Two cases of androgen insensitivity due to somatic mosaicism

Natalie J. Nokoff; Sharon Travers; Naomi Meeks; Natalie J. Nokoff; Sharon Travers; Naomi Meeks

doi:10.3934/genet.2015.2.104

AIMS Genetics

2015, Volume 2, Issue 2: 104-109. doi: 10.3934/genet.2015.2.104

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Two cases of androgen insensitivity due to somatic mosaicism

1.
Pediatric Endocrinology, Children's Hospital Colorado, Aurora, CO 80045, USA;
2.
Genetics, Children's Hospital Colorado, Aurora, CO 80045, USA

Received: 26 November 2014 Accepted: 26 February 2015 Published: 03 March 2015

Androgen insensitivity syndrome (AIS) is caused by mutations in the gene encoding the androgen receptor (AR). The incidence of AIS is estimated to be 1 in 99,000. Complete androgen insensitivity syndrome (CAIS) is characterized by a 46,XY karyotype with external genitalia that appear typically female and results from mutations that render the androgen receptor non-functional. Partial androgen insensitivity syndrome (PAIS) results from partial loss of function mutations in AR. Rarely, PAIS results from somatic mosaicism for an AR mutation and not from a hypomorphic variant. We present two cases of PAIS due to somatic mosaicism, one caused by a novel nonsense mutation and one caused by a missense mutation previously reported in CAIS. Two patients with atypical genitalia presented to our multidisciplinary clinic for disorders of sex development and sequencing of AR was performed as part of the diagnostic evaluation. In case one, AR sequencing revealed mosaicism for a nonsense mutation, c.1331T > A; p.Leu444Ter. This mutation has not previously been reported, but is presumed to be pathogenic. In case two, AR sequencing revealed a mosaic missense mutation, c.2279 C > A; p.Ser760Tyr, which has previously been reported in CAIS but not in PAIS. Similar phenotypes may result from AR mutations that are present in a mosaic state with full loss of function or hypomorphic mutations that partially impair the function of the protein in either all tissues or in a mosaic state.
- disorders of sex development,
- androgen insensitivity,
- partial androgen insensitivity,
- mosaicism
Citation: Natalie J. Nokoff, Sharon Travers, Naomi Meeks. Two cases of androgen insensitivity due to somatic mosaicism[J]. AIMS Genetics, 2015, 2(2): 104-109. doi: 10.3934/genet.2015.2.104

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Abstract

Androgen insensitivity syndrome (AIS) is caused by mutations in the gene encoding the androgen receptor (AR). The incidence of AIS is estimated to be 1 in 99,000. Complete androgen insensitivity syndrome (CAIS) is characterized by a 46,XY karyotype with external genitalia that appear typically female and results from mutations that render the androgen receptor non-functional. Partial androgen insensitivity syndrome (PAIS) results from partial loss of function mutations in AR. Rarely, PAIS results from somatic mosaicism for an AR mutation and not from a hypomorphic variant. We present two cases of PAIS due to somatic mosaicism, one caused by a novel nonsense mutation and one caused by a missense mutation previously reported in CAIS. Two patients with atypical genitalia presented to our multidisciplinary clinic for disorders of sex development and sequencing of AR was performed as part of the diagnostic evaluation. In case one, AR sequencing revealed mosaicism for a nonsense mutation, c.1331T > A; p.Leu444Ter. This mutation has not previously been reported, but is presumed to be pathogenic. In case two, AR sequencing revealed a mosaic missense mutation, c.2279 C > A; p.Ser760Tyr, which has previously been reported in CAIS but not in PAIS. Similar phenotypes may result from AR mutations that are present in a mosaic state with full loss of function or hypomorphic mutations that partially impair the function of the protein in either all tissues or in a mosaic state.

