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X-linked acrogigantism due to Xq26 microduplication(XLAG)

MedGen UID:
856021
Concept ID:
C3891556
Disease or Syndrome
Synonyms: CHROMOSOME Xq26 MICRODUPLICATION SYNDROME; Chromosome Xq26.3 duplication syndrome; X-LINKED ACROGIGANTISM
SNOMED CT: X-linked acrogigantism due to Xq26 microduplication (789187001); Chromosome Xq26 microduplication syndrome (789187001); X-LAG (X-linked acrogigantism) due to Xq26 microduplication (789187001)
 
Gene (location): GPR101 (Xq26.3)
 
Monarch Initiative: MONDO:0010491
OMIM®: 300942

Disease characteristics

Excerpted from the GeneReview: X-Linked Acrogigantism
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. [from GeneReviews]
Authors:
Donato Iacovazzo  |  Márta Korbonits   view full author information

Additional descriptions

From OMIM
X-linked acrogigantism (XLAG), due to microduplications of chromosome Xq26.3, is characterized by excessive growth, usually beginning during the first year of life in previously normal infants. The overgrowth is caused by growth hormone (GH1; 139250) hypersecretion from pituitary hyperplasia and/or a pituitary macroadenoma. XLAG can occur as a sporadic condition or present as familial isolated pituitary adenomas (FIPAs) in acrogigantism kindreds (Beckers et al., 2015).  http://www.omim.org/entry/300942
From MedlinePlus Genetics
X-linked acrogigantism (X-LAG) is a condition that causes abnormally fast growth beginning early in life. Babies with this condition are a normal size at birth but begin to grow rapidly in infancy or early childhood, and affected children are taller than their peers.

This rapid growth is caused by an abnormality of the pituitary gland. The pituitary gland, which is found at the base of the brain, produces hormones that control many important body functions, including growth. Individuals with X-LAG may have the condition as a result of enlargement (hyperplasia) of the gland or development of a noncancerous tumor in the gland (called a pituitary neuroendocrine tumor or PitNET). Rarely, an affected individual has both pituitary hyperplasia and a pituitary neuroendocrine tumor. The abnormal gland releases excess amounts of growth hormone, a hormone that normally helps direct growth of the body's bones and tissues. The abnormal gland can also release excess amounts of another hormone called prolactin, which helps control the function of the internal reproductive organs (gonads). 

Some people with X-LAG have additional signs and symptoms such as facial features that are described as coarse; disproportionately large hands or feet (acral enlargement); an increased appetite; and a skin condition called acanthosis nigricans, in which the skin in body folds and creases becomes thick, dark, and velvety.  https://medlineplus.gov/genetics/condition/x-linked-acrogigantism

