Adrenocortical Dysplasia Research Articles

Carney complex predisposes to breast cancer: prospective study of 50 women.

Carney complex (CNC) is a rare genetic syndrome, mostly due to germline loss-of-function pathogenic variants in PRKAR1A. Carney complex includes pigmented skin lesions, cardiac myxomas, primary pigmented nodular adrenocortical dysplasia, and various breast benign tumors. The present study was designed to describe the characteristics of breast lesions in CNC patients and their association with other manifestations of CNC and PRKAR1A genotype. A 3-year follow-up multicenter French prospective study of CNC patients included 50 women who were analyzed for CNC manifestations and particularly breast lesions, with breast imaging, genotyping, and hormonal settings. Among the 38 women with breast imaging, 14 (39%) had breast lesions, half of them bilateral. Ten women (26%) presented with benign lesions and six with breast carcinomas (16%): one had ductal carcinoma in situ at 54, and five had invasive cancer before 50 years old, whom one with contralateral breast cancer during follow-up. The occurrence of breast cancer was more frequent in women with PRKAR1A pathogenic variant odds ratio = 6.34 (1.63-17.91) than in general population of same age. The mean age at breast cancer diagnosis was 44.7 years old: 17 years younger than in the general population. Breast cancer patients had good prognosis factors. All breast carcinomas occurred in individuals with familial CNC and PRKAR1A pathogenic variants. Loss of heterozygosity at the PRKAR1A locus in the 2 invasive breast carcinomas analyzed suggested a driver role of this tumor suppressor gene. As CNC could predispose to breast carcinoma, an adequate screening strategy and follow-up should be discussed in affected women. ClinicalTrial.gov NCT00668291.

THU504 Is Carney Complex A Predisposing Syndrome For Breast Cancer? Prospective Study Of 50 Women

Abstract Disclosure: P. Vaduva: None. F. Violon: None. A. Jouinot: None. L. Bouys: None. S. Espiard: None. F. Bonnet-Serrano: None. N. Marie Odile: None. C. Cardot-bauters: None. G. Raverot: None. S. Hieronimus: None. H. Lefebvre: None. M.L. Nunes: None. A. Tabarin: None. L. Groussin Rouiller: None. G. Assié: None. M. Sibony: None. M. Vantyghem: None. P. Eric: None. J. Bertherat: None. Objective: Carney Complex (CNC) is a rare hereditary genetic syndrome, mostly due to inactivating pathogenic variants of the tumor suppressor gene PRKAR1A. It has a wide spectrum of manifestations with frequent pigmented skin lesions, cardiac myxomas, primary pigmented nodular adrenocortical dysplasia (PPNAD) causing Cushing syndrome, acromegaly and thyroid cancers. Breast benign tumors (fibroadenomas, ductal adenomas and myxoid lesions) have been associated with CNC, but so far, association with malignancy has not been investigated. Methods: The present study was designed to describe the characteristics of breast tumors diagnosed in CNC patients and their association with other manifestations of CNC and PRKAR1A genotype. Since breast cancer is the most frequent cancer in women and the leading cause of death from cancer worldwide, malignant breast lesions were carefully analyzed. This cohort comes from a 3 years’ follow-up multicenter French prospective study of CNC patients (Espiard, JCEM 2020). The 50 included women were investigated for CNC manifestations and particularly breast tumors, with breast imaging (echography+/-mammography), genetic and hormonal investigations, in order to characterize them and assess the frequency and average age of breast cancer. Results: Among the 38 women with breast imaging, 14 (28%) had breast tumors, half of them being bilateral. Ten women (20%) presented with benign tumors. Six women presented (12%) with breast carcinomas: five had invasive cancer under 50 years of age (10%) with one contralateral recurrence (4 ductal adenocarcinomas and one solid intracystic papillary carcinoma) and one had ductal carcinoma in situ. The occurrence of breast cancer was more frequent in the CNC women with PRKAR1A pathogenic variants than in the general population (OR=6.2[1.6-17.3]; p=0.006). The mean age at breast cancer diagnosis was 44.7 years old, 17 years younger than in the general population. Cumulative risk of breast cancer for women under 40 years of age was much higher in CNC women, compared to women worldwide (OR=592.1[79.7-3817.4]; p=9.58). Breast cancer had good prognosis factors: 5 out of 6 tumors were T1N0M0, so stage I. One woman had metastatic breast cancer, still alive after 15 years follow up. All breast cancers were negative for HER2, with 100% positivity for estrogen receptor and 50% for progesterone receptor. They all occurred in individuals with familial CNC and PRKAR1A pathogenic variants. Loss of heterozygosity at the PRKAR1A locus observed in 2 investigated breast carcinomas tumor tissue suggests that PRKAR1A bi-allelic inactivation could promote breast cancer development. Conclusions: Breast carcinoma occurs frequently and at an early age in women with CNC, suggesting that CNC predisposes to breast carcinoma. This suggests that adequate screening strategy (starting around 40 years old) and follow up should be discussed in CNC women. Presentation: Thursday, June 15, 2023