References

[1]	Gottlieb B, Beitel LK, Trifiro MA (1999 Mar 24 Updated 2014 Jul 10.) Androgen Insensitivity Syndrome. GeneReviews® Internet. Seattle (WA): University of Washington, Seattle; 1993-2014 Available from: http://wwwncbinlmnihgov/books/NBK1429/.
[2]	Galani A, Kitsiou-Tzeli S, Sofokleous C, et al. (2008) Androgen insensitivity syndrome: clinical features and molecular defects. Hormones 7: 217-229. doi: 10.14310/horm.2002.1201
[3]	Boehmer ALM, Brüggenwirth H, van Assendelft C, et al. (2001) Genotype Versus Phenotype in Families with Androgen Insensitivity Syndrome. J Clin Endocrinol Metab 86: 4151-4160. doi: 10.1210/jcem.86.9.7825
[4]	Hiort O, Sinnecker GH, Holterhus PM, et al. (1998) Inherited and de novo androgen receptor gene mutations: investigation of single-case families. J Pediatr 132: 939-943. doi: 10.1016/S0022-3476(98)70387-7
[5]	Holterhus PM, Bruggenwirth HT, Hiort O, et al. (1997) Mosaicism due to a somatic mutation of the androgen receptor gene determines phenotype in androgen insensitivity syndrome. J Clin Endocrinol Metab 82: 3584-3589.
[6]	Holterhus P-M, Wiebel J, Sinnecker GHG, et al. (1999) Clinical and Molecular Spectrum of Somatic Mosaicism in Androgen Insensitivity Syndrome. Pediatr Res 46: 684-684. doi: 10.1203/00006450-199912000-00009
[7]	Boehmer AL, Brinkmann AO, Niermeijer MF, et al. (1997) Germ-line and somatic mosaicism in the androgen insensitivity syndrome: implications for genetic counseling. Am J Hum Genet 60: 1003-1006.
[8]	Köhler B, Lumbroso S, Leger J, et al. (2005) Androgen insensitivity syndrome: somatic mosaicism of the androgen receptor in seven families and consequences for sex assignment and genetic counseling. J Clin Endocrinol Metab 90: 106-111. doi: 10.1210/jc.2004-0462
[9]	Hughes IA, Werner R, Bunch T, et al. (2012) Androgen insensitivity syndrome. Semin Reprod Med 30: 432-442. doi: 10.1055/s-0032-1324728
[10]	Gottlieb B, Beitel LK, Nadarajah A, et al. (2012) The androgen receptor gene mutations database: 2012 update. Human Mutation 33: 887-894. doi: 10.1002/humu.22046
[11]	Sperling M (2014) Pediatric endocrinology fourth edition. Philadelphia, PA: Saunders/Elsevier.
[12]	Gottlieb B, Beitel LK, Trifiro MA (2001) Somatic mosaicism and variable expressivity. Trends Genet 17: 79-82. doi: 10.1016/S0168-9525(00)02178-8
[13]	Hook EB, Warburton D (2014) Turner syndrome revisited: review of new data supports the hypothesis that all viable 45,X cases are cryptic mosaics with a rescue cell line, implying an origin by mitotic loss. Hum Genet 133: 417-424. doi: 10.1007/s00439-014-1420-x
[14]	Zoppi S, Wilson CM, Harbison MD, et al. (1993) Complete testicular feminization caused by an amino-terminal truncation of the androgen receptor with downstream initiation. J Clin Invest 91: 1105-1112. doi: 10.1172/JCI116269
[15]	Trifiro M, Prior RL, Sabbaghian N, et al. (1991) Amber mutation creates a diagnostic MaeI site in the androgen receptor gene of a family with complete androgen insensitivity. Am J Med Genet 40: 493-499. doi: 10.1002/ajmg.1320400425
[16]	Hiort O, Wodtke A, Struve D, et al. (1994) Detection of point mutations in the androgen receptor gene using non-isotopic single strand conformation polymorphism analysis. German Collaborative Intersex Study Group. Hum Mol Genet 3: 1163-1166.
[17]	Batch JA, Williams DM, Davies HR, et al. (1992) Androgen receptor gene mutations identified by SSCP in fourteen subjects with androgen insensitivity syndrome. Hum Mol Genet 1: 497-503. doi: 10.1093/hmg/1.7.497

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