I-Fanconi anemia (FA) 

I-Fanconi anemia (FA) yisifo sofuzo esingavamile esibonakala ngeziphambeko ezihlukahlukene zomzimba, ukulahleka komnkantsha wamathambo, kanye nengozi eyengeziwe yokonakala. I-FA ingabangelwa amaphutha (ukuguqulwa) kwesinye sezakhi zofuzo okungenani eziyi-15 ezihlukene, ngokocwaningo. Amaprotheni akhiqizwa yilezi zakhi zofuzo akha “umshini” weselula osiza amangqamuzana egazi egazi namanye amangqamuzana asemzimbeni abone futhi alungise i-DNA eyonakele (isenzakalo esivamile, sansuku zonke). Lokhu kulungiswa kwe-DNA kubambezelekile ku-FA. Ngenxa yalokho, i-DNA eyonakele iqoqana emangqamuzaneni egazi (emnkantsheni wamathambo), futhi ayafa.

I-FA ivame ukutholwa phakathi kweminyaka yobudala eyodwa neyishumi. Kukhona nokho amacala ahlonziwe kubantu abadala. I-FA ithinta kokubili amadoda nabesifazane ngokulinganayo. Itholakale kubantu bezinhlanga ezahlukene. Abacwaningi basahlanganisa futhi baveza izakhi zofuzo ezibangela i-FA, benza intuthuko enkulu ekuxilongeni nasekuqondeni ukugula.

Yini ebangela i-Fanconi anemia?

Abantu abane-FA banama-chromosome angakwazi ukulungisa umonakalo we-deoxyribonucleic acid (DNA), okubavumela ukuba baphuke kalula futhi bahlele kabusha (ukungaqini kwe-chromosome). I-DNA ingumthwali wekhodi yofuzo, futhi yonakaliswa nsuku zonke. Ukulimala kwe-DNA ngokuvamile kuyalungiswa kubantu abaningi. Abantu abane-FA, ngakolunye uhlangothi, bathola ukuphuka nokuhlelwa kabusha okwengeziwe, futhi imizimba yabo iyabambezeleka noma iyehluleka ukuqeda umonakalo.

I-FA ibangelwa ukuguquka kwezakhi zofuzo okungenani eziyi-18. Uma kwenzeka umonakalo we-DNA, amaprotheni akhiqizwa yilezi zakhi zofuzo asebenza ndawonye endleleni eyaziwa ngokuthi i-FA pathway, eqala lapho ukulimala kwe-DNA kwenzeka. Umzila we-FA uthutha amaprotheni athile uwayise endaweni yokulimala kwe-DNA, evumela ukuthi ilungiswe futhi ikopishwe (iphindaphindwe). I-FA core complex yakhiwa amaprotheni ayisishiyagalombili asebenzisa izakhi zofuzo ezimbili ukuze zikhiqize amaprotheni i-FANCD2 ne-FANCI. Lapho la maprotheni amabili esebenza, amaprotheni okulungisa i-DNA adonseleka endaweni yomonakalo we-DNA.

Ukuguqulwa kofuzo olulodwa kwezintathu, i-FANCA, FANCC, noma i-FANCG, kubangela u-80% kuya ku-90% wezenzakalo ze-FA. Lezi zakhi zofuzo zinikeza imiyalelo yokuthi ungenziwa kanjani izingxenye eziyinkimbinkimbi ze-FA. Noma iziphi izakhi zofuzo eziningi ezixhumene ne-FA core complex zingaguqulwa, zenze inkimbinkimbi ingasebenzi futhi iphazamise indlela yonke ye-FA. Uma lo mzila uphazamiseka, umonakalo we-DNA uyanqwabelana, okungase kubangele ukufa kwamangqamuzana aphikisayo noma ukwanda. Ukuncipha kwamangqamuzana egazi kanye nokungajwayelekile komzimba okuhlobene ne-FA kuvela ekufeni kwamangqamuzana. I-acute myeloid leukemia kanye neminye imidlavuza ingabangelwa ukukhula kwamaseli okungalawuleki.

