A Chinese Case of X-Linked Acrogigantism and Systematic Review.

INTRODUCTION: This study described a Chinese case of X-linked acrogigantism (X-LAG) and summarized the characteristics and treatment of all reported cases. METHODS: Clinical materials and biological samples from a 5-year and 2-month-old female due to "growth acceleration for 4 years" were collected. Array comparative genomic hybrid (aCGH) and further verification were performed. All X-LAG cases from the PubMed and Web of Science databases were collected and summarized with available data. RESULTS: The patient presented accelerating growth since 1 year, and her height reached 134.6 cm (+5.24 standard deviation score [SDS]) when she was 5-year and 2-month old. She also had coarsening facial features, snoring, and acral enlargement. Growth hormone (GH) was not suppressed by the glucose-GH inhibition test, and insulin-like growth factor 1 (IGF-1) and prolactin (PRL) levels were elevated. Pituitary MRI revealed a pituitary enlargement with a maximum diameter of 22.3 mm. Octreotide imaging indicated the presence of a pituitary adenoma. The tumor shrank slightly after 3 courses of somatostatin analog but without clinical or biochemical remissions, of which the GH nadir value was 9.4 ng/mL, and IGF-1 was elevated to 749 ng/mL. Therefore, she underwent transsphenoidal surgery. Immunohistochemistry showed GH-positive and PRL-positive cells in the pituitary adenoma. Xq26.3 microduplication of the patient's germline DNA was identified by aCGH. Of all 35 reported cases, females accounted for 71.43%. There were 93.10% and 53.83% patients with hyperprolactinemia and hyperinsulinemia, respectively. Pathology showed that 75.00% of cases were adenomas. Ninety percent of cases had germline variants. The clinical and biochemical remission rates were 78.26% and 82.61%, respectively. However, the rate of complication occurrence during therapy reached 80%. CONCLUSION: It is important to recognize the possibility of X-LAG when a child under 2-year old presents overgrowth. Early diagnosis and treatment are of great importance for better treatment efficacy and clinical outcome.

[Overgrowth in children and in adults: novel clinical view, novel genes, novel phenotypes]. / Nadmerný rust u detí a dospelých: nový klinický pohled, nové geny, nové fenotypy.

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.

Childhood acromegaly due to X-linked acrogigantism: long term follow-up.

PURPOSE: Acromegaly in infancy is extremely rare. We describe a 32 year old woman who presented at 6 months of age with isolated macrocephaly, followed by accelerated linear growth. At 21 months of age, her head circumference was 55 cm (+5.5 SD), height was 97.6 cm (+4.4 SD) and weight was 20.6 kg (+6.2 SD). She had markedly elevated levels of growth hormone (GH) (135 ng/ml), IGF-1 (1540 ng/ml) and prolactin (370 ng/ml). A pituitary macroadenoma was surgically resected. Immunohistochemical staining was positive for GH. Post-operatively, she developed ACTH and TSH deficiency and diabetes insipidus. METHODS: Long term clinical follow-up and genetic testing with chromosomal microarray analysis. RESULTS: Despite GH deficiency, she grew well until 7 ½ years old, with subsequent decline in growth velocity, and received GH therapy for 5 years. Puberty was initiated with estrogen therapy. As an adult, she has no stigmata of acromegaly, with a height of 164.5 cm and non-acromegalic features. IGF-1 has remained in the low normal range. Prolactin has been mildly elevated. Serial MRIs have shown no evidence of tumor recurrence. She receives replacement therapy with hydrocortisone, levothyroxine and DDAVP. Chromosomal microarray analysis revealed that she has X-linked acrogigantism (X-LAG) due to a de novo duplication of Xq26.3 (516 kb). She recently became pregnant following ovarian stimulation and chorionic villus sampling revealed that she is carrying a male with the same duplication. CONCLUSION: This report provides detailed long term clinical follow-up of a patient with X-LAG syndrome.

Pasireotide: potential treatment option for McCune-Albright-associated acromegaly.