Clinical features

From HPO
Arthralgia
MedGen UID:
13917
Concept ID:
C0003862
Sign or Symptom
Joint pain.
Body odor
MedGen UID:
43213
Concept ID:
C0085595
Finding
A perceived unpleasant smell given off by the body.
Pituitary adenoma
MedGen UID:
45933
Concept ID:
C0032000
Neoplastic Process
A benign epithelial tumor derived from intrinsic cells of the adenohypophysis (anterior pituitary).
Ventricular hypertrophy
MedGen UID:
87400
Concept ID:
C0340279
Disease or Syndrome
Enlargement of the cardiac ventricular muscle tissue with increase in the width of the wall of the ventricle and loss of elasticity. Ventricular hypertrophy is clinically differentiated into left and right ventricular hypertrophy.
Tall stature
MedGen UID:
69137
Concept ID:
C0241240
Finding
A height above that which is expected according to age and gender norms.
Acral overgrowth
MedGen UID:
1789172
Concept ID:
C1735881
Disease or Syndrome
Excessive growth of hands and feet (predominantly due to soft tissue swelling). Typical manifestations include shoe size increase, foot enlargement, glove tightness, and hand enlargement.
Overgrowth
MedGen UID:
376550
Concept ID:
C1849265
Finding
Excessive postnatal growth which may comprise increased weight, increased length, and/or increased head circumference.
Headache
MedGen UID:
9149
Concept ID:
C0018681
Sign or Symptom
Cephalgia, or pain sensed in various parts of the head, not confined to the area of distribution of any nerve.
Polyphagia
MedGen UID:
9369
Concept ID:
C0020505
Finding
A neurological anomaly with gross overeating associated with an abnormally strong desire or need to eat.
Hypopituitarism
MedGen UID:
9386
Concept ID:
C0020635
Disease or Syndrome
A condition of diminution or cessation of secretion of one or more hormones from the anterior pituitary gland. This may result from surgical or radiation ablation, non-secretory pituitary neoplasms, metastatic tumors, infarction, pituitary apoplexy, infiltrative or granulomatous processes, and other conditions.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Sleep apnea
MedGen UID:
11458
Concept ID:
C0037315
Disease or Syndrome
An intermittent cessation of airflow at the mouth and nose during sleep is known as sleep apnea. Apneas that last at least 10 seconds are considered significant, but individuals with sleep apnea may experience apneas lasting from 20 seconds up to 2 or 3 minutes. Patients may have up to 15 events per hour of sleep.
Snoring
MedGen UID:
20006
Concept ID:
C0037384
Sign or Symptom
Deep, noisy breathing during sleep, accompanied by hoarse or harsh sounds, is caused by the vibration of respiratory structures, especially the soft palate. This vibration results in sound due to obstructed air movement during breathing while sleeping.
Increased circulating prolactin concentration
MedGen UID:
1702649
Concept ID:
C5200994
Finding
The presence of abnormally increased levels of prolactin in the blood. Prolactin is a peptide hormone produced by the anterior pituitary gland that plays a role in breast development and lactation during pregnancy.
Kyphosis
MedGen UID:
44042
Concept ID:
C0022821
Anatomical Abnormality
Exaggerated anterior convexity of the thoracic vertebral column.
Accelerated skeletal maturation
MedGen UID:
154262
Concept ID:
C0545053
Finding
An abnormally increased rate of skeletal maturation. Accelerated skeletal maturation can be diagnosed on the basis of an estimation of the bone age from radiographs of specific bones in the human body.
Widely spaced teeth
MedGen UID:
337093
Concept ID:
C1844813
Finding
Increased spaces (diastemata) between most of the teeth in the same dental arch.
Coarse facial features
MedGen UID:
335284
Concept ID:
C1845847
Finding
Absence of fine and sharp appearance of brows, nose, lips, mouth, and chin, usually because of rounded and heavy features or thickened skin with or without thickening of subcutaneous and bony tissues.
Acanthosis nigricans
MedGen UID:
54
Concept ID:
C0000889
Disease or Syndrome
A dermatosis characterized by thickened, hyperpigmented plaques, typically on the intertriginous surfaces and neck.
Hyperhidrosis
MedGen UID:
5690
Concept ID:
C0020458
Finding
Abnormal excessive perspiration (sweating) despite the lack of appropriate stimuli like hot and humid weather.
Elevated circulating growth hormone concentration
MedGen UID:
66732
Concept ID:
C0235986
Finding
Acromegaly is a condition resulting from overproduction of growth hormone by the pituitary gland in persons with closed epiphyses, and consists chiefly in the enlargement of the distal parts of the body. The circumference of the skull increases, the nose becomes broad, the tongue becomes enlarged, the facial features become coarsened, the mandible grows excessively, and the teeth become separated. The fingers and toes grow chiefly in thickness.
Increased circulating insulin-like growth factor 1 concentration
MedGen UID:
390982
Concept ID:
C2676198
Finding
An elevated level of insulin-like growth factor 1 (IGF1) in the blood circulation.
Hemianopia
MedGen UID:
9193
Concept ID:
C0018979
Finding
Partial or complete loss of vision in one half of the visual field of one or both eyes.

