Estimation of the false-negative rate in newborn screening for congenital adrenal hyperplasia

Abstract

Objective: Newborn screening based on measurement of 17a-hydroxyprogesterone (17-OHP) in a dried blood spot on filter paper is an effective tool for early diagnosis of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. Its most important rationale is prevention of a life-threatening salt-wasting (SW) crisis; in moderate forms of CAH, early diagnosis and treatment may prevent permanent negative effects of androgen overproduction. Our target was to analyse if all CAH patients who had been identified clinically before puberty would have been detected by the newborn screening. Methods: Newborn screening cards of 110 CAH patients born between 1988 and 2000 in five MiddleEuropean countries and diagnosed prior to puberty (77 SW and 33 moderate) and cards from 920 random, healthy newborn controls were analysed. CAH screening had not yet been introduced during this time. The diagnosis was based on clinical and laboratory signs and, in most cases, on CYP21 gene mutation analysis. All 17-OHP measurements in dried blood spots were carried out using a time-resolved fluoroimmunoassay kit. Results: In the newborn screening blood spots, the median of 17-OHP levels was 561 nmol/l (range 91 -1404 nmol/l) in subjects with the SW form and 40 nmol/l (4 -247 nmol/l) in the moderate form. All 77 SW patients would have been detected by newborn screening using the recommended cut-off limits (30 nmol/l). However, 10 of 33 patients with moderate CAH would have been missed. 17-OHP levels of all controls were below the cut-off. Conclusion: Newborn screening is efficient for diagnosing the SW form of CAH, but is inappropriate for identifying all patients with a moderate form of CAH. It appears that the false-negative rate is at least one-third in children with the moderate form of CAH.European Journal of Endocrinology 152 869-874

Szteroid-21-hidroxiláz-deficientia, a congenitalis adrenalis hyperplasia leggyakoribb oka

“…Tekintettel a sóvesztő krízis életveszélyes voltára és arra, hogy az érintett fiúújszülöttekben a felismerés klinikailag, a tünetek jelentkezése előtt gyakorlatilag nem lehetséges, a világ számos országában a 21-OHD irányába történő szűrés az újszülöttkori tömegszűrés része [13]. A klasszikus 21-OHD-s újszülöttek laboratóriumi diagnosztikája a 21-OH-áz szubsztrátjának, a 17-OHP-nek magas szérumszintjén alapul, amely a legtöbb esetben 105 nmol/l koncentráció feletti, de mindig meghaladja a 36 nmol/l-t. Amennyiben a csecsemők tömegszűrése során a szűrőpapírra beszárított vércseppből mérnek magas 17-OHP-eredményt, a második, szérumból történő megerősítő vizsgálat elvégzése is feltétlenül szükséges.…”

Problems of neonatal screening on congenital adrenal hyperplasia

“…Êîaeíó òðåòþ ä³â÷èíêó ç IV-V ñòóïåíåì â³ðèë³çàö³¿ çà Ïðàäåðîì [36] ËÅÊÖ²í àðîäaeåííÿ ðåºñòðóâàëè ó ÷îëîâ³÷³é ñòàò³. Â÷àñ-íî íå ä³àãíîñòîâàí³ â³ðèëüíà òà ï³çíÿ íåêëàñè÷-íà ôîðìè ÂÃÊÍÇ ñïðè÷èíÿëè ó ïàö³ºíò³â îáîõ ñòàòåé ã³ïåðàíäðîãåí³þ, çìåíøåííÿ ¿õ ê³íöåâî-ãî çðîñòó, ïîðóøåííÿ ñòàòåâîãî ðîçâèòêó òà íåïë³äí³ñòü, ó ä³â÷èíîê òà ¿õ áàòüê³â -ïñèõîëî-ã³÷í³ ïðîáëåìè, ïîâ'ÿçàí³ ç âèðàaeåíèì ã³ðñóòèç-ìîì ³ íàâ³òü íåîáõ³äí³ñòþ çì³íè ñòàò³ äèòèí³ ç êàð³îòèïîì 46ÕÕ (ó ðàç³ ïîïåðåäíüî¿ ¿¿ ðåºñòðà-ö³¿ ó ÷îëîâ³÷³é ñòàò³ âíàñë³äîê âðîäaeåíî¿ ã³ïåð-àíäðîãåí³¿) [2,5,9,10,21,25,40,45]. Çã³äíî ç âëàñíèìè äàíèìè, ñåðåä 48 ä³â÷èíîê ³ç ÂÃÊÍÇ, ÿê³ ïðîõîäèëè ë³êóâàííÿ ç 2007 ïî 2012 ðîêè, ø³ñòüîõ (12,5%) áóëî çàðåºñòðîâàíî íà ÷àñ íà-ðîäaeåííÿ ó ÷îëîâ³÷³é ñòàò³, ñïðàâaeíþ ñòàòü áóëî âñòàíîâëåíî ëèøå ï³ä ÷àñ ãîñï³òàë³çàö³¿ ó â³ää³-ëåííÿ.…”