I-FA izuzwa njengefa ezimweni eziningi njenge-autosomal recessive trait. Lapho umuntu ethola amakhophi amabili esakhi sofuzo esinesici sesici esifanayo, elilodwa kumzali ngamunye, izifo zofuzo eziphindaphindekayo ziyavela. Uma umuntu ethola isakhi sofuzo esisodwa esivamile kanye nofuzo olulodwa lokugula, uzoba umthwali wesifo kodwa ngokuvamile ngeke abonise izimpawu. Ngokukhulelwa ngakunye, kunamathuba angama-25% okuthi abazali ababili abathwele bobabili badlulise isakhi sofuzo esiguquliwe futhi babe nengane ehlukumezekile. Ngokukhulelwa ngakunye, kunamathuba angama-50% okuba nengane ethwalayo njengabazali. Ingane inamathuba angu-25% okuthola ufuzo oluvamile kubo bobabili abazali. Abesilisa nabesifazane basengozini ngokulinganayo.

Izihlobo ezisondelene (i-consanguineous) zinethuba elikhulu lokuthwala isakhi sofuzo esinephutha kunabazali abangahlobene, okwandisa ingozi yokuba nezingane ezinesimo sofuzo esiphindaphindayo.

I-BRCA2, BRIP1, FANCB, FANCD2, FANCE, FANCF, FANCI, ERCC4, FANCL, FANCM, PALB2, RAD51C, SLX4, kanye ne-UBE2T zonke zinezinguquko ezidala i-FA futhi zizuzwa njengefa ngendlela ye-autosomal recessive.

I-FANCB gene itholakala ku-X chromosome futhi ilandisa ngaphansi kuka-1% wazo zonke izimo ze-FA. Lesi sakhi sofuzo se-FA sizuzwa njengefa njengesici esiphindelelayo esixhunywe ku-X.

Abesilisa banamathuba amaningi okuthola izifo zofuzo ezixhumene no-X, ezibangelwa isakhi sofuzo esinephutha ku-X chromosome. Abesifazane abaphatha ushintsho kwenye yama-X chromosome abo bangabathwali bokugula. Ngenxa yokuthi abesifazane banama-X chromosome amabili, eyodwa yawo ephethe isakhi sofuzo esiguquliwe, abesifazane abaphethe ngokuvamile abazibonisi izimpawu. Abesilisa bane-X chromosome eyodwa, abayizuza kunina, futhi uma leyo chromosome iqukethe isakhi sofuzo esiguquliwe, owesilisa uzophathwa yilesi sifo. Ngokukhulelwa ngakunye, abesifazane abathwele isifo esixhumene ne-X banamathuba angama-25% okuba nendodakazi ethwele njengabo, amathuba angama-25% okuba nendodakazi engazali, ubungozi obungama-25% bokuba nendodana ehlaselwe yilesi sifo, kanye namathuba angu-25% okuba nendodana engathinteki. Uma indoda enesifo esixhumene no-X ikwazi ukuzala, isakhi sofuzo esishintshile sizodluliselwa kuwo wonke amadodakazi ayo angabathwali. Ngenxa yokuthi abesilisa ngokuvamile badlulisela i-Y chromosome yabo enzalweni yesilisa esikhundleni se-X chromosome yabo, owesilisa akakwazi ukudlulisela isakhi sofuzo esixhumene no-X emadodaneni akhe.

I-Autosomal dominant FA ibangelwa ukuguquka kofuzo lwe-RAD51. Lapho kudingeka ikhophi eyodwa kuphela yofuzo olukhubazekile ukuze kubangele isifo, kwaziwa njengesifo esilawula ufuzo. Isakhi sofuzo esinephutha singatholwa kumzali noma kubangelwe ukuguqulwa okusha (ukuguqulwa kofuzo) kumuntu othintekile. Ukukhulelwa ngakunye kunamathuba angama-50% okudlulisa isakhi sofuzo esinephutha sisuka kumzali othintekile siye enzalweni. Abesilisa nabesifazane basengozini ngokulinganayo. Kuze kube manje, bonke abantu abane-FA ngenxa yokuguqulwa kofuzo lwe-RAD51 banokushintsha kofuzo okuzenzakalelayo (de novo) eqandeni labo noma kuseli yesidoda. Ezimweni ezinjalo, ukugula akudluliswa kusuka kwesinye isizukulwane kuya kwesinye.

