Acromegaly is characterized by excess skin and soft tissue growth due to increased growth hormone (GH) levels. Patients with similar physical findings but without somatotroph axis abnormalities are considered to have pseudoacromegaly. The list of pseudoacromegaly differential diagnoses is long. It may be caused by several congenital and acquired conditions and diagnosis can be challenging due to its rarity and occasional overlapping of some of these conditions. The presence of a pituitary tumour in such cases may lead to a misdiagnosis of acromegaly, and thus, biochemical evaluation is key. Here, we present a case of pseudoacromegaly with an acromegaloid phenotype, normal IGF levels, a supressed GH response to an oral glucose tolerance test, moderate insulin resistance and non-functioning pituitary microadenoma.

Pituitary adenomas (PAs) are intracranial tumors associated with significant morbidity due to hormonal dysregulation, mass effects and have a heavy treatment burden. Growth hormone (GH)-secreting PAs (somatotropinomas) cause acromegaly-gigantism. Genetic forms of somatotropinomas due to germline AIP mutations (AIPmut+) have an early onset and are aggressive and resistant to treatment with somatostatin analogs (SSAs), including octreotide. The molecular underpinnings of these clinical features remain unclear. We investigated the role of miRNA dysregulation in AIPmut+ vs AIPmut- PA samples by array analysis. miR-34a and miR-145 were highly expressed in AIPmut+ vs AIPmut- somatotropinomas. Ectopic expression of AIPmut (p.R271W) in Aip-/- mouse embryonic fibroblasts (MEFs) upregulated miR-34a and miR-145, establishing a causal link between AIPmut and miRNA expression. In PA cells (GH3), miR-34a overexpression promoted proliferation, clonogenicity, migration and suppressed apoptosis, whereas miR-145 moderately affected proliferation and apoptosis. Moreover, high miR-34a expression increased intracellular cAMP, a critical mitogenic factor in PAs. Crucially, high miR-34a expression significantly blunted octreotide-mediated GH inhibition and antiproliferative effects. miR-34a directly targets Gnai2 encoding Gαi2, a G protein subunit inhibiting cAMP production. Accordingly, Gαi2 levels were significantly lower in AIPmut+ vs AIPmut- PA. Taken together, somatotropinomas with AIP mutations overexpress miR-34a, which in turn downregulates Gαi2 expression, increases cAMP concentration and ultimately promotes cell growth. Upregulation of miR-34a also impairs the hormonal and antiproliferative response of PA cells to octreotide. Thus, miR-34a is a novel downstream target of mutant AIP that promotes a cellular phenotype mirroring the aggressive clinical features of AIPmut+ acromegaly.

Carney complex (CNC) is characterized by skin pigmentary abnormalities, myxomas, endocrine tumors or overactivity, and schwannomas. Pale brown to black lentigines are the most common presenting feature of CNC and typically increase in number at puberty. Cardiac myxomas occur at a young age, may occur in any or all cardiac chambers, and can manifest as intracardiac obstruction of blood flow, embolic phenomenon, and/or heart failure. Other sites for myxomas include the skin, breast, oropharynx, and female genital tract. Primary pigmented nodular adrenocortical disease (PPNAD), which causes Cushing syndrome, is the most frequently observed endocrine tumor in CNC, occurring in approximately 25% of affected individuals. Large-cell calcifying Sertoli cell tumors (LCCSCTs) are observed in one third of affected males within the first decade and in most adult males. Up to 75% of individuals with CNC have multiple thyroid nodules, most of which are nonfunctioning thyroid follicular adenomas. Clinically evident acromegaly from a growth hormone (GH)-producing adenoma is evident in approximately 10% of adults. Psammomatous melanotic schwannoma (PMS), a rare tumor of the nerve sheath, occurs in an estimated 10% of affected individuals. The median age of diagnosis is 20 years.