Professional guidelines

PubMed

Mangupli R, Rostomyan L, Castermans E, Caberg JH, Camperos P, Krivoy J, Cuauro E, Bours V, Daly AF, Beckers A
Pituitary 2016 Oct;19(5):507-14. doi: 10.1007/s11102-016-0732-3. PMID: 27287035
Lodish MB, Trivellin G, Stratakis CA
Curr Opin Endocrinol Diabetes Obes 2016 Feb;23(1):72-80. doi: 10.1097/MED.0000000000000212. PMID: 26574647Free PMC Article

Recent clinical studies

Etiology

Mangupli R, Rostomyan L, Castermans E, Caberg JH, Camperos P, Krivoy J, Cuauro E, Bours V, Daly AF, Beckers A
Pituitary 2016 Oct;19(5):507-14. doi: 10.1007/s11102-016-0732-3. PMID: 27287035
Castinetti F, Daly AF, Stratakis CA, Caberg JH, Castermans E, Trivellin G, Rostomyan L, Saveanu A, Jullien N, Reynaud R, Barlier A, Bours V, Brue T, Beckers A
Horm Metab Res 2016 Jun;48(6):389-93. Epub 2016 Jan 21 doi: 10.1055/s-0042-100733. PMID: 26797872Free PMC Article
Rostomyan L, Daly AF, Petrossians P, Nachev E, Lila AR, Lecoq AL, Lecumberri B, Trivellin G, Salvatori R, Moraitis AG, Holdaway I, Kranenburg-van Klaveren DJ, Chiara Zatelli M, Palacios N, Nozieres C, Zacharin M, Ebeling T, Ojaniemi M, Rozhinskaya L, Verrua E, Jaffrain-Rea ML, Filipponi S, Gusakova D, Pronin V, Bertherat J, Belaya Z, Ilovayskaya I, Sahnoun-Fathallah M, Sievers C, Stalla GK, Castermans E, Caberg JH, Sorkina E, Auriemma RS, Mittal S, Kareva M, Lysy PA, Emy P, De Menis E, Choong CS, Mantovani G, Bours V, De Herder W, Brue T, Barlier A, Neggers SJ, Zacharieva S, Chanson P, Shah NS, Stratakis CA, Naves LA, Beckers A
Endocr Relat Cancer 2015 Oct;22(5):745-57. Epub 2015 Jul 17 doi: 10.1530/ERC-15-0320. PMID: 26187128Free PMC Article

Diagnosis

Liang H, Gong F, Liu Z, Yang Y, Yao Y, Wang R, Wang L, Chen M, Pan H, Zhu H
Neuroendocrinology 2021;111(12):1164-1175. Epub 2020 Oct 13 doi: 10.1159/000512240. PMID: 33049741
Wise-Oringer BK, Zanazzi GJ, Gordon RJ, Wardlaw SL, William C, Anyane-Yeboa K, Chung WK, Kohn B, Wisoff JH, David R, Oberfield SE
J Clin Endocrinol Metab 2019 Oct 1;104(10):4667-4675. doi: 10.1210/jc.2019-00817. PMID: 31166600Free PMC Article
Rodd C, Millette M, Iacovazzo D, Stiles CE, Barry S, Evanson J, Albrecht S, Caswell R, Bunce B, Jose S, Trouillas J, Roncaroli F, Sampson J, Ellard S, Korbonits M
J Clin Endocrinol Metab 2016 May;101(5):1927-30. Epub 2016 Mar 16 doi: 10.1210/jc.2015-4366. PMID: 26982009Free PMC Article
Rostomyan L, Daly AF, Petrossians P, Nachev E, Lila AR, Lecoq AL, Lecumberri B, Trivellin G, Salvatori R, Moraitis AG, Holdaway I, Kranenburg-van Klaveren DJ, Chiara Zatelli M, Palacios N, Nozieres C, Zacharin M, Ebeling T, Ojaniemi M, Rozhinskaya L, Verrua E, Jaffrain-Rea ML, Filipponi S, Gusakova D, Pronin V, Bertherat J, Belaya Z, Ilovayskaya I, Sahnoun-Fathallah M, Sievers C, Stalla GK, Castermans E, Caberg JH, Sorkina E, Auriemma RS, Mittal S, Kareva M, Lysy PA, Emy P, De Menis E, Choong CS, Mantovani G, Bours V, De Herder W, Brue T, Barlier A, Neggers SJ, Zacharieva S, Chanson P, Shah NS, Stratakis CA, Naves LA, Beckers A
Endocr Relat Cancer 2015 Oct;22(5):745-57. Epub 2015 Jul 17 doi: 10.1530/ERC-15-0320. PMID: 26187128Free PMC Article
Beckers A, Lodish MB, Trivellin G, Rostomyan L, Lee M, Faucz FR, Yuan B, Choong CS, Caberg JH, Verrua E, Naves LA, Cheetham TD, Young J, Lysy PA, Petrossians P, Cotterill A, Shah NS, Metzger D, Castermans E, Ambrosio MR, Villa C, Strebkova N, Mazerkina N, Gaillard S, Barra GB, Casulari LA, Neggers SJ, Salvatori R, Jaffrain-Rea ML, Zacharin M, Santamaria BL, Zacharieva S, Lim EM, Mantovani G, Zatelli MC, Collins MT, Bonneville JF, Quezado M, Chittiboina P, Oldfield EH, Bours V, Liu P, W de Herder W, Pellegata N, Lupski JR, Daly AF, Stratakis CA
Endocr Relat Cancer 2015 Jun;22(3):353-67. Epub 2015 Feb 24 doi: 10.1530/ERC-15-0038. PMID: 25712922Free PMC Article