Ukucula nezimpawu ze-Fanconi anemia

Izimpawu ze-FA ziyehluka kumuntu oyedwa kuye komunye. Ukungajwayelekile komzimba, ukulahlekelwa umnkantsha, kanye nengozi enkulu yokuba nomdlavuza ngezinye zezimpawu ezihlonziwe. Ukungajwayelekile komzimba kuvame ukuvela ebuntwaneni, nakuba ezimweni ezithile, ukuxilonga kwenziwa kamuva ekuphileni. Phakathi kweminyaka engu-6 nengu-8, izinkinga ngokukhiqizwa kwegazi zivamile. Ukwehluleka komnkantsha kuhlasela iningi labantu ngesikhathi esithile, nakuba izinga lokwenzeka neminyaka yokuqala kwehluka. Ukuthi noma ngabe banezinkinga zegazi zangaphambili, iziguli eziphila kuze kube abantu abadala maningi amathuba okuba zithole umdlavuza wekhanda nentamo, izifo zabesifazane kanye/noma wamathumbu besebancane kakhulu kunabantu bebonke.

Ukungajwayelekile Emzimbeni
Okungenani u-60% wabantu abathinteke nge-FA bazalwa benokuphazamiseka okungokomzimba okungenani okukodwa. Lokhu kungase kuhlanganise noma yikuphi kokulandelayo:

-isiqu esifushane
-okudidayo kwesithupha nengalo: izithupha neminwe eyengeziwe noma engalungile noma engekho noma indawo engaphelele noma engekho (elinye lamathambo omphambili)
- ukuphazamiseka kwamathambo ezinqulwini, umgogodla, noma izimbambo
-izinkinga zesakhiwo sezinso
-isikhumba sombala (okuthiwa i-café au lait spots)
-ikhanda elincane
-amehlo amancane, aphambene, noma ahlukene kakhulu
-isisindo sokuzalwa esiphansi
-izinkinga zesisu
-izitho zokuzala ezincane kwabesilisa
-ukukhubazeka kwezicubu ezihlukanisa amagumbi enhliziyo

Abantu abane-anemia bangase babe nokukhathala, isidingo esikhulayo sokulala, ubuthakathaka, ikhanda elilula, isiyezi, ukucasuka, ikhanda elibuhlungu, umbala wesikhumba ompofu, ukuphefumula kanzima, nezimpawu zenhliziyo.

Kungase kube nemihuzuko eminingi kulandela ukulimala okuncane nokopha okuzenzakalelayo olwelwesini lwamafinyila, ikakhulukazi lelo lezinsini nekhala.

Ukwehluleka komnkantsha

I-spongiy substance etholakala enkabeni yamathambo amade omzimba ibizwa ngokuthi umnkantsha. Amaseli e-Hematopoietic stem akhiqizwa emnkantsheni futhi anda abe amangqamuzana egazi abomvu (ama-erythrocyte), amangqamuzana egazi amhlophe (ama-leukocyte), nama-platelet. Amaseli adedelwa emgudwini wegazi ukuze aqedele imisebenzi yawo njengoba ehamba wonke umzimba. Amangqamuzana abomvu egazi athwala umoya-mpilo kuwo wonke umzimba, amangqamuzana amhlophe egazi alwa nezifo, nama- platelet asiza umzimba ukuba umise ukopha ngokwenza amahlule.

Ukwehluleka okuqhubekayo komnkantsha wethambo ngokuvamile kubonakala lapho eneminyaka eyishumi ubudala, futhi kuhambisana nezibalo eziphansi zeplatelet noma amangqamuzana amhlophe egazi. Ukwehluleka komnkantsha wamathambo kubikezelwa njengesenzakalo sokuqala esikhulu kubantu abangaphezu kwesigamu abaphakathi kweminyaka engu-40 no-50.

Abantu abathintekile baba namazinga aphansi azo zonke izakhi zamangqamuzana omnkantsha- amangqamuzana egazi abomvu namhlophe namaplatelet- okungaholela kulokhu okulandelayo:
-izinga eliphansi lokujikeleza kwamangqamuzana abomvu egazi - i-anemia
- Izinga eliphansi lamaseli amhlophe egazi - i-leukopenia
-izinga eliphansi lama-neutrophils (uhlobo lwamangqamuzana amhlophe egazi) - i-neutropenia
Izinga eliphansi lamaplatelet - thrombocytopenia

Ukwanda Kwengozi Yokugula
Abantu abane-FA basengozini enkulu kunomphakathi jikelele wokuba nezinhlobo ezithile zomdlavuza kuhlanganisa i-acute myeloid leukemia kanye nezimila ezithile eziqinile. Abantu abathintekile bangase babe sengozini enkulu kakhulu yokuthuthuka umdlavuza othinta ikhanda nentamo isifunda, i-gastrointestinal tract, i-esophagus noma izifunda ze-gynecologic. Eziningi zalezi ziwuhlobo oluthile lomdlavuza, olwaziwa nge-squamous cell carcinoma. Iziguli ze-FA ukwehluleka kwazo komnkantsha wethambo zelashwa ngamahomoni wesilisa (abizwa ngokuthi “ama-androgens”) zisengozini enkulu yokuba nezimila zesibindi.