X-linked acrogigantism is the occurrence of pituitary gigantism in an individual heterozygous or hemizygous for a germline or somatic duplication of GPR101. X-linked acrogigantism is characterized by acceleration of linear growth in early childhood – in most cases during the first two years of life – due to growth hormone (GH) excess. Most individuals with X-linked acrogigantism present with associated hyperprolactinemia due to a mixed GH- and prolactin-secreting pituitary adenoma with or without associated hyperplasia; less commonly they develop diffuse hyperplasia of the GH- and prolactin-secreting pituitary cells without a pituitary adenoma. Most affected individuals are females. Growth acceleration is the main presenting feature; other frequently observed clinical features include enlargement of hands and feet, coarsening of the facial features, and increased appetite. Neurologic signs or symptoms are rarely present. Untreated X-linked acrogigantism can lead to markedly increased stature, with obvious severe physical and psychological sequelae.

Novel genetic findings allow to more reliably elucidate the aetiology and pathogenesis of overgrowth syndromes in children and in adults. The relatively prevalent overgrowth syndromes in foetuses and neonates include Beckwith-Wiedemann (BWS) and Sotos syndromes; in addition, several rare conditions may occur e.g. Simpson-Golabi-Behmel and Weaver syndromes. These syndromes are not connected with overproduction of growth hormone. Their carriers are at risk of hypoglycaemia (in BWS), of congenital malformations and of childhood tumours. Targeted oncologic screening may improve the outcomes. Despite rapid growth even postnatally, the final height is mostly normal. In childhood and adolescence, the increased growth velocity results from hormonal overproduction - of precocious production of sexual hormones, hyperthyroidism, or of growth hormone overproduction due to pituitary adenoma that may lead to gigantism or acrogigantism and may be familiar (familiar isolated pituitary adenoma; FIPA). In 15-25 % of affected families, FIPA is caused by autosomal dominantly inherited mutations of AIP gene encoding a tumour suppressor protein named AIP (aryl hydrocarbon receptor-interacting protein). X-linked acrogigantism (X-LAG) is due to GPR101 gene mutations or microduplications of Xq26 chromosomal region. GPR101 encodes G-protein coupled receptor with unknown ligand. X-LAG is associated with recurrent and highly-penetrant pituitary macroadenomas. Mutations of additional at least 10 genes may lead to pituitary tumour with growth hormone overproduction. Gigantism in adults results from untreated or insufficiently treated pituitary adenoma in childhood. Some of the well-known current or past giants were found to carry pathogenic genetic variants of GPR101 or AIP.

Referral for an assessment of tall stature is less common than for short stature. Tall stature is defined as a height more than two standard deviations above the mean for age. The majority of subjects with tall stature show a familial tall stature or a constitutional advance of growth (CAG), which is a diagnosis of exclusion. After a careful physical evaluation, tall subjects may be divided into two groups: tall subjects with normal appearance and tall subjects with abnormal appearance. In the case of normal appearance, the paediatric endocrinologist will have to evaluate the growth rate. If it is normal for age and sex, the subject may be classified as having familial tall stature, CAG or obese subject, while if the growth rate is increased it is essential to evaluate pubertal status and thyroid status. Tall subjects with abnormal appearance and dysmorphisms can be classified into those with proportionate and disproportionate syndromes.A careful physical examination and an evaluation of growth pattern are required before starting further investigations. Physicians should always search for a pathological cause of tall stature, although the majority of children are healthy and they generally do not need treatment to cease growth progression.The most accepted and effective treatment for an excessive height prediction is inducing puberty early and leading to a complete fusion of the epiphyses and achievement of final height, using testosterone in males and oestrogens in females. Alternatively, the most common surgical procedure for reducing growth is bilateral percutaneous epiphysiodesis of the distal femur and proximal tibia and fibula.This review aims to provide up-to-date information and suggestions about the diagnosis and management of children with tall stature.

