Dermatovenerološka klinika, Univerzitetni klinični center Ljubljana, Ljubljana, Slovenija IZVLEČEK Blaschkove linije predstavljajo vzorec na koži in sluznicah, ki ga lahko razkrijejo raznovrstne nevoidne tvorbe ali kožne bolezni. Prvič jih je opisal nemški dermatolog Blaschko pred več kot 100 leti. Od ostalih linearnih vzorcev kot so Voightove ali Langerjeve linije ali pa dermatomi, se razlikujejo, saj ne sledijo poteku žil, živcev ali limfe. Vzrok leži v mozaicizmu, ki ga lahko prepoznamo pri kongenitalnih kožnih boleznih, nevoidnih tvorbah kot je linearni nevus sebaceous ali pridobljenih kožnih boleznih kot je lichen striatus in linearna psoriaza. V članku predstavimo bolezen incontinentia pigmenti, kjer prav videz kože z lezijami v poteku Blaschkovih linij omogoči postavitev pravilne diagnoze. Ključne besede: Blaschkove linije, embriologija, incontinentia pigmenti, koža, otroci. ABSTRACT Blaschko's lines are the pattern assumed by different naevoid and acquired skin diseases on the human skin and mucous membranes. They were described and drawn by a German dermatologist, Blaschko, more than 100 years ago. These lines are to be distinguished from other linear patterns, such as Voight's lines, Langer's lines, and the lines of dermatomes, as they do not follow the course of nervous, vascular or lymphatic structures in the skin. The cause of the distribution is a form of mosaicism, which can be manifested in a congenital skin diseases, many naevoid skin conditions such as linear sebaceous naevus or many of the acquired skin diseases, such as lichen striatus and linear psoriasis. In the article we present Incontinentia pigmenti as an example of a disease, where the skin lesions, which follow Blaschko s lines, enable us to make the correct diagnosis. Key words: Blaschko s lines, embryology, skin, incontinentia pigmenti, children.

10 328 UVOD Med razvojem ploda celice epidermisa proliferirajo in migrirajo na svoja končna mesta v koži. To že pri novorojenčku lahko opazimo kot Blaschkove linije. Vzorec lahko opazimo tudi kasneje, pri nevoidnih spremembah ali pri pridobljenih kožnih boleznih. Čeprav se na prvi pogled zdi, da se spremembe nahajajo v dermatomu, temu ni tako. Blaschkove linije ne sledijo poteku živcev, žil ali limfe. V zgornjem delu trupa spominjajo na črko V, ki ima vrh točno v sredini trupa oziroma na trnastih odrastkih hrbtenice, ter se nato kot zvrnjena črka U razširijo na roke; na trebuhu imajo črte obliko črke S, na nogah pa so nakazano vzporedne obrisu nog. Črte se na sprednjem delu trupa združijo in potekajo po sredini ter ne prehajajo na drugo polovico telesa (Slika 1). Praviloma jih ne vidimo. Opazimo jih lahko šele kot posledico podedovanih ali pridobljenih kožnih bolezni oz. stanj, ki s sebi lastno morfologijo razkrijejo potek teh linij (1). Blaschkove linije se imenujejo po nemškem zdravniku Alfredu Blaschku ( ), ki je svoje življenje posvetil dermatologiji. Ukvarjal se je s poklicnimi dermatozami in preprečevanjem spolno prenosljivih bolezni. Ustanovil je nemško Ligo proti veneričnim boleznim. Vzorec Blaschkovih linij je predstavil na sedmem kongresu Nemškega združenja dermatologov leta 1901 v kraju Breslau. Opisal jih je kot linearne dermatoze, ki pri odraslih bolnikih nimajo anatomskega vzroka, pač pa najverjetneje embrionalnega, in ne sledijo poteku žil ali živcev. Blaschko je tudi opisal, da je vzorec pri različnih bolnikih presenetljivo enak in da se pojavlja pri različnih boleznih, kar ga je navedlo na razmišljanje o embrionalnih vzrokih tega pojava (3). VZROK NASTANKA BLASCHKOVIH LINIJ Kloni genetsko identičnih celic, ki so nastale iz embrionalnega ektoderma, sestavljajo Blaschkove linije. Ti kloni že zgodaj v embrionalnem razvoju sledijo stereotipni ekspanziji in migraciji, ki je določena tako genetsko kot s položajem v embriju. Pri večini posameznikov se kloni med seboj neznatno razlikujejo oziroma Blaschkovih linij zaradi alelnih različic sploh ne opazimo. Pri nekaterih posameznikih zaradi mozaicizma pride do razlikovanja med posamičnimi kloni, kar se na koži izrazi kot Blaschkove linije. Najbolj pogosti vzroki za mozaicizem so lionizacija inaktivacija kromosoma X pri ženskah, somatska mutacija, epigenetski mehanizmi in redka oblika tetragametnega himerizma. Slika 1. Blaschkove linije na obrazu in telesu (prirejeno po (2)). Figure 1. Blaschko's lines on the face and body (adapted from (2)). Kljub temu, da so Blaschkove linije manifestacija genetskega mozaicizma, pa je to izredno težko dokazati. Celo v vzorcih kožnih biopsij pogosto ugotavljamo mešanico celic dveh genotipov in le v vzorcih linearne epidermolitične hiperkeratoze so uspeli dokazati mutirani klon v obarvani koži (4). Blaschkove linije tako najverjetneje lahko pripišemo mutaciji v genih, ki se izražajo v epidermalnih celicah, torej keratinocitih in melanocitih, ne pa v dermalnih fibroblastih (5). PREPOZNAVANJE BLASCHKOVIH LINIJ Blaschkove linije pri večini ljudi predstavljajo nevidni linearni vzorec na koži, ki ga lahko opazimo šele pri nevoidnih spremembah ali pri pridobljenih kožnih bolezni. Pri nekaterih redkih dednih bolezni pa so prav te črte lahko opozorilo, da ima novorojenček morda sistemsko bolezen (Tabela 1).

