Hereditary Pheochromocytoma as a Main Manifestation of von Hippel Lindau Disease (vHL) in Childhood - A Long-term Follow-up of 5 Patients with vHL from One Family.

Von Hippel-Lindau disease (vHL) is a hereditary, autosomal dominant syndrome manifested by a predisposition to the occurrence of benign and malignant neoplasms. The spectrum of vHL-related neoplasms includes: pheochromocytoma (PHEO), central nervous system and retinal hemangioblastomas, renal clear cell carcinoma, epididymal cystadenomas, pancreatic neuroendocrine tumors as well as visceral (renal and pancreatic) cysts. We report the family (5 patients) with genetically confirmed vHL in which every member had PHEO diagnosed during pediatric care. The presented family had a missense variant in the VHL gene (ex1 g.A451G gene, p. S80G) which is connected with an increased risk of PHEO. Performing screening laboratory and imaging tests in patients with genetically confirmed vHL disease can help to avoid the occurrence of disease symptoms and to perform an elective surgery in safe conditions. Due to the risk of coexisting pathologies and the complexity of the disease, patients with vHL require long-term care.

The quality of life in adult patients treated for Cushing's disease in childhood.

INTRODUCTION: Numerous studies assessed the quality of life (QoL) of adult patients after Cushing's disease (CD) treatment. Available professional literature reveals that hypercortisolemia caused by CD may negatively impact the mood and social life. However, data on QoL of adult patients after CD treatment in childhood are scarce. Aim of the study: To study the QoL of adult patients treated for CD in childhood. MATERIAL AND METHODS: Eighteen out of 29 adult patients diagnosed in childhood with CD and/or treated at one center participated in a survey and completed WHO Quality of Life-BREF questionnaire. The influence of selected prognostic factors for the QoL has been analyzed. Patients data were compared with a control group with the same age and sex. RESULTS: Participants (10 women and 8 men) were at the mean age of 28.93 years (19.75-40.33). No significant difference in the QoL was noted between analyzed patients and controls. Patients with hypopituitarism had lower results in domain 4 in comparison with patients without hypopituitarism (p = 0.31) and lower results in domain 2 in comparison with the control group (p = 0.045). Patients with a higher age at disease onset had lower results of the QoL in domain 1 (p = 0.031). CONCLUSIONS: During long-term follow-up the QoL of patients after CD treatment in childhood is not significantly different wit QoL of healthy controls. Further studies are needed to expand the knowledge of factors that may contribute to the QoL in CD patients who were treated in childhood.

Ectopic ACTH production by thymic and appendiceal neuroendocrine tumors - two case reports.

OBJECTIVES: Ectopic adrenocorticotropic syndrome (EAS) causes approximately 10-18% of cases of Cushing's syndrome (CS) in adults, while in children it occurs much less frequently. CASE PRESENTATION: We report two cases of neuroendocrine tumors (of the thymus and the appendix) in a 12-year-old boy and a 15-year-old girl who presented with the clinical features of CS. Elevated serum cortisol, ACTH, and chromogranin levels were observed in both patients. Diagnoses were made on the basis of a mass in the thymus/appendix region visualized with chest/abdominal CT scan and radiotracer accumulation in scintigraphy in the same areas. Histopathological examinations confirmed the diagnoses of NET. CONCLUSION: EAS is an extremely rare endocrine disorder. However, it should be taken into consideration in the diagnostic process of every case of ACTH-dependent CS.

Is there a common cause for paediatric Cushing's disease?

INTRODUCTION: According to recent literature, somatic mutations in the ubiquitin-specific protease 8 (USP8) gene are the most common changes in patients with Cushing's disease (CD). Data on the frequency of these mutations in the paediatric population are limited. The aim of the presented study was to determine the frequency of the USP8 gene mutations in a group of paediatric patients with CD treated at the Children's Memorial Health Institute (CMHI). MATERIAL AND METHODS: Eighteen patients (nine females) with CD were treated at CMHI, Warsaw, Poland between 1993 and 2019. All patients underwent transsphenoidal surgery (TSS) as a primary treatment for CD. The average age of all patients at TSS was 13.10 years (5.42-17.25). DNA was extracted from formalin-fixed paraffin-embedded resected tumour tissue. Sanger sequencing was performed on DNA sequence corresponding to the exon 14 of USP8 gene. RESULTS: The mean age at diagnosis of CD was 13.08 years, and the average duration of symptoms before diagnosis was 2.96 years. All patients were operated at CMHI by the same neurosurgeon. Fifteen out of 18 patients (83.33%) had initial biochemical remission after a single TSS procedure (post-operative serum cortisol < 1.8 µg/dL). The result of genetic testing was negative for all samples at the hotspot area of the USP8 gene. CONCLUSION: The current retrospective study demonstrates that mutations in the USP8 gene may not be as common a cause of paediatric Cushing's disease, as previously reported.