Cishe amaphesenti angama-30 ezimo ezihambisana nomdlavuza, ukuvela kwesifo esiyingozi kwandulela ukuxilongwa kwe-FA.

Ukuxilongwa kwe-Fanconi anemia

Ukuhlolwa okuphelele komtholampilo, umlando wesiguli onemininingwane eminingi, ukuhlonzwa kwezimpawu ezihlukile, kanye nenhlobonhlobo yokuhlolwa kochwepheshe kusetshenziselwa ukuxilonga i-FA.

Ngalesi sikhathi, ukuphela kokuxilonga okuqinisekile kwe-FA ukuhlola ukuphuka kwechromosome, okuhlanganisa ukwelapha amanye amangqamuzana egazi esiguli eshubhuni lokuhlola ngento ehlanganisa i-DNA. Amaseli avamile angalungisa umonakalo omkhulu futhi awathinteki, kuyilapho amaseli e-FA enokwephuka kwechromosome okuphawulekayo. I-DEB (diepoxybutane) kanye ne-MMC (methoxymethylcellulose) yizinhlanganisela ezimbili ezivame ukusetshenziswa kulokhu kuhlolwa (mitomycin C). Lokhu kuhlolwa kungenziwa kumaseli e-chorionic villi noma ama-amniotic fluid ngesikhathi sokukhulelwa.

Amazinga amangqamuzana egazi abomvu namhlophe, kanye nama-platelet, anganqunywa ngokuhlolwa kwegazi. Ama-X ray angakwazi ukubona ubukhona kanye nezinga lokukhubazeka kwamathambo kanye nokungajwayelekile kwesakhiwo emzimbeni.

Amacala amaningi e-FA awaxilongwa noma awatholakali isikhathi eside. Noma imuphi usana olusanda kuzalwa lunokungalungi kwesithupha nengalo okuvezwe ngenhla kufanele kusolwe i-FA futhi luhlolwe. Ngisho noma zingekho ezinye izinkinga ezisobala, noma ubani ohlakulela i-aplastic anemia kunoma iyiphi iminyaka kufanele ahlolelwe i-FA. Noma isiphi isiguli esinomlando wokusebenzisa ugwayi noma utshwala esiba ne-squamous cell carcinoma yekhanda nentamo, i-gastrointestinal, noma uhlelo lwe-gynecologic sisebancane kufanele sihlolelwe i-FA. Abaningi abane-FA abanazo izimpawu ezengeziwe. Ukwelashwa ngamakhemikhali okujwayelekile kanye nokwelashwa ngemisebe kungase kube yingozi ezigulini ze-FA, yingakho ukuhlolwa kwe-FA kuyadingeka ngaphambi kokucabangela ukufakelwa kwe-stem cell nge-aplastic anemia noma ukwelashwa komdlavuza.

Zonke izakhi zofuzo eziyi-18 ezixhumene ne-FA zingahlolwa kusetshenziswa ufuzo lwamamolekyuli. Ukuhlolwa kokugcwalisa kuvame ukwenziwa ekuqaleni ukuze kutholwe ukuthi yiluphi ufuzo lwe-FA olushintshiwe. Ukuguqulwa okuthile kulelo fuzo kunganqunywa kamuva kusetshenziswa ukuhlaziya kokulandelana kofuzo olusebenzayo. Uma ukuguquguquka kungatholakali, ukuhlaziya ukususwa/ukuphindaphinda komtholampilo kwezakhi zofuzo ezixhunywe ku-FA kuyatholakala.

Ukuhlaziywa koguquko okuhlosiwe kuyatholakala kuma-Ashkenazi Jewish ajwayelekile I-FANCC ukuguquka kwesimo.