Only 30% of patients with McCune-Albright syndrome (MAS)-associated acromegaly achieve biochemical control under first-generation somatostatin receptor ligands (fg-SRLs), while pegvisomant fails to normalize insulin-like growth factor 1 (IGF-I) in >20% of cases. Here, we report all the patients with MAS-associated acromegaly treated with pasireotide long-acting release (LAR) in our center. Pasireotide LAR 20 mg/month resulted in rapid and long-term IGF-I normalization in patients #1 and #3. Patient #3 was resistant to fg-SRLs, while patient #1 was also controlled on fg-SRLs. In patient #2, resistant to fg-SRLs and uncontrolled on pegvisomant 40 mg/day combined with cabergoline 0.5 mg/day, pegvisomant was replaced with pasireotide LAR 40 mg/month, resulting in the near normalization of IGF-I levels. All 3 patients developed intermittent impaired fasting glucose, without the need for glucose-lowering drugs. Thus, pasireotide LAR is clearly useful as third-line therapy, and potentially even as second-line therapy, in MAS-associated acromegaly.

The Genetic Pathophysiology and Clinical Management of the TADopathy, X-Linked Acrogigantism.

Pituitary gigantism is a rare manifestation of chronic growth hormone (GH) excess that begins before closure of the growth plates. Nearly half of pituitary gigantism patients have an identifiable genetic cause. X-linked acrogigantism (X-LAG; 10% of pituitary gigantism) typically begins during infancy and can lead to the tallest individuals described. In the 10 years since its discovery, about 40 patients have been identified. Patients with X-LAG usually develop mixed GH and prolactin macroadenomas with occasional hyperplasia that secrete copious amounts of GH, and frequently prolactin. Circulating GH releasing hormone (GHRH) is also elevated in a proportion of patients. X-LAG is caused by constitutive or sporadic mosaic duplications at chromosome Xq26.3 that disrupt the normal chromatin architecture of a topologically associating domain (TAD) around the orphan G protein coupled receptor (GPCR), GPR101. This leads to the formation of a neoTAD in which GPR101 over-expression is driven by ectopic enhancers ("TADopathy"). X-LAG has been seen in three families due to transmission of the duplication from affected mothers to sons. GPR101 is a constitutively active receptor with an unknown natural ligand that signals via multiple G proteins and protein kinases A and C to promote GH/prolactin hypersecretion. Treatment of X-LAG is challenging due to the young patient population and resistance to somatostatin analogs; the GH receptor antagonist pegvisomant is often an effective option. GH, insulin-like growth factor 1 (IGF-1) and prolactin hypersecretion and physical overgrowth can be controlled before definitive adult gigantism occurs, often at the cost of permanent hypopituitarism.

Effective Long-term Pediatric Pegvisomant Monotherapy to Final Height in X-linked Acrogigantism.

X-linked acrogigantism (X-LAG) is characterized by extreme tall stature from early childhood resulting from duplication of the GPR101 gene, in turn resulting in GH excess. Most cases present with pituitary tumors secreting GH and prolactin. Diffuse pituitary hyperplasia is uncommon and normal prolactin is rare. We present a girl with tall stature from 3 years of age; her height was +4.25 SD score at 5 years, with no signs of syndromic disease. She had significant GH excess, serum IGF-1 4 times the upper limit of normal and normal circulating GHRH, with normal pituitary magnetic resonance imaging over 13 years. No abnormalities were found in either the AIP or MEN1 genes. Treatment with somatostatin analogues and dopamine agonists showed minimal therapeutic benefit, but significant side effects. She tested positive for duplication of GPR101 6 years after the initial diagnosis. She was then initiated on pegvisomant aged 12 years, achieving prompt IGF-1 normalization and growth cessation. Aged 16.5 years, she showed escape from IGF-1 control, and height velocity increased, but this responded well to a dose increase in pegvisomant, with reassuring long-term pediatric safety over 7 years. Her final height is +2.9 SD score. Currently, life-long pegvisomant treatment is planned with genetic counselling regarding future offspring.

The X-linked acrogigantism-associated gene gpr101 is a regulator of early embryonic development and growth in zebrafish.

We recently described X-linked acrogigantism (X-LAG), a condition of early childhood-onset pituitary gigantism associated with microduplications of the GPR101 receptor. The expression of GPR101 in hyperplastic pituitary regions and tumors in X-LAG patients, and GPR101's normally transient pituitary expression during fetal development, suggest a role in the regulation of growth. Nevertheless, little is still known about GPR101's physiological functions, especially during development. By using zebrafish models, we investigated the role of gpr101 during embryonic development and somatic growth. Transient ectopic gpr101 expression perturbed the embryonic body plan but did not affect growth. Loss of gpr101 led to a significant reduction in body size that was even more pronounced in the absence of maternal transcripts, as well as subfertility. These changes were accompanied by gastrulation and hypothalamic defects. In conclusion, both gpr101 loss- and gain-of-function affect, in different ways, fertility, embryonic patterning, growth and brain development.