Transcription factors β-catenin and Hex in postnatal development of the rat adrenal cortex: implication in proliferation control

Transcriptional regulation of growth, maturation, and cell turnover in adrenal cortex during postnatal development has been significantly less studied than in embryonic period, while elucidation of factors mediating its normal postnatal morphogenesis could clarify mechanisms of tumorigenesis in adrenal cortex. Expression of transcription factors Hex, β-catenin, and Wnt signaling in the adrenal cortex of male pubertal and postpubertal Wistar rats were examined. Adrenal cortex morphology and hormone production during postnatal development were also studied. Adrenocortical zones demonstrated similar reduction of Ki-67-expressing cells, but different patterns of morphological and functional changes. Age-dependent decrease in percentage of cells with membrane localization of β-catenin and stable rate of cells with nuclear β-catenin, indicative of Wnt signaling activation, were revealed in each cortical zone. Nuclear β-catenin was not observed in immature areas of zona fasciculata. No association between Wnt signaling activation and rates of proliferation as well as changes in secretion of adrenocortical hormones was observed in postnatal development of rat adrenal cortex. Hex, known as antiproliferative factor, showed up-regulation of expression after puberty. Strong inverse correlations between ratio of Hex-positive cells and proliferating cells were found in zona glomerulosa and zona fasciculata. Zona reticularis demonstrated moderate correlation. Thus, these findings suggest a role for Hex in proliferation control during postnatal development of the rat adrenal cortex and possible implication of Hex down-regulation in adrenocortical dysplasia and neoplasia, which requires further study. Evaluation of Hex expression may also be considered a potent tool in assessment of cell proliferation in rat adrenal cortex.

High-throughput gene expression analysis identifies p53-dependent and -independent pathways contributing to the adrenocortical dysplasia (acd) phenotype

In mammalian cells TPP1, encoded by the Acd gene, is a key component of the shelterin complex, which is required for telomere length maintenance and telomere protection. In mice, a hypomorphic mutation in Acd causes the adrenocortical dysplasia (acd) phenotype, which includes limb and body axis anomalies, and perinatal lethality. p53 deficiency partially rescues limb and body axis anomalies in acd mutant embryos, but not perinatal lethality, implicating p53-independent mechanisms in the acd phenotype. Loss of function of most shelterin proteins results in early embryonic lethality. Thus, study of the hypomorphic acd allele provides a unique opportunity to understand telomere dysfunction at an organismal level. The aim of this study was to identify transcriptome alterations in acd mutant and acd, p53 double mutant embryos to understand the p53-dependent and –independent factors that contribute to the mutant phenotypes in the context of the whole organism. Genes involved in developmental processes, cell cycle, metabolic pathways, tight junctions, axon guidance and signaling pathways were regulated by p53-driven mechanisms in acd mutant embryos, while genes functioning in immune response, and RNA processing were altered independently of p53 in acd, p53 double mutant embryos. To our best of knowledge, this is the first study revealing detailed transcriptomic alterations, reflecting novel p53-dependent and -independent pathways contributing to the acd phenotype. Our data confirm the importance of cell cycle and DNA repair pathways, and suggest novel links between telomere dysfunction and immune system regulation and the splicing machinery. Given the broad applicability of telomere maintenance in growth, development, and genome stability, our data will also provide a rich resource for others studying telomere maintenance and DNA damage responses in mammalian model systems.