X-linked acrogigantism (XLAG) is a recently identified condition of early-onset GH excess resulting from the germline or somatic duplication of the GPR101 gene on chromosome Xq26.3. Thirty patients have been formally reported so far. The disease affects mostly females, occurs usually sporadically, and is characterised by early onset and marked overgrowth. Most patients present with concomitant hyperprolactinaemia. Histopathology shows pituitary hyperplasia or pituitary adenoma with or without associated hyperplasia. XLAG-related pituitary adenomas present peculiar histopathological features that should contribute to raise the suspicion of this rare condition. Treatment is frequently challenging and multi-modal. While females present with germline mutations, the sporadic male patients reported so far were somatic mosaics with variable levels of mosaicism, although no differences in the clinical phenotype were observed between patients with germline or somatic duplication. The GPR101 gene encodes an orphan G protein-coupled receptor normally expressed in the central nervous system, and at particularly high levels in the hypothalamus. While the physiological function and the endogenous ligand of GPR101 are unknown, the high expression of GPR101 in the arcuate nucleus and the occurrence of increased circulating GHRH levels in some patients with XLAG, suggest that increased hypothalamic GHRH secretion could play a role in the pathogenesis of this condition. In this review, we summarise the published evidence on XLAG and GPR101 and discuss the results of recent studies that have investigated the potential role of GPR101 variants in the pathogenesis of pituitary adenomas.

Gigantism and acromegaly are rare disorders that are caused by excessive GH secretion and/or high levels of its mediator, IGF-1. Gigantism occurs when excess GH or IGF-1 lead to increased linear growth, before the end of puberty and epiphyseal closure. The majority of cases arise from a benign GH-secreting pituitary adenoma, with an incidence of pituitary gigantism and acromegaly of approximately 8 and 11 per million person-years, respectively. Over the past two decades, our increasing understanding of the molecular and genetic etiologies of pituitary gigantism and acromegaly yielded several genetic causes, including multiple endocrine neoplasia type 1 and 4, McCune-Albright syndrome, Carney complex, familial isolated pituitary adenoma, pituitary adenoma association due to defects in familial succinate dehydrogenase genes, and the recently identified X-linked acrogigantism. The early diagnosis of these conditions helps guide early intervention, screening, and genetic counseling of patients and their family members. In this review, we provide a concise and up-to-date discussion on the genetics of gigantism and acromegaly.

Growth hormone has been known to be diabetogenic for almost a century and it's diabetogenic properties fostered consideration of excessive and abnormal GH secretion as a cause of diabetes, as well as a role in the microvascular complications, especially retinopathy. However, besides inducing insulin resistance, GH also is lipolytic and a major anabolic hormone for nitrogen retention and protein synthesis. These actions are best illustrated at the extremes of GH secretion: Gigantism/acromegaly is characterized by excessive growth, CHO intolerance, hyperplasia of bone, little body fat and prominent muscle development, whereas total deficiency of GH secretion or action is associated with adiposity, poor growth, and poor muscle development. These actions also become apparent during puberty and pregnancy, times when GH secretion is increased and account for the characteristic changes in body composition and tendency to diabetes. More recently, tissue specific deletions of the GH receptor (GHR), have uncovered newer metabolic effects including it's essential role in triglyceride export from the liver when GHR is deleted in the liver, leading to hepatic steatosis and ultimately to hepatic adenoma formation, effects which may explain these findings in obesity, a state of diminished GH secretion and action. In addition deletion of GH action in muscle and fat is associated with specific patterns of disturbed phenotype and metabolic effects in CHO, fat, and protein metabolism affecting the specific tissue and whole body function. This chapter provides an overview of these classic and newer metabolic functions of GH, placing this hormone and its actions in a central role of body fuel economy in health and disease.

Pituitary gigantism is a rare endocrine disorder caused by hypersecretion of growth hormone during growing period. Individuals with this disorder have an enormous growth in height and associated degenerative changes. The continued hypersecretion of growth hormone during adulthood leads to acromegaly, a condition related to the disproportionate bone growth of the skull, hands and feet. The skeletal remains studied belong to a young adult male from the Jewish necropolis of "Ronda Sur" in Lucena (Córdoba, Spain, VIII-XII centuries CE). The individual shows a very large and thick neurocranium, pronounced supraorbital ridges, an extremely prominent occipital protuberance, and an extremely large and massive mandible. Additional pathologies include enlargement of the vertebral bodies with degenerative changes, thickened ribs, and a slight increased length of the diaphysis with an increased cortical bone thickness of lower limbs. Comparative metric analysis of the mandible with other individuals from the same population and a contemporary Mediterranean population shows a trend toward acromegalic morphology. This case is an important contribution in paleopathological literature because it is a rare condition that has not been widely documented in ancient skeletal remains.