Genetics of Acromegaly and Gigantism.

Growth hormone (GH)-secreting pituitary tumours represent the most genetically determined pituitary tumour type. This is true both for germline and somatic mutations. Germline mutations occur in several known genes (AIP, PRKAR1A, GPR101, GNAS, MEN1, CDKN1B, SDHx, MAX) as well as familial cases with currently unknown genes, while somatic mutations in GNAS are present in up to 40% of tumours. If the disease starts before the fusion of the epiphysis, then accelerated growth and increased final height, or gigantism, can develop, where a genetic background can be identified in half of the cases. Hereditary GH-secreting pituitary adenoma (PA) can manifest as isolated tumours, familial isolated pituitary adenoma (FIPA) including cases with AIP mutations or GPR101 duplications (X-linked acrogigantism, XLAG) or can be a part of systemic diseases like multiple endocrine neoplasia type 1 or type 4, McCune-Albright syndrome, Carney complex or phaeochromocytoma/paraganglioma-pituitary adenoma association. Family history and a search for associated syndromic manifestations can help to draw attention to genetic causes; many of these are now tested as part of gene panels. Identifying genetic mutations allows appropriate screening of associated comorbidities as well as finding affected family members before the clinical manifestation of the disease. This review focuses on germline and somatic mutations predisposing to acromegaly and gigantism.

HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: The roles of AIP and GPR101 in familial isolated pituitary adenomas (FIPA).

Familial isolated pituitary adenoma (FIPA) is one of the most frequent conditions associated with an inherited presentation of pituitary tumors. FIPA can present with pituitary adenomas of any secretory/non-secretory type. Mutations in the gene for the aryl-hydrocarbon receptor interacting protein (AIP) have been identified in approximately 20% of FIPA families and are the most frequent cause (29%) of pituitary gigantism. Pituitary tumors in FIPA are larger, occur at a younger age and display more aggressive characteristics and evolution than sporadic adenomas. This aggressiveness is especially marked in FIPA kindreds with AIP mutations. Special attention should be paid to young patients with pituitary gigantism and/or macroadenomas, as AIP mutations are prevalent in these groups. Duplications on chromosome Xq26.3 involving the gene GPR101 lead to X-linked acrogigantism (X-LAG), a syndrome of pituitary gigantism beginning in early childhood; three kindreds with X-LAG have presented in the setting of FIPA. Management of pituitary adenomas in the setting of FIPA, AIP mutations and GPR101 duplications is often more complex than in sporadic disease due to early onset disease, aggressive tumor growth and resistance to medical therapy.

Mutations in GPR101 as a potential cause of X-linked acrogigantism and acromegaly.

X-linked acrogigantism (XLAG) is a recently described early-onset gigantism due to GPR101 duplication that induces growth hormone (GH) oversecretion. GPR101, which belongs to Family A rhodopsin-like family of G protein-coupled receptors, is predominantly expressed in hypothalamus and pituitary, suggesting that GPR101 might be important in regulating diverse functions such as energy balance and reproduction. Most mammalian GPR101s have extremely long third intracellular loops (ICL3); however, zebrafish GPR101 has a much shorter ICL3, but a longer C-terminus. GnRH-(1-5), a GnRH metabolite, can modulate the hypothalamus-pituitary-gonad axis and cancer cell migration via activating GPR101. GPR101 couples to both Gαs and Gαi proteins. GPR101 duplication has a causative role in XLAG, while GPR101 variants, especially c.924G>C (E308D), located at ICL3, are attributed to acromegaly. Some GPR101 mutations that are associated with a small proportion of pituitary tumors without GH oversecretion have also been identified recently. This chapter will summarize studies on GPR101, including its molecular cloning and tissue distribution, physiology, pharmacology, and pathophysiology.

An orphan G-protein-coupled receptor causes human gigantism and/or acromegaly: Molecular biology and clinical correlations.

