Romolo Sandrini

An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma

The incidence of pediatric adrenal cortical carcinoma (ACC) in southern Brazil is 10–15 times higher than that of pediatric ACC worldwide. Because childhood ACC is associated with Li-Fraumeni syndrome, we examined the cancer history and p53 status of 36 Brazilian patients and their families. Remarkably, 35 of 36 patients had an identical germ-line point mutation of p53 encoding an R337H amino acid substitution. Differences within intragenic polymorphic markers demonstrated that at least some mutant alleles arose independently, thus eliminating a founder effect. In tumor cells, the wild-type allele was deleted, and mutant p53 protein accumulated within the nuclei. Although these features are consistent with Li-Fraumeni syndrome-associated adrenal tumors, there was no history of increased cancer incidence among family members. Therefore, this inherited R337H p53 mutation represents a low-penetrance p53 allele that contributes in a tissue-specific manner to the development of pediatric ACC.

Penetrance of adrenocortical tumours associated with the germline TP53 R337H mutation

Background: An inherited germline P53 mutation has been identified in cases of childhood adrenocortical carcinoma (ACT), a neoplasm with a high incidence in southern Brazil. The penetrance of ACT in carriers of the point mutation, which encodes an arginine-to-histidine substitution at codon 337 of TP53 (R337H), has not been determined. Objective: To investigate the penetrance of childhood ACT in carriers of the R337H TP53 mutation. Methods: The family histories of 30 kindreds of 41 southern Brazilian children with ACT were obtained. A PCR based assay was used to detect this P53 mutation in a large number of relatives of children with ACT. In all, 927 individuals were tested for the mutation, 232 from the non-carrier and 695 (including the 40 probands) from the carrier parental lines. Results: 40 children with ACT carried the TP53 R337H mutation; the remaining child with ACT was not tested. There was no evidence of Li-Fraumeni syndrome in any of the kindreds; however, seven met the criteria for Li-Fraumeni-like syndrome. The carrier parental line was identified in each kindred. Of the 695 individuals tested in the carrier parental line, 240 (34.5%) were positive for the mutation, while none of the 232 individuals in the other parental line carried the mutation. The penetrance of ACT was 9.9% (95% confidence interval, 8.7% to 11.1%). Conclusions: The TP53 R337H mutation dramatically increases predisposition to childhood ACT but not to other cancers, and explains the increased frequency of ACT observed in this geographic region.

Adrenocortical tumors in children

Childhood adrenocortical tumors (ACT) are rare. In the USA, only about 25 new cases occur each year. In Southern Brazil, however, approximately 10 times that many cases are diagnosed each year. Most cases occur in the contiguous states of São Paulo and Paraná. The cause of this higher rate has not been identified. Familial genetic predisposition to cancer (p53 mutations) and selected genetic syndromes (Beckwith-Wiedemann syndrome) have been associated with childhood ACT in general but not with the Brazilian counterpart. Most of the affected children are young girls with classic endocrine syndromes (virilizing and/or Cushing). Levels of urinary 17-ketosteroids and plasma dehydroepiandrosterone sulfate (DHEA-S), which are abnormal in approximately 90% of the cases, provide the pivotal clue to a diagnosis of ACT. Typical imaging findings of pediatric ACT consist of a large, well-defined suprarenal tumor containing calcifications with a thin capsule and central necrosis or hemorrhage. The pathologic classification of pediatric ACT is troublesome. Even an experienced pathologist can find it difficult to differentiate carcinoma from adenoma. Surgery is the single most important procedure in the successful treatment of ACT. The role of chemotherapy in the management of childhood ACT has not been established although occasional tumors are responsive to mitotane or cisplatin-containing regimens. Because of the heterogeneity and rarity of the disease, prognostic factors have been difficult to establish in pediatric ACT. Patients with incomplete tumor resection or with metastatic disease at diagnosis have a dismal prognosis. In patients with localized and completely resected tumors, the size of the tumor has predictive value. Patients with large tumors have a much higher relapse rate than those with small tumors.