Ukuhlolwa Komtholampilo/ Ukusebenza Ngokuqhubekayo
Ukuze kutholwe izinga lesifo kumuntu otholakala ene-FA, kunconywa ukuhlolwa okulandelayo njengoba kudingeka:

-Ukuhlolwa kwe-Ultrasound yezinso kanye nomgudu womchamo
-Ukuhlolwa kokuzwa okuhlelekile
-Ukuhlola okuthuthukayo (okubalulekile ikakhulukazi ezinganeni ezisacathula kanye nezingane ezisafunda)
- Ukudluliselwa ku-ophthalmologist, i-otolaryngologist, i-endocrinologist, udokotela ohlinzayo wezandla, udokotela wezifo zabesifazane (okwabesifazane njengoba kukhonjisiwe), i-gastroenterologist, i-urologist, i-dermatologist, udokotela ohlinzayo we-ENT, umeluleki wezofuzo.
-Ukuhlolwa kwe-hematologist, kufaka phakathi inani legazi eliphelele, i-hemoglobin yengane, kanye nesifiso somnkantsha we-cell morphology kanye ne-chromosome study (cytogenetics), kanye ne-biopsy ye-cellularity
-Ukuthayipha kwe-HLA komuntu othintekile, izingane zakwabo, nabazali ukuze kucatshangelwe ukufakelwa kwe-hematopoietic stem cell
-Ukuthayipha kwegazi eligcwele
-Amakhemikhali egazi (ukuhlola isibindi, izinso, indlala yegilo, i-lipids, nesimo sensimbi).

Ukwelashwa kwe-Fanconi Anemia

Ukwelashwa kwe-FA kuhambisana nezimpawu eziboniswa umuntu ngamunye. Ukwelashwa kungase kudinge ukusebenzisana kweqembu lochwepheshe. Odokotela bezingane, odokotela abahlinzayo, odokotela benhliziyo, ochwepheshe bezinso (odokotela bezifo ezithinta inhliziyo), odokotela bomchamo, odokotela bezifo zesisu, ochwepheshe bezindlebe (izazi zokuzwa kanye nezazi ze-otolaryngologists), ochwepheshe bamehlo, nabanye ochwepheshe bezempilo kungase kudingeke bahlele ukwelashwa komuntu othintekayo ngendlela ehlelekile nebanzi.

Ukulawulwa kwe-Androgen (ihomoni yabesilisa): I-Androgens ithuthukisa izibalo zegazi cishe ku-50% wabantu abane-FA. Ukusabela kwasekuqaleni kubonakala kumaseli abomvu, nokwanda kwe-hemoglobin ngokuvamile kwenzeka phakathi nenyanga yokuqala noma ezimbili zokwelashwa. Izimpendulo esibalweni samaseli amhlophe nokubala kweplatelet ziyahlukahluka. Izimpendulo ze-platelet ngokuvamile aziphelele futhi zingase zingabonwa ngaphambi kwezinyanga ezimbalwa zokwelashwa. Ukuthuthukiswa ngokuvamile kukhulu esibalweni samaseli abomvu. Ukumelana nokwelashwa kungase kuthuthuke ngokuhamba kwesikhathi.

-Izici zokukhula kwe-Hematopoietic: I-Granulocyte colony-stimulating factor (G-CSF) ingase ithuthukise isibalo sama-neutrophil kwabanye abantu. Ngokuvamile isetshenziselwa ukusekela kuphela phakathi nezifo ezithintanayo.

-I-Hematopoietic stem cell transplantation (HSCT): okuwukuphela kokwelashwa kokwelapha kokubonakaliswa kwe-hematologic ye-FA. Ama-stem cells angatholakala kumnkantsha, egazini le-peripheral, noma egazini lentambo.

-Ukwelashwa komdlavuza: Ukwelashwa kwezifo ezibulalayo kuyinselele yesibili ekwenyukeni kobuthi obuhambisana nokwelashwa ngamakhemikhali nemisebe ku-FA. Ukunakekelwa kufanele kutholwe ezikhungweni ezinolwazi ekwelapheni iziguli ze-FA.

Kungase kudingeke ukuhlinzwa ukuze kulungiswe ukukhubazeka kwamathambo okufana nalokhu okuthinta izithupha namathambo omphambili, ukukhubazeka kwenhliziyo, nokungalungi kwesisu okufana ne-tracheoesophageal fistula noma i-atresia yommizo, kanye ne-anresia.

Amakhemikhali athile angase andise ingozi yokuphuka kwe-chromosomal kubantu abane-FA futhi kufanele agwenywe noma nini lapho kunokwenzeka. Lawa makhemikhali ahlanganisa intuthu kagwayi, i-formaldehyde, imithi yokubulala ukhula, nezinyibilikisi zemvelo ezifana nophethiloli noma okokunciphisa upende.

Ukwelulekwa ngokofuzo kunconywa kubantu abathintekile kanye nemindeni yabo.