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Douglas A Husmann - One of the best experts on this subject based on the ideXlab platform.
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the androgen insensitive Micropenis long term follow up into adulthood
Journal of Pediatric Endocrinology and Metabolism, 2004Co-Authors: Douglas A HusmannAbstract:Aim: To assess the adult stretched penile length (SPL) and sexuality in patients with Micropenis who exhibited an inadequate response to exogenous testosterone therapy and were raised as males. Patients and Methods: Patients with Micropenis who had an equivocal response to exogenous testosterone therapy and were raised as males were evaluated at adulthood (>17 yr). Results and Conclusions: Twenty patients with Micropenis, initial median SPL -3.3 SD below the mean (range -5.5 to -2.6) had a suboptimal response to initial testosterone therapy, median SPL post-treatment -2.7 SD (-3.3 to -2.2), and were raised as males. At adulthood, 90% (18/20) had a Micropenis, median SPL -3.4 (-5.9 to -2.2). All have a male gender identity, five are undergoing psychiatric counseling (fear of sexual rejection - five patients, one of whom also has suicidal ideation). Eight have not pursued a sexual relationship; 12 are sexually active, one of whom is bisexual.
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Micropenis an animal model and its human correlates
Advances in Experimental Medicine and Biology, 2002Co-Authors: Douglas A HusmannAbstract:Micropenis is defined as a perfectly formed abnormally small penis, with a stretched penile length that is lt; 2.5 standard deviations below the established mean value for race. The psychological concern and anxiety of the parents and patient regarding the adequacy of penile size makes treatment of this entity challenging. Since the early 1970’s androgen therapy for Micropenis has been the mainstay of treatment. Although testosterone will usually enhance penile growth in the prepubertal microphallic patient, not all of the infants or children that experience a response to androgens maintain their enhanced phallic size into adulthood. Indeed several of these patients will redevelop Micropenis as they mature. Although most of the adults with Micropenis adjust well to the male sexual role and develop stable heterosexual relationships, some refuse to become sexually active. Indeed occasional patients will prefer to maintain a life of sexual abstinence, rather than face their fears of rejection. The social and psychological consequences seen within this latter select group of patients is what prompted our interest into research on penile development and the treatment of Micropenis. (Schonfeld et al, 1942; Walsh, et al, 1978; Allen, 1986; Lee, et al, 1980; Money, 1984; Reilly et al, 1989; Woodhouse, 1998).
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characterization of penile androgen receptor expression in Micropenis due to hypogonadotropic hypogonadism
The Journal of Urology, 1998Co-Authors: Douglas N Tietjen, Greg Y Uramoto, Donald J Tindall, Douglas A HusmannAbstract:AbstractPurpose: The recommendation to treat Micropenis with androgen early in infancy and childhood is based on the fact that the normal penile androgen receptor decreases in concentration 2 to 3-fold in early adulthood. Hypothetically the early administration of androgen takes advantage of elevated penile androgen receptor concentration, resulting in optimal penile growth. We verify that there are similar patterns of androgen receptor expression in Micropenis and the normal penis.Materials and Methods: We used a strain of mice with Micropenis due to congenital hypogonadotropic hypogonadism (HPG). Affected mice and normal controls were sacrificed before puberty, and during puberty and early and late adulthood (15, 30, 60 and 90 days, respectively). At autopsy the penis was removed, weighed, pooled and processed for protein extraction. Androgen receptor concentration was determined by Western blot analysis.Results: In controls penile androgen receptor expression increased 2-fold from before puberty (0.49 ...
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Micropenis secondary to growth hormone deficiency does treatment with growth hormone alone result in adequate penile growth
The Journal of Urology, 1996Co-Authors: Jay B Levy, Douglas A HusmannAbstract:AbstractPurpose: Congenital growth hormone deficiency is associated with aberrant androgen physiology and Micropenis. We investigated whether treatment with growth hormone alone is adequate to restore normal phallic growth.Materials and Methods: In all patients the diagnosis was isolated growth hormone deficiency and Micropenis, and growth hormone was the only therapy. Stretched penile length, and somatic height and weight measurements were available from diagnosis through puberty for all patients.Results: Eight patients diagnosed with isolated congenital growth hormone deficiency and Micropenis were treated and evaluated. Mean z-score (number of standard deviations below mean stretched penile length) at diagnosis was −4.25 (range 3.1 to −6.6) with −2.5 representing Micropenis. In adulthood mean final stretched penile length z-score was −1.73 (range −0.91 to −2.66). Seven of the 8 patients (87.5 percent) had stretched penile length within normal range.Conclusions: Our findings suggest that growth hormone ...