Clinical characteristics of small functioning adrenocortical tumors in children

Twenty of 67 children registered on the International Registry of Childhood Adrenocortical Tumors between May 1988 and December 1994 had small adrenocortical tumors (defined for this study as measuring < or = 200 cm3 and/or weighing < or = 100 g). We reviewed the records of these 20 patients to characterize the clinical and pathologic findings and outcomes of children with small adrenocortical tumors. Median patient age was 2 years (range, 4 months to 5 years). There was only one boy. All had clinical signs of virilization, and seven had signs or symptoms of Cushing syndrome. A median 5.5 months (range, 1-40 months) had elapsed between the first signs of endocrine dysfunction and diagnosis. All tumors were surgically resected. Tumor volume was 3.3-195 cm3 (median, -8.7 cm3), and weight was 3.7-100 g (median, 36 gm Tumor samples were histologically reviewed in 18 cases. Eight were adenomas, and 10 were carcinomas (6 low grade and 4 high grade). Pathology records described tumor with diagnostic features of adrenocortical carcinoma in two patients. One patient received mitotane for 8 months after surgery. Only one patient had recurrent disease, which was detected 6 months after diagnosis and proved rapidly fatal. Another has been lost to follow-up. The remaining 18 patients are alive with no evidence of disease at a median 2.3 years (range, 6 months to 6.1 years) after diagnosis. Our data suggest that children with small adrenocortical tumors have an excellent prognosis with surgery as the sole therapy, regardless of tumor histiotype.

In vitro and in vivo responses to short-term recombinant human insulin-like growth factor-1 (IGF-I) in a severely growth-retarded girl with ring chromosome 15 and deletion of a single allele for the type 1 IGF receptor gene

Patients with single allele defects in the gene encoding the type 1 IGF receptor have been reported to have growth failure, but fibroblasts from affected patients have not exhibited insensitivity to the effects of IGF‐I in vitro. The in vitro and in vivo responses to short‐term recombinant human IGF‐I (rhIGF‐I) in a severely growth‐retarded girl with ring chromosome 15 and deletion of a single allele for the type 1 IGF receptor gene have been investigated.

Amplification of 9q34 in childhood adrenocortical tumors: a specific feature unrelated to ethnic origin or living conditions

Adrenocortical tumors (ACT) in children under 15 years of age exhibit some clinical and biological features distinct from ACT in adults. Cell proliferation, hypertrophy and cell death in adrenal cortex during the last months of gestation and the immediate postnatal period seem to be critical for the origin of ACT in children. Studies with large numbers of patients with childhood ACT have indicated a median age at diagnosis of about 4 years. In our institution, the median age was 3 years and 5 months, while the median age for first signs and symptoms was 2 years and 5 months (N = 72). Using the comparative genomic hybridization technique, we have reported a high frequency of 9q34 amplification in adenomas and carcinomas. This finding has been confirmed more recently by investigators in England. The lower socioeconomic status, the distinctive ethnic groups and all the regional differences in Southern Brazil in relation to patients in England indicate that these differences are not important to determine 9q34 amplification. Candidate amplified genes mapped to this locus are currently being investigated and Southern blot results obtained so far have discarded amplification of the abl oncogene. Amplification of 9q34 has not been found to be related to tumor size, staging, or malignant histopathological features, nor does it seem to be responsible for the higher incidence of ACT observed in Southern Brazil, but could be related to an ACT from embryonic origin.

Tumores do córtex adrenal na infância

Adrenocortical tumors (ACT) in children are uncommon. However, the incidence of these tumors in Parana, Brazil, is 15 times higher than that worldwide. We describe the clinical, laboratory and treatment characteristics and outcome of 125 patients treated in a single institution in the State of Parana. The median age at diagnosis was 4.3 years, with a female:male ratio of 2.6:1. The most common forms of presentation were isolated virilization (51.2%) and virilization and Cushings syndrome (42%). Nonfunctioning tumors comprised 4.8% of the cases. Two patients (1.6%) had isolated Cushings syndrome and 1 (0.8%) had Conns syndrome. Fifty-six percent presented hypertension. Surgery is the only curative treatment. Our data show that disease stage 1, absence of spillage during surgery and absence of intravenous thrombus were associated with better survival rates.

