Citation: Mohamed Samy El-Feky, Passant Youssef, Ahmed El-Tair, Mohamed Serag. Indirect sonication effect on the dispersion, reactivity, and microstructure of ordinary portland cement matrix[J]. AIMS Materials Science, 2019, 6(5): 781-797. doi: 10.3934/matersci.2019.5.781
[1] | Ruthie Su, Margaret P. Adam, Linda Ramsdell, Patricia Y. Fechner, Margarett Shnorhavorian . Can the external masculinization score predict the success of genetic testing in 46,XY DSD?. AIMS Genetics, 2015, 2(2): 163-172. doi: 10.3934/genet.2015.2.163 |
[2] | Roberta Risso, Silvia Einaudi, Chiara Crespi, Angela Caldarera, Francesca Verna, Emilio Merlini, Roberto Lala . Sex attribution, gender identity and quality of life in disorders of sex development due to 45,X/46,XY mosaicism: methods for clinical and psychosocial assessment. AIMS Genetics, 2015, 2(2): 127-147. doi: 10.3934/genet.2015.2.127 |
[3] | Alena V Malakhova, Olga I Rudko, Vladimir V Sobolev, Artemii V Tretiakov, Elena A Naumova, Zarema G Kokaeva, Julia E Azimova, Eugene A Klimov . PDE4B gene polymorphism in Russian patients with panic disorder. AIMS Genetics, 2019, 6(3): 55-63. doi: 10.3934/genet.2019.3.55 |
[4] |
Hossein Mozdarani, Sohail Mozdarani .
De novo cytogenetic alterations in spermatozoa of subfertile males might be due to genome instability associated with idiopathic male infertility: Experimental evidences and Review of the literature . AIMS Genetics, 2016, 3(4): 219-238. doi: 10.3934/genet.2016.4.219 |
[5] | Jarrett Barnhill, James Bedford, James Crowley, Takahiro Soda . A search for the common ground between Tic; Obsessive-compulsive and Autism Spectrum Disorders: part I, Tic disorders. AIMS Genetics, 2017, 4(1): 32-46. doi: 10.3934/genet.2017.1.32 |
[6] | Sraboni Chaudhury . Epigenetic regulation in Autism spectrum disorder. AIMS Genetics, 2016, 3(4): 292-299. doi: 10.3934/genet.2016.4.292 |
[7] | Eun Jeong Kim, Yong-Ku Kim . Panic disorders: The role of genetics and epigenetics. AIMS Genetics, 2018, 5(3): 177-190. doi: 10.3934/genet.2018.3.177 |
[8] | M. Reza Jabalameli, Ignacio Briceno, Julio Martinez, Ignacio Briceno, Reuben J. Pengelly, Sarah Ennis, Andrew Collins . Aarskog-Scott syndrome: phenotypic and genetic heterogeneity. AIMS Genetics, 2016, 3(1): 49-59. doi: 10.3934/genet.2016.1.49 |
[9] | Neha Mittal, Anand kumar Srivastava . Cd2++Cr6+causes toxic effects on chromosomal development of microspore in Carthamus tinctorius. AIMS Genetics, 2019, 6(1): 1-10. doi: 10.3934/genet.2019.1.1 |
[10] | Carlos García-Padilla, Amelia Aránega, Diego Franco . The role of long non-coding RNAs in cardiac development and disease. AIMS Genetics, 2018, 5(2): 124-140. doi: 10.3934/genet.2018.2.124 |
Androgen insensitivity syndrome (OMIM #300068) is an X-linked condition in which 46,XY individuals have varying degrees of undervirilization secondary to defects in androgen action due to mutations in the androgen receptor (AR) gene (OMIM#313700) [1]. There are three main types of androgen insensitivity syndrome (AIS): complete androgen insensitivity syndrome (CAIS), partial androgen insensitivity syndrome (PAIS) and mild androgen insensitivity syndrome [1]. Individuals with CAIS have a 46,XY karyotype and due to the complete inaction of androgens in utero, infants are born with phenotypically normal female external genitalia. Internal structures typically consist of a short vagina ending in a blind pouch. Testes are present in the abdomen, but structures derived from the Wolffian ducts are absent, including the vas deferens, epididymis, seminal vesicles and prostate [2]. The phenotypes associated with PAIS are wide-ranging due to varying degrees of androgen resistance [2]. Those with mild androgen insensitivity can have impaired spermatogenesis, impaired pubertal virilization or gynecomastia in puberty [1]. Mutations in the gene AR are the primary cause of AIS [1]. The estimated incidence of AIS (complete and partial) is at least one in 99,000 [3]. While genotype-phenotype correlations for CAIS are quite consistent, the phenotype in PAIS can show significant variation [3]. There are reports of individuals from families with the same AR mutation with a different sex of rearing and undergoing different reconstructive surgeries [3]. AIS due to somatic mosaicism has been reported as a rare cause of PAIS [4, 5, 6, 7, 8].
