Cardiovascular morbidity following conventional therapy versus allogeneic hematopoietic stem cell transplantation after childhood, adolescent, and young adult leukemia in Finland.

Allogeneic hematopoietic stem cell transplantation (aHSCT) represents a therapeutic choice for high-risk and relapsed leukemia at a young age. In this retrospective population-based study, we evaluated cardiovascular complications after aHSCT (N = 272) vs conventional therapy (N = 1098) among patients diagnosed with acute lymphoblastic or acute myeloid leukemia below 35 years between 1985 and 2004. Additionally, siblings from a prior comparison group served as population controls (N = 39 217). Childhood leukemia and aHSCT was associated with a 16-fold HR for developing arterial hypertension (HR 16.8, 95%CI 1.5-185.5) compared with conventional therapy. A 2-fold HR for any cardiovascular complication was observed after AYA leukemia and aHSCT vs conventional treatment (HR 2.7, 95% CI 1.4-5.1). After AYA leukemia and aHSCT, the HR of cardiac arrhythmia was significantly elevated vs conventional therapy (HR 14.4, 95% CI 1.5-125.2). Moreover, after aHSCT in childhood, elevated hazard ratios (HRs) were found for cardiomyopathy/ cardiac insufficiency (HR 105.0, 95% CI 10.0-1100.0), cardiac arrhythmia, and arterial hypertension (HR 20.1, 95%CI 2.5-159.7 and HR 20.0, 95%CI 4.1-97.4) compared with healthy controls. After adolescent and young adult (AYA) leukemia and aHSCT, markedly increased HRs were observed for cardiac arrhythmia (HR 29.2, 95%CI 6.6-129.2), brain vascular thrombosis/ atherosclerosis and cardiomyopathy/cardiac insufficiency (HR 23.4, 95%CI 7.1-77.4 and HR 19.2, 95%CI 1.5-245.2) compared with healthy controls. As the cumulative incidence for cardiovascular complications rose during the follow-up of childhood and AYA leukemia patients, long-term cardiovascular surveillance is warranted to optimize the quality of life after childhood and AYA leukemia following both conventional treatment and aHSCT.

Purchases of antidepressants after cancer at a young age in Finland.

According to previous studies, childhood cancer survivors have an elevated risk for late mental health effects. However, only few studies exist on young adulthood (YA) cancer survivors' mental health outcomes. In our study, we examined first time antidepressant (AD) medication purchases of childhood and YA cancer patients compared to siblings. The first time AD medication purchases of 7,093 cancer patients aged 0-34 years at diagnosis and a sibling cohort (N = 26,882) were retrieved from the Social Insurance Institution of Finland (Kela) since 1.1.1993. Cancer patients diagnosed between 1.1.1994 and 31.12.2004 were identified from the Finnish Cancer Registry and sibling controls via the Population Registry Centre. Statistical analyses were performed via the Cox regression model, and the hazard ratios (HR) were adjusted for age and gender. Increased hazard ratios for AD purchases were found in the younger (0-19 years at cancer diagnosis) [HR 5.2, 95%CI (3.7-7.2)] and older (age 20-34 years at cancer diagnosis) [HR 4.5, 95%CI (3.9-5.2)] cancer patient groups compared to siblings. The gender effect was similar in patients and controls, showing that females have higher risk for AD purchases than males. Males in the younger patient group had highest HR (5.6) for AD purchases compared to siblings. Patients with sarcoma or CNS tumor in the younger age group and leukemia or CNS malignancy in the older age group had the highest risk for AD medication purchases. The frequency and risk for AD purchases has been increasing during recent decades in both cancer patient age groups compared to siblings. Thus, cancer patients' psychological support should be properly assessed already after primary treatment. Certain diagnostic groups as well as female patients may require more psychological support than others.

Partial thyrocyte-specific Gαs deficiency leads to rapid-onset hypothyroidism, hyperplasia, and papillary thyroid carcinoma-like lesions in mice.

Thyroid function is controlled by thyroid-stimulating hormone (TSH), which binds to its G protein-coupled receptor [thyroid-stimulating hormone receptor (TSHR)] on thyrocytes. TSHR can potentially couple to all G protein families, but it mainly activates the Gs- and Gq/11-mediated signaling cascades. To date, there is a knowledge gap concerning the role of the individual G protein cascades in thyroid pathophysiology. Here, we demonstrate that the thyrocyte-specific deletion of Gs-protein α subunit (Gαs) in adult mice [tamoxifen-inducible Gs protein α subunit deficient (iTGαsKO) mice] rapidly impairs thyrocyte function and leads to hypothyroidism. Consequently, iTGαsKO mice show reduced food intake and activity. However, body weight and the amount of white adipose tissue were decreased only in male iTGαsKO mice. Unexpectedly, hyperplastic follicles and papillary thyroid cancer-like tumor lesions with increased proliferation and slightly increased phospho-ERK1/2 staining were found in iTGαsKO mice at an older age. These tumors developed from nonrecombined thyrocytes still expressing Gαs in the presence of highly elevated serum TSH. In summary, we report that partial thyrocyte-specific Gαs deletion leads to hypothyroidism but also to tumor development in thyrocytes with remaining Gαs expression. Thus, these mice are a novel model to elucidate the pathophysiological consequences of hypothyroidism and TSHR/Gs/cAMP-mediated tumorigenesis.-Patyra, K., Jaeschke, H., Löf, C., Jännäri, M., Ruohonen, S. T., Undeutsch, H., Khalil, M., Kero, A., Poutanen, M., Toppari, J., Chen, M., Weinstein, L. S., Paschke, R., Kero, J. Partial thyrocyte-specific Gαs deficiency leads to rapid-onset hypothyroidism, hyperplasia, and papillary thyroid carcinoma-like lesions in mice.

