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Somatic mosaicism has been implicated as a causative mechanism in a number of genetic and genomic disorders. X-linked acrogigantism (XLAG) syndrome is a recently characterized genomic form of pediatric gigantism due to aggressive pituitary tumors that is caused by submicroscopic chromosome Xq26.3 duplications that include GPR101 We studied XLAG syndrome patients (n= 18) to determine if somatic mosaicism contributed to the genomic pathophysiology. Eighteen subjects with XLAG syndrome caused by Xq26.3 duplications were identified using high-definition array comparative genomic hybridization (HD-aCGH). We noted that males with XLAG had a decreased log2ratio (LR) compared with expected values, suggesting potential mosaicism, whereas females showed no such decrease. Compared with familial male XLAG cases, sporadic males had more marked evidence for mosaicism, with levels of Xq26.3 duplication between 16.1 and 53.8%. These characteristics were replicated using a novel, personalized breakpoint junction-specific quantification droplet digital polymerase chain reaction (ddPCR) technique. Using a separate ddPCR technique, we studied the feasibility of identifying XLAG syndrome cases in a distinct patient population of 64 unrelated subjects with acromegaly/gigantism, and identified one female gigantism patient who had had increased copy number variation (CNV) threshold for GPR101 that was subsequently diagnosed as having XLAG syndrome on HD-aCGH. Employing a combination of HD-aCGH and novel ddPCR approaches, we have demonstrated, for the first time, that XLAG syndrome can be caused by variable degrees of somatic mosaicism for duplications at chromosome Xq26.3. Somatic mosaicism was shown to occur in sporadic males but not in females with XLAG syndrome, although the clinical characteristics of the disease were similarly severe in both sexes.

X-linked acrogigantism (X-LAG) is a new syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the gene GPR101, which is highly upregulated in pituitary tumors. We conducted this study to explore the clinical, radiological, and hormonal phenotype and responses to therapy in patients with X-LAG syndrome. The study included 18 patients (13 sporadic) with X-LAG and microduplication of chromosome Xq26.3. All sporadic cases had unique duplications and the inheritance pattern in two families was dominant, with all Xq26.3 duplication carriers being affected. Patients began to grow rapidly as early as 2-3 months of age (median 12 months). At diagnosis (median delay 27 months), patients had a median height and weight standard deviation scores (SDS) of >+3.9 SDS. Apart from the increased overall body size, the children had acromegalic symptoms including acral enlargement and facial coarsening. More than a third of cases had increased appetite. Patients had marked hypersecretion of GH/IGF1 and usually prolactin, due to a pituitary macroadenoma or hyperplasia. Primary neurosurgical control was achieved with extensive anterior pituitary resection, but postoperative hypopituitarism was frequent. Control with somatostatin analogs was not readily achieved despite moderate to high levels of expression of somatostatin receptor subtype-2 in tumor tissue. Postoperative use of adjuvant pegvisomant resulted in control of IGF1 in all five cases where it was employed. X-LAG is a new infant-onset gigantism syndrome that has a severe clinical phenotype leading to challenging disease management.

BACKGROUND: Increased secretion of growth hormone leads to gigantism in children and acromegaly in adults; the genetic causes of gigantism and acromegaly are poorly understood. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.).

A small proportion of the patients with acromegaly present with apparently normal basal GH levels and suppressible GH levels despite increased IGF-1 levels, a pattern called micromegaly by some authors. Whether this pattern represents a distinct entity or is just an expression of acromegaly in its early stages is still a matter of debate. Nevertheless, these patients have some peculiar characteristics such as being more likely older and male, mostly harbour microadenomas or small macroadenomas, and have lower IGF-1 and postglucose GH levels. Even though, the frequency and severity of clinical signs and comorbidities are similar to those of patients with classic acromegaly. In conclusion, micromegaly seems to be a distinct clinical entity with a different biological behavior characterized by a low GH output. [ABSTRACT FROM AUTHOR]