11 Slov Pediatr 2012; Od ostalih linearnih sprememb na koži (Tabela 2) moramo poleg Blaschkovih linij razlikovati spremembe, ki potekajo po dermatomih, in fiziološke Voightove ali Futcherjeve linije (6). Kadar smo v dvomu, vedno sledimo črti. Blaschkove linije namreč ne sledijo poteku živcev, žil ali limfe in z izjemo lumbalnega predela ter skalpa ne prečkajo sredine telesa. Zanimivo, da so opisali tudi ekvivalent Blaschkovih linij na zobeh in očeh (7). Incontitentia pigmenti ali Bloch-Sulzbergerjev sindrom (tudi Bloch-Siemensov sindrom ali melanoblastosis cutis linearis) je redka, na kromosom X vezana dominantna bolezen, za katero so značilne spremembe osrednjega živčevja, zob, oči in kože. Bolezen je pri moških plodih smrtonosna in se konča s splavom oziroma z mrtvorojenostjo. Le izjemoma ugotavljamo bolezen pri moških s Klinefelterjevim sindromom (47, XXY) oziroma kot posledico spontane mu- Tabela 1. Kožne spremembe, ki lahko razkrijejo potek Blaschkovih linij. Vrstni red je določen glede na pojavljanje od najbolj pogostih do redkih kožnih sprememb. Table 1. Inherited and some acquired skin conditions that are distributed along Blaschko s lines. They are listed according to their occurrence rate, from the most common to the rarest. Prirojene kožne spremembe Pridobljene kožne spremembe epidermalna znamenja pigmentne spremembe na kromosom X vezane dominantne kožne bolezni keratinocitni nevusi linearni verukozni epidermalni nevusi ILVEN (angl. Inflammatory Linear Verrucous Epidermal Naevus) organoidni nevusi (nevus sebaceous) neorganoidni nevusi naevus achromicus (vključuje Hypomelanosis Ito) McCune Albrightov sindrom incontinentia pigmenti fokalna dermalna hipoplazija sindrom CHILD (angl. Congenital Hypoplasia with Ichthyosiform naevus and Limb defects) sindrom MLS (angl. Microphthalmia with Linear Skin defects) orofaciodigitalni sindrom tipa 1 lichen striatus linearna morphoea linearni lichen planus linearna oblika psoriaze linearni kutani eritematozni lupus Tabela 2. Linearni vzorci na koži. Table 2. Linear skin patterns. Linearni vzorec Opis Pomen Voightove ali Futcherjeve linije fiziološka demarkacija med temno in svetlo kožo, pogosto nad bicepsom ali zgornjim delom trupa, lahko poteka fiziološka različica pri temno pigmentiranih posameznikih, črncih, Azijcih; včasih vidne med nosečnostjo navpično ali obročasto Langerjeve ali Kraisslove linije topološke črte, ki označujejo naravni potek kolagenskih vlaken v dermisu, določene na truplih; pri živih posameznikih jih imenujemo Kraisslove črte plastična kirurgija, forenzična medicina Dermatomi Blasckhove linije področja kože, ki jih oživčuje določena živčna korenina oziroma določen spinalni živec praviloma nevidne linije, ki jih sestavljajo kloni epidermalnih celic in ne sledijo poteku živcev, žil ali limfe virusi, npr. Herpes zoster, ki hibernirajo v spinalnih ganglijih, lahko povzročijo bolečino ali izpuščaj, ki poteka po dermatomu genetski mozaicizem

