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Agneta Nordenskjold - One of the best experts on this subject based on the ideXlab platform.
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Hypospadias associated with hypertelorism the mildest phenotype of opitz syndrome
Journal of Human Genetics, 2011Co-Authors: Agneta Nordenskjold, Xufeng Zhang, Yougen Chen, Shentiang Zhao, Ellen MarkljungAbstract:Hypospadias is a common congenital malformation in boys in which the urethral meatus opens on the underside of the penis. It is considered a complex disorder with several genes involved and the molecular etiology is just beginning to be revealed. As more than 85% of Opitz G/BBB syndrome (OS) patients with MID1 mutations are manifested with Hypospadias, we have investigated the association between the MID1 gene and Hypospadias. DNA from 114 Hypospadias cases was analyzed with direct sequencing of the MID1 gene. Genotyping analysis was performed for the single-nucleotide polymorphism (SNP) c.1230G>A in 370 individuals with varying degrees of Hypospadias and compared with 759 healthy controls. We identified one nonsense mutation c.712G>T (p.E238X), one missense mutation c.1679A>G (p.K560R) and two synonymous variants c.1230G>A (p.S410S) and c.1284T>G (p.V428V). We also detected a significant difference in the rare allele frequency of SNP c.1230G>A in Hypospadias patients as compared with controls (P=0.016). Our finding suggests that Hypospadias associated with hypertelorism is the mildest phenotype in OS caused by MID1 mutations.
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studies of a co chaperone of the androgen receptor fkbp52 as candidate for Hypospadias
Reproductive Biology and Endocrinology, 2007Co-Authors: Ana Belezameireles, Agneta Nordenskjold, Michela Barbaro, Anna Wedell, Virpi TohonenAbstract:Background: Hypospadias is a common inborn error of the male urethral development, for which the aetiology is still elusive. Polymorphic variants in genes involved in the masculinisation of male genitalia, such as the androgen receptor, have been associated with some cases of Hypospadias. Coregulators of the androgen receptor start being acknowledged as possible candidates for hormoneresistance instances, which could account for Hypospadias. One such molecule, the protein FKBP52, coded by the FKBP4 gene, has an important physiological role in up-regulating androgen receptor activity, an essential step in the development of the male external genitalia. The presence of Hypospadias in mice lacking fkbp52 encouraged us to study the sequence and the expression of FKBP4 in boys with isolated Hypospadias. Patients and methods: The expression of FKBP52 in the genital skin of boys with Hypospadias and in healthy controls was tested by immunohistochemistry. Mutation screening in the FKBF4 gene was performed in ninety-one boys with non syndromic Hypospadias. Additionally, two polymorphisms were typed in a larger cohort. Results: Immunohistochemistry shows epithelial expression of FKBP52 in the epidermis of the penile skin. No apparent difference in the FKBP52 expression was detected in healthy controls, mild or severe Hypospadias patients. No sequence variants in the FKBP4 gene have implicated in Hypospadias in our study. Conclusion: FKBP52 is likely to play a role in growth and development of the male genitalia, since it is expressed in the genital skin of prepubertal boys; however alterations in the sequence and in the expression of the FKBP4 gene are not a common cause of non-syndromic Hypospadias.