Neural Network Based Classification of Melanocytic Lesions in Dermoscopy: Role of Input Vector Encoding

DOI: 10.26650/electrica.2018.97856 Melanocytic lesions are the main cause of death from skin cancer, and early diagnosis is the key to decreasing the mortality rate. This study assesses the role of input-vector encoding in neural network-based classification of melanocytic lesions in dermoscopy. Twelve dermoscopic measures from 200 melanocytic lesions are encoded by compact encoding, adrenocortical dysplasia (ACD) encoding, 1-of-N encoding, normalized encoding, and raw encoding, resulting in five different input-vector sets. Feed-forward neural networks with one hidden layer and one output layer are designed with several neurons in the hidden layer, ranging from two to twenty-two for each type of input-vector set, to classify a melanocytic lesion into common nevus, atypical nevus, and melanoma. Accordingly, 105 networks are designed and trained using supervised learning and then tested by performing a 10-fold cross validation. All the neural networks achieve high sensitivities, specificities, and accuracies in classification. However, the network with seven neurons in the hidden layer and raw encoded dermoscopic measures as the input vector realizes the highest sensitivity (97.0%), specificity (98.1%), and accuracy (98.0%). The practical use of the network can facilitate lesion classification by retaining the needed expertise and minimizing diagnostic variability among dermatologists.

Silencing of telomere-binding protein adrenocortical dysplasia (ACD) homolog enhances radiosensitivity in glioblastoma cells

Adrenocortical dysplasia (ACD) is a shelterin protein involved in the maintenance of telomere length and in cancer radioresistance. This study investigated the expression profile of ACD in human gliomas and its role in radioresistance of glioma cells. The expression of ACD was analyzed in 62 different grades of glioma tissues and correlated with prognosis. A radioresistant cell line was generated from U87MG cells. For mechanistic studies, ACD was inhibited by small interfering RNA-targeting ACD and the effect on cell radioresistance, telomerase activity, cyclinD1, caspase-3, hTERT, and BIRC1 was evaluated. Clonogenic assay was performed after irradiation, to investigate the effect of ACD silencing on radiation sensitivity. ACD expression appeared strongly upregulated in higher grade gliomas, and its expression was significantly correlated to grading and poor prognosis. In glioma cell lines, ACD expression pattern was similar to those observed in glioma tissues. In irradiated cells, ACD expression was increased in an ionizing radiation dose-dependent manner. A higher expression of ACD was observed in the radioresistant clones than parental cells. Silencing of ACD led to the enhanced radiation sensitivity, decreased telomerase activity and cyclin D1 expression, reduced expression of BIRC1, and finally to the upregulation of caspase-3. This study represents the first report, which demonstrated the expression pattern of ACD in gliomas and its prognostic value. Our results suggested that ACD is involved in glioblastoma radioresistance, likely through the modulation of telomerase activity, proliferation, and apoptosis. ACD might represent a potential molecular biomarker and a novel therapeutic target in glioblastoma.

Shelterin genes, germ line mutations and chronic lymphocytic leukemia

Telomeres are distinctive DNA-protein structures that cap the ends of linear chromosomes; they are essential to maintain chromosomal integrity and genome stability. Telomeres are composed by tandem repeats of the non-codificante DNA sequence TTAGGG bound by the shelterin complex. It contains six core proteins: telomeric repeat binding factor 1 (TERF1), TERF2, protection of telomeres 1 (POT1), adrenocortical dysplasia homolog (ACD), telomeric repeat-binding factor 2-interacting protein (TERF2IP) and TERF1 interacting nuclear factor 2 (TINF2), which play fundamental roles in telomere protection, chromosomal stability and regulation of telomere length (TL) (1). In addition, the shelterin complex modulates telomerase activity at chromosome ends, recognizes telomeric DNA and remodels it into a t-loop, which protects the 3’ overhang from being recognized as DNA damage. Alterations in the structure and function of any of these proteins may lead to undesirable DNA damage responses that could be associated to a role in tumorigenesis and cancer progression.