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Copyright of Arquivos de Neuro-Psiquiatria is the property of Thieme Medical Publishing Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: The aim was to study the lipid and lipoprotein profiles of patients with actively secreting GH tumors and in previously affected patients considered cured of the acromegaly.Methods: Experimental design, cross-sectional study. We studied the lipid and lipoprotein profile of 38 patients (21 females; 17 males; aged 42.5 +/- 1.7 y) who were divided into three groups: group A-12 patients with active acromegaly in treatment with octreotide (0.2-0.3 mg); group B-11 untreated patients with active acromegaly; and group C-15 previously acromegalic patients considered cured (suppression of serum GH below 1 ng/mL during oral glucose tolerance test and normal serum IGF-I).Results: GH (0.9 +/- 0.4 ng/mL) and IGF-I (199 +/- 22.6 ng/mL) serum levels were significantly lower in patients in group C than in those of the A and B groups (GH - A = 14.9 +/- 6.7 ng/mL; B = 25.3 +/- 11.3 ng/mL; IGF-I - A = 471.8 +/- 30 ng/mL; B = 740.7 +/- 77.9 ng/mL). Lipoprotein(a) serum levels were higher than 30 mg/dL in 68% of patients with active acromegaly (A + B groups) and only in one patient (6.6%) in group C. Apolipoprotein A1 serum levels were significantly higher in patients in group C (150.5 +/- 7.4 mg/dL) than in those in groups A and B (101.8 +/- 8.9 mg/dL and 95.4 +/- 7.7 mg/dL, respectively). The apolipoprotein B/apolipoprotein A1 ratio was significantly lower in patients in C group (0.71 +/- 0.06) than in patients in groups A (1.02 +/- 0.14) and B (1.08 +/- 0.12), whereas serum low-density lipoprotein cholesterol (LDL-c) was significantly higher in patients in C group (141.3 +/- 28.3 mg/dL) than in those in group B (103.5 +/- 27.0 mg/dL). A total cholesterol/high-density lipoprotein cholesterol (HDL-c) ratio higher than 5.0 and a LDL-c/ HDL-c ratio higher than 3.5 were most frequent in group C (60% and 50%, respectively) than in group A + B (35.8% and 28.6%, respectively). There were no differences among the three groups in serum levels of apolipoprotein B, HDL-c, VLDL-c, total cholesterol, and triglyceride.Conclusions: The effective treatment of acromegaly decreases the lipoprotein(a) and increases the apolipoprotein A1 levels, and might be a factor of protection from atherosclerosis and contributes to reduced mortality and morbidity in these patients. The higher LDL-c serum levels after treatment of acromegaly might reflect a deficiency of GH in cured patients. [ABSTRACT FROM AUTHOR]

Hypoxemia secondary to sleep apnea is commonly seen in patients with acromegaly, and this alteration apparently leads to considerable morbidity and mortality among such patients. With the objective of identifying hypoxemia based on clinical data, we conducted a cross-sectional study of 34 patients with acromegaly, all of whom were submitted to nocturnal oximetry and evaluation of snoring, as well as to the determination of body mass index (BMI) and neck circumference. In addition, daytime sleepiness was evaluated using the Epworth sleepiness scale (ESS). In this study, sleep hypoxemia was defined as five or more episodes of desaturation per hour. The sensitivity and specificity of the various parameters in predicting such hypoxemia were, respectively, as follows: snoring (92.9% and 35%); BMI >28.5 kg/m² (71.4% and 60%); neck circumference >44 cm (28.6% and 95%); ESS score >10 (42.9% and 70%). For patients with a neck circumference of more than 44 cm, the probability of sleep hypoxemia was found to increase from 41% (pre-test) to 80% (post-test). For patients with a neck circumference of less than 44 cm, positivity for two or three of the other parameters (snoring, ESS score >10 and BMI >28.5 kg/m²) increased the post-test probability to 62%, whereas positivity for only one (or none) reduced post-test probability to 8%. We can conclude that the clinical parameters evaluated allowed us to predict, with considerable accuracy, whether or not sleep hypoxemia would occur in patients with acromegaly. [ABSTRACT FROM AUTHOR]