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linkage between cryptorchidism Hypospadias and ggn repeat length in the androgen receptor gene
The Journal of Clinical Endocrinology and Metabolism, 2004Co-Authors: Elin L Aschim, Agneta Nordenskjold, Aleksander Giwercman, Kristina Lundin, Yasir Ruhayel, Trine B Haugen, Tom Grotmol, Yvonne Lundberg GiwercmanAbstract:Although sufficient androgen receptor (AR) function is crucial for normal male sexual differentiation, single-point mutations in the AR gene are infrequent in the two most common male congenital malformations, Hypospadias and cryptorchidism. Because polymorphic CAG and GGN segments regulate AR function, we investigated whether there was any association between these polymorphisms and mentioned malformations. Genotyping was performed by direct sequencing of DNA from patients diagnosed with Hypospadias (n 51) and cryptorchidism (n 23) and controls (n 210). The subjects with Hypospadias were divided into subgroups of glanular, penile, and penoscrotal Hypospadias. Median GGN lengths were significantly higher (24 vs. 23) among both subjects with cryptorchidism, compared with controls (P 0.001), and those with penile Hypospadias, compared with either controls (P 0.003) or glanular and penoscrotal Hypospadias combined (P 0.018). The frequency of cases with GGN 24 or more vs. GGN 23, differed significantly among those with cryptorchidism (65/35%), compared with controls (31/54%) (P 0.012), and among subjects with penile Hypospadias (69/31%), compared with either controls (P 0.035) or glanular or penoscrotal Hypospadias combined (32/55%) (P 0.056). There were no significant differences in CAG lengths between the cases and controls. Our findings indicate an association between GGN length and the risk of cryptorchidism and penile Hypospadias, both conditions considered consequences of low androgenicity. (J Clin Endocrinol Metab 89: 5105–5109, 2004)
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A novel duplication in the HOXA13 gene in a family with atypical hand-foot-genital syndrome
Journal of Medical Genetics, 2003Co-Authors: Louise Frisén, Ingrid Kockum, Kristina Lagerstedt, Margareta Tapper-persson, Agneta NordenskjoldAbstract:Hypospadias, when the urethral opening is located on the ventral side of the penis, is one of the most common congenital malformations with an incidence of 3 per 1000 males.1 Hypospadias is considered a complex trait caused by several genetic and environmental factors; low birth weight, for example, is associated with an increased risk for Hypospadias.2–5 Most cases of Hypospadias are sporadic but about 10% of the boys have a relative with the malformation.4,6–9 There are families with an autosomal dominant inheritance pattern of Hypospadias.4,10 Hypospadias is also a manifestation in some rare single gene traits affecting sex differentiation, for example, the X linked partial androgen insensitivity syndrome and the recessive 5-alpha-reductase deficiency.11–13 However, these syndromes are characterised by severe Hypospadias in association with other genital malformations such as cryptorchidism, bifid scrotum, and penoscrotal transposition. Hand-foot-genital syndrome (HFGS) is an autosomal dominant syndrome that may include Hypospadias.14,15 HFGS is characterised by skeletal anomalies and urogenital malformations. The skeletal manifestations affect the distal limbs and include short, proximally placed thumbs with hypoplastic thenar eminences, ulnar deviation of the second finger, clinodactyly of the fifth finger, short, medially deviated halluces, brachydactyly of the second to fifth toes, and shortening of the carpals and tarsals. Typical urogenital abnormalities in females are bicornuate uterus, vaginal septum, and ectopic localisation of ureteric and urethral orifices. Vesicoureteral reflux and ureteropelvic obstruction has been observed in females as well as in males.16 The syndrome was initially called hand-foot-uterus syndrome by Stern et al ,17 but the observation of Hypospadias in some affected males prompted the change of nomenclature.18,19 ### Key points
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heredity of Hypospadias and the significance of low birth weight
The Journal of Urology, 2002Co-Authors: Louise Fredell, Ingrid Kockum, Einar Hansson, Staffan Holmner, Lars Lundquist, Goran Lackgren, Jorgen Pedersen, Arne Stenberg, Gunnar Westbacke, Agneta NordenskjoldAbstract:Purpose: We analyzed a large group of patients with Hypospadias regarding familial aggregation, phenotype, twin rate and ethnic origin and assessed the correlation of low birth weight with Hypospadias.Materials and Methods: We mailed questionnaires to 2,503 boys operated on for Hypospadias in Sweden asking for additional cases of Hypospadias in the family, the number of brothers in the nuclear family, and birth weight of the boys with Hypospadias and their brothers.Results: Of the boys 7% reported 1 or more additional family members with Hypospadias. The birth weight of the boys with Hypospadias was significantly lower (p = 5 × 10−13) than the birth weight of their unaffected brothers. Phenotyping of 676 individuals revealed glandular Hypospadias in 53%, penile forms in 39%, penoscrotal or perineal variants in 6% and cleaved prepuce as the only manifestation in 2%. There were 50% more twins than expected compared to the general population and established zygosity in 83% (67% monozygotic, 33% dizygotic). N...
Laurence S Baskin - One of the best experts on this subject based on the ideXlab platform.