Germ line mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia

AbstractChronic lymphocytic leukemia (CLL) can be familial; however, thus far no rare germ line disruptive alleles for CLL have been identified. We performed whole-exome sequencing of 66 CLL families, identifying 4 families where loss-of-function mutations in protection of telomeres 1 (POT1) co-segregated with CLL. The p.Tyr36Cys mutation is predicted to disrupt the interaction between POT1 and the telomeric overhang. The c.1164-1G>A splice-site, p.Gln358SerfsTer13 frameshift, and p.Gln376Arg missense mutations are likely to impact the interaction between POT1 and adrenocortical dysplasia homolog (ACD), which is a part of the telomere-capping shelterin complex. We also identified mutations in ACD (c.752-2A>C) and another shelterin component, telomeric repeat binding factor 2, interacting protein (p.Ala104Pro and p.Arg133Gln), in 3 CLL families. In a complementary analysis of 1083 cases and 5854 controls, the POT1 p.Gln376Arg variant, which has a global minor allele frequency of 0.0005, conferred a 3.61-fold increased risk of CLL (P = .009). This study further highlights telomere dysregulation as a key process in CLL development.

The shelterin complex and hematopoiesis.

Mammalian chromosomes terminate in stretches of repetitive telomeric DNA that act as buffers to avoid loss of essential genetic information during end-replication. A multiprotein complex known as shelterin prevents recognition of telomeric sequences as sites of DNA damage. Telomere erosion contributes to human diseases ranging from BM failure to premature aging syndromes and cancer. The role of shelterin telomere protection is less understood. Mutations in genes encoding the shelterin proteins TRF1-interacting nuclear factor 2 (TIN2) and adrenocortical dysplasia homolog (ACD) were identified in dyskeratosis congenita, a syndrome characterized by somatic stem cell dysfunction in multiple organs leading to BM failure and other pleiotropic manifestations. Here, we introduce the biochemical features and in vivo effects of individual shelterin proteins, discuss shelterin functions in hematopoiesis, and review emerging knowledge implicating the shelterin complex in hematological disorders.

Downregulation of telomerase maintenance-related ACD expression in patients undergoing immunosuppresive therapy following kidney transplantation.

Chronic administration of immunosuppressants has been associated with long-term consequences, including a higher risk of neoplasm development. The processes regulating telomere function exert a major influence on human cancer biology. The present study aimed to assess the effect of immunosuppressive therapy on the expression of genes associated with telomere maintenance and protection in patients following renal transplantation. A total of 51 patients that had undergone kidney transplantation and 54 healthy controls were enrolled in the study. The 51 transplant patients received a three-drug immunosuppressive regimen consisting of cyclosporine A, prednisone and mycophenolate mofetil. In stage 1 of the study, the expression profiles of 123 transcripts, which represented 70 genes, were assessed in peripheral mononuclear blood cells using an oligonucleotide microarray technique in 8 transplant recipients and 4 healthy control subjects. Among the analyzed transcripts, the expression levels of 4 differed significantly between the studied groups; however, only the ACD (adrenocortical dysplasia homolog) gene, encoding the telomere-binding protein POT1-interacting protein 1 (TPP1), was sufficiently specific for telomere homeostasis. The expression of ACD was downregulated in transplant recipients (fold change, 2.11; P=0.006). In stage 2 of the study, reverse transcription-quantitative polymerase chain reaction analysis of ACD, DKC1 and hTERT mRNA was conducted for all transplant patients and control subjects. The results confirmed the downregulation of the ACD gene in patients that had received immunosuppressive therapy (P=0.002). The results of the present study indicate that the downregulation of ACD gene transcription, and thus TPP1 protein expression, may enhance the capacity for cell immortalization, despite normal levels of other key telomere maintenance factors, in patients undergoing immunosuppressive therapy. Furthermore, the results indicate that TPP1 has potential for use as an early clinical marker and/or therapeutic target for cancer in patients following organ transplantation.

TPP1 as a versatile player at the ends of chromosomes

Telomeres, the ends of linear eukaryotic chromosomes, are tandem DNA repeats and capped by various telomeric proteins. These nucleoprotein complexes protect telomeres from DNA damage response (DDR), recombination, and end-to-end fusions, ensuring genome stability. The human telosome/shelterin complex is one of the best-studied telomere-associated protein complexes, made up of six core telomeric proteins TRF1, TRF2, TIN2, RAP1, POT1, and TPP1. TPP1, also known as adrenocortical dysplasia protein homolog (ACD), is a putative mammalian homolog of TEBP-β and belongs to the oligonucleotide binding (OB)-fold-containing protein family. Three functional domains have been identified within TPP1, the N-terminal OB fold, the POT1 binding recruitment domain (RD), and the carboxyl-terminal TIN2-interacting domain (TID). TPP1 can interact with both POT1 and TIN2 to maintain telomere structure, and mediate telomerase recruitment for telomere elongation. These features have indicated TPP1 play an essential role in telomere maintenance. Here, we will review important findings that highlight the functional significance of TPP1, with a focus on its interaction with other telosome components and the telomerase. We will also discuss potential implications in disease therapies.