12 330 Slov Pediatr 2012; 19 tacije somatskega mozaicizma (normalni kariotip 46, XY). Pri nekaterih preživelih moških dojenčkih z boleznijo incontinentia pigmenti najdemo manj težke (hipomorfne) mutacije, ki se kažejo z ektodermalno displazijo in imunsko pomanjkljivostjo. 1. najzgodnješo vezikularno z rdečimi, mehurjastimi spremembami, ki sledijo Blaschkovim linijam in se pojavljajo takoj po rojstvu ali v prvih tednih življenja; prisotna je lahko eozinofilija (Slika 2); 2. verukozno s pustularnimi in z verukoznimi spremembami ter s hiperpigmentacijami, ki sledi vezikularnemu obdobju in praviloma izzveni v prvem letu življenja (Sliki 3a, 3b); 3. hiperpigmentirano obdobje, ko se koža v značilnem vzorcu obarva modro-sivo ali rjavo in se pojavi nekaj mesecev po rojstvu (Slika 4); 4. atrofično/hipopigmentirano obdobje, ko se koža brazgotini in postane bleda, ter navadno ni poraščena; to obdobje vztraja v odraslo dobo in se razvije pri % bolnikov. Slika 2. Novorojenček z vezikularno obliko bolezni incontinentia pigmenti. Rdeče, mehurjaste kožne spremembe sledijo Blaschkovim linijam, ki zlasti na zgornjih udih spominjajo na potek motoričnih živčnih vlaken. Nepozorni opazovalec lahko ob tem pomisli tudi na okužbo z virusom Herpes. Figure 2. A newborn with the vesicular form of incontinentia pigmenti. Red, blister-like skin lesions follow Blaschko's lines. Particularly in the upper limbs, they seem to be grouped along the course of the motor nerve fibres. An inattentive observer may also consider a herpetic infection. Gen za bolezen incontinentia pigmenti se nahaja na kromosomu Xq28 in kodira protein, jedrni faktor KB esencialni modulatorski protein. Imenujemo ga tudi NF-kB esencialni modulator. Gen se imenuje NEMO (angl. NF kappa B essential modulator), poznamo pa ga tudi pod simbolnim imenom IKK- -gama ali IKBKG. Gen preko NEMO-kinaz vpliva na signalno transdukcijo predvsem s fosforilacijo serinskih ali treoninskih ostankov, ki jim sledi prolin. Približno 80 % vseh mutacij najdemo v regiji NEMO kot delecijo v eksonih Pri preživelih moških dojenčkih lahko najdemo manj težke, hipomorfne mutacije v tem genu (8). Kožne spremembe so prisotne ob rojstvu oziroma se pokažejo pri 90 % bolnikov v prvih tednih življenja. Kožne spremembe lahko glede na časovno pojavnost razdelimo v štiri stopnje: 3a 3b Sliki 3a, 3b. Novorojenček z verukozno obliko bolezni incontinentia pigmenti. Včasih se že pri plodu in utero pokažejo kožne vezikularne spremembe, ki se nato pri novorojenčku nadaljujejo v verukozno obliko. Spremembe se spontano celijo in za seboj lahko pustijo hiperpigmentirane predele kože. Na sliki rumenkaste kruste nekoliko spominjajo na impetigizacijo, vendar v tem primeru ne gre za okužbo.