Predictive factors for the recurrence of Cushing's disease after surgical treatment in childhood.

INTRODUCTION: Cushing's disease (CD) is a rare cause of hypercortisolaemia caused by excessive adrenocorticotropic hormone (ACTH) excretion by a pituitary adenoma. Data on the predictive factors for the recurrence of the disease are limited in comparison with those for the adult population. The identification of the predictive factors for CD recurrence in patients after surgical treatment in childhood was the aim of the presented study. MATERIAL AND METHODS: A retrospective analysis of 26 CD patients, mean age at the time of diagnosis 13.46 years, treated at the Children's Memorial Health Institute (CMHI) in the years 1994-2018. Two time points were set at which the follow-up (FU) of patients was finished. The first time point (shorter FU, 24 patients) was set when the patients completed their treatment at the CMHI. The second time point (longer FU, 26 patients) was determined on the basis on the time when adult patients (previous CMHI patients) completed the author's questionnaire. In the case of the other patients (current CMHI paediatric patients and patients who did not respond to the questionnaire), the latest FU in this second time point was made during the last visit to the CMHI. The predictors of disease recurrence were evaluated by the construction of a logistic regression model and receiver operating characteristics. RESULTS: The average FU after transsphenoidal pituitary surgery (TSS) of 26 patients was 10.23 years (0.67-24.50). Recurrence of CD occurred in four out of 26 patients (15.4%) after an average time of 3.6 years (0.92-8.08) following definitive treatment. The results of the statistical analysis of potential predictive factors for CD recurrence were not conclusive, with no variables confirmed above the statistical significance threshold of p < 0.05. As regards the longer FU, two potential predictors: mean cortisol level at night (p = 0.10) and max. ACTH level after ovine corticotropin-releasing hormone (oCRH) test (p = 0.10), were the closest to meeting the assumed threshold of statistical significance. CONCLUSION: Recurrence of CD may be diagnosed even a long time after its effective treatment. It is possible that cortisol levels at night and ACTH values in oCRH test before TSS may be helpful to predict which patients may experience a recurrence after successful initial treatment. However, further studies on a larger sample are needed to confirm this hypothesis.

Paediatric Cushing's disease - a literature review of epidemiology, pathogenesis, clinical symptoms, and diagnostics.

Cushing's disease (CD) is characterised by excess production of adrenocorticotropic hormone (ACTH) by a pituitary corticotroph adenoma, which results in hypercortisolaemia. CD is extremely rare in the paediatric population, and few paediatric endocrinology centres have experience in diagnosing and treating this disease. The clinical presentation of hypercortisolaemia is variable, so proper and rapid diagnosis of CD is often challenging. The molecular pathogenesis of CD was largely unknown until recently. The latest research has revealed somatic mutations in the USP8 gene as the most common pathogenic molecular variants of this disease. Herein, we describe the current state of knowledge of paediatric CD epidemiology, molecular pathogenesis, clinical symptoms, and diagnostics.

Long-term outcome in patients after treatment for Cushing's disease in childhood.