Childhood adrenocortical tumours: a review.

Childhood adrenocortical tumour (ACT) is not a common disease, but in southern Brazil the prevalence is 15 times higher than in other parts of the world. One hundred and thirty-seven patients have been identified and followed by our group over the past four decades. Affected children are predominantly girls, with a female-to-male ratio of 3.5:1 in patients below 4 years of age. Virilization alone (51.6%) or mixed with Cushings syndrome (42.0%) was the predominant clinical picture observed in these patients. Tumours are unilateral, affecting both glands equally. TP53 R337H germline mutations underlie most childhood ACTs in southern Brazil. Epidemiological data from our casuistic studies revealed that this mutation has ~10% penetrance for ACT. Surgery is the definitive treatment, and a complete resection should always be attempted. Although adjuvant chemotherapy has shown some encouraging results, its influence on overall outcome is small. The survival rate is directly correlated to tumour size; patients with small, completely excised tumours have survival rates close to 90%, whereas in those patients with inoperable tumours and/or metastatic disease it is less than 10%. In the group of patients with large, excisable tumours, half of them have an intermediate outcome. Recent molecular biology techniques and genomic approaches may help us to better understand the pathogenesis of ACT, the risk of developing a tumour when TP53 R337H is present, and to predict its outcome. An ongoing pilot study consisting of close monitoring of healthy carriers of the TP53 R337H mutation - siblings and first-degree relatives of known affected cases - aims at the early detection of ACTs and an improvement of the cure rate.

Concordance of phenotypic expression and gender identity in a large kindred with a mutation in the androgen receptor

A 14‐year‐old female presented to the Pediatric Endocrine Clinic, Universidade Federal o Parana Curitiba, Brazil, for obesity. A few years later, despite normal breast development, the patient had failed to menstruate and lacked pubic and axillary hair. Laboratory analyses revealed high levels of testosterone. Karyotype analysis was XY. Direct sequencing of her genomic DNA showed a G to T transition at nucleotide 2089 at exon 2 in the androgen receptor gene, resulting in a substitution of Phe for Cys at position 576. This mutation disrupts the first Zn finger critical to DNA binding and transcriptional activity and results in complete androgen‐insensitivity syndrome (CAIS). This individual was part of 700‐member multigenerational kindred of German origin living in small villages in Southern Brazil. Family members who gave informed consent were screened using a polymerase chain reaction‐based method. Nineteen CAIS‐affected individuals and carriers were identified. All presented with infertility and lack of or sparse pubic hair. The prevalence of common AIS within the kindred greatly exceeds that of the general population and is due in part to their isolated familial and community structures. All individuals are genuinely feminine in their appearance, sex behavior, gender identity, and integration within their communities. We conclude that CAIS leads to complete feminization of XY individuals and results in individuals who are psychologically and socially established and integrated as women within the familial and cultural contexts of their communities.

Densidade mineral óssea de crianças e adolescentes com hipotireoidismo congênito

Realizou-se estudo transversal com 60 pacientes (9,9 ± 1,8 anos) com hipotireoidismo congenito (HC) (grupo A): 40 meninas (23 pre-puberes) e 20 meninos (18 pre-puberes), com grupo controle (grupo B) constituido por 28 individuos (10,4 ± 2,1 anos): 18 meninas (8 pre-puberes) e 10 meninos (9 pre-puberes). OBJETIVOS: Avaliar a densidade (DMO) e o conteudo mineral osseo (CMO) e correlaciona-los com idade cronologica e ossea (IO), sexo, maturacao sexual, dose de l-T4, TSH, TT4, FT4, e etiologia do HC. IO, DMO e CMO de corpo total (DXA) foram obtidos dos 2 grupos; TSH, TT4 e FT4, apenas dos pacientes. DMO foi menor no grupo A (0,795 ± 0,075 g/cm2 vs. 0,832 ± 0,092; p = 0,04) e maior nas meninas puberes do que nas pre-puberes (p = 0,004). Nao houve diferenca significativa de DMO e CMO quanto ao sexo e etiologia do HC. Nosso estudo mostra que a DMO foi significativamente menor no grupo com HC, diferente dos dados da literatura.