13 Slov Pediatr 2012; Figure 3a, 3b. A newborn with the verrucous form of incontinentia pigmenti. Vesicular lesions may already be present in utero and may evolve a few weeks later into wart-like or pustular lesions. Thick crusts or scabs form over healing blisters leaving behind hyperpigmented areas of skin. As seen on the picture, the yellow crusts may remind us of impetigo, but this was not the case here. Poleg kožnih sprememb imajo bolniki lahko težave pri izraščanju zob in slabše oblikovane zobne krone. Ob displaziji mrežnice imajo lahko težave z vidom. Pri % bolnikov so lahko prisotne nevrološke težave: krči, spastičnost in umska manjrazvitost (9, 10). Vzročnega zdravljenja ne poznamo. Pri bolnikih preprečujemo predvsem zaplete v smislu sekundarne bakterijske okužbe kože, redno skrbimo za ustno higieno in zobe ter zagotavljamo nadzor s strani oftalmologa in otroškega nevrologa, saj je tveganje za razvoj epilepsije in možganske kapi pri teh otrocih večje (10). Slika 4. Pri dojenčku lahko čez nekaj tednov opazimo hkrati vezikularne, verukozne in hiperpigmentirane spremembe, ki pa ne sledijo dermatomom, ampak Blaschkovim linijam. Najtemneje obarvana območja sčasoma zbledijo. Figure 4. A few weeks later we can see in a baby vesicular, verrucous, and hyperpigmented skin lesions which are following the lines of Blaschko and not dermatomes. Heavy pigmentation tends to fade slowly with increasing age. ZAKLJUČEK Blaschkove linije so skrivni zemljevid, ki kaže zgodovino naše kože. Ob oploditvi namreč nismo določeni kot ena sama genetska diploidna različica, pač pa so naše celice podvržene različnim, tudi epigenetskim spremembam, ki nas določajo. Tako v posamični Blaschkovi liniji najdemo genetsko identične klone celic. Blaschkove linije predstavljajo vzorec embrionalne migracije kožnih celic. Včasih se spremembe na koži pojavljajo skupaj s spremembami v drugih organskih sistemih. Zato ne pozabimo na natančni in skrbni pregled kože v celoti, saj bomo le tako lahko posumili na redke, a pomembne sistemske bolezni. LITERATURA 1. Jackson R. The lines of Blaschko: a review and reconsideration. Br J Dermatol 1976; 95: Textbook of Dermatology. Rook's Textbook of Dermatology. Burns T, Breathnach S, Cox N, Griffiths C, eds. Wiley-Blackwell, Blaschko A. Die Nervenverteilung in der Haut ihrer Beziehung zu den Erkrankungen der Haut. Wien: Wilhelm Braumueller, Paller AS, Syder AJ, Chan YM, Yu QC, Hutton E, Tadini G et al. Genetic and clinical mosaicism in a type of epidermal nevus. N Engl J Med 1994; 331: Moss C. Cytogenetic and molecular evidence for cutaneous mosaicism: The ectodermal origin of Blaschko lines. Am J Med Genet 1999; 85: Somani VK, Razvi F, Sita VV. Pigmentary demarcation lines over the face. Indian J Dermatol Venereol Leprol [serial online] 2004 [cited 2012 Apr 23]; 70: Bolognia JL, Orlow SJ, Glick SA. Liones of Blaschko. J Am Acad Dermatol 1994; 31: The International IP Consortium. Survival of Male Patients with Incontinentia Pigmenti Carrying a Lethal Mutation Can Be Explained by Somatic Mosaicism or Klinefelter Syndrome. Am J Hum Genet 2001; 69(6): Kirtona A, deveber G. Therapeutic approaches and advances in pediatric stroke. Neurorx 2006; 3:

14 332 Slov Pediatr 2012; Pulst SM. Incontinentia pigmenti. In: Encyclopedia of the neurological sciences. Elsevier Science USA, 2003: Kontaktna oseba / Contact person: Tina Bregant, dr. med. Klinični oddelek za otroško, mladostniško in razvojno nevrologijo Pediatrična klinika Univerzitetni klinični center Ljubljana Bohoričeva 20 SI-1525 Ljubljana e-naslov: tina.bregant@siol.net Prispelo / Received: Sprejeto / Accepted:

15 333 ABSTRACTS FROM THE 18 TH ANNUAL MEETING OF THE MIDDLE-EUROPEAN SOCIETY FOR PAEDIATRIC ENDOCRINOLOGY (MESPE) NOVEMBER 9-11, 2012 GOZD MARTULJEK, SLOVENIA

16 334 Slov Pediatr 2012; 19: 334 IMPROVEMENT IN METABOLIC CONTROL IN LONG-TERM FOLLOW-UP OF SLOVENIAN CHILDREN AND ADOLESCENTS WITH TYPE 1 DIABETES K. Dovč, N. Bratina, T. Battelino Department of Endocrinology, Diabetes and Metabolism, University Children s Hospital, UKC Ljubljana, Ljubljana, Slovenia Background: Large studies in children and adults with type 1 diabetes have shown that long-term improvement in metabolic control plays an important role in reducing micro- and macro- vascular complications associated with diabetes. Continuous subcutaneous insulin infusion (CSII) therapy and real - time continuous glucose monitoring systems (RT-CGM) have beneficial effects on strict glucose regulation. More and more patients in different countries are improving their metabolic control with this modern technology. Subjects: In Slovenia, all children with type 1 diabetes are treated in the University Children s Hospital in Ljubljana up to the age of 25 years. In the last 12 years, CSII has become the leading therapy for children and adolescents with type 1 diabetes in our country. At present, more than 75% of all Slovenian children with diabetes are using CSII as the preferred form of insulin therapy. Among them is a small group of 35 children below the age of 6 years, who have also started to regularly use RT-CGM since Babies and toddlers start with pump treatment immediately after diagnosis. The parents of these children are very interested in using RT-CGM alongside CSII from the beginning. Results: A recent national analysis for the last 12-year period showed improved metabolic control in our patients (767 patients, 402 boys, 365 girls, mean age at diagnosis 9.42 years). The median follow-up time was 5 years. HbA1c significantly (P < 0.001) decreased over the 12-year period: from 9.25% in 2000 to 7.78% in BMI SDS showed a slight but significant decrease (0.41 to 0.39). The daily insulin dose also decreased over this period (0.76 to 0.68). The duration of CSII treatment was significantly associated with a decrease in HbA1c (P <.001). The incidence rate of severe acute complications was very low in all patients, did not change with time, and was 1.40 per 100 patient-years for severe diabetic ketoacidosis and 0.73 per 100 patient-years for severe hypoglycaemia Conclusions: The results of our analysis, which are of extreme importance for patients and the diabetic team, could be the result of improved technological possibilities and strict, comprehensive education. Subanalysis showed that even in the most vulnerable populations i.e. toddlers and patients with eating disorders, metabolic control also improved. Prospective long-term follow-up in the next decades will show the importance of this metabolic improvement for late diabetes complications.

