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We present the unique case of an adult Brazilian woman with severe short stature due to growth hormone deficiency with a heterozygous G to T substitution in the donor splice site of intron 3 of the growth hormone 1 (GH1) gene (c.291+1G>T). In this autosomal dominant form of growth hormone deficiency (type II), exon 3 skipping results in expression of the 17.5 kDa isoform of growth hormone, which has a dominant negative effect over the bioactive isoform, is retained in the endoplasmic reticulum, disrupts the Golgi apparatus, and impairs the secretion of other pituitary hormones in addition to growth hormone deficiency. This mechanism led to the progression of central hypothyroidism in the same patient. After 5 years of growth and thyroid hormone replacement, at the age of 33, laboratory evaluation for increased weight gain revealed high serum and urine cortisol concentrations, which could not be suppressed with dexamethasone. Magnetic resonance imaging of the sella turcica detected a pituitary macroadenoma, which was surgically removed. Histological examination confirmed an adrenocorticotropic hormone (ACTH)-secreting pituitary macroadenoma. A ubiquitin-specific peptidase 8 (USP8) somatic pathogenic variant (c.2159C>G/p.Pro720Arg) was found in the tumor. In conclusion, we report progression of isolated growth hormone deficiency due to a germline GH1 variant to combined pituitary hormone deficiency followed by hypercortisolism due to an ACTH-secreting macroadenoma with a somatic variant in USP8 in the same patient. Genetic studies allowed etiologic diagnosis and prognosis of this unique case.

Background: Thyroid cancer is the most common endocrine gland malignancy. Advances in understanding the genetic basis for thyroid cancer revealed the potential involvement of several genes in the formation of thyroid tumors. Mutations in the gene coding for succinate dehydrogenase subtype B (SDHB) have been implicated in papillary thyroid cancer (PTC). Succinate dehydrogenase (SDH) is a heterotetrameric protein composed of four subunits, SDHA,SDHB,SDHC, and SDHD, and participates in both the electron transport chain and the tricarboxylic acid cycle. The aim of the study was to evaluate the association between variants in the SDHA,SDHB,SDHC, and SDHD genes and familiar PTC in a large Brazilian family. Method: Four patients with PTC, 1 patient with PTC and gastrointestinal stromal tumor (GIST), 1 patient with GIST, and their relatives - several of them with different thyroid problems - from a large Brazilian family were screened for genetic variations of SDHx genes with the use of polymerase chain reaction-single-stranded conformational polymorphism and direct sequencing. Results: Only one rare variation in SDHA was found in some of the family members, but not segregating with the disease. No other genetic variants of these genes were detected in the family members that presented with PTC and/or GIST. Conclusion: Familiar PTC and a GIST were not associated with SDHx mutations; additional genetic defects, yet unknown, may be responsible for the development of tumor.

Introduction: Hypopituitarism is defined as a deficiency of one or more pituitary hormones. Pathogenic allelic variants in genes implicated in pituitary development were associated in 15% of the patients with congenital hypopituitarism (CH). To improve the molecular diagnosis we performed whole exome sequencing of ten patients born from consanguineous parents with CH. One patient with GH, TSH, ACTH and LH/FSH deficiencies presented an allelic variant c.865G>A, p.V289I in CDH2 gene (exon 7) in homozygous state that was absent in populational databanks. CDH2 produces an N-cadherin protein implicated in cellular adhesion and is responsible for epithelial-mesenchymal transition during pituitary development and differentiation. Aim: To analyze the CDH2 gene in a cohort of unrelated patients with CH. Methods: We selected 143 patients with CH from a single Brazilian center. Genomic DNA, extracted by salting out technique, was submitted to PCR amplification of 15 coding regions, except CG rich exon 1, of the CDH2 gene followed by the Sanger sequencing. Rare allelic variant frequency (MAF<1%) was searched in the populational data bank (ExAC, gnomAD, ABraom). Bioinformatic sites (Human Splicing Finder, Polyphen2, Mutation Taster and Mutation assessor) were used to look for deleterious effects. Results: Three allelic variants were found in this cohort. The allelic variant CDH2 (c.865G>A, p.V289I) was found in heterozygous state in a male patient with short stature diagnosed with GH and TSH deficiencies at the age of 11 that evolved with LH/FSH and ACTH deficiencies. Family segregation showed 3 among 11 normal siblings heterozygous carriers. This variant is rare, in heterozygous state, in populational data bank and it was predicted as deleterious or possibly harmful. The allelic variant c.1202C> A (p.A401D), in exon 9, was found in heterozygous state in a female patient with isolated GH deficiency and intellectual disability. The variant was absent in the databases and predicted as deleterious or disease-causing. The variant was absent in the mother and stepsister and the father was not available for testing. The c.1430_1431delCCinsTG allelic variant (p.P477L) was found in heterozygous state in a patient with septo-optic dysplasia, GH, TSH and ACTH deficiencies. It was absent in the databases and was predicted as deleterious or disease causing. The Human Splicing Finder predicted exonic splicing enhancer breakdown leading to the loss of 93 nucleotides. Normal mother is heterozygous carrier suggesting incomplete penetrance. Conclusion: Heterozygous variants in CDH2 were found in 2% of a cohort of Brazilian patients with congenital hypopituitarism and none in homozygous or compound heterozygous state. Further CDH2 analyses in unrelated patients from different ethnic backgrounds are needed to establish the role CDH2 variants in the etiology of congenital hypopituitarism.