We present two males with PAIS due to somatic mosaicism, one caused by a novel nonsense mutation that has not previously been reported and another caused by a missense mutation that has been reported to cause CAIS [9], but not PAIS.
We reviewed the records of two individuals with known somatic mosaicism for an AR mutation. The case history was obtained by a Pediatric Endocrinologist and Clinical Geneticist. Approval for this case series was obtained from the Colorado Multiple Institutional Review Board and written informed consent was obtained.
Commercially available sequencing of the AR gene was performed in each case. In case one, sequencing was performed by GeneDx (www.genedx.com) and in case two, sequencing was performed by Denver Genetic Laboratories (www.denvergenetics.org). Following peripheral venipuncture, DNA was extracted and amplified using the polymerase chain reaction. Bidirectional Sanger (dideoxynucleotide chain termination) sequencing was performed of the eight coding exons of the AR gene and flanking intronic regions.
In cases one and two, LH and FSH were measured using an electrochemiluminescent immunoassay. In case one inhibin B and anti-müllerian hormone were measured using a quantitative enzyme-linked immunosorbent assay. In case one testosterone was measured using tandem mass spectrometry and in case two by competitive amino assay. In both cases dihydrotestosterone was measured using tandem mass spectrometry.
A full term infant presented with atypical genitalia and was assigned a female sex of rearing. The infant was born to a 23-year-old gravida 2 para 2 mother. No prenatal genetic studies or amniocentesis were performed. Family history was unremarkable and consanguinity was denied.
At the first well child examination, genital ambiguity was noted. Examination by an urologist, geneticist and endocrinologist at three months of age revealed a one centimeter phallus, dark, rugated and bifid labioscrotal folds, perineal hypospadias, palpable inguinal gonads and orthotopic anus.
Karyotype revealed 46,XY chromosomal complement. Studies obtained at 3 months of age included: follicle stimulating hormone 1.0 mIU/mL, luteinizing hormone 0.8 mIU/mL, inhibin B 425 pg/mL, anti-müllerian hormone of greater than 225 ng/mL, testosterone 12 ng/dL and dihydrotestosterone 7.8 ng/dL. AR sequencing revealed mosaicism for a nonsense mutation, c.1331T > A; p.Leu444Ter.
At five months of age, sex of rearing was reassigned to male and he was treated with intra-muscular testosterone cypionate 50 mg monthly for four months. Phallic length increased to four centimeters. He was also noted to develop Tanner II breast tissue after the testosterone injections.
Cystovaginoscopy performed at age 13 months demonstrated a normal bladder neck, a female urethra, rudimentary vagina measuring 1 cm in length and no evidence of a verumontanum or müllerian structures.
He subsequently underwent bilateral inguinal orchiopexy and herniorrhaphy. He then had a vaginectomy, first-stage hypospadias repair with labial mucosal graft, tunica albuginea plication and circumcision. At that time, findings were notable for perineal hypospadias, ventral penile angulation, a rudimentary vagina and bifid scrotum. Pathology revealed stratified squamous epithelium overlying a fibrovascular submucosa consistent with a rudimentary vagina. This was followed by second-stage hypospadias repair and scrotoplasty at 28 months of age. Parents report a male gender role at three years of age although he has not had formal assessment of either gender identity or gender role.
A now 20 year old male presented with atypical genitalia noted at one week of life. He was born in Iraq and initial medical records were not available. He had bilateral undescended testes and bilateral orchiopexies were performed in childhood. Family history was significant for a paternal uncle with undescended testes. There was no family history of consanguinity.
