Increased secretion of growth hormone leads to gigantism in children and acromegaly in adults; the genetic causes of gigantism and acromegaly are poorly understood. We performed clinical and genetic studies of samples obtained from 43 patients with gigantism and then sequenced an implicated gene in samples from 248 patients with acromegaly. We observed microduplication on chromosome Xq26.3 in samples from 13 patients with gigantism; of these samples, 4 were obtained from members of two unrelated kindreds, and 9 were from patients with sporadic cases. All the patients had disease onset during early childhood. Of the patients with gigantism who did not carry an Xq26.3 microduplication, none presented before the age of 5 years. Genomic characterization of the Xq26.3 region suggests that the microduplications are generated during chromosome replication and that they contain four protein-coding genes. Only one of these genes, GPR101, which encodes a G-protein–coupled receptor, was overexpressed in patients' pituitary lesions. We identified a recurrent GPR101 mutation (p.E308D) in 11 of 248 patients with acromegaly, with the mutation found mostly in tumors. When the mutation was transfected into rat GH3 cells, it led to increased release of growth hormone and proliferation of growth hormone–producing cells. We describe a pediatric disorder (which we have termed X-linked acrogigantism [X-LAG]) that is caused by an Xq26.3 genomic duplication and is characterized by early-onset gigantism resulting from an excess of growth hormone. Duplication of GPR101 probably causes X-LAG. We also found a recurrent mutation in GPR101 in some adults with acromegaly. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.)

CPEB (cytoplasmic polyadenylation element-binding protein) is an important regulator of translation in oocytes and neurons. Although previous studies of CPEB in late Xenopus oocytes involve the eIF4E-binding protein maskin as the key factor for the repression of maternal mRNA, a second mechanism must exist, since maskin is absent earlier in oogenesis. Using co-immunoprecipitation and gel filtration assays, we show that CPEB specifically interacts, via protein/protein interactions, with the RNA helicase Xp54, the RNA-binding proteins P100(Pat1) and RAP55, the eIF4E-binding protein 4E-T, and an eIF4E protein. Remarkably, these CPEB complex proteins have been characterized, in one or more organism, as P-body, maternal, or neuronal granule components. We do not detect interactions with eIF4E1a, the canonical cap-binding factor, eIF4G, or eIF4A or with proteins expressed late in oogenesis, including maskin, PARN, and 4E-BP1. The eIF4E protein was identified as eIF4E1b, a close homolog of eIF4E1a, whose expression is restricted to oocytes and early embryos. Although eIF4E1b possesses all residues required for cap and eIF4G binding, it binds m(7)GTP weakly, and in pull-down assays, rather than binding eIF4G, it binds 4E-T, in a manner independent of the consensus eIF4E-binding site, YSKEELL. Wild type and Y-A mutant 4E-T (which binds eIF4E1b but not eIF4E1a), when tethered to a reporter mRNA, represses its translation in a cap-dependent manner, and injection of eIF4E1b antibody accelerates meiotic maturation. Altogether, our data suggest that CPEB, partnered with several highly conserved RNA-binding partners, inhibits protein synthesis in oocytes using a novel pairing of 4E-T and eIF4E1b.

Context: Primary aldosteronism is one of the leading causes of secondary hypertension, causing significant morbidity and mortality. A number of genetic defects have recently been identified in primary aldosteronism, whereas we identified mutations in ARMC5, a tumor-suppressor gene, in cortisol-producing primary macronodular adrenal hyperplasia. Objective: We investigated a cohort of 56 patients who were referred to the National Institutes of Health for evaluation of primary aldosteronism for ARMC5 defects. Methods: Patients underwent step-wise diagnosis, with measurement of serum aldosterone and plasma renin activity followed by imaging, saline suppression and/or oral salt loading tests, plus adrenal venous sampling. Cortisol secretion was also evaluated; unilateral or bilateral adrenalectomy was performed, if indicated. DNA, protein, and transfection studies in H295R cells were conducted by standard methods. Results: We identified 12 germline ARMC5 genetic alterations in 20 unrelated and two related individuals in our cohort (39.3%). ARMC5 sequence changes in 6 patients (10.7%) were predicted to be damaging by in silico analysis. All affected patients carrying a variant predicted to be damaging were African Americans (P = .0023). Conclusions: Germline ARMC5 variants may be associated with primary aldosteronism. Additional cohorts of patients with primary aldosteronism and metabolic syndrome, particularly African Americans, should be screened for ARMC5 sequence variants because these may underlie part of the known increased predisposition of African Americans to low renin hypertension.

Pituitary adenomas are a common feature of a subset of endocrine neoplasia syndromes, which have otherwise highly variable disease manifestations. We provide here a review of the clinical features and human molecular genetics of multiple endocrine neoplasia (MEN) type 1 and 4 (MEN1 and MEN4, respectively) and Carney complex (CNC). MEN1, MEN4, and CNC are hereditary autosomal dominant syndromes that can present with pituitary adenomas. MEN1 is caused by inactivating mutations in the MEN1 gene, whose product menin is involved in multiple intracellular pathways contributing to transcriptional control and cell proliferation. MEN1 clinical features include primary hyperparathyroidism, pancreatic neuroendocrine tumours and prolactinomas as well as other pituitary adenomas. A subset of patients with pituitary adenomas and other MEN1 features have mutations in the CDKN1B gene; their disease has been called MEN4. Inactivating mutations in the type 1α regulatory subunit of protein kinase A (PKA; the PRKAR1A gene), that lead to dysregulation and activation of the PKA pathway, are the main genetic cause of CNC, which is clinically characterised by primary pigmented nodular adrenocortical disease, spotty skin pigmentation (lentigines), cardiac and other myxomas and acromegaly due to somatotropinomas or somatotrope hyperplasia.

Owing to the worldwide increase in life expectancy, the high incidence of diabetes in older individuals and the improved survival of people with diabetes, about one-third of all individuals with diabetes are now older than 65 years. Evidence is accumulating that type 2 diabetes is associated with cognitive impairment, dementia and frailty. Older people with diabetes have significantly more comorbidities, such as myocardial infarction, stroke, peripheral arterial disease and renal impairment, compared with those without diabetes. However, as a consequence of the increased use of multifactorial risk factor intervention, a considerable number of older individuals can now survive for many years without any vascular complications. Given the heterogeneity of older individuals with type 2 diabetes, an individualised approach is warranted, which must take into account the health status, presence or absence of complications, and life expectancy. In doing so, undertreatment of otherwise healthy older individuals and overtreatment of those who are frail may be avoided. Specifically, overtreatment of hyperglycaemia in older patients is potentially harmful; in particular, insulin and sulfonylureas should be avoided or, if necessary, used with caution. Instead, glucose-dependent drugs that do not induce hypoglycaemia are preferable since older patients with diabetes and impaired kidney function are especially vulnerable to this adverse event.

In Cushing’s syndrome, comorbidities often persist after remission of glucocorticoid excess. Here, we aim to identify factors predicting long-term comorbidities in patients with Cushing’s syndrome in remission.