X-linked acrogigantism (X-LAG) is a recently described form of familial or sporadic pituitary gigantism characterized by very early onset GH and IGF-1 excess, accelerated growth velocity, gigantism and/or acromegaloid features. Germline or somatic microduplications of the Xq26.3 chromosomal region, invariably involving the GPR101 gene, constitute the genetic defect leading to X-LAG. GPR101 encodes a class A G protein-coupled receptor that activates the 3',5'-cyclic adenosine monophosphate signaling pathway. Highly expressed in the central nervous system, the main physiological function and ligand of GPR101 remain unknown, but it seems to play a role in the normal development of the GHRH-GH axis. Early recognition of X-LAG cases is imperative because these patients require clinical management that differs from that of other patients with acromegaly or gigantism. Medical treatment with pegvisomant seems to be the best approach, since X-LAG tumors are resistant to the treatment with somatostatin analogues and dopamine agonists; surgical cure requires near-total hypophysectomy. Currently, the efforts of our research focus on the identification of GPR101 ligands; in addition, the long-term follow-up of X-LAG patients is of extreme interest as this is expected to lead to better understanding of GPR101 effects on human pathophysiology.

[Investigation of tall stature in children: Diagnostic work-up, review of the main causes]. / Exploration d'une avance staturale chez l'enfant : conduite à tenir pratique, principales étiologies à évoquer.

Tall stature is not a common motive for medical consultation, even though by definition 2.5 % of children in the general population are concerned. It is usually defined as height greater than+2 standard deviations (SD) using the appropriate growth chart for age and gender, or a difference greater than +2 SD between actual height and target height. With a patient presenting tall stature, the physician has to determine whether it is a benign feature or a disease. Indeed, making the diagnosis is essential for hormonal disease or genetic overgrowth syndromes. The past medical history including parents' height, prenatal and birth data, physical examination along with anthropometry (height, weight, head circumference, body mass index), and growth chart evaluation with the detailed growth pattern are generally sufficient to make the diagnosis such as familial tall stature, obesity, or early puberty. Bone age estimation may be helpful for some specific etiologies and is also necessary to help predict final adult height. After exclusion of common causes, further investigation is required. Sudden growth acceleration often reveals endocrine pathology such as early puberty, hyperthyroidism, or acrogigantism. Tall stature accompanied by dysmorphic features, congenital malformations, developmental delay, or a family medical history may be related to genetic disorders such as Marfan, Sotos, or Wiedemann-Beckwith syndromes. We relate here the most frequent etiologies of overgrowth syndromes.

Two case reports of X-linked acrogigantism and pathogenic gene detection / 中华内分泌代谢杂志

Objective:To report the clinical characteristics, diagnosis, and treatment of 2 cases of X-linked acrogigantism(X-LAG).Methods:The clinical information of two patients were retrospectively reported, and peripheral blood DNA was collected for copy number variations detection.Results:Both patients had onset at age of two, with common clinical characteristics including linear growth acceleration, mild facial coarsening, enlargement of hands and feet, increased appetite, and snoring, etc. The heights Z scores of the two patients before treatment were + 6.86 and + 6.53, respectively. Growth hormone(GH) glucose inhibition test showed that GH nadir values were over 1 ng/mL and insulin-like growth factor-Ⅰ(IGF-Ⅰ) were 586.0 ng/mL and 1 042.0 ng/mL, respectively. Patient 1 received three cycles of octreotide microspheres therapy followed by surgery, and achieved clinical and biochemical remission. Patient 2 had lanreotide for 5.5 years but failed biochemical remission. Microduplication of Xq26.3, which contained pathogenic gene G-protein coupled receptor 101(GPR101), was found in germline DNA of two patients through copy number variation detection, leading to the diagnosis of X-LAG.Conclusion:It should be cautious of X-LAG when children below 2 years old presents symptoms such as overgrowth and so on. Medication combined with surgery is effective.

X-LAG: How did they grow so tall?

X-linked acrogigantism (XLAG) is a new, pediatric-onset genetic syndrome, due to Xq26.3 microduplications encompassing the GPR101 gene. XLAG has a remarkably distinct phenotype with disease onset occurring before the age of 5 in all cases described to date, which is significantly younger than in other forms of pituitary gigantism. These patients have mixed GH and prolactin positive adenomas and/or mixed-cell hyperplasia and highly elevated levels of GH/IGF-1 and prolactin. Given their particularly young age of onset, the significant GH hypersecretion can lead to a phenotype of severe gigantism with very advanced age-specific height Z-scores. If not adequately treated in childhood, this condition results in extreme final adult height. XLAG has a clinical course that is highly similar to some of the tallest people with gigantism in history.

Aggressive tumor growth and clinical evolution in a patient with X-linked acro-gigantism syndrome.