17 Slov Pediatr 2012; Slov Pediatr 2012; 19: 335 THE PREVALENCE OF ZnT8 AUTOANTIBODIES IN CZECH CHILDREN AT THE ONSET OF TYPE 1 DIABETES MELLITUS AND DYNAMIC CHANGES IN SERUM ZnT8 AUTOANTIBODY CONCENTRATIONS OVER TIME J. Vcelakova¹, L. Petruzelkova¹, R Ananieva-Jordanova², K. Stechova¹, J. Lebl¹, P. Dušátkova¹, Z. Sumnik¹, R. Coles², M. Powell², J. Furmaniak², B. Rees Smith², S. Kolouskova¹ (1) Department of Paediatrics, University Hospital Motol, 2nd Medical Faculty, Charles University, Czech Republic (2) FIRS Laboratories, RSR Ltd, Parc Ty Glas, Llanishen, Cardiff, CF14 5DU, UK Background: Zinc transporter (ZnT8) is an important islet autoantigen in T1D. Objective: To investigate the prevalence of ZnT8Ab at T1D onset and dynamic changes in serum ZnT8Ab concentrations over time in the Czech child population. Study design: Serum samples collected at T1D onset were tested for ZnT8Ab using a new ELISA (RSR Ltd,Cardiff,UK). In addition, IAA, IA-2Ab and GADAb were tested by RIA. The study group comprised 227 patients (130 males) diagnosed with T1D in the period at our hospital. The median age at T1D onset was 8 years. Serum samples from 101 healthy children without a family history of autoimmune disease (68 males, median age 7 years) were used as controls. In addition, ZnT8Ab, IA-2Ab and GADAb were tested in 170 samples from 90 patients at the onset (within 1 month after T1D diagnosis) and at a median 1, 3, 5 and 10 years after disease onset. Results: ZnT8Ab, GADAb and IAA were detected in 163(72%), 162(71%) and 118(52%) samples, respectively. However the most frequent autoantibody was IA-2Ab, detected in 175(77%) samples. In 6 samples (3%), single ZnT8Ab positivity confirmed the T1D diagnosis. The prevalence of ZnT8Ab, IA-2Ab and IAA in healthy controls was <1%, while that of GADAb was 2%. Serum concentrations of ZnT8Ab increased with the age of T1D onset (p<0.001). However, ZnT8Ab and IA-2Ab serum levels decreased significantly in all monitored periods after T1D onset (p<0.001) compared to GADAb, which significantly decreased only during the first year after T1D onset. Duringthe disease duration of 97 months, 24% ZnT8Ab positive patients seroconverted to a negative level (p<0,001). Similarly, seroconversion was observed in IA-2Ab and GADAb levels. Conclusions: The prevalence of ZnT8Ab in the Czech child population at the onset of diabetes was 72%. The measurements of ZnT8Ab contributed to the diagnosis of autoimmune diabetes. However, the test should be carried out at the time of diagnosis of diabetes since the serum concentrations of ZnT8Ab tend to decrease over time.

18 336 Slov Pediatr 2012; 19 Slov Pediatr 2012; 19: 336 CLINICAL AND GENETIC FEATURES OF MODY IN THE SLOVENIAN POPULATION AGED UP TO 24 YEARS J. Šuput Omladič, N. Bratanič, M. Žerjav Tanšek, M. Avbelj Stefanija, P. Kotnik, N. Bratina, T. Battelino Department of Endocrinology, Diabetes and Metabolic Diseases, University Children s Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia Background: The expression MODY is used to describe a monogenic, clinically heterogenic group of disorders, characterised by dysfunction of pancreatic β-cells. The estimated prevalence of MODY amongst diabetic patients is 1-2 %. To date, there has been no report on the prevalence of MODY in Slovenia. We analysed all diabetic patients aged up to 24 years in Slovenia and discovered that MODY is present in 1 % patients. Methods: Patients with a strong family history of diabetes and clinical features of MODY underwent diagnostic genetic testing for the most common forms of MODY (glucokinase (GCK), hepatocyte nuclear factor (HNF)1-α, HNF4-α). Results: The diagnosis was confirmed in 8 out of 10 patients. Since there are 800 diabetic patients in this age group in Slovenia, the prevalence of MODY is 1 %. MODY 2 patients make up 75 % and MODY 3 patients 25 %of patients with MODY. The female: male ratio is 1:1.7, the average age at diagnosis 13 years and the average duration of illness prior to diagnosis is 2 years. All patients are so far without chronic complications and only one patient is being treated withoral drugs sulfonylurea. Conclusion: Most of the patients were diagnosed with MODY 2, which corresponds with the published data on paediatric patients in other European countries. Since only young patients aged up to 24 years were included, we believe that the total prevalence of MODY in Slovenia is considerably higher.

