Cushing disease due to a somatic USP8 mutation in a patient with evolving pituitary hormone deficiencies due to a germline GH1 splicing variant

SUMMARY 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.

Differential Expression of Stem Cell Markers in Human Adamantinomatous Craniopharyngioma and Pituitary Adenoma

Background/Aims: Although craniopharyngioma (CP) is histologically benign, it is a pituitary tumour that grows rapidly and often recurs. Adamantinomatous CP (ACP) was associated with an activating mutation in ß-catenin, and it has been postulated that pituitary stem cells might play a role in oncogenesis in human ACP. Stem cells have also been identified in pituitary adenoma. Our aim was to characterize the expression pattern of ABCG2, CD44, DLL4, NANOG, NOTCH2, POU5F1/OCT4, SOX2, and SOX9 stem cell markers in human ACP and pituitary adenoma. Methods and Results: We studied 33 patients (9 ACP and 24 adenoma) using real-time quantitative PCR (RT-qPCR) and immunohistochemistry. SOX9 was up-regulated in ACP, exhibiting positive immunostaining in the epithelium and stroma, with the highest expression in patients with recurrence. CD44 was overexpressed in ACP as confirmed by immunohistochemistry. SOX2 did not significantly differ among the tumour types. The RT-qPCR array showed an increased expression of MKI67,OCT4/POU5F1, and DLL4 in all tumours. NANOG was decreased in ACP. ABCG2 was down-regulated in most of the tumours. NOTCH2 was significantly decreased in the adenomas. Conclusion: Our results confirm the presence of stem cell markers in human pituitary tumours as well as the different expression patterns of ACP and adenoma. These findings suggest that ACP may originate from a more undifferentiated cell cluster. Additionally, SOX9 immunodetection in the stroma and the highest expression levels related to the relapse of patients suggest a contribution to the aggressive behaviour and high recurrence of this tumour type.

Tall stature and poor breast development after estrogen replacement in a hypergonadotrophic hypogonadic patient with a 45,X/46,X,der(X) karyotype with SHOX gene overdosage / Estatura alta e hipodesenvolvimento mamário após reposição estrogênica em paciente com hipogonadismo hipergonadotrófico e cariótipo 45,X/46,X, der(X) com superdosagem do gene SHOX

SHOX is exclusively expressed in the developing distal limb bones of human embryos and in the first and second pharyngeal arches. It works as a promoter for linear growth and as a repressor of growth plate fusion. It was reported, recently, that SHOX overdosage and gonadal estrogen deficiency have led to tall stature due to continued growth. We report, in the present study, a female patient with 45,X/46,X, psu idic(X)(pter→q21::q21→pter) karyotype, tall stature, and hypergonadotrophic hypogonadism without Turner stigmas. She did not present breast development even after long term therapy with high estrogen doses. Fluorescence in situ hybridization depicted the presence of three copies of SHOX gene. Microsatellite studies showed paternal origin of der(X). Further studies in similarly affected patients will clarify if the absence of breast development, despite previous high-dose estrogen treatment, is associated to triple copy of SHOX gene.

O gene SHOX é expresso, exclusivamente, no primeiro e no segundo arcos faríngeos, assim como nas extremidades dos ossos dos membros em embriões humanos. SHOX normalmente atua como um promotor para o crescimento linear e como um repressor do fechamento da placa de crescimento. Recentemente, foi descrito que o excesso da proteína SHOX associada à deficiência estrogênica gonadal leva à estatura alta devido ao contínuo crescimento. Neste estudo descrevemos uma paciente do sexo feminino com cariótipo 45,X/46,X,psu idic(X)(pter→q21::q21→pter), estatura alta, hipogonadismo hipergonadotrófico e sem estigmas de Turner. A paciente não apresentou desenvolvimento de mamas, mesmo depois do tratamento prolongado com altas doses de estrógenos. FISH evidenciou a presença de três cópias do SHOX. Estudo de microssatélites demonstrou a origem paterna do der(X). Estudos futuros em pacientes com semelhanças clínicas esclarecerão se a ausência de desenvolvimento de mamas, apesar do tratamento com altas doses de estrógenos, está associada à tripla cópia do SHOX.

Análise do gene HESX1 em pacientes portadores de deficiência do hormônio de crescimento associada ou não a defeitos de linha média / Analysis of HESX1 gene in patients with growth hormone deficiency associated or not with midline defects

O HESX1 é um gene envolvido na embriogênese cerebral e hipofisária. A primeira mutação (R160C) foi associada à displasia septo óptica e hipopituitarismo, seguida de 4 mutações associadas a fenótipos mais leves. Entre 80 pacientes com deficiência de GH (DGH) isolada ou associada a outras deficiências hormonais, identificamos a mutação N125S, previamente descrita como polimorfismo afro-caribenho, em 4 pacientes com hipopituitarismo e a mutação I26T em uma paciente com hipopituitarismo evolutivo. A mutação I26T localiza-se no domínio eh1 implicado na repressão da transcrição. Nos ensaios de gel shift a mutação I26T apresenta ligação à sonda P3 semelhante a do selvagem e nos experimentos de transfecção transitória ocorre um prejuízo na repressão da transcrição por dificuldade de recrutar o co-repressor TLE-1.HESX1 is a gene involved in cerebral and pituitary embriogenesis. The first mutation (R160C) was associated with septo optic dysplasia and hypopituitarism, followed by 4 mutations associated with mild phenotypes. Among 80 patients with growth hormone deficiency isolated or combined with other hormonal deficiencies, we identified N125S mutation, previously described as afro-caribean polymorphism, in 4 patients with hypopituitarism and 126T mutation in a patient with envolving hypopituitarism. I26T mutation lies on eh1 domain implicated with repression of the transcription. In the gel shift assays, 126T mutation present a similar binding to the P3 probe as the wild type and transient transfection assays show an impaired repression due to difficulty to recruit corepressor...

Duplicação da hipófise e da haste hipofisária: relato de um caso e revisão da literatura / Duplication of pituitary gland and stalk: case report and review of the literature

Os autores relatam um caso de uma paciente do sexo feminino, com idade cronológica de sete anos, idade óssea de 11 anos, aparecimento de mamas Tanner III bilateralmente, cuja investigação diagnóstica confirmou quadro de puberdade precoce dependente de gonadotrofinas, e a ressonância magnética da hipófise evidenciou duplicação da haste e da glândula hipofisária associada a hamartoma hipotalâmico.

The authors report a case of a female patient with chronological age of 7 years and bone age of 11 years, presenting with bilateral breast stage Tanner III and gonadotrophin-dependent precocious puberty. Magnetic resonance imaging of the sellar region demonstrated duplication of the pituitary gland and stalk associated with a hypothalamic hamartoma.

Carcinoma adrenocortical virilizante: relato de caso / Virilizing adrenocortical carcinoma: report of a case

A incidência do Carcinoma adrenocortical é aproximadamente de 1 : 1.7000.000. Isso perfaz somente 0.025 dos tumores malignos. A manifestação clínica depende dos hormônios predominantemente produzidos, estando a sindrome de cushing presente em 30-40 (por cento) dos pacientes com carcinoma adrenocortical e a virilização ocorrendo em 20-30 (por cento) dos adultos. Relatamos o caso de uma paciente que se apresentou com quadro clínico de virilização às custas de carcinoma adrenocortical produtor de andrógenos (principlamente testoterona), associado à produção de cortisol, não tendo sido exuberante o quadro clínico de Síndrome de Cushing, devido ao curto tempo de duração da doença