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Micropenis does early treatment with testosterone do more harm than good
The Journal of Urology, 1995Co-Authors: Daniel R Mcmahon, Stephen A Kramer, Douglas A HusmannAbstract:AbstractMicropenis secondary to hypogonadotropic hypogonadism was induced in the Sprague-Dawley rat using long acting microspheres of the gonadotropic agonist leuprolide acetate. Following the induction of Micropenis treatment was initiated with testosterone at day 7, 28, 56 or 84 of life. All treatment protocols resulted in improved phallic growth compared to the untreated animals with Micropenis (p less than 0.01). Treatment of animals with testosterone beginning on day 7 of life resulted in premature growth of the penis and the redevelopment of Micropenis in adulthood. In contrast, delaying testosterone therapy until day 56 (pubertal) or 84 (early postpubertal) resulted in complete penile development. These findings suggest that early exposure of the penis to androgens in childhood may eventually result in a significant reduction of phallic size in adulthood.
Melvin M Grumbach - One of the best experts on this subject based on the ideXlab platform.
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a window of opportunity the diagnosis of gonadotropin deficiency in the male infant
The Journal of Clinical Endocrinology and Metabolism, 2005Co-Authors: Melvin M GrumbachAbstract:A common cause of Micropenis is congenital hypogonadotropic hypogonadism, whether isolated or associated with multiple pituitary hormone deficiencies. The postnatal surge in FSH, LH, and testosterone in the male infant as a consequence of the continued function of the fetal GnRH pulse generator provides a 6-month window of opportunity to establish the diagnosis of hypogonadotropic hypogonadism and alert the clinician to the possibility of its association with multiple pituitary hormone deficiencies. When ACTH or GH deficiency or both deficiencies are present, hypoglycemia and cortisol deficiency can lead to neonatal and infantile death or increased morbidity. Establishing the diagnosis of hypogonadotropic hypogonadism in infancy preempts the uncertainties and delays in distinguishing constitutional delay in puberty from hypogonadotropic hypogonadism. Accordingly, hormone replacement therapy can be initiated at the normal age of pubertal onset. The ontogenesis of infantile testicular function, including the possible significance of the infantile surge in gonadotropins and testosterone, is reviewed. The molecular basis for certain developmental disorders associated with hypogonadotropic hypogonadism and Micropenis is considered and the management and treatment of congenital hypopituitarism discussed.
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commentary a window of opportunity the diagnosis of gonadotropin deficiency in the male infant
2005Co-Authors: Melvin M GrumbachAbstract:A common cause of Micropenis is congenital hypogonadotropic hypogonadism, whether isolated or associated with multiple pituitary hormone deficiencies. The postnatal surge in FSH, LH, and testosterone in the male infant as a consequence of the continued function of the fetal GnRH pulse generator provides a 6-month window of opportunity to establish the diagnosis of hypogonadotropic hypogonadism and alert the clinician to the possibility of its association with multiple pituitary hormone deficiencies. When ACTH or GH deficiency or both deficiencies are present, hypoglycemia and cortisol deficiency can lead to neonatal and infantile death or increased morbidity. Establishing the diagnosis of hypogonadotropic hypogonadism in infancy preempts the uncertainties and delays in distinguishing constitutional delay in puberty from hypogonadotropic hypogonadism. Accordingly, hormone replacement therapy can be initiated at the normal age of pubertal onset. The ontogenesis of infantile testicular function, including the possible significance of the infantile surge in gonadotropins and testosterone, is reviewed. The molecular basis for certain developmental disorders associated with hypogonadotropic hypogonadism and Micropenis is considered and the management and treatment of congenital hypopituitarism discussed. (J Clin Endocrinol Metab 90: 3122–3127, 2005)
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congenital hypogonadotropic hypogonadism and Micropenis effect of testosterone treatment on adult penile size why sex reversal is not indicated
The Journal of Pediatrics, 1999Co-Authors: Bassam S Binabbas, Melvin M Grumbach, Felix A Conte, Selna L KaplanAbstract:Micropenis is commonly due to fetal testosterone deficiency. The clinical management of this form of Micropenis has been contentious, with disagreement about the capacity of testosterone treatment to induce a functionally adequate adult penis. As a consequence, some clinicians recommend sex reversal of affected male infants. We studied 8 male subjects with Micropenis secondary to congenital pituitary gonadotropin deficiency from infancy or childhood to maturity (ages 18 to 27 years). Four patients were treated with testosterone before 2 years of age (group I) and four between age 6 and 13 years (group II). At presentation, the mean penile length in group I was 1.1 cm (-4 SD; range, 0.5 to 1.5 cm) and in group II it was 2.7 cm (-3.4 SD; range, 1.5 to 3.5 cm). All patients received one or more courses of 3 intramuscular injections of testosterone enanthate (25 or 50 mg) at 4-week intervals in infancy or childhood. At the age of puberty the dose was gradually increased to 200 mg monthly and later to an adult replacement regimen. As adults, both group I and II had attained a mean final penile length of 10.3 cm 2.7 cm with a range of 8 to 14 cm (mean adult stretched penile length for Caucasians is 12.4 2.7 cm). Six of 8 men were sexually active, and all reported normal male gender identity and psychosocial behavior. We conclude that 1 or 2 short courses of testosterone therapy in infancy and childhood augment penile size into the normal range for age in boys with Micropenis secondary to fetal testosterone deficiency; replacement therapy at the age of puberty results in an adult size penis within 2 SD of the mean. We found no clinical, psychologic, or physiologic indications to support conversion of affected male infants to girls. Further, the results of this study do not support the notion, derived from data in the rat, that testosterone treatment in infancy or childhood impairs penile growth in adolescence and compromises adult penile length.