Carney's complex: a successful pregnancy after bilateral adrenalectomy.

Carney's complex: a successful pregnancy after bilateral adrenalectomy.

Additive effect of TAp63 deficiency on the adrenocortical dysplasia (acd) phenotype.

Adrenocortical dysplasia (acd) is a spontaneous autosomal recessive mouse mutation exhibiting caudal truncation, vertebral segmentation defects, hydronephrosis, limb hypoplasia, and perinatal lethality. Acd encodes TPP1, a component of the shelterin complex that maintains telomere integrity, and consequently acd mutant mice have telomere dysfunction and genomic instability. We previously showed that apoptosis is the primary mechanism causing the acd skeletal phenotype, and that p53 deficiency rescues the skeletal defects of the acd phenotype but has no effect on the perinatal lethality. The Trp63 gene encodes multiple isoforms, which play a role in proliferation, apoptosis, and stem/progenitor cell maintenance. Different p63 isoforms exhibit both proapoptotic (TAp63) and antiapoptotic (ΔNp63) functions. We hypothesized that deficiency of proapoptotic TAp63 isoforms might rescue the acd skeletal phenotype, similar to our previous observations with deficiency of p53. Mice heterozygous for a null allele of TAp63 were crossed to heterozygous acd mice to determine the effect of TAp63 deficiency on the acd mutant phenotype. In contrast to our results with the acd×p53 cross, skeletal anomalies were not rescued by deficiency of TAp63. In fact, the limb and vertebral anomalies observed in double-mutant embryos were more severe than those of embryos with the acd mutation alone, demonstrating a dose-dependent effect. These studies suggest that TAp63 isoforms do not facilitate p53-like apoptosis during development in response to acd-mediated telomere dysfunction and are consistent with the proposed roles of TAp63 in maintaining genomic stability.

Hematopoietic Defects In ACD/TPP1-Deficient Mice Reveal An Essential Role for the Shelterin Complex In Blood-Forming Stem Cell Homeostasis

AbstractAbstract 882Bone marrow failure syndromes can be caused by loss-of-function mutations in telomerase components. Besides the enzymatic activity of telomerase, telomere maintenance requires the protective function of the shelterin protein complex. This complex consists of six proteins that bind to the telomere and prevent an inappropriate DNA damage response from being elicited by exposed telomeric DNA. Within this complex, TPP1, encoded by the gene Acd, plays a central role in complex organization as it links elements that bind the double-stranded portion of the telomere to those that bind the single-stranded overhang. We report an essential function for the shelterin complex and specifically for TPP1 in the maintenance of hematopoietic stem cells (HSCs). Utilizing adrenocortical dysplasia (acd), a spontaneous autosomal recessive mouse mutation causing profoundly hypomorphic Acd expression, we identified phenotypic and functional abnormalities in fetal hematopoietic progenitors. acd mutant Fetal liver HSCs were larger, more granular, and expressed higher levels of the cell surface protein Sca-1, as compared to wild-type counterparts. BrdU incorporation analysis showed an accumulation of Acd-deficient progenitors in the G2M phase of the cell cycle, consistent with G2M arrest. Absolute quantification of fetal liver HSCs revealed a significant reduction in stem cell numbers in acd mutants as compared to control littermates. p53 deficiency rescued the HSC depletion phenotype, but induced a paradoxical exacerbation of the increased progenitor cell size and Sca-1 expression. These findings suggest that p53-dependent and p53-independent elements contribute to the acd HSC phenotype. In competitive repopulation assays, acd HSCs failed to provide tri-lineage hematopoietic reconstitution in lethally irradiated recipients, indicating a profound functional defect. To further study the effects of Acd deficiency in adult HSCs, we generated an Acd allele in which exons 3–8 are flanked by loxP sites, allowing conditional inactivation following Mx1-Cre induction via poly(I:C) administration. Acd inactivation resulted in rapid HSC depletion within 2 weeks after initiation of poly(I:C) injections. To assess whether Acd exerted exclusively cell-autonomous effects in HSCs, we transplanted Acdf/–Mx1-Cre+ HSCs into wild-type recipients. Poly(I:C)-mediated Acd inactivation in these bone marrow chimeric mice resulted in rapid HSC loss and failure of tri-lineage hematopoiesis in animals reconstituted with Acd-deficient bone marrow. These data indicate an exquisite cell-autonomous requirement for Acd/TPP1 in adult mouse HSCs. In view of the extremely rapid HSC loss after Acd inactivation, these observations cannot be explained by telomere shortening. Together, our findings represent the first report of an essential role for Acd/TPP1 and the shelterin complex in HSC maintenance and hematopoietic homeostasis, independently of telomerase function. Disclosures:No relevant conflicts of interest to declare.

