BACKGROUND CSHS refers to the association of epidermal nevus syndrome (ENS), skeletal dysplasia, and hypophosphatemic osteomalacia (OM) mediated by FGF23 resulting from post zygotic mutations in RAS signaling pathway, with known by relationship with human cancers. CLINICAL CASE Patient 1 presented ENS since birth at right hemibody. At 1.6-yr-old, she underwent treatment for a left inguinal rhabdomyosarcoma. At 3-yr-old, she had an atraumatic right femur fracture associated with muscle weakness, and laboratory data and X-rays suggesting OM. Phosphate and calcitriol were initiated, but with poor adherence, and no improvement; skeletal deformities got worse and the girl became wheelchair user at 13-yr-old. Skeletal CT scan at age 17 showed dysplastic lesions with lytic changes at right dimidium (skull, jaw, ribs, pelvis and femur) with systemic OM signs confirmed by bone biopsy. The progressive enlargement of the jaw lesion required surgical removal after 2 years; histopathology revealed giant cell tumor. Patient 2 also had congenital ENS on the right dimidium with complaint of bone pain and muscle weakness since 2-yr-old. She evolved with bone fractures and deformities at 4-yr-old, becoming wheelchair user after 2 years. Iliac crest biopsy confirmed OM, already suspected based on laboratorial and X-rays findings at age 7. She had few improvements with phosphate and calcitriol treatment also due to low compliance. During follow-up, symptomatic nephrolithiasis occurred and, in regions affected by EN, multiple basal cell carcinomas (BCCs) emerged requiring excisions. Skeletal CT scan at age 36 showed dysplastic lesions at right hemibody (skull, ribs, pelvis, and limbs) with diffuse bone rarefaction and signs of OM. Sanger sequencing of DNA from EN and jaw tumor samples of patient 1 and from EN and BCC samples of patient 2 disclosed heterozygous HRAS p.G13R mutation, and this mutation was absent in leukocytes DNA from both patients confirming CSHS mosaicism. Owing to the CSHS associated increase risk of cancer, screening with thyroid and breast ultrasound, mammography, CT of skull, chest, abdomen, and pelvis ruled out presence of tumors in patient 1. Patient 2 is waiting for similar screening. Nowadays, patient 1 is 25-yr-old and patient 2 is 36-yr-old; both women have maintenance of OM, characterized by persistent hypophosphatemia with elevated bone formation makers despite treatment with phosphate and calcitriol. CONCLUSION CHSC is a very rare syndrome with less than 10 cases with molecular characterization in literature. Although Collins et al suggest an age-dependent improvement in mineral abnormalities, we reported two women without OM recovery probably because of extensive bone dysplasia. These cases also reinforce association of CSHS with neoplasms, including first descriptions of patients with rhabdomyosarcoma and giant cell tumor of jaw and the longest follow-ups described until.

Background: Hypermineralocorticism (hypertension, hypokalemia, and low plasma renin activity) due to deoxycorticosterone (DOC) excess associated with adrenocortical carcinoma is extremely rare. DOC-producing tumors cause primary aldosteronism-like symptoms presenting low plasma aldosterone with very high DOC levels, and due to weak hormonal DOC activity, its diagnostic is done lately. Generally, malignant cases are progressive with a dismal prognosis. Clinical case: A 61-year-old woman was admitted to our hospital presenting lumbar pain and weight loss of 8 kg, in 2018. Previously, arterial hypertension was diagnosed in 2015, showing a satisfactory control with two classes of antihypertensive drugs. Physical exam: The patient presented no features of Cushing syndrome, but a palpable abdominal mass was noticed in the right flank. Blood pressure was 160x100 mmHg, with sustained high levels, despite regular treatment. Laboratory data: a hypokalemia (K 2.4 mEq/L, nr 3.5 -5.0 mEq/L) and hypernatremia (Na 146 mEq/L, nr 135 to 145 mEq/L), with metabolic alkalosis (venous pH 7.46 and serum bicarbonate 32 mmol/L, nr 23-27 mmol/L) was confirmed. Hormonal tests excluded hypercortisolism and pheocromocytoma. Serum aldosterone and renin were suppressed. Mineralocorticoid precursors dosage was extremely high, DOC (654 ng/dL, nr < 25 ng/dL) and progesterone (5.0 ng/mL, nr <0.89 ng/mL), as well 11-deoxycortisol (7.2 ng/mL, nr <0.5 ng/mL). Radiological imaging: abdominal CT showed a heterogeneous hypervascular adrenal mass (13.0x13.0x21.0 cm) exhibiting central necrosis, suggesting malignancy. FDG-PET/CT scan showed a hypermetabolic adrenal mass (SUVmax=13.8). Also, two metabolically active pulmonary nodules (SUVmax=3.7) measuring 0.7 and 0.4 cm were detected. The patient underwent right adrenalectomy, and the tumor was removed (24x13x13 cm). According to Weiss criteria (8/9) and modified Weiss criteria (5/7), the tumor was considered an adrenocortical carcinoma. Immunohistochemistry revealed a low Ki-67 index (10%). After the surgical procedure, all adrenal steroid levels normalized, and mitotane was prescribed as adjuvant therapy. Although the pulmonary nodules were stable at the four-month follow-up, the abdominal CT-scan revealed a heterogeneous nodule (3.7cm) in the left adrenal gland, which was suspicious of metastasis. Conclusion: DOC-producing adrenocortical tumors are heterogeneous regarding tumor size, clinical behavior, hormonal and metabolites secretion, and disease-free and overall survival; however, it is common hypokalemia, hypertension, and other symptoms as abdominal pain, due to tumor growth, and weight loss. The association of arterial hypertension with hypokalemia and elevated 11-deoxycortisol, with normal aldosterone and renin, lead to the need for mineralocorticoid precursors evaluation in patients with adrenocortical tumor.