Late mortality among 5-year survivors of early onset cancer: a population-based register study.

To date, only few studies have been published documenting late mortality among early onset cancer survivors, especially regarding young adulthood (YA) malignancies. Our nation-wide population-based registry study provides information concerning cause-specific long-term mortality among 16,769 5-year survivors of early onset cancer (aged 0-34 years at diagnosis), with follow-up for death extending from 1971 through 2012. A sibling cohort and population data were used as reference. The overall standardized mortality ratio (SMR) of cancer patients was 4.6-fold, (95% CI 4.4-4.8). Highest SMRs were found for malignancies (12.8, 95% CI 12.3-13.3), infectious (4.8, 95%CI 2.9-6.7) and cardiovascular diseases (1.9, 95% CI 1.7-2.1). Malignancies and cardiovascular diseases accounted for the largest number of deaths. Childhood and YA cancer survivors with the same primary cancer site had a similarly elevated overall SMR with the exception of markedly higher SMRs after childhood Hodgkin lymphoma. The highest cumulative non-malignancy-related mortality was due to cardiovascular disease with a steady rise throughout the follow-up, but strongly dependent on the primary cancer site and age at diagnosis. In childhood cancer survivors, the cumulative cardiovascular mortality did not reduce over time. However, overall and malignancy-related mortality showed a declining tendency towards the most recent periods after both, childhood and YA cancer. Our findings on non-malignancy-related mortality stress the need to set up long-term individual follow-up with a focus on cardiovascular late effects for early onset cancer survivors, especially for YA cancer survivors still lacking those.

Jansen de Vries syndrome: Report of four new patients and review of the literature.

Jansen de Vries syndrome (JDVS, OMIM: 617450) is a rare neurodevelopmental disorder associated with hypotonia, behavioral features, high threshold to pain, short stature, ophthalmological abnormalities, dysmorphism and occasionally a structural cardiac condition. It is caused by truncating variants of the last and penultimate exons of PPM1D. So far, 21 patients with JVDS have been reported in the literature. Here, we describe four novel cases of JVDS and review the current literature. Notably, our patients 1, 3 and 4 do not have intellectual disability albeit they have significant developmental difficulties. Thus, the phenotype may span from a classic intellectual disability syndrome to a milder neurodevelopmental disorder. Interestingly, two of our patients have received successful growth hormone treatment. Considering the phenotype of all the known JDVS patients, a cardiological consultation is recommended, as at least 7/25 patients showed a structural cardiac defect. Episodic fever and vomiting may associate with hypoglycemia and may even mimic a metabolic disorder. We also report the first JDVS patient with a mosaic gene defect and a mild neurodevelopmental phenotype.

Congenital Hypothyroidism and Hyperthyroidism Alters Adrenal Gene Expression, Development, and Function.

Background: The human adrenal cortex undergoes several rapid remodeling steps during its lifetime. In rodents, similar remodeling occurs postnatally in the "X-zone" layer through unknown mechanisms. Furthermore, little is known regarding the impact of thyroid hormone (TH) on adrenal glands in humans. Methods: To investigate the impact of TH on adrenal pathophysiology, we created two genetic murine models mimicking human nonautoimmune hypothyroidism and hyperthyroidism. Moreover, we analyzed serum thyrotropin (TSH) and steroid hormone concentrations in patients diagnosed with congenital hypothyroidism and premature adrenarche (PA). Results: We found that TH receptor beta-mediated hypertrophy of the X-zone significantly elevated the adrenal weights of hyperthyroid women. In the hypothyroid model, the X-zone was poorly developed in both sexes. Moreover, large reciprocal changes in the expression levels of genes that regulate adrenal cortical function were observed with both models. Unexpectedly, up- and downregulation of several genes involved in catecholamine synthesis were detected in the adrenal glands of the hypothyroid and hyperthyroid models, respectively. Furthermore, TSH and adrenal steroid concentrations correlated positively in pediatric patients with congenital hypothyroidism and PA. Conclusions: Our results revealed that congenital hypothyroidism and hyperthyroidism functionally affect adrenal gland development and related steroidogenic activity, as well as the adrenal medulla.

Detection of Novel Gene Variants Associated with Congenital Hypothyroidism in a Finnish Patient Cohort.

BACKGROUND: Congenital hypothyroidism (CH) is defined as the lack of thyroid hormones at birth. Mutations in at least 15 different genes have been associated with this disease. While up to 20% of CH cases are hereditary, the majority of cases are sporadic with unknown etiology. Apart from a monogenic pattern of inheritance, multigenic mechanisms have been suggested to play a role in CH. The genetics of CH has not been studied in Finland so far. Therefore, multigenic sequencing of CH candidate genes was performed in a Finnish patient cohort with both familial and sporadic CH. METHODS: A targeted next-generation sequencing (NGS) panel, covering all exons of the major CH genes, was applied for 15 patients with sporadic and 11 index cases with familial CH. RESULTS: Among the familial cases, six pathogenic mutations were found in the TPO, PAX8, and TSHR genes. Furthermore, pathogenic NKX2.1 and TG mutations were identified from sporadic cases, together with likely pathogenic variants in the TG, NKX2.5, SLC26A4, and DUOX2 genes. All identified novel pathogenic mutations were confirmed by Sanger-sequencing and characterized in silico and/or in vitro. CONCLUSION: In summary, the CH panel provides an efficient, cost-effective, and multigenic screening tool for both known and novel CH gene mutations. Hence, it may be a useful method to identify accurately the genetic etiology for dyshormogenic, familial, or syndromic forms of CH.