INTRODUCTION: Cushing's disease (CD) is a rare cause of hypercortisolemia presenting a major diagnostic and therapeutic challenge. Data on pituitary function in long-term follow-up after CD treatment in childhood is limited. AIM: Long-term assessment of patients of the Children's Memorial Health Institute (CMHI) after CD treatment in childhood. MATERIALS AND METHODS: Retrospective analysis of 29 CD patients, mean age at the time of diagnosis 13.46 yrs. The long-term follow-up (FU) was done by: 1) obtaining the data from a patient's questionnaire (75% of adult patients); 2) using the data from the last clinic visit for patients who did not respond to the questionnaire and for current CMHI patients. The average long-term FU from transsphenoidal pituitary surgery (TSS) was 10.23 yrs. RESULTS: At the latest FU: 18 patients (62%) had long-term disease remission after TSS1, 2 patients (6.9%) after TSS2, 1 patient (3.4%) after the post-TSS radiotherapy (XRT) cycle and 3 patients (10.3%) after bilateral adrenalectomy (BA). One patient (3.4%) died after TSS2 due to postoperative complications, 1 patient (3.4%) had persistent disease at latest FU, in 1 patient (3.4%) the long-term FU was not possible to perform. CD recurrence occurred in 4 out of 28 patients (14%) at an average time 3.6 yrs. from definitive treatment. One patient (3.4%) after BA was operated because of Nelson's syndrome. Two patients (6.9%) were suspected of relapse at latest assessment. At the time of the last evaluation, 17 patients (63%) were on levothyroxine therapy since definitive treatment, 16 patients (59%) were on hydrocortisone treatment, 10 patients (37%) were taking sex hormones replacement, 4 patients (15%)-antidiuretic hormone. CONCLUSIONS: Relatively large number of patients after CD treatment in childhood have hormonal pituitary deficits as well as mood and cognitive disorders. CD recurrence can occur even after a long time post effective treatment.

Treatment challenges in pediatric Cushing's disease: Review of the literature with particular emphasis on predictive factors for the disease recurrence.

Cushing's disease (CD) is a rare endocrine condition caused by a corticotroph pituitary tumor that produces adrenocorticotropic hormone. The current state of knowledge of CD treatment is presented in this article including factors that can be helpful in predicting remission and/or recurrence of the disease. The primary goals in CD treatment are quick diagnosis and effective, prompt treatment as the persistent disease is associated with increased morbidity and mortality. Cooperation of a team consisting of experienced pediatrician/adult endocrinologist, neuroradiologist, transsphenoidal neurosurgeon and (if necessary) radiotherapist contribute to the best treatment effects.

Coexistence of neurofibromatosis type 1 with multiple malignant neoplasia.

Neurofibromatosis type 1 (NF1, von Recklinghausen disease) is inherited in autosomal dominant way genetic disorder, with an incidence at birth 1:3000. It is one of the most common congenital disorders. It is characterized by café-au-lait spots, neurofibromas, and less common MPTST and gliomas of the optic nerve. It is caused by germline mutations of the NF1 gene, which acts as tumor suppressor. Inactivation of the gene leads to increased activation of the kinase pathways, and in consequence, uncontrolled proliferation of cells. The disease predisposes to the development of both benign and malignant tumors. Malignant tumors, but not related to the nervous system occur in neurofibromatosis quite rare. The aim of the study is a literature review of NF1, with presentation of a patient with NF1 and coexisting numerous tumors: synchronous somatostatinoma and gastrointestinal stromal tumor with metachronous prostate adenocarcinoma and non-small cell lung carcinoma. And attempt to answer the question if there is a common pathway for oncogenesis of these four tumors.

Detection of new potentially pathogenic mutations in two patients with primary pigmented nodular adrenocortical disease (PPNAD) - case reports with literature review.

INTRODUCTION: Primary pigmented nodular adrenocortical disease (PPNAD) is a rare form of ACTH-independent Cushing's syndrome (CS). Half of patients with PPNAD are sporadic cases and the other half familial. MATERIAL AND METHODS: We present two patients with PPNAD confirmed by genetic analysis. RESULTS: In both patients there were no abnormal findings on diagnostic imaging of both adrenals and heart. Patients underwent bilateral two-stage adrenalectomy. Histopathological examination confirmed PPNAD. Genetic testing showed the following mutations in the PRKAR1A gene coding for the regulatory subunit type 1A of the protein kinase A enzyme: c.125dupG (patient 1) and c.15dupT (patient 2). Both these defects lead to inactivation of the PRKAR1A protein and are consequently causative of PPNAD in these patients. CONCLUSIONS: The novel mutations presented in this article are considered to be pathogenic for PPNAD.