Impact of neonatal screening and surveillance for the TP53 R337H mutation on early detection of childhood adrenocortical tumors

Abstract

Purpose: The incidence of pediatric adrenocortical tumors (ACTs) is remarkably high in southern Brazil, where more than 90% of patients carry the germline TP53 mutation R337H. We assessed the impact of early detection of this mutation and of surveillance of carriers.

Patients and methods: Free newborn screening was offered at all hospitals in the state of Paraná. Parents of positive newborns were tested, and relatives in the carrier line were offered screening. Positive newborns and their relatives age < 15 years were offered surveillance (periodic clinical, laboratory, and ultrasound evaluations). ACTs detected by imaging were surgically resected.

Results: Of 180,000 newborns offered screening, 171,649 were screened, and 461 (0.27%) were carriers. As of April 2012, ACTs had been diagnosed in 11 of these carriers but in only two neonatally screened noncarriers (P < .001); six patient cases were identified among 228 carrier relatives age < 15 years (total, 19 ACTs). Surveillance participants included 347 (49.6%) of 699 carriers. Tumors were smaller in surveillance participants (P < .001) and more advanced in nonparticipants (four with stage III disease; two deaths). Neonatally screened carriers also had neuroblastoma (n = 1), glioblastoma multiforme (n = 1), choroid plexus carcinoma (n = 2), and Burkitt lymphoma (n = 1). Cancer histories and pedigrees were obtained for 353 families that included 1,704 identified carriers. ACTs were the most frequent cancer among carrier children (n = 48).

Conclusion: These findings establish the prevalence of the TP53 R337H mutation in Paraná state and the penetrance of ACTs among carriers. Importantly, screening and surveillance of heterozygous carriers are effective in detecting ACTs when readily curable.

Fig 1.

Flowchart of screening and surveillance protocols; TP53 R337H screening (after precounseling) and adrenocortical tumor (ACT) surveillance; 15 years of follow-up planned (2006 to 2021). Surveillance procedures were scheduled at staggered times to allow broader coverage. Although our surveillance included testosterone and cortisol, only dehydroepiandrosterone sulfate (DHEAS) provided predictive value.

Fig 2.

Prevalence (per 1,000) of TP53 R337H germline mutation in 22 health districts of southern Brazilian state of Paraná (population 10.5 million), estimated on basis of newborn screening. Estimated range of prevalence in each district is color coded. (*) Analyzed with health district 22.

Fig 3.

Mutation screening and adrenocortical tumor (ACT) detection in surveillance versus nonsurveillance groups as defined for outcome analysis. Newborns and relatives positive for TP53 R337H mutation and children diagnosed with ACT during study period are shown according to analysis; those not eligible for analysis as surveillance participants listed as not in ACT surveillance group. (*) Two relatives age < 15 years who were homozygous for R337H mutation had ACTs but were excluded from analysis (one would have been assigned to surveillance group and one to nonsurveillance group). (†) Two newborns who did not carry R337H mutation later developed ACTs.