IGSF1 is a membrane glycoprotein highly expressed in the anterior pituitary. Pathogenic mutations in the IGSF1 gene (on Xq26.2) are associated with X-linked central hypothyroidism and testicular enlargement in males. In this study, we tested the hypothesis that IGSF1 is involved in the development of pituitary tumors, especially those that produce growth hormone (GH). IGSF1 was sequenced in 21 patients with gigantism or acromegaly and 92 healthy individuals. Expression studies with a candidate pathogenic IGSF1 variant were carried out in transfected cells and immunohistochemistry for IGSF1 was performed in the sections of GH-producing adenomas, familial somatomammotroph hyperplasia, and in normal pituitary. We identified the sequence variant p.N604T, which in silico analysis suggested could affect IGSF1 function, in two male patients and one female with somatomammotroph hyperplasia from the same family. Of 60 female controls, two carried the same variant and seven were heterozygous for other variants. Immunohistochemistry showed increased IGSF1 staining in the GH-producing tumor from the patient with the IGSF1 p.N604T variant compared with a GH-producing adenoma from a patient negative for any IGSF1 variants and with normal control pituitary tissue. The IGSF1 gene appears polymorphic in the general population. A potentially pathogenic variant identified in the germline of three patients with gigantism from the same family (segregating with the disease) was also detected in two healthy female controls. Variations in IGSF1 expression in pituitary tissue in patients with or without IGSF1 germline mutations point to the need for further studies of IGSF1 action in pituitary adenoma formation.

The efficacy of combined treatment in active acromegaly with both long-acting somatostatin analogs (SRIF) and pegvisomant (PEG-V) has been well established. The aim was to describe the PEG-V dose reductions after the conversion from daily PEG-V to combination treatment. To clarify the individual beneficial and adverse effects, in two acromegaly patients, who only normalized their insulin like growth factor (IGF-I) levels with high-dose pegvisomant therapy. We present two cases of a 31 and 44 years old male with gigantism and acromegaly that were controlled subsequently by surgery, radiotherapy, SRIF analogs and daily PEG-V treatment. They were converted to combined treatment of monthly SSA and (twice) weekly PEG-V. High dose SSA treatment was added while the PEG-V dose was decreased during carful monitoring of the IGF-I. After switching from PEG-V monotherapy to SRIF analogs plus pegvisomant combination therapy IGF-I remained normal. However, the necessary PEG-V dose, to normalize IGF-I differed significantly between these two patients. One patient needed twice weekly 100 mg, the second needed 60 mg once weekly on top of their monthly lanreotide Autosolution injections of 120 mg. The weekly dose reduction was 80 and 150 mg. After the introducing of lanreotide, fasting glucose and glycosylated haemoglobin concentrations increased. Diabetic medication had to be introduced or increased. No changes in liver tests or in pituitary adenoma size were observed. In these two patients, PEG-V in combination with long-acting SRIF analogs was as effective as PEG-V monotherapy in normalizing IGF-I levels, although significant dose-reductions in PEG-V could be achieved. However, there seems to be a wide variation in the reduction of PEG-V dose, which can be obtained after conversion to combined treatment.