Therapy

Mangupli R, Rostomyan L, Castermans E, Caberg JH, Camperos P, Krivoy J, Cuauro E, Bours V, Daly AF, Beckers A
Pituitary 2016 Oct;19(5):507-14. doi: 10.1007/s11102-016-0732-3. PMID: 27287035
Rodd C, Millette M, Iacovazzo D, Stiles CE, Barry S, Evanson J, Albrecht S, Caswell R, Bunce B, Jose S, Trouillas J, Roncaroli F, Sampson J, Ellard S, Korbonits M
J Clin Endocrinol Metab 2016 May;101(5):1927-30. Epub 2016 Mar 16 doi: 10.1210/jc.2015-4366. PMID: 26982009Free PMC Article
Daly AF, Lysy PA, Desfilles C, Rostomyan L, Mohamed A, Caberg JH, Raverot V, Castermans E, Marbaix E, Maiter D, Brunelle C, Trivellin G, Stratakis CA, Bours V, Raftopoulos C, Beauloye V, Barlier A, Beckers A
Endocr Relat Cancer 2016 Mar;23(3):161-70. Epub 2015 Dec 15 doi: 10.1530/ERC-15-0478. PMID: 26671997Free PMC Article

Prognosis

Liang H, Gong F, Liu Z, Yang Y, Yao Y, Wang R, Wang L, Chen M, Pan H, Zhu H
Neuroendocrinology 2021;111(12):1164-1175. Epub 2020 Oct 13 doi: 10.1159/000512240. PMID: 33049741
Beckers A, Rostomyan L, Potorac I, Beckers P, Daly AF
Ann Endocrinol (Paris) 2017 Jun;78(2):131-136. Epub 2017 Apr 27 doi: 10.1016/j.ando.2017.04.013. PMID: 28457479
Trivellin G, Bjelobaba I, Daly AF, Larco DO, Palmeira L, Faucz FR, Thiry A, Leal LF, Rostomyan L, Quezado M, Schernthaner-Reiter MH, Janjic MM, Villa C, Wu TJ, Stojilkovic SS, Beckers A, Feldman B, Stratakis CA
J Mol Endocrinol 2016 Aug;57(2):97-111. Epub 2016 Jun 9 doi: 10.1530/JME-16-0045. PMID: 27282544Free PMC Article
Rostomyan L, Daly AF, Petrossians P, Nachev E, Lila AR, Lecoq AL, Lecumberri B, Trivellin G, Salvatori R, Moraitis AG, Holdaway I, Kranenburg-van Klaveren DJ, Chiara Zatelli M, Palacios N, Nozieres C, Zacharin M, Ebeling T, Ojaniemi M, Rozhinskaya L, Verrua E, Jaffrain-Rea ML, Filipponi S, Gusakova D, Pronin V, Bertherat J, Belaya Z, Ilovayskaya I, Sahnoun-Fathallah M, Sievers C, Stalla GK, Castermans E, Caberg JH, Sorkina E, Auriemma RS, Mittal S, Kareva M, Lysy PA, Emy P, De Menis E, Choong CS, Mantovani G, Bours V, De Herder W, Brue T, Barlier A, Neggers SJ, Zacharieva S, Chanson P, Shah NS, Stratakis CA, Naves LA, Beckers A
Endocr Relat Cancer 2015 Oct;22(5):745-57. Epub 2015 Jul 17 doi: 10.1530/ERC-15-0320. PMID: 26187128Free PMC Article