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caucasian male infants and boys with Hypospadias exhibit reduced anogenital distance
Human Reproduction, 2012Co-Authors: Michael H. Hsieh, Michael L Eisenberg, Adam B Hittelman, Jason M Wilson, Gregory E Tasian, Laurence S BaskinAbstract:background: Animal models of endocrine dysfunction have associated male genital defects with reduced anogenital distance (AGD). Human studies have correlated shorter AGD with exposure to putative endocrine disruptors in the environment but have not examined AGD in hypospadiac boys. We measured AGD in boys with Hypospadias and those with normal genitals. methods: Data were collected prospectively on boys undergoing urologic procedures at the University of California San Francisco and the Children’s Hospital of Oakland, CA, USA. Data included age, race, height, weight, BMI, urologic diagnoses and AGD. To minimize any potential effects of race on observed AGD, we examined only Caucasian boys. Differences between boys with Hypospadias and those with normal genitals were examined through two-tailed Student’s t-tests. results: One hundred and nineteen Caucasian boys ranging in age from 4 to 86 months underwent AGD measurement, of which 42 and 77 were boys with normal genitals and Hypospadias, respectively. The mean (+SD) AGD of boys with Hypospadias was 67+ 1.2 versus 73+ 1 mm for boys with normal genitals (P ¼ 0.002). In these age-unmatched patient groups, there were also differences in age, height and weight (P ¼ 0.0001, 0.0002 and 0.0004, respectively). After age matching (all ,2 years of age), boys with Hypospadias (n ¼ 26) still featured a shorter AGD than boys with normal genitals (n ¼ 26; 62+ 2 versus 68+ 2 mm respectively, P ¼ 0.033) but the differences in age, height and weight were no longer significant. conclusions: In humans, Hypospadias may indeed be associated with reduced AGD. Additional studies are needed to corroborate these preliminary findings and to determine their etiology.
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Associations among Hypospadias, cryptorchidism, anogenital distance, and endocrine disruption
Current Urology Reports, 2008Co-Authors: Michael H. Hsieh, Michael L Eisenberg, Benjamin N. Breyer, Laurence S BaskinAbstract:Endocrine disruptors, such as environmental compounds with endocrine-altering properties, may cause Hypospadias and crytorchidism in several species, including humans. Anogenital distance is sexually dimorphic in many mammals, with males having longer anogenital distance on average than females. Animal models of proposed endocrine disruptors have associated prenatal exposure with Hypospadias, cryptorchidism, and reduced anogenital distance. Human studies have correlated shorter anogenital distance to in utero exposure to putative endocrine disruptors. We review preliminary data suggesting that anogenital distance is reduced in boys with hypospadia and cryptorchidism. Hence, human Hypospadias and cryptorchidism may be associated with reduced anogenital distance as a result of endocrine disruption.
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endocrine disruptors and Hypospadias role of genistein and the fungicide vinclozolin
Urology, 2007Co-Authors: Marcelo Vilela, Jill C Buckley, Emily Willingham, Koray Agras, Ben Chun Liu, Yoshiyuki Shiroyanagi, Laurence S BaskinAbstract:OBJECTIVES The phytoestrogen (plant estrogen) genistein, present in soy products, is of interest because in utero exposure to genistein can cause Hypospadias in our mouse model and maternal consumption of soy is prevalent in human populations. Another compound of interest is the fungicide vinclozolin, which also causes Hypospadias in the mouse and rat and can occur concurrently with genistein in the diet as a residue on exposed foods. A study in the United Kingdom found no relationship between a maternal organic vegetarian diet and Hypospadias frequency, but women who consumed nonorganic vegetarian diets had a greater percentage of sons with Hypospadias. Because nonorganic diets can include residues of pesticides such as vinclozolin, we sought to assess the interaction of realistic daily exposures to genistein and vinclozolin and their effects on the incidence of Hypospadias. METHODS Pregnant mice were fed a soy-free diet and orally gavaged from gestational days 13 to 17 with 0.17 mg/kg/day of genistein, 10 mg/kg/day of vinclozolin, or genistein and vinclozolin together at the same doses, all in 100 μL of corn oil. The controls received the corn oil vehicle. The male fetuses were examined at gestational day 19 for Hypospadias, both macroscopically and histologically. RESULTS We identified no Hypospadias in the corn oil group. The incidence of Hypospadias was 25% with genistein alone, 42% with vinclozolin alone, and 41% with genistein and vinclozolin together. CONCLUSIONS These findings support the idea that exposure to these compounds during gestation could contribute to the development of Hypospadias.