Caudal regression in adrenocortical dysplasia (acd) mice is caused by telomere dysfunction with subsequent p53-dependent apoptosis

Adrenocortical dysplasia (acd) is a spontaneous autosomal recessive mouse mutation that exhibits a pleiotropic phenotype with perinatal lethality. Mutant acd embryos have caudal truncation, vertebral segmentation defects, hydronephrosis, and limb hypoplasia, resembling humans with Caudal Regression syndrome. Acd encodes Tpp1, a component of the shelterin complex that maintains telomere integrity, and consequently acd mutant mice have telomere dysfunction and genomic instability. While the association between genomic instability and cancer is well documented, the association between genomic instability and birth defects is unexplored. To determine the relationship between telomere dysfunction and embryonic malformations, we investigated mechanisms leading to the caudal dysgenesis phenotype of acd mutant embryos. We report that the caudal truncation is caused primarily by apoptosis, not altered cell proliferation. We show that the apoptosis and consequent skeletal malformations in acd mutants are dependent upon the p53 pathway by genetic rescue of the limb hypoplasia and vertebral anomalies with p53 null mice. Furthermore, rescue of the acd phenotype by p53 deficiency is a dosage-sensitive process, as acd/acd, p53(-/-) double mutants exhibit preaxial polydactyly. These findings demonstrate that caudal dysgenesis in acd embryos is secondary to p53-dependent apoptosis. Importantly, this study reinforces a significant link between genomic instability and birth defects.

Genetic p53 Deficiency Partially Rescues the Adrenocortical Dysplasia Phenotype at the Expense of Increased Tumorigenesis

Telomere dysfunction and shortening induce chromosomal instability and tumorigenesis. In this study, we analyze the adrenocortical dysplasia (acd) mouse, harboring a mutation in Tpp1/Acd. Additional loss of p53 dramatically rescues the acd phenotype in an organ-specific manner, including skin hyperpigmentation and adrenal morphology, but not germ cell atrophy. Survival to weaning age is significantly increased in Acd(acd/acd) p53(-/-) mice. On the contrary, p53(-/-) and p53(+/-) mice with the Acd(acd/acd) genotype show a decreased tumor-free survival, compared with Acd(+/+) mice. Tumors from Acd(acd/acd) p53(+/-) mice show a striking switch from the classic spectrum of p53(-/-) mice toward carcinomas. The acd mouse model provides further support for an in vivo role of telomere deprotection in tumorigenesis.

Tpp1/Acd maintains genomic stability through a complex role in telomere protection

Telomeres serve to protect the ends of chromosomes, and failure to maintain telomeres can lead to dramatic genomic instability. Human TPP1 was identified as a protein which interacts with components of a telomere cap complex, but does not directly bind to telomeric DNA. While biochemical interactions indicate a function in telomere biology, much remains to be learned regarding the roles of TPP1 in vivo. We previously reported the positional cloning of the gene responsible for the adrenocortical dysplasia (acd) mouse phenotype, which revealed a mutation in the mouse homologue encoding TPP1. We find that cells from homozygous acd mice harbor chromosomes fused at telomere sequences, demonstrating a role in telomere protection in vivo. Surprisingly, our studies also reveal fusions and radial structures lacking internal telomere sequences, which are not anticipated from a simple deficiency in telomere protection. Employing spectral karyotyping and telomere FISH in a combined approach, we have uncovered a striking pattern; fusions with telomeric sequences involve nonhomologous chromosomes while those lacking telomeric sequences involve homologues. Together, these studies show that Tpp1/Acd plays a vital role in telomere protection, but likely has additional functions yet to be defined.