The efficacy and safety of the long-acting repeatable formulation of octreotide (OCT-LAR) treatment in patients suffering from acromegaly was investigated retrospectively in Shizuoka prefecture, Japan. Thirty patients (11 male, 19 female; average age, 48.9 years old), 29 of whom had undergone transsphenoidal surgery previously, were treated with OCT-LAR. OCT-LAR was injected i.m. every 4 weeks with an intended protocol of 20 mg over 24 months, however, 46.7% of patients required the dose of OCT-LAR to be increased. The final average dose of OCT-LAR was 25.0 +/- 6.8 mg. Administering OCT-LAR significantly decreased serum GH and insulin-like growth factor 1 (IGF-1) levels (from 13.7 +/- 11.9 to 5.8 +/- 7.3 microg/L and from 585 +/- 263 to 339 +/- 193.7 microg/L after 3 months, respectively). Among patients treated with OCT-LAR, 56.7% expressed <or=2.5 microg/L serum GH and 53.3% displayed serum IGF-1 levels within the normal range, while 36.7% met both criteria that indicated treatment success. A sufficient outcome was achieved in 73.3% of patients when the rate of GH <or=2.5 microg/L or normalization of IGF-1 was accumulated. OCT-LAR did not have a negative effect on glucose tolerance when hemoglobin A1c was used as a marker. A gallbladder polyp was found only in 1 patient but it was uncertain whether OCT-LAR was involved in its development because the patient was not examined before OCT-LAR treatment. There were no abnormalities on liver function tests in any patients. In conclusion, our results showed that OCT-LAR was safe and effective as a therapeutic option for Japanese patients with acromegaly in a postoperative setting, by controlling the disease activity.

The use of octreotide-LAR and cabergoline therapy has shown great promise in adults with acromegaly; however, the experience in pediatric patients has rarely been reported. We described a clinical course of a 15-year-old boy of McCune-Albright syndrome (MAS) with pituitary gigantism. At the age of 8 years, a growth hormone (GH) and prolactin (PRL) producing pituitary adenoma was diagnosed at our hospital. He also had multiple fibrous dysplasia, so that he was diagnosed as having MAS. The tumor was partially resected, and GNAS1 gene mutation (R201C) was identified in affected tissues. We introduced octreotide to suppress GH secretion (100 mug 2/day s.c). During therapy with octreotide, IGF-1 and GH levels could not be suppressed and the patient frequently complained of nausea from octreotide treatment. Therefore, the therapy was changed to monthly injections of octreotide-LAR at the age of 12.3 years and was partially effective. However, as defect of left visual field worsened due to progressive left optic canal stenosis, he underwent second neurological decompression of the left optic nerve at 13.4 years of age. After surgery, in addition to octreotide-LAR, cabergoline (0.25 mg twice a month) was started. This regimen normalized serum levels of GH and IGF-1; however, he showed impaired glucose tolerance and gallstones at 15.7 years of age. Therefore, the dose of octreotide-LAR was reduced to 10 mg and the dose of cabergoline increased. This case demonstrated the difficulty of treating pituitary gigantism due to MAS. The use of octreotide-LAR and cabergoline should be considered even in pediatric patients; however, adverse events due to octreotide-LAR must be carefully examined.

Chronic growth hormone (GH)/insulin-like growth factor I (IGF-I) excess is associated with considerable mortality in acromegaly, but no data are available in pituitary gigantism. The aim of the study was to evaluate the long-term effects of early exposure to GH and IGF-I excess on cardiovascular and metabolic parameters in adult patients with pituitary gigantism. Six adult male patients with newly diagnosed gigantism due to GH secreting pituitary adenoma were studied and compared with 6 age- and sex-matched patients with acromegaly and 10 healthy subjects. Morphologic and functional cardiac parameters were evaluated by Doppler echocardiography. Glucose metabolism was assessed by evaluating glucose tolerance and homeostasis model assessment index. Disease duration was significantly longer (P<.05) in patients with gigantism than in patients with acromegaly, whereas GH and IGF-I concentrations were comparable. Left ventricular mass was increased both in patients with gigantism and in patients with acromegaly, as compared with controls. Left ventricular hypertrophy was detected in 2 of 6 of both patients with gigantism and patients with acromegaly, and isolated intraventricular septum thickening in 1 patient with gigantism. Inadequate diastolic filling (ratio between early and late transmitral flow velocity<1) was detected in 2 of 6 patients with gigantism and 1 of 6 patients with acromegaly. Impaired glucose metabolism occurrence was higher in patients with acromegaly (66%) compared with patients with gigantism (16%). Concentrations of IGF-I were significantly (P<.05) higher in patients with gigantism who have cardiac abnormalities than in those without cardiac abnormalities. In conclusion, our data suggest that GH/IGF-I excess in young adult patients is associated with morphologic and functional cardiac abnormalities that are similar in patients with gigantism and in patients with acromegaly, whereas occurrence of impaired glucose metabolism appears to be higher in patients with acromegaly, although patients with gigantism are exposed to GH excess for a longer period.