In the past, he had received testosterone injections while living in Iraq and Syria although exact doses and the ages at which he received the injections are not available. The patient reported that at age 20 years he noticed progression in male secondary sex characteristics including more facial hair, acne and deepening of his voice after receiving testosterone. However, he noted that his facial hair growth was asymmetric. He did not notice any enlargement of his penis or testes after testosterone. He reports a male gender identity and exhibits a male gender role although these have not been formally assessed.
Cystoscopy performed at age 20 years showed that his urethra started at the mid-bulbous region and extended into the membranous region. The prostate and verumontanum were absent.
Physical exam revealed a height of 172 cm (25th percentile for height on CDC growth curve), arm span 174 cm, mild acne on his face and chest, moderate axillary hair and no gynecomastia. Genitourinary exam was significant for tanner V pubic hair, a 4.5 cm phallus, no chordee, subcoronal hypospadias, partially bifid scrotum, non-palpable right gonad and 12 mL left testis in the scrotum.
Labs at age 20 years were significant for: follicle stimulating hormone 4.7 mIU/mL, luteinizing hormone 8.42 mIU/mL, total testosterone 1040 ng/dL and dihydrotestosterone 40 ng/dL. He was not on testosterone at the time these labs were drawn. AR sequencing revealed a mosaic missense mutation, c.2279 C > A; p.Ser760Tyr (Figure 1).
We present two males with PAIS due to somatic mosaicism for AR mutations. In the first case, the c.1331T > A; p.Leu444Ter nonsense mutation has not previously been reported in the literature or in a database of known mutations in the AR gene (http://androgendb.mcgill.ca/) [10]. This results in premature truncation of the protein. In the second case, the c.2279C > A; p.Ser760Tyr missense mutation has been reported to cause CAIS [9], but not PAIS. This is also a rare variant and is not found in population databases including 1000 Genomes, NHLBI Exome sequencing Project (ESP) Exome Variant Server or the Exome Aggregation Consortium (ExAC). Three in silico analysis programs predict this change is disease-causing. 46,XY individuals are hemizygous for AR, which is on the X chromosome and therefore a single nonsense mutation will result in complete resistance to the action of androgens. The androgen receptor is a nuclear receptor that is bound by either testosterone or dihydrotestosterone. In the bound state, the androgen receptor regulates gene transcription to cause typical embryonic male development and typical male pubertal progression [11]. If only some tissues or cells carry a nonsense mutation or other null allele, then a phenotype of PAIS may result. Mosaicism, or the presence of a genetic variant in only a subset of cells, is presumed to result from a mitotic error in cell replication after fertilization. This is in contrast with germ line mutations or those that arise in meiosis, which are present in all cells of the body. In many genetic conditions, the resultant phenotype depends on which tissues carry the mutation and the percentage of mosaicism in those tissues [12]. For example, newer evidence suggests that Turner syndrome may represent mosaicism in every case th at is not lethal in utero [13].
Although nonsense mutations in AR are typically reported in CAIS [14, 15, 16, 17], mosaicism for both missense and nonsense mutations have been reported in PAIS [5, 6, 8]. As in case one, some individuals will have increase in phallic length after a course of testosterone, suggesting significant amounts of the functional wild-type receptor in genital tissue despite under-virilization at birth [8]. The child in case one was also noted to develop Tanner II breast tissue after the testosterone injections, likely from aromatization to estrogen. The male in case two did not have any penile growth after treatment with testosterone, suggesting that the genitalia did not have significant expression of the functional androgen receptor protein. However, he did report increase in facial hair, worsening of acne and deepening of his voice after testosterone injections, suggesting that those tissues may have more expression of functional androgen receptor protein. One limitation of this report is the lack of sequencing of AR in other tissues and no functional analysis of the protein.
Reports of PAIS caused by a somatic mutation of the AR gene are rare in the scientific literature but they represent an important subset of AIS cases [4, 5, 6, 7, 10]. There is a database of known mutations in the AR gene (http://androgendb.mcgill.ca/) and the number of individuals in the database with known somatic mosaicism for mutations is small [10]. 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. Mutations in the AR gene may be under-represented since sequencing is usually only performed in blood. If another tissue is readily available, sequencing of AR in that tissue may be considered.