IMAGe association and congenital adrenal hypoplasia: No disease-causing mutations found in the ACD gene

The spontaneous mouse mutant adrenocortical dysplasia ( acd) is characterized by defects in the adrenals, kidneys, and gonads of adult mutant mice and by caudal dysgenesis and vertebral segmentation defects in acd embryos. This association of defects mirrors those identified in patients with known or suspected abnormalities in adrenocortical development, including adrenal hypoplasia congenita and IMAGe association. The identification of the Acd gene in mice has prompted the study of its human homolog ACD, which has recently been shown to be a regulator of telomere length. Sequencing of ACD in 15 patients revealed no coding mutations, but three novel SNPs were identified.

Adrenal masses falsely diagnosed as adenomas on unenhanced and delayed contrast-enhanced computed tomography: Pathological correlation

To assess the accuracy of CT for the diagnosis of histologically confirmed adrenal adenoma and nonadenoma using CT numbers. Our study included 91 adrenal masses in 83 patients; histopathological diagnoses were 45 adenomas, 31 pheochromocytomas, 6 hyperplasias, 4 metastasis, and 5 miscellaneous lesions. Unenhanced CT in 46 patients and unenhanced and delayed contrast-enhanced (DCE) CT in 37 patients were retrospectively reviewed to examine the correlation between CT findings and those on pathological examination and to obtain diagnostic accuracy. Sensitivity, specificity, and accuracy for adenoma were 40% (18/45), 91% (42/46), and 66% (60/91) with unenhanced CT, and 96% (24/25), 61% (11/18), and 81% (35/43) with DCE CT. Adrenal masses falsely diagnosed as adenoma on unenhanced CT included three hyperplasias and one endothelial cyst, and those falsely diagnosed as adenoma on DCE CT were five pheochromocytomas, one oncocytic cortical tumor, and one primary pigmented nodular adrenocortical dysplasia. Twenty-five lipid-poor adenomas were falsely diagnosed as nonadenomas on unenhanced CT and one degenerated adenoma both on unenhanced CT and on DCE CT. Diagnosing adenoma merely on CT numbers can lead to misdiagnosis. The lower specificity than expected is due to pheochromocytomas presenting as false positives.

Urogenital and caudal dysgenesis in adrenocortical dysplasia ( acd ) mice is caused by a splicing mutation in a novel telomeric regulator

Adrenocortical dysplasia (acd) is a spontaneous autosomal recessive mouse mutant with developmental defects in organs derived from the urogenital ridge. In surviving adult mutants, adrenocortical dysplasia and hypofunction are predominant features. Adults are infertile due to lack of mature germ cells, and 50% develop hydronephrosis due to ureteral hyperplasia. We report the identification of a splice donor mutation in a novel gene, which is the mouse ortholog of a newly discovered telomeric regulator. This gene (Acd) has recently been characterized as a novel component of the TRF1 protein complex that controls telomere elongation by telomerase. Characterization of Acd transcripts in mutant animals reveals two abnormal transcripts, consistent with a splicing defect. Expression of a wild-type Acd transgene in acd mutants rescues the observed phenotype. Most mutants die within 1-2 days of life on the original genetic background. Analysis of these mutant embryos reveals variable, yet striking defects in caudal specification, limb patterning and axial skeleton formation. In the tail bud, reduced expression of Wnt3a and Dll1 correlates with phenotypic severity of caudal regression. In the limbs, expression of Fgf8 is expanded in the dorsal-ventral axis of the apical ectodermal ridge and shortened in the anterior-posterior axis, consistent with the observed loss of anterior digits in older embryos. The axial skeleton of mutant embryos shows abnormal vertebral fusions in cervical, lumbar and caudal regions. This is the first report to show that a telomeric regulator is required for proper urogenital ridge differentiation, axial skeleton specification and limb patterning in mice.