Serum levels of growth hormone (GH) in the human body vary and can influence the levels of insulin-like growth factor I (IGF-1). Low levels of GH can result in a dwarf phenotype and have been positively correlated with an increased life expectancy. High levels of GH can lead to gigantism or a clinical syndrome termed acromegaly, and also have been implicated in diabetic eye and kidney damage. Additionally, it has been postulated that the GH-IGF-I system can be involved in several types of cancers. Overall, both elevated and suppressed circulating levels of GH can have pronounced physiological effects. More than a decade ago a new class of drug, a GH antagonist, was discovered. It is now being tested for its ability to combat the effects of high circulating levels of GH. In this review, we will discuss some of the detrimental actions of GH and how a GH antagonist may be used to combat these effects.

Serum levels of growth hormone (GH) can vary. Low levels of GH can result in a dwarf phenotype and have been positively correlated with an increased life expectancy. High levels of GH can lead to gigantism or a clinical syndrome termed acromegaly and has been implicated in diabetic eye and kidney damage. Additionally the GH/IGF-1 system has been postulated as a risk factor for several types of cancers. Thus both elevated and suppressed circulating levels of GH can have pronounced physiological effects. More than a decade ago the first drug of a new class, a GH antagonist, was discovered. This molecule is now being tested for its ability to combat the effects of high circulating levels of GH. Here, we discuss some of the detrimental actions of GH, and how a GH antagonist can be used to combat these effects.

Hypersecretion of GH is usually caused by a pituitary adenoma and about 40% of these tumors exhibit missense gsp mutations in Arg201 or Gln227 of the Gs, gene. We studied 20 pituitary tumors obtained from patients with GH hypersecretion. One tumor was resected from an 11 year-old boy with a 3 year history of accelerated growth, associated with increased concentrations of serum GH and IGF-I, which were not suppressed by glucose administration. The remaining 19 tumors were obtained from adult acromegalic patients, who had elevated baseline serum GH levels that did not show evidence of suppression after administration of glucose. The gsp mutations were studied by enzymatic digestion of the amplified PCR fragment of exon 8 (Arg201) and exon 9 (Gln227) with the enzymes NlaIII and NgoAIV, respectively. The tumors obtained from the boy and from nine of the 19 patients with acromegaly exhibited the gsp mutation R201H. None of the tumors had the Gln227 mutation. The gsp positive patients tended to be older, had smaller tumors, and had preoperative basal serum GH levels which were significantly lower (21 +/- 6 vs 56 +/- 16 microg/l, p<0.05) than the gsp negative patients. In this study, we documented the presence of a gsp mutation in Arg201 in a boy with gigantism and in approximately half of 19 Chilean adult patients with acromegaly, similar to other populations.

A 41-year-old male presented with progressive visual defects, acromegaly and hyperthyroidism. After clinical evaluation a giant GH/TSH-secreting pituitary adenoma was diagnosed. Administration of the somatostatin analog octreotide at doses of 150 microg s.c. per day inhibited the secretion of both GH and TSH. A three-week treatment with octreotide prior to surgery led to slight visual improvement and CT scan showed some new necrotic areas within the tumor mass. Transcranial surgery was performed. By immunohistochemical analyses of the adenoma tissue GH, prolactin and beta-chorionic gonadotropin were detected; TSH was negative. Electron microscopy revealed an undifferentiated, monomorphous adenoma with morphological features of an acidophil stem cell adenoma such as the presence of misplaced exocytoses, fibrous bodies and mitochondrial gigantism. However, the tumor cells contained small secretory granules (up to 250 nm) accumulated along the cell membrane characteristic of thyrotrope cells. Furthermore, some adenoma cells were fusiform with long cytoplasmic processes resembling thyrotropes. Two months after the operation CT scan revealed a large residual tumor. Serum GH and TSH levels had increased again and the TSH level was even higher than before the treatment. The patient died suddenly, most probably of lethal arrhythmia. Specimens of the adenoma tissue obtained at autopsy confirmed the previous findings with the exception of positive immunostaining for TSH which was found in less than 1% of the adenoma cells. This undifferentiated, monomorphous GH/TSH-secreting pituitary adenoma represents an entity that is unusual both in its ultrastructural features and clinical manifestations suggesting a cytogenesis from an early, undifferentiated stem cell.