19 Slov Pediatr 2012; Slov Pediatr 2012; 19: 337 PLASMA INSULIN LEVELS DURING OGTT ARE POSITIVELY CORRELATED WITH HEIGHT IN BOTH OBESE PRE-PUBERTAL CHILDREN AND ADOLESCENTS IMPLICATIONS FOR OGTT INTERPRETATION M. Žakelj, Z. Velagić, T. Battelino, P. Kotnik Department of Endocrinology, Diabetes and Metabolism, University Children s Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia Bacground: There is a negative relationship between body height and glucose half-life in the intestine. Aim: To determine a possible correlation between a subject s height and levels of plasma glucose and insulin during OGTT in obese children and adolescents. Subjects and Methods: Forty-four obese pre-pubertal girls (age < 8 years, BMI 3.2 ±.1 SDS), 48 obese pre-pubertal boys (age < 9 years, BMI 3.0 ±.1 SDS), 228 obese adolescent girls (BMI 2.6 ±.1 SDS) and 169 obese adolescent boys (BMI 2.5 ±.1 SDS) were included in the study. Both pre-pubertal and pubertal boys were taller than the corresponding girls (131 ± 2 vs. 123 ± 2 and 164 ± 1 vs. 160 ± 1 cm respectively; P < 0.01). Following an overnight fast, plasma glucose and insulin levels were determined by a standard OGTT (1.75 g glucose/kg, max. 75 g at time 0 ). Blood was collected at 0, 30, 60 and 120. To determine the differences between girls and boys in the respective groups, a t-test was performed. Correlations between plasma glucose and insulin levels and height and height SDS were determined by Pearson s correlation coefficient for each study group respectively. P < 0.05 was considered statistically significant. Results: Pre-pubertal girls and boys did not differ regarding glucose and insulin levels at any time point during the OGTT. Adolescent girls had significantly higher insulin levels at 60 (107 ± 5 vs. 87 ± 5 mu/l) and 120 (96 ± 5 vs. 82 ± 5 mu/l) when compared to boys. They also had significantly higher BMI SDS when compared to adolescent boys (2.67 ±.03 vs ±.03 kg/m 2 ). Most interestingly, height (and height SDS) positively and significantly correlated with plasma insulin levels at all time points during the OGTT in pre-pubertal and adolescent girls and boys. No such correlation could be determined for glucose levels. Conclusions: Plasma insulin levels during OGTT are positively correlated with height in both obese pre-pubertal children and adolescents. A subject s height should therefore be considered in the interpretation of OGTT, especially in relation to plasma insulin levels.

20 338 Slov Pediatr 2012; 19: 338 LOWER SERUM ADIPONECTIN AND TOTAL CHOLESTEROL IN SMALL FOR GESTATIONAL AGE NEONATES P. Fister 1, B. Bratanič 1, D. Paro-Panjan 1, N. Bratanič 2, M. Zupančič 3, A. Jerin 4, M. Skitek 4, T. Battelino 2 (1) Department of Neonatology, University Children s Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia (2) Department of Endocrinology, Diabetes and Metabolic Diseases, University Children s Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia (3) Department of Clinical Biochemistry, University Children s Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia (4) Institute of Clinical Chemistry and Biochemistry, University Medical Centre Ljubljana, Ljubljana, Slovenia Aim: Small for gestational age (SGA) infants have an increased risk of developing metabolic syndrome (MS) later in life. Our aim was to analyze some of the potential MS biomarkers in SGA neonates and to investigate the association between these biomarkers and being SGA. Methods: Cross-sectional prospective study of 37 SGA and 23 appropriate for gestational age (AGA) neonates that were hospitalized at Department of Neonatology, University Children s Hospital, Ljubljana, Slovenia. SGA neonates were subdivided in two groups according to the severity of growth restriction (the lower tertile for birth weight vs. the rest SGA) and both groups compared. All newborns in both groups had similar maternal and prenatal history in terms of maternal diseases, maternal age and social status and comparable perinatal characteristics and problems. There were no significant differences in the type and amount of milk on daily basis. Also, the growth patterns in the two groups did not differ. Serum adiponectin, fasting glucose, insulin, total cholesterol, high and low density lipoprotein cholesterol, and triglycerides were evaluated in the third week of life. Results: Multivariate analysis of the association between clinical characteristics and being SGA indicated that SGA neonates had significantly lower adiponectin (P=0.029) and lower cholesterol levels (P=0.049) in comparison to AGA neonates. The mean serum adiponectin in SGA was 20 % lower than in AGA neonates. Mean adiponectin concentrations were significantly higher in SGA girls than in SGA boys (P = 0.049). When SGA neonates were subdivided in two groups according to the severity of growth restriction, there were no significant differences in any of the measured biomarkers between groups. Conclusion: Serum levels of adiponectin and cholesterol in SGA infants in the first month of life could suggest metabolic adaptive changes soon after birth.