Background: Congenital Adrenal Hyperplasia (CAH) comprises a spectrum of autosomal recessive diseases, resulting in enzymatic defects in the cortisol secretion. CAH newborn screening can avoid neonatal mortality in children with the salt-wasting form and prevent incorrect gender assignments in females. The occurrence of false-positive results creates diagnostic difficulties presenting therapeutic implications. Beckwith Wiedemann Syndrome (BWS) is a congenital disease characterized by somatic overgrowth, increased risk of neonatal hypoglycemia, and development of embryonic tumors. BWS is due to (epi)genetic changes involving growth-regulating genes with good genotype-phenotype correlation. The adrenal gland is frequently involved and may present diffuse cytomegaly of the adrenal cortex1. We reported a BWS newborn girl with a false-positive diagnosis of CAH in the screening. Case report: The patient was born at 39 weeks from an uneventful cesarean section, 5.6kg (>p97) and 52cm (>p97), referred to the Endocrinology service due to abnormal neonatal tests (neonatal 17-OHP: 96ng/mL) collected at 6 days old. At 14 days old, she was 6.3 kg (Z:+5.59), and 58cm (Z:+2.47), BMI: 18.7 kg/m2 (Z:+4.45), and with typical female external genitalia, ruling out the diagnosis of classic CAH. She presented some syndromic characteristics as macroglossia, ogival palate, orbital hypertelorism, hepatomegaly, and umbilical hernia. At 1 month and 14 days old, serum 17OHP was 7.4ng/mL, androstenedione: 6.1 ng/mL, total testosterone: 279ng/dL, 11-deoxycortisol: 2.11ng/mL, cortisol: 5.0ug/dL, and ACTH: 54pg/mL. At five months old she evolved with normalization of serum 17OHP, androstenedione and testosterone levels (1.36ng/mL, <0.50ng/mL, and 37ng/dL, respectively), but still with high DHEAS levels: 2913ng/mL. At 11 months old, DHEAS also normalized, confirming that it was transient hyperactivity of the zona reticulata. A molecular test was performed in a blood sample by MLPA, showing a gain of methylation in the imprinting control region 1 (ICR1) of chromosome 11p15, which controls two imprinted genes, H19 and IGF-2, confirming the clinical diagnosis of BWS. The hypermethylation of ICR1 is largely related to the Wilms tumor. The patient was diagnosed with bilateral Wilms tumor at 11 months old and undergone chemotherapy without adequate response requiring left nephrectomy at 1 year and 5 days old. Conclusion: We presented the first description of false-positive diagnosis of CAH in the newborn screening of a girl with Beckwith Wiedemann syndrome, probably due to a transient overactivation of the zona reticulata. References: 1.Brioude F, Kalish JM, Mussa A, Foster AC, Bliek J, Ferrero GB, et al. Expert consensus document: clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement. Nat Rev Endocrinol. 2018;14(4):229-49.

BACKGROUND: Solitary Fibrous Tumor is a mesenchymal neoplasm composed of CD34+ fibroblastic cells that can produce spontaneous hypoglycemia by the overproduction of IGF-2. It closely resembles the hypoglycemia characteristic of functioning islet cell tumors. CLINICAL CASE A 77-year-old male was found unconscious and taken to an emergency department with evidence of hypoglycemia and clinical improvement following intravenous glucose administration. He did not have a history of diabetes mellitus and was not taking any glucose lowering medications. He was discharged with nutritional orientation and for control of capillary glycaemia to prevent hypoglycemia. He had 3 episodes of capillary hypoglycemia (50, 45 and 38) at home, that was predominant in the fasting morning and during its occurrence he presented mild sweating, speech difficulty, staring and diplopia, with complete improvement of symptoms after oral glucose replacement. Months earlier, he sought an otolaryngologist for intermittent mild dyspnea; denied cough, hemoptysis, chest pain and unintentional weight loss. He performed chest X-ray with evidence of large right hemithorax mass. Physical examination revealed diminished breath sounds in the right middle and lower lung fields and dullness to percussion. Despite marked hypoglycemia (31 mg/dl), the serum insulin level was less than 0.6  μIU/mL (less than 3 μIU/mL), the C-peptide level was 0.24 nmol/L (less than 0,6 nmol/L), had negative ketonemia and a positive response after glucagon administration (glycaemia increased in 50 mg/dl). Anti-insulin antibodies were negative. Serum cortisol secretion and adrenocorticotropic hormone were normal. The serum level of growth hormone (GH) was 0,03 (less than 0,97ng/ml). The serum IGF-2 level was 227 ng/ml  (267 - 616 ng/ml), the IGF-I level was 72 ng/ml (37,1 - 172 ng/ml) and the IGF2/ IGF1 was 3,15 (equal or greater than 3). Computed tomographic (CT) scan revealed a large heterogeneous mass with dimensions of 17,4 × 15× 12.2 cm. It determines almost total atelectasis of the lower lobe on this side and maintains broad medial contact with the mediastinum, compressing the right atrium and the inferior pulmonary vein on this side. Preoperatively, was administered 40 mg oral prednisone with capillary glucose normalization. The tumor was completely resected and was a grayish-white solid, with dimensions of 17 x 16 x 12 cm. Immunohistochemical stains demonstrated positivity for CD34 and IGF2 expression. Postoperatively, serum glucose and insulin levels returned to normal, and episodes of hypoglycemia are resolved. CONCLUSION This case reinforce the importance of investigate IGF-2 tumor production as a cause of hypoinsulinemic hypoglycemia and reports the complete resolution of hypoglycemia after corticoid administration and/or tumor resection.