We report a case of pyodermia chronica glutealis complicated by acromegalic gigantism associated with hyperprolactinemia. The serum prolactin, growth hormone, adrenocorticotropic hormone, and 11-deoxycortisol levels were elevated, but the estradiol and dehydroepiandrosterone-sulphate levels were within normal limits. However, the testosterone level was very low. Histopathologically, we found sinus tracts and scarring in a specimen from the buttocks. We could not immunohistochemically detect clear androgen, growth hormone, or prolactin receptors at any site. The patient was a man with a height of 197 cm and weight of 140 kg, he had clinical features of active acromegaly such as excessive sweating and increased thickness of soft tissue. He was also diagnosed with diabetes mellitus. Under such conditions, bacteria could easily grow and lesions might have been aggravated by the heavy pressure from his weight, a possible causes of his pyodermia chronica glutealis.

A 36 year old white female came to our service after having been evaluated on repetitive occasions in the past for a workup of gigantism and acromegalic features. Since childhood she had developed tall stature, frontal bossing, prominence of zygomatic bones, separated teeth, large hands and size 14 shoes. Human growth hormone and somatomedin serum levels had been normal on all occasions tested. Her past history was significant for primary amenorrhea and a 12 year history of hypertension. On physical examination BP was 140/100, height 6' 2", weight 2571 bs. Her phenotype was truly acromegalic. There was absence of axillary and pubic hair with no breast development. External genitalia was of female appearance. Laboratory evaluation showed increased FSH of 88 mlU/ml, increase LH of 65.6 mlU/ml and decreased E2 of 12.6 pg/ml. Other findings were low serum cortisol of 0.2 mg/dl, high ACTH of 344 pg/ml, low 17-Ketosteroids, high pregnenolone levels of 595 mg/dl, low 17-hydroxypregnenolone less than 10 ng/dl, very high aldosterone of 31 ng/dl and suppressed PRA of less than 0.1 ng/ml. A pelvic sonogram showed a right ovoid structure which could represent a gonad and failed to identify the uterus and left gonad. A bone densitometry showed a decrease bone mineral density compatible with osteoporosis. Chromosome study showed a karyotype of 46-XY. A diagnosis was made of congenital adrenal hyperplasia secondary to 17-alpha-hydroxylase deficiency in a genotypic male. Our patient was referred to the department of gynecology for surgical removal of the gonads. It is amazing how a patient with severe adrenal insufficiency can withstand 36 years of her life undiagnosed without going into an adrenal crisis. Her tall stature and acromegalic features were the striking signs confusing all physicians and delaying the correct diagnosis and appropriate treatment. There has been reported worldwide, nearly 120 cases with documented severe 17-alpha-hydroxylase deficiency. To our knowledge this is the first case identified in Puerto Rico of male pseudohermaphroditism secondary to 17-alpha-hydroxylase enzyme deficiency.

We report a case of giant pituitary adenoma in a child. Computerized tomography (CT) scan revealed a suprasellar extension tumor mass with hydrocephalus. There was no clinical evidence of acromegaly, gigantism, and other hormonal symptoms. Endocrinologic studies showed within normal value of serum growth hormone (GH: 4.2 ng/mL) and slightly increased levels of prolactin (PRL: 78 ng/mL) and other pituitary hormone values were within normal range. On suppression test by bromocryptin, both GH and PRL levels were reduced. Histopathological findings revealed that the tumor consisted of predominantly chromophobic and partly eosinophilic adenoma cells. Immunohistochemical staining detected GH and PRL in a small number of distinctly different adenoma cells, respectively. Nonradioactive in situ hybridization (ISH) also showed GH and PRL mRNA expression in identical immunopositive cells. Electron microscopy (EM) demonstrated adenoma cells with moderate or small numbers of two types of dense granules and without fibrous body which are characteristic of sparsely granulated GH-cell adenomas. The adenoma does not fit into any classification but may be an atypical acidophil cell line tumor showing focal differentiation toward both GH and PRL cells.