21 339 Slov Pediatr 2012; 19: 339 INFLAMMATORY MICROENVIRONMENT REGULATES EXPRESSION OF AN ADIPOKINE INVOLVED IN WHOLE-BODY INSULIN SENSITIVITY - RBP4 P. Kotnik 1,2, M. Keuper 1, M. Wabitsch 1, P. Fischer-Posovszky 1 (1) Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics and Adolescent Medicine, Ulm University, Ulm, Germany (2) Department of Paediatric Endocrinology, Diabetes and Metabolism, University Children s Hospital, UKC Ljubljana, Ljubljana, Slovenia Background: Obesity is a state of low-grade inflammation associated with an altered adipocyte secretion profile. Retinol- binding protein 4 (RBP4) is an adipokine implicated in the development of whole-body insulin resistance associated with obesity. Aim: To determine the effect of an inflammatory environment on RBP4 expression and secretion in human adipocytes. Methods: Human adipocytes were cultured with conditioned media from human THP-1 macrophages (MacCM) or selected cytokines (TNFalpha, IL-1beta, IL-6 and IL-8). RBP4 production was studied by quantitative real-time PCR and ELISA. The correlation between RBP4 and IL-1 beta mrna expression was studied in human adipose tissue explants. Results: RBP4 mrna expression and secretion was significantly reduced upon incubation with MacCM in SGBS (by ~70 % using 10 % MacCM for 48 h) as well as in human primary adipocytes. IL-1beta was identified as a new and potent cytokine regulating RBP4, as it down-regulated RBP4 mrna and secretion in a time- and dose-dependent manner (inhibition by ~50 % at 50 ng/ml after 48 h). Blocking IL-1beta signalling using a neutralizing IL-1R and an NFkB inhibitor (CAPE) abrogated the inhibitory effect of IL-1beta on RBP4 production. Most interestingly, RBP4 mrna was negatively correlated with IL-1beta mrna in subcutaneous adipose tissue obtained from 18 healthy female subjects (R = -.535; p < 0.05). Summary and Conclusions: RBP4 expression and secretion was inhibited in an in vitro model of inflamed adipose tissue. IL-1beta was identified as a new and potent inhibitor of RBP4 production. Adipose tissue inflammation and increased RBP4 levels are associated with the development of insulin resistance. We found that inflammatory conditions lead to a down-regulation of RBP4 in adipocytes, suggesting that adipose inflammation and the increase in circulating RBP4 are two unrelated processes.

22 340 Slov Pediatr 2012; 19: 340 ANOPHTHALMIA AND HYPOPITUITARISM: DEFECT IN EARLY EMBRYONIC TRANSCRIPTIONAL REGULATION J. Lebl 1, Z. Sumnik 1, B. Obermannova 1, Z. Zmitkova 2, P. Dusatkova 1, M. Simandlova 2, E. Zemankova 3, Z. Sedlacek 2 (1) Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic (2) Department of Biology and Medical Genetics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic (3) Genetic and Paediatric Clinic, Benesov, Czech Republic Two unrelated children were referred within the first year of life for growth failure associated with anophthalmia, mild facial dysmorphism and partial hearing loss. Both were found to be suffering from profound growth hormone deficiency. MRI revealed bilateral agenesis of the eyes, optic nerves, chiasma and optic tracts and an undetectable anterior pituitary. Other brain structures were normal. Genes implicated in both eye and pituitary morphogenesis mainly encode transcription factors responsible for early embryonic development SOX2 (SRY box-2), OTX2 (Orthodenticle homeobox 2), and BMP4 (Bone Morphogenetic Protein 4). Of these, the OTX2 seems to be most frequently linked to the anophthalmia-hypopituitarism syndrome. Therefore, we began our search for the aetiopathogenesis by sequencing all exons of OTX2. No gene derangement was identified. As the next step, we continued with sequencing of SOX2, which also yielded negative results. Finally, using microarray analysis, we were able to determine two different de novo submicroscopic deletions of 14q22q23, 5.8 and 8.9 Mb in size respectively, and including deletion of one copy of OTX2, in both children. Growth hormone therapy administered in a daily dose of ug/kg partially reversed the progressive growth retardation, but did not lead to the full catch-up growth expected in children with profound growth hormone deficiency. Additional genes affected by the continuous gene deletion syndrome might have also influenced the growth potential of our two patients. We conclude that microdeletions of 14q22q23 are associated with eye anomalies and other symptoms. Of these, pituitary deficiency and growth retardation are very significant, and are difficult to correct with growth hormone therapy. The study was supported by an institutional grant from the Czech Ministry of Health (grant MZ NT13692).

