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.)

Objective: The long-term outcome of non-functioning pituitary adenoma (NFPA) patients is not clearly established, probably due to the low annual incidence and prolonged natural history of these rare tumors. The aim of this study was to evaluate clinical data at presentation and long-term post-surgery and radiotherapy outcome in a cohort of patients with NFPA. Design and methods: A computerized database was developed using Access 2000 software (Microsoft Corporation, 1999). Retrospective registration of 295 NFPA patients was performed in seven Endocrinological Centers of North West Italy. Data were analyzed by STATA software. Results: The main presenting symptoms were visual defects (67.8%) and headache (41.4%) and the most frequent pituitary deficit was hypogonadism (43.3%), since almost all tumors were macroadenomas (96.5%). Surgery was the first choice treatment (98% of patients) and total debulking was achieved in 35.5%. Radiotherapy was performed as adjuvant therapy after surgery in 41% of patients. At the follow-up, recurrence occurred in 19.2% of patients without post-surgical residual tumor after 7.5 ± 2.6 years, regrowth in 58.4% of patients with post-surgical remnant after 5.3 ± 4.0 years and residue enlargement in 18.4% of patients post-surgically treated with radiotherapy after 8.1 ± 7.3 years. Conclusions: Our database indicates that the goal of a definitive surgical cure has been achieved during the last decade in a low percentage of patients with NFPA. This tumor database may help to reduce the delay between symptom onset and diagnosis, to assess prognostic parameters for the follow-up of patients with different risk of recurrence and to define the efficacy and safety of different treatments and their association with mortality/morbidity.

Mutations of the Gsα gene inherited from the mother lead to pseudohypoparathyroidism (PHP) type Ia (PHP Ia), in which Albright’s hereditary osteodistrophy is associated to resistance to the action of different hormones, whereas the same mutations inherited from the father lead to isolated Albright’s hereditary osteodistrophy [pseudo-PHP (PPHP)]. Accordingly, it has been suggested that Gsα is under tissue-specific imprinting control, and recent studies provided evidence for a predominant maternal origin of Gsα transcripts in different endocrine organs involved in the PHP Ia phenotype. To establish whether Gsα is imprinted also in tissues that are site of alteration both in PHP Ia and PPHP, we selected 20 bone and 10 adipose tissue samples, which were heterozygous for a known polymorphism in exon 5. Expression from both parental alleles was evaluated by RT-PCR and enzymatic digestion of the resulting fragments. By this approach, the great majority of the samples analyzed showed an equal expression of the two alleles. Our results provide evidence for the absence of Gsα imprinting in human bone and fat and suggest that the clinical finding of osteodystrophy and obesity in PHP Ia and PPHP patients despite the presence of a normal Gsα allele is likely due to Gsα haploinsufficiency in these tissues.

It is debated if acromegalic patients have an increased risk to develop malignancies. The aim of the present study was to assess the standardized incidence ratios (SIRs) of different types of cancer in acromegaly on a large series of acromegalic patients managed in the somatostatin analogs era. It was evaluated the incidence of cancer in an Italian nationwide multicenter cohort study of 1512 acromegalic patients, 624 men and 888 women, mean age at diagnosis 45 ± 13 years, followed up for a mean of 10 years (12573 person-years) in respect to the general Italian population. Cancer was diagnosed in 124 patients, 72 women and 52 men. The SIRs for all cancers was significantly increased compared to the general Italian population (expected: 88, SIR 1.41; 95% CI, 1.18–1.68, P < 0.001). In the whole series, we found a significantly increased incidence of colorectal cancer (SIR 1.67; 95% CI, 1.07–2.58, P = 0.022), kidney cancer (SIR 2.87; 95% CI, 1.55–5.34, P < 0.001) and thyroid cancer (SIR 3.99; 95% CI, 2.32–6.87, P < 0.001). The exclusion of 11 cancers occurring before diagnosis of acromegaly (all in women) did not change remarkably the study outcome. In multivariate analysis, the factors significantly associated with an increased risk of malignancy were age and family history of cancer, with a non-significant trend for the estimated duration of acromegaly before diagnosis. In conclusion, we found evidence that acromegaly in Italy is associated with a moderate increase in cancer risk.

The aim of the study was to evaluate the hypothalamus-pituitary-adrenal (HPA) axis in patients (nine males, three females; mean age ± sem 51 ± 2 yr) with adult-onset GH deficiency (GHD) due to surgically treated pituitary tumors with preserved HPA function and without evidence of tumor recurrence before and during recombinant human (rh) GH replacement therapy (duration 31 ± 6 months). HPA function was assessed by urinary free cortisol and morning serum cortisol levels as well as cortisol responses to 1 μg ACTH test (n = 7 patients) or insulin tolerance test (n = 5 patients) before and during rhGH therapy, the cut-off for the diagnosis of hypoadrenalism being a cortisol peak less than 18 μg/dl (<500 nmol/liter) after stimulatory tests. Serum cortisol and urinary free cortisol levels were significantly lower on therapy than before [7.6 ± 0.8 vs. 11.5 ± 0.9 μg/dl (208 ± 22 vs. 317 ± 24 nmol/liter), P < 0.01, and 19.6 ± 2.5 vs. 32.2 ± 3.2 μg per 24 h (54 ± 7 vs. 89 ± 9 nmol per 24 h), P < 0.05, respectively], whereas no change in cortisol-binding globulin levels was observed. Cortisol peak after either ACTH test or insulin tolerance test was lower on rhGH therapy than before [15.9 ± 1.5 vs. 20.2 ± 1.1 μg/dl (437 ± 43 vs. 557 ± 31), P = 0.01, and 13.1 ± 2.6 vs. 20.4 ± 1.4 μg/dl (362 ± 71 vs. 564 ± 37 nmol/liter), P = 0.03, respectively]. Accordingly, central hypoadrenalism was detected in nine of 11 patients. In conclusion, low GH and IGF-I levels, likely enhancing the conversion of cortisone to cortisol, may mask a condition of central hypoadrenalism. Therefore, the reassessment of HPA function in GHD patients during rhGH therapy is mandatory.

Objective: Our objective was to describe the effects of surgery and radiotherapy on hormonal control and tumor mass in short- and long-term follow-up of TSH-secreting pituitary adenomas (TSHomas). Methods: This was a retrospective multicenter study. Results: We collected data of 70 TSHomas (70% macroadenomas). The mean follow-up was 64.4 (range 3–324) months. Overall, 97% of patients were treated with surgery; in 27% of them radiotherapy was associated. After surgery, 75% of patients normalized thyroid function, 58% normalized both pituitary imaging and hormonal profile, 9% developed pituitary deficiencies, and 3% had tumor or hormonal recurrence, all within the first 2 years after surgery. Presurgical medical treatment did not significantly improve surgical outcome (63% vs 57%). Radiotherapy controlled hypersecretion in 37% of patients within 2 years, whereas 32% of patients developed new pituitary deficiencies from 18 to 96 months from treatment. At last follow-up, 80% of patients normalized thyroid function, whereas 20% were currently on medical treatment: 85% with somatostatin analog (SSA) alone and 15% with SSA combined with methimazole. Subjects who achieved disease control had surgery as the only treatment in 80% of cases and surgery combined with irradiation in 20%. Conclusions: Surgery remains the first-choice treatment for TSHoma. If surgery is successful, recurrence is rare. When surgery is unsuccessful or contraindicated, SSA and radiotherapy are effective in controlling hyperthyroidism and tumor growth in the majority of patients. The effects of radiotherapy on TSH secretion and tumor mass are greater within the first years after treatment, whereas pituitary deficiencies may occur several years later.