In this report we describe the first case of a girl with acromegaloidism in Japan. She had large and coarse facial features with acral enlargement accompanying height overgrowth; these resemble the manifestations of acromegaly and gigantism due to growth hormone (GH) overproduction. However, pituitary function studies revealed a dysfunction of her GH secretion. Moreover, markedly decreased serum somatomedin C (SM-C) levels also indicated impairment of GH secretion. Therefore, GH and SM-C cannot have been responsible for promoting somatic growth. However, serum alkaline-phosphatase (Al-P) and osteocalcin, were increased, indicating that stimulation of bone metabolism was increased without GH and SM-C effects. The patient is a typical case showing growth without GH, and these data suggest the existence of an unidentified growth promoting factor that is independent of GH and SM-C.

50 patients with autonomous growth hormone excess (48 with adult acromegaly and 2 with gigantism) were studied between 1966 to 1986 (2.38 pts/year). Characteristic clinical presentation, an increase in growth hormone (GH) uninhibited by glucose, and/or hyperphosphemia and hyperhydroxiprolinuria were present in all patients. No cases of hypercalcemia were recorded. Phosphemia was increased in 55.8%, alkaline phosphatases in 61.7%, calciuria in 26.9% and hydroxyprolinuria in 74.2% of the patients. Basal GH was over 5 ng/ml (89.9 DS +/- 170.9) in 42 pts, and in 37 was not suppressed after glucose administration, 38% had an increased (paradoxical response) and 62% a flat response (less than 50% change of basal values). TRH test was performed in 14 patients, 8 presented an increase in GH titer. Hyperprolactinemia was seen in 4 of 12 patients in whom this hormone was measured. The size of the sella turcica was increased in 93%, and although the larger sellar size correlated to higher levels of GH, correlation was not significant. 20% of the pts had rheumatological disease, 14% goiter, 12% cardiac disease, 26.5% had diastolic hypertension and 4% renal lithiasis (hypercalciuric pts). 38% had hyperglycemia with a diabetic glucose tolerance test and 18% had non-diabetic abnormal glucose tolerance test.

Using mice transgenic for the growth hormone gene (TGHM), we have studied the effects of a systemic elevation of growth hormone on vascular growth with the aim of investigating the role of vascular mass changes in producing hypertension. In contrast to human acromegaly or gigantism, there was no elevation of blood pressure in TGHM, but there were significant increases in vascular wall mass. In accordance with a presumably increased perfusion of larger organs, the medial cross-sectional areas of thoracic aorta and mesenteric resistance vessels were greater in the TGHM. These differences could be normalized in the aorta by body weight and in the mesenteric vessel by small intestine weight. Furthermore, the brain was not significantly heavier in the TGHM, and their carotid and cerebral vessels also were not larger. Wall-to-lumen ratios were similar in the aorta, carotid, and middle cerebral arteries suggesting that wall stress was the controlling factor in wall thickness. Surprisingly, the mesenteric vessels had increased wall-to-lumen ratio, which was similar to that seen in hypertensive vascular remodeling but in a normotensive animal. In an attempt to explain this finding it was noted that the pattern of mesenteric vascular networks and even organized structure within the vessel wall itself appeared to be fixed, perhaps by genetic mechanisms. Thus, vascular network structure may be a potentially limiting factor in the ability of the vessel wall to remodel and may have been responsible for the greater wall-to-lumen ratio in TGHM mesenteric vessels. A similar situation in human acromegaly or gigantism could result in a circulation marginally able to correct for other demands on blood flow resulting in about one third of cases being hypertensive.