X-linked Acrogigantism

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This entry is adapted from the peer-reviewed paper https://medlineplus.gov/genetics/condition/x-linked-acrogigantism

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.

genetic conditions

1. Introduction

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 adenoma). Rarely, an affected individual has both pituitary hyperplasia and an adenoma. The abnormal gland releases excess amounts of growth hormone, a hormone that normally helps direct growth of the body's bones and tissues. Some people with X-LAG also have excess amounts of a hormone called growth hormone releasing hormone (GHRH), which is produced by a part of the brain called the hypothalamus. This hormone stimulates the release of growth hormone from the pituitary gland.

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.

2. Frequency

X-LAG is thought to be a rare condition, although the prevalence is not known. It occurs more frequently in females than in males. X-LAG accounts for one in ten cases of abnormally fast growth in children that is caused by pituitary gland abnormalities (pituitary gigantism).

3. Causes

X-LAG is caused by a genetic change in which a small amount of genetic material on the X chromosome is abnormally copied (duplicated). The duplication, often referred to as an Xq26.3 microduplication, occurs on the long (q) arm of the chromosome at a location designated q26.3. It can include several genes, but only duplication of the GPR101 gene is necessary to cause X-LAG.

The GPR101 gene provides instructions for making a protein whose function is unknown. Studies suggest that the GPR101 protein is involved in the growth of cells in the pituitary gland or in the release of growth hormone from the gland.

Duplication of the GPR101 gene leads to an excess of GPR101 protein. It is unclear how extra GPR101 protein results in the development of a pituitary adenoma or hyperplasia or in the release of excess growth hormone or GHRH.

4. Inheritance

X-LAG follows an X-linked dominant inheritance pattern. The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In females (who have two X chromosomes), a duplication of one of the two copies of the GPR101 gene in each cell is sufficient to cause the disorder. In males (who have only one X chromosome), a duplication of the only copy of the gene in each cell causes the disorder. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

In females, the condition results from new (de novo) duplications involving the GPR101 gene that occur during the formation of a parent's reproductive cells (eggs or sperm). The duplication is found in all of the cells in the affected person's body.

In males, the condition often results from somatic mosaicism, in which some of an affected person's cells have the duplication and others do not. The genetic changes, which are called somatic mutations, arise randomly in one cell during embryonic development. As cells continue to divide, only cells arising from the first abnormal cell will have the mutation. Other affected males inherit the duplication from their affected mother, and it is found in all the body's cells.

5. Other Names for This Condition

chromosome Xq26 microduplication syndrome
chromosome Xq26.3 duplication syndrome
X-LAG
X-linked acrogigantism syndrome
XLAG

References

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. X-linked acrogigantism syndrome: clinical profile and therapeuticresponses. Endocr Relat Cancer. 2015 Jun;22(3):353-67. doi: 10.1530/ERC-15-0038.
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, BoursV, Raftopoulos C, Beauloye V, Barlier A, Beckers A. GHRH excess and blockade inX-LAG syndrome. Endocr Relat Cancer. 2016 Mar;23(3):161-70. doi:10.1530/ERC-15-0478.
Daly AF, Yuan B, Fina F, Caberg JH, Trivellin G, Rostomyan L, de Herder WW,Naves LA, Metzger D, Cuny T, Rabl W, Shah N, Jaffrain-Rea ML, Zatelli MC, FauczFR, Castermans E, Nanni-Metellus I, Lodish M, Muhammad A, Palmeira L, Potorac I, Mantovani G, Neggers SJ, Klein M, Barlier A, Liu P, Ouafik L, Bours V, Lupski JR,Stratakis CA, Beckers A. Somatic mosaicism underlies X-linked acrogigantismsyndrome in sporadic male subjects. Endocr Relat Cancer. 2016 Apr;23(4):221-33.doi: 10.1530/ERC-16-0082.
Iacovazzo D, Caswell R, Bunce B, Jose S, Yuan B, Hernández-Ramírez LC, KapurS, 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. Germline or somatic GPR101 duplication leads to X-linkedacrogigantism: a clinico-pathological and genetic study. Acta Neuropathol Commun.2016 Jun 1;4(1):56. doi: 10.1186/s40478-016-0328-1.
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. Somatic GPR101 Duplication Causing X-Linked Acrogigantism(XLAG)-Diagnosis and Management. J Clin Endocrinol Metab. 2016May;101(5):1927-30. doi: 10.1210/jc.2015-4366.
Rostomyan L, Daly AF, Petrossians P, Nachev E, Lila AR, Lecoq AL, LecumberriB, 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, EmyP, 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. Clinical and genetic characterization of pituitary gigantism: an internationalcollaborative study in 208 patients. Endocr Relat Cancer. 2015 Oct;22(5):745-57. doi: 10.1530/ERC-15-0320.
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, WuTJ, Stojilkovic SS, Beckers A, Feldman B, Stratakis CA. Characterization ofGPR101 transcript structure and expression patterns. J Mol Endocrinol. 2016Aug;57(2):97-111. doi: 10.1530/JME-16-0045.
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, KamenickýP, Farrell WE, Barlier A, Quezado M, Bjelobaba I, Stojilkovic SS, Wess J,Costanzi S, Liu P, Lupski JR, Beckers A, Stratakis CA. Gigantism and acromegalydue to Xq26 microduplications and GPR101 mutation. N Engl J Med. 2014 Dec18;371(25):2363-74. doi: 10.1056/NEJMoa1408028.

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Bruce Ren

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Table of Contents

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1. Introduction

2. Frequency

3. Causes

4. Inheritance

5. Other Names for This Condition

References

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1. Introduction

2. Frequency

3. Causes

3.1 The gene and chromosome associated with X-linked acrogigantism

4. Inheritance

5. Other Names for This Condition

References