X-linked acro-gigantism (X-LAG) syndrome is a newly described disease caused by microduplications on chromosome Xq26.3 leading to copy number gain of GPR101. We describe the clinical progress of a sporadic male X-LAG syndrome patient with an Xq26.3 microduplication, highlighting the aggressive natural history of pituitary tumor growth in the absence of treatment. The patient first presented elsewhere aged 5 years 8 months with a history of excessive growth for >2 years. His height was 163 cm, his weight was 36 kg, and he had markedly elevated GH and IGF-1. MRI showed a non-invasive sellar mass measuring 32.5 × 23.9 × 29.1 mm. Treatment was declined and the family was lost to follow-up. At the age of 10 years and 7 months, he presented again with headaches, seizures, and visual disturbance. His height had increased to 197 cm. MRI showed an invasive mass measuring 56.2 × 58.1 × 45.0 mm, with compression of optic chiasma, bilateral cavernous sinus invasion, and hydrocephalus. His thyrotrope, corticotrope, and gonadotrope axes were deficient. Surgery, somatostatin analogs, and cabergoline did not control vertical growth and pegvisomant was added, although vertical growth continues (currently 207 cm at 11 years 7 months of age). X-LAG syndrome is a new genomic disorder in which early-onset pituitary tumorigenesis can lead to marked overgrowth and gigantism. This case illustrates the aggressive nature of tumor evolution and the challenging clinical management in X-LAG syndrome.

Screening for genetic causes of growth hormone hypersecretion.

Growth hormone (GH) secreting pituitary tumors may be caused by genetic abnormalities in a variety of genes including AIP, MEN1, CDKN1B, and PRKAR1A. These can lead to GH secreting pituitary adenomas as an isolated occurrence (e.g. as aggressive sporadic adenomas or in familial isolated pituitary adenomas (FIPA)) or as part of syndromic conditions such as MEN1 or Carney complex. These tumors have more aggressive features than sporadic acromegaly, including a younger age at disease onset and larger tumor size, and they can be challenging to manage. In addition to mutations or deletions, copy number variation at the GPR101 locus may also lead to mixed GH and prolactin secreting pituitary adenomas in the setting of X-linked acrogigantism (X-LAG syndrome). In X-LAG syndrome and in McCune Albright syndrome, mosaicism for GPR101 duplications and activating GNAS1 mutations, respectively, contribute to the genetic pathogenesis. As only 5% of pituitary adenomas have a known cause, efficient deployment of genetic testing requires detailed knowledge of clinical characteristics and potential associated syndromic features in the patient and their family.

Clinical and genetic characterization of pituitary gigantism: an international collaborative study in 208 patients.

Despite being a classical growth disorder, pituitary gigantism has not been studied previously in a standardized way. We performed a retrospective, multicenter, international study to characterize a large series of pituitary gigantism patients. We included 208 patients (163 males; 78.4%) with growth hormone excess and a current/previous abnormal growth velocity for age or final height >2 s.d. above country normal means. The median onset of rapid growth was 13 years and occurred significantly earlier in females than in males; pituitary adenomas were diagnosed earlier in females than males (15.8 vs 21.5 years respectively). Adenomas were ≥10 mm (i.e., macroadenomas) in 84%, of which extrasellar extension occurred in 77% and invasion in 54%. GH/IGF1 control was achieved in 39% during long-term follow-up. Final height was greater in younger onset patients, with larger tumors and higher GH levels. Later disease control was associated with a greater difference from mid-parental height (r=0.23, P=0.02). AIP mutations occurred in 29%; microduplication at Xq26.3 - X-linked acrogigantism (X-LAG) - occurred in two familial isolated pituitary adenoma kindreds and in ten sporadic patients. Tumor size was not different in X-LAG, AIP mutated and genetically negative patient groups. AIP-mutated and X-LAG patients were significantly younger at onset and diagnosis, but disease control was worse in genetically negative cases. Pituitary gigantism patients are characterized by male predominance and large tumors that are difficult to control. Treatment delay increases final height and symptom burden. AIP mutations and X-LAG explain many cases, but no genetic etiology is seen in >50% of cases.

Pituitary gigantism: Causes and clinical characteristics.

Acromegaly and pituitary gigantism are very rare conditions resulting from excessive secretion of growth hormone (GH), usually by a pituitary adenoma. Pituitary gigantism occurs when GH excess overlaps with the period of rapid linear growth during childhood and adolescence. Until recently, its etiology and clinical characteristics have been poorly understood. Genetic and genomic causes have been identified in recent years that explain about half of cases of pituitary gigantism. We describe these recent discoveries and focus on some important settings in which gigantism can occur, including familial isolated pituitary adenomas (FIPA) and the newly described X-linked acrogigantism (X-LAG) syndrome.