In case 1, the c.1331T > A; p.Leu444Ter nonsense mutation has not previously been reported. In case 2, the c.2279C > A; p.Ser760Tyr missense mutation has been reported to cause CAIS, but not PAIS. Both nonsense and missense mutations can cause mosaic PAIS and the phenotypes can be variable. These findings underscore the importance of considering somatic mosaicism as a genetic etiology for PAIS.
All authors declare no conflict of interest in this manuscript.
[1] |
Damineli BL, Pileggi RG, John VM (2017) Influence of packing and dispersion of particles on the cement content of concretes. Rev IBRACON Estrut Mater 10: 998–1024. doi: 10.1590/s1983-41952017000500004
![]() |
[2] | Alshehy AM, Ahmed SA, El-Feky MS, et al. (2018) Utilizing nano- to micro-scale particles based additives to enhance cement-dune sand composites. IJMTER 5: 104–114. |
[3] |
Hani N, Nawawy O, Ragab KS, et al. (2018) The effect of different water/binder ratio and nano-silica dosage on the fresh and hardened properties of self-compacting concrete. Constr Build Mater 165: 504–513. doi: 10.1016/j.conbuildmat.2018.01.045
![]() |
[4] |
Hamed N, El-Feky MS, Kohail M, et al. (2019) Effect of nano-clay de-agglomeration on mechanical properties of concrete. Constr Build Mater 205: 245–256. doi: 10.1016/j.conbuildmat.2019.02.018
![]() |
[5] |
Ahmed SA, El-Feky MS, Hefne EE (2018) Naphthalenesulfonate based super-plasticizer and ultra-sonication effects on the dispersion of CNTs in cement composites subjected to cyclic loading. IJMTER 5: 269–279. doi: 10.21884/IJMTER.2018.5136.OMKKB
![]() |
[6] | Youssef P, El-Feky MS, Serag MI (2017) The influence of nano silica surface area on its reactivity in cement composites. IJSER 8: 2016–2024. |
[7] | Sharobim KG, Mohamadien HA, Hanna NF, et al. (2017) Optimizing sonication time and solid to liquid ratio of nano-silica in high strength concrete. IJSER 8: 687–693. |
[8] | Sharobim KG, Mohammedin H, Hanna NF, et al. (2017) Optimizing sonication time and solid to liquid ratio of nano-silica in high strength mortars. IJSER 3: 6–16. |
[9] | Serag MI, Yasien AM, El-Feky MS, et al. (2017) Effect of nano silica on concrete bond strength modes of failure. Int J GEOMATE 12: 73–80. |
[10] | Serag M, Elkady H, Elfeky M (2014) The effect of indirect sonication on the reactivity of nano silica concrete. IJSER 334–345. |
[11] | El-Feky MS, Serag MI, Yasien AM, et al. (2016) Bond strength of nano silica concrete subjected to corrosive environments. ARPN-JEAS 11: 13909–13924. |
[12] | Sobolev K, Gutierrez MF (2005) How nanotechnology can change the concrete world, Am Ceram Soc Bull 10: 14–18. |
[13] | Lee J, Mahendra S, Alvarez P (2010) Nanomaterials in the construction industry, A review of their applications and environmental health and safety considerations. Am Ceram Soc Bull 4: 3580–3590. |
[14] | Alyasri S (2010) The use of nanotechnology in construction sector. QJES 7: 68–80. . |
[15] |
Raki L, Beaudoin J, Alizadeh R, et al. (2010) Cement and concrete nano science and nano technology. Materials 3: 918–942. doi: 10.3390/ma3020918
![]() |
[16] | Kumar RA (2011) Opportunities & challenges for use of nanotechnology in cement-based materials. NBMCW. |
[17] | Patel AS (2013) An overview on application of nanotechnology in construction industry, IJIRSET 2: 6094–6098. |
[18] | Collepardi M, Collepardi S, Skarp U, et al. (2004) Optimization of silica fume, fly ash and amorphous nano–silica in auperplasticized high-performance concrete. Proceedings of 8th CANMET/ACI International Conference on Fly Ash, Silica Fume, Slag and Natural Pozzolans in Concrete, Las Vegas, USA, 221: 495–506. |