Clinical prediction guides

Liang H, Gong F, Liu Z, Yang Y, Yao Y, Wang R, Wang L, Chen M, Pan H, Zhu H
Neuroendocrinology 2021;111(12):1164-1175. Epub 2020 Oct 13 doi: 10.1159/000512240. PMID: 33049741
Beckers A, Rostomyan L, Potorac I, Beckers P, Daly AF
Ann Endocrinol (Paris) 2017 Jun;78(2):131-136. Epub 2017 Apr 27 doi: 10.1016/j.ando.2017.04.013. PMID: 28457479
Iacovazzo D, Caswell R, Bunce B, Jose S, Yuan B, Hernández-Ramírez LC, Kapur S, Caimari F, Evanson J, Ferraù F, Dang MN, Gabrovska P, Larkin SJ, Ansorge O, Rodd C, Vance ML, Ramírez-Renteria C, Mercado M, Goldstone AP, Buchfelder M, Burren CP, Gurlek A, Dutta P, Choong CS, Cheetham T, Trivellin G, Stratakis CA, Lopes MB, Grossman AB, Trouillas J, Lupski JR, Ellard S, Sampson JR, Roncaroli F, Korbonits M
Acta Neuropathol Commun 2016 Jun 1;4(1):56. doi: 10.1186/s40478-016-0328-1. PMID: 27245663Free PMC Article
Beckers A, Lodish MB, Trivellin G, Rostomyan L, Lee M, Faucz FR, Yuan B, Choong CS, Caberg JH, Verrua E, Naves LA, Cheetham TD, Young J, Lysy PA, Petrossians P, Cotterill A, Shah NS, Metzger D, Castermans E, Ambrosio MR, Villa C, Strebkova N, Mazerkina N, Gaillard S, Barra GB, Casulari LA, Neggers SJ, Salvatori R, Jaffrain-Rea ML, Zacharin M, Santamaria BL, Zacharieva S, Lim EM, Mantovani G, Zatelli MC, Collins MT, Bonneville JF, Quezado M, Chittiboina P, Oldfield EH, Bours V, Liu P, W de Herder W, Pellegata N, Lupski JR, Daly AF, Stratakis CA
Endocr Relat Cancer 2015 Jun;22(3):353-67. Epub 2015 Feb 24 doi: 10.1530/ERC-15-0038. PMID: 25712922Free PMC Article
Trivellin G, Daly AF, Faucz FR, Yuan B, Rostomyan L, Larco DO, Schernthaner-Reiter MH, Szarek E, Leal LF, Caberg JH, Castermans E, Villa C, Dimopoulos A, Chittiboina P, Xekouki P, Shah N, Metzger D, Lysy PA, Ferrante E, Strebkova N, Mazerkina N, Zatelli MC, Lodish M, Horvath A, de Alexandre RB, Manning AD, Levy I, Keil MF, Sierra Mde L, Palmeira L, Coppieters W, Georges M, Naves LA, Jamar M, Bours V, Wu TJ, Choong CS, Bertherat J, Chanson P, Kamenický P, Farrell WE, Barlier A, Quezado M, Bjelobaba I, Stojilkovic SS, Wess J, Costanzi S, Liu P, Lupski JR, Beckers A, Stratakis CA
N Engl J Med 2014 Dec 18;371(25):2363-74. Epub 2014 Dec 3 doi: 10.1056/NEJMoa1408028. PMID: 25470569Free PMC Article

Recent systematic reviews

Liang H, Gong F, Liu Z, Yang Y, Yao Y, Wang R, Wang L, Chen M, Pan H, Zhu H
Neuroendocrinology 2021;111(12):1164-1175. Epub 2020 Oct 13 doi: 10.1159/000512240. PMID: 33049741

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