“…Íà ÷àñ âñòàíîâëåííÿ ä³àãíîçó ö³ ïàö³ºí-òè ìàþòü îòðèìóâàòè ë³êóâàííÿ ãëþêîêîðòèêî¿-äàìè çã³äíî ç ïðîòîêîëîì [8]. Äî òðåòüî¿ ãðóïè âõîäÿòü ä³òè, ó ÿêèõ ìîaeëèâèé ðîçâèòîê ï³çíüî¿ íåêëàñè÷íî¿ ôîðì³ ÂÃÊÍÇ ³ ÿê³ ÷àñòî º íîñ³ÿìè ãîìîçèãîòíî¿ ìóòàö³¿ V281L òà ³íîä³ ìîaeóòü ìàòè ãåòåðîçèãîòí³ ìóòàö³¿ ãåíà CYP21, îäíà ç ÿêèõ ïðèòàìàííà íåêëàñè÷í³é ôîðì³ ÂÃÊÍÇ, ³íøà -êëàñè÷í³é ôîðì³ õâîðîáè, ùî îáóìîâëþº íåçíà÷-íå çá³ëüøåííÿ ð³âíÿ 17-ÎÍÐ ï³ä ÷àñ ñêðèí³íãó [5,9,20,23,45]. ²íøà ïðîáëåìà, ùî âèíèêຠï³ä ÷àñ ïðîâå-äåííÿ ñêðèí³íãó, öå õèáíî-íåãàòèâí³ ïîêàçíèêè 7-ÎÍÐ.…”

“…Çà òàêèõ óìîâ áóäå ä³àãíîñòóâàòèñÿ ëèøå òÿaeêà ñ³ëü-âòðàòíà ôîðìà çàõâîðþâàííÿ, àëå áëèçüêî 30% â³ðèëüíî¿ ôîðìè íå áóäå ä³àã-íîñòîâàíî. Âèñîê³ ïîêàçíèêè cut off 17-ÎÍÐ âè-êîðèñòîâóþòü ó ïðîãðàìàõ ñêðèí³íãó Øâåö³¿ òà Øâåéöàð³¿, ùî ï³äâèùèëî ïîçèòèâíó ïðîãíîñ-òè÷íó éîãî ö³íí³ñòü äî 24% ³ 50% â³äïîâ³äíî, àëå çíèçèëî ÷óòëèâ³ñòü ìåòîäó äî 92-97% [5,45]. Çã³äíî ç íàøèìè äàíèìè, çà ðåçóëüòàòàìè ñêðèí³íãó 2012 ðîêó ó Êè¿âñüê³é îáëàñò³ éîãî ïîçèòèâíà ïðîãíîñòè÷íà ö³íí³ñòü ñêëàëà 1,6%.…”

“…Òàê, äëÿ ñ³ëü-âòðàòíî¿ ôîðìè õàðàêòåðíîþ º íàÿâ-í³ñòü äåëåö³é ³ çíà÷íèõ ãåííèõ êîíâåðñ³é (Q318X, R356W, 12 spl), äëÿ â³ðèëüíî¿ ôîðìè -òî÷êîâî¿ ìóòàö³¿ I172N. Òî÷êîâ³ ìóòàö³¿ V281L, P30L, P453S º õàðàêòåðíèìè òàêîae äëÿ íåêëàñè÷íî¿ ôîðìè ÂÃÊÍÇ [1,2,3,5,9,10,22,23,35,45]. Àëå ç îãëÿäó íà âåëèêó ê³ëüê³ñòü ôåðìåíò³â, ùî áå-ðóòü ó÷àñòü ó ñòåðî¿äî´åíåç³, çíà÷íó ê³ëüê³ñòü âàð³àíò³â ìóòàö³é òà ¿õ êîìá³íàö³é íå äèâíî, ùî ó ñâ³ò³ êîaeí³ 2-3 ðîêè â÷åí³ â³äêðèâàþòü íîâ³ ãåíí³ ìóòàö³¿, ÿê³ ïðèçâîäÿòü äî óðàaeåííÿ êîðè ÍÇ ³ç ðîçâèòêîì ð³çíèõ ôîðì ¿¿ äèñôóíêö³¿.…”