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management of chordee in children and young adults
Urologic Clinics of North America, 2002Co-Authors: Gerald C Mingin, Laurence S BaskinAbstract:Penile curvature is a spectrum of disease affecting boys with and without Hypospadias. The etiology of chordee includes skin tethering, fibrotic bucks or dartos fascia, corporeal body disproportion and rarely a fibrotic urethra. Several surgical techniques (plication, excision, and graft insertion) are currently employed to repair penile curvature. Recent neuroanatomical studies of the developing fetal penis have shown that the dorsal nerve branches from the 11 and 1 o'clock positions to the 5 and 7 o'clock positions, being absent in the midline. Since the neuroanatomy is similar in both the hypospadiac and normal penis, we now recommend performing penile straightening in both hypospadiac and non hypospadiac patients with significant curvature by the placement of plication sutures at the 12 o'clock position. Placement of dorsal midline plication sutures corrects curvature without risk to the underlying nerve structures.
Salvatore Cascio - One of the best experts on this subject based on the ideXlab platform.
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increased occurrence of disorders of sex development prematurity and intrauterine growth restriction in children with proximal Hypospadias associated with undescended testes
The Journal of Urology, 2013Co-Authors: Prabhu Sekaran, Stuart Otoole, Martyn Flett, Salvatore CascioAbstract:Purpose: Proximal Hypospadias represents 20% of Hypospadias cases, which are considered to have a higher incidence of associated urological, nonurological, developmental and sexual development disorders, and chromosomal anomalies. We compared associated anomalies in boys with proximal Hypospadias and undescended testis with those in boys with proximal Hypospadias and descended testes.Materials and Methods: We reviewed the medical records of 69 boys who underwent 2-stage Hypospadias repair for proximal Hypospadias at a single institution during the 11-year period of 2001 to 2011. Collected data included demographics, birth history, associated urological and extra-urological anomalies, karyotype analysis and gonad palpability. Patients were divided into group 1—those with proximal Hypospadias and undescended testis, and group 2—those with proximal Hypospadias and descended testes. Statistical analysis was performed using the 2-tailed Fisher exact test.Results: There were 17 patients (25%) in group 1 with a ...
Alan B Retik - One of the best experts on this subject based on the ideXlab platform.
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tubularized incised plate urethroplasty expanded use in primary and repeat surgery for Hypospadias
The Journal of Urology, 2001Co-Authors: Joseph G Borer, Stuart B Bauer, Craig A Peters, David A Diamond, Anthony Atala, G Bartley J R Cilento, Alan B RetikAbstract:Purpose: We evaluated the impact of tubularized incised plate urethroplasty on primary and repeat Hypospadias repair.Materials and Methods: We retrospectively reviewed the medical records of all boys who underwent Hypospadias repair at our institution during a recent 3-year period. The level of the Hypospadias defect, technique of repair, primary repair versus reoperation, age at surgery and complications were recorded.Results: A total of 520 Hypospadias repairs were done from May 1996 through June 1999. We began to perform tubularized incised plate urethroplasty in November 1996. During the ensuing consecutive 32 months 181 primary and 25 repeat Hypospadias repairs were done using this technique. Mean patient age at surgery was 22 months (range 3 months to 30 years). During the 6 months immediately before we began to use this method the Mathieu flip-flap procedure was the most commonly performed technique, accounting for 38% of all Hypospadias repairs. In contrast, during the last 6 months reviewed tubul...
Amilal Bhat - One of the best experts on this subject based on the ideXlab platform.
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Extended Urethral Mobilization in Incised Plate Urethroplasty for Severe Hypospadias: A Variation in Technique to Improve Chordee Correction
Journal of Urology, 2007Co-Authors: Amilal BhatAbstract:Purpose: The feasibility of tubularized incised plate urethroplasty in proximal Hypospadias with severe chordee was studied after correction of chordee by extended urethral mobilization.Materials and Methods: Boys with severe Hypospadias who underwent tubularized incised plate urethroplasty were included. A total of 34 patients (28 with proximal penile/penoscrotal Hypospadias and 6 with scrotal Hypospadias) 18 months to 13 years old (mean 5 years) with severe Hypospadias underwent tubularized incised plate urethroplasty between January 1999 and March 2006. A Gittes test was performed to assess the chordee after penile degloving and preservation of the urethral plate. Subsequently, the urethral plate with divergent corpus spongiosum and proximal healthy urethra were mobilized up to the bulbar urethra. Glanular chordee was corrected by mobilizing the urethral plate into the glans. The urethral plate was tubularized with or without incision and spongioplasty to complete the urethroplasty.Results: Chordee cor...