[19] | Lai F, Sika SK, Zain M, wt al. (2010) Nano cement additives development for OPC strength enhancer and carbon neutral cement. Proceedings of 35th Conference on Our World in Concrete in Structures, Singapore. |
[20] | Gopalakrishnan K, Birgisson B, Tylor P, et al. (2011) Nanotechnology in Civil Infrastructure, Berlin: Springer. |
[21] | Mahajan YR (2012) Nanotechnology in the cement industry. Available from: http://www.nanowerk.com/spotlight/spotid=28101.php. |
[22] | Birgisson B, Mukhopadhyay A, Geary G (2012) Nanotechnology in concrete materials. Available from: http://cvl.araku.ac.ir/download/Nano-and-concrete. |
[23] | Aitcin PC, Jolicoeur C, MacGregor JG (1994) Superplasticizers: how they work and why they occasionally don't. Concr Int 16: 45–52. |
[24] | Ramachandran VS, Malhotra VM, Jolicoeur C, et al. (1998) Superplasticizers: Properties and Applications in Concrete, Canada: CANMET Publication. |
[25] | Sakai E, Daimon M (1995) Mechanisms of superplastification, in: Skalny J, Mindess S, Materials Science of Concrete, Westerville: Amercian Ceramic Society, 4: 91–111. |
[26] | Sakai E, Daimon M (1997) Dispersion mechanisms of alite stabilized by superplasticizers containing polyethylene oxide graft chains, Proceedings of the 5th Canmet/ACI International Conference on Superplasticizers and Other Chemical Admixtures in Concrete, American Concrete Institute, Detroit, US, 187–202. |
[27] | Uchikawa H (1999) Function of organic admixture supporting high performance concrete, In: Cabrera JG, Rivera-Villarreal R, Proceedings of the International RILEM Conference on the Role of Admixtures in High Performance Concrete, France: RILEM Publications, 69–96. |
[28] | Lewis JA, Matsuyama H, Kirby G, et al. (2000) Polyelectrolyte effects on the rheological properties of concentrated suspensions. J Am Ceram Soc 83: 1905–1913. |
[29] | Flatt RJ (2001) Polymeric dispersants in concrete, In: Hackley VA, Somasundaran P, Lewis JA, Polymers in Particulate Systems: Properties and Applications , Boca Raton: CRC Press, 247–294. |
[30] |
Flatt RJ, Houst YF (2001) A simplified view on chemical effects perturbing the action of superplasticizers. Cement Concrete Res 31: 1169–1176. doi: 10.1016/S0008-8846(01)00534-8
![]() |
[31] | El-feky MS, Serag MI, Elkady H (2013) Effect of nano silica de-agglomeration, and methods of adding super-plasticizer on the compressive strength, and workability of nano silica concrete. Civ Environ Res 3: 21–34. |
[32] | Hashem MM, Serag MI, Elkady H, et al. (2015) Increasing the reactivity of silica fume particles using indirect sonication: effect of process parameters. Civ Environ Res 2: 537–557. |
[33] |
Jones CA, Grasley ZC, Ohlhausen JA (2012) Measurement of elastic properties of calcium silicate hydrate with atomic force microscopy. Cem Concrete Comp 34: 468–477. doi: 10.1016/j.cemconcomp.2011.11.008
![]() |
[34] |
Taylor HFW (1993) Nanostructure of C–S–H: current status. Adv Cem Based Mater 1: 38–46. doi: 10.1016/1065-7355(93)90006-A
![]() |
[35] | Nonat A (2004), the structure and stoichiometry of C–S–H. Cem Concrete Res 34: 1521–1528. |
[36] | Gauffinet S, Finot E, Lesniewska E, et al. (1998) AFM and SEM studies of CSH growth on C3S surface during its early hydration, Proceedings of the International Conference on Cement Microscopy , Guadalajara, Mexico, 337–356. |
1. | Sarah Gold, Christina Huang, Rakan Radi, Pranav Gupta, Eric I. Felner, Jeehea Sonya Haw, Krista Childress, Nancy Sokkary, Vin Tangpricha, Michael Goodman, Howa Yeung, Dermatologic care of patients with differences of sex development, 2023, 9, 2352-6475, e106, 10.1097/JW9.0000000000000106 |