23 341 Slov Pediatr 2012; 19: 341 TWO PREVALENT MUTATIONS IN THE PROP1 GENE CAUSING HYPOPITUITARISM IN EUROPEAN POPULATIONS: COHORT DESCRIPTION AND GENOTYPE ANALYSIS B. Obermannova, P. Dusatkova, J. Malikova, O. Cinek, J. Lebl and MESPE collaborative group Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague, Czech Republic and collaborators from 14 countries Background: The most common genetic causes of combined deficiency of pituitary hormones are recessively inherited mutations in the gene PROP1. In the Central and Eastern Europe, the most frequent genetic causes of hypopituitarism are mutations c.296delga and c.150dela in the PROP1 gene. Aim of our collaborative research project was to investigate whether this mutation clustering reflects a presence of a common ancestor or a mutation hot-spot in a large group of PROP1 deficient patients. Patients: We genotyped 134 carriers (83 males) of c.296delga and/or c.150dela mutations from 116 kindred represented with one proband (status as of August 2012) and their 14 healthy relatives (6 males). The probands originated from 14 countries (Austria, Belarus, Bosnia and Herzegovina, Canada, Croatia, Czech Republic, Germany, Hungary, Italy, Lithuania, Russia, Slovakia, Slovenia and USA). The average age of the patients was 21.8 years (14 26 years), median 21 years (SD 11.6 years). Results: The mutation c.296delga was detected in homozygous form in 69 probands, in heterozygous form (mutation c.296delga combined with some other PROP1 mutation except c.150dela) in 10 probands. The mutation c.150dela was found in homozygous form in 8 probands, in heterozygous form (mutation c.150dela combined with some other PROP1 mutation except c.296delga) in 1 proband. The combined heterozygocity c.296delga/ c.150dela was found in 28 probands. Conclusion: We conclude that the most prevalent mutation in PROP1 gene causing combined pituitary hormone deficiency in Central and Eastern Europe is c.296delga followed by c.150dela mutation. The investigation is performed thanks to the MESPE collaborative research project in conjunction with Genetics and Neuroendocrinology of Short Stature International Study (GeNeSiS). The study was supported by the institutional grant from the Czech Ministry of Health (grant MZ NT13692).

24 342 Slov Pediatr 2012; 19: 342 TWO PREVALENT MUTATIONS IN THE PROP1 GENE CAUSING HYPOPITUITARISM IN EUROPEAN POPULATIONS: SUGGESTION OF A FOUNDER EFFECT P. Dusatkova 1, B. Obermannova 1, J. Malikova 1, O. Cinek 1, J. Lebl 1 and paediatric endocrinologists from Austria, Hungary, Slovakia, Slovenia, Belarus, Bosnia and Herzegovina, Canada, Croatia, Germany, Italy, Lithuania, Russia, USA and the Czech Republic (1) Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague, Prague, Czech Republic Background. The most common genetic causes of combined deficiency of pituitary hormones in Central and Eastern Europe are recessively inherited mutations c.296delga and c.150dela in the PROP1 gene. The aim of our collaborative research project was to investigate whether this mutation clustering reflected the presence of a common ancestor or a mutation hot-spot. Patients and Methods. We genotyped 134 carriers of the c.296delga and/or c.150dela mutations and their 14 healthy relatives from 116 families, as well as 94 Czech controls, using 16 single nucleotide polymorphism markers that cover a 9.6 Mb region around the PROP1 gene and are not in mutual linkage disequilibrium in the general population (Pearson s r for all pairs). Haplotypes were reconstructed using the Phase and Haploview programmes. Results. Preliminary results indicate that both investigated mutations have arisen due to a founder effect. The c.296delga mutation was associated with a conserved haplotype spanning approximately 97 kb, and the c.150dela mutation with a haplotype spanning about 0.6 Mb. However, further analyses of additional markers localized in the proposed genetic region of linkage disequilibrium will allow precise delimitation of the haplotype and also the estimation of the age of these mutations in the PROP1 gene. Conclusion. We report the preliminary data suggesting the presence of common ancestors carrying the c.296delga and c.150dela mutations in the PROP1 gene in the past, although further investigation is needed to clarify these findings. The investigation has been made possible by the MESPE collaborative research project in conjunction with the Genetics and Neuroendocrinology of Short Stature International Study (GeNeSiS). The study was supported by an Eli Lilly IIT grant (B9R-CY-O057).