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congenital hypogonadotropic hypogonadism and Micropenis effect of testosterone treatment on adult penile size 403
Pediatric Research, 1998Co-Authors: Bassam S Binabbas, Felix A Conte, Selna L Kaplan, Melvin M GrumbachAbstract:Congenital Hypogonadotropic Hypogonadism and Micropenis: Effect of Testosterone Treatment on Adult Penile Size. • 403
Tsutomu Ogata - One of the best experts on this subject based on the ideXlab platform.
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human chorionic gonadotropin stimulation test in prepubertal children with Micropenis can accurately predict leydig cell function in pubertal or postpubertal adolescents
Hormone Research in Paediatrics, 2015Co-Authors: Tomohiro Ishii, Tsutomu Ogata, Seiji Sato, Goro Sasaki, Nobutake Matsuo, Shinya Tamai, Makoto Anzo, Tsutomu Kamimaki, Mikako Inokuchi, Naoaki HoriAbstract:Background/Aim: To evaluate the accuracy of the human chorionic gonadotropin (hCG) stimulation test in children with Micropenis in predicting later Leydig cell function. Methods: We conducted a retrospective investigation of testosterone response to a 3-day hCG test (3,000 IU/m2/day) in prepuberty to indicate the need for hormone replacement therapy (HRT) in adolescence. Results: Fifty Japanese boys (range, 0.8-15.4 years of age; median, 8.9) with Micropenis were enrolled. Thirty-four spontaneously developed puberty and preserved the ability of testosterone production (group 1), while 16 did not develop any pubertal signs without HRT (group 2). Serum testosterone levels after the hCG test (post-hCG T) in group 2 (range, Conclusions: The hCG test in prepubertal children with Micropenis can be useful for predicting Leydig cell function in pubertal or postpubertal adolescents. The post-hCG T cut-off level of 1.1 ng/ml is recommended to screen for those who will likely require HRT for pubertal development.
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de novo frameshift mutation in fibroblast growth factor 8 in a male patient with gonadotropin deficiency
Hormone Research in Paediatrics, 2014Co-Authors: Erina Suzuki, Mami Miyado, Shuichi Yatsuga, Maki Igarashi, Kazuhiko Nakabayashi, Keiko Hayashi, Kenichirou Hata, Akihiro Umezawa, Gen Yamada, Tsutomu OgataAbstract:Background/Aims: Missense, nonsense, and splice mutations in the Fibroblast Growth Factor 8 (FGF8) have recently been identified in patients with hypothalamo-pituitary dysfunction and craniofacial anomalies. Here, we report a male patient with a frameshift mutation in FGF8 . Case Report: The patient exhibited Micropenis, craniofacial anomalies, and ventricular septal defect at birth. Clinical evaluation at 16 years and 8 months of age revealed delayed puberty, hypos
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Association of Severe Micropenis with Gly146Ala Polymorphism in the Gene for Steroidogenic Factor-1
Endocrine Journal, 2005Co-Authors: Yuka Wada, Michiyo Okada, Tomonobu Hasegawa, Tsutomu OgataAbstract:Steroidogenic factor-1 (SF-1) regulates the transcription of multiple genes involved in the androgen biosynthesis, and SF-1 Gly146Ala polymorphism is known to reduce the transactivation function by ~20%. To examine whether the Gly146Ala polymorphism constitutes a susceptibility factor for the development of Micropenis (MP), we analyzed this polymorphism in a total of 52 patients with Micropenis (T-MP) consisting of 30 patients with severe MP below –2.5 SD (S-MP) and 22 patients with mild MP from –2.1 SD to –2.5 SD (M-MP), together with 115 control males. The Ala allele, the Ala/Gly genotype, and the Ala/Ala plus Ala/Gly genotype frequencies were significantly higher in the S-MP patients than in the control males, whereas the allele and the genotype frequencies were comparable between the M-MP patients and the control males. The results suggest that the SF-1 Gly146Ala polymorphism may constitute a susceptibility factor for the development of S-MP, and that M-MP can be regarded as a normal variation in terms of the polymorphism effect.
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testosterone enanthate therapy is effective and independent of srd5a2 and ar gene polymorphisms in boys with Micropenis
The Journal of Urology, 2004Co-Authors: Tomohiro Ishii, Tomonobu Hasegawa, Seiji Sato, Goro Sasaki, Nobutake Matsuo, Tsutomu OgataAbstract:ABSTRACTPurpose: We report penile length (PL) responses to testosterone enanthate (TE) therapy for Micropenis, and the relevance of the V89L polymorphism of SRD5A2 encoding the 5α-reductase type 2 ...
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Micropenis and the 5α reductase 2 srd5a2 gene mutation and v89l polymorphism analysis in 81 japanese patients
The Journal of Clinical Endocrinology and Metabolism, 2003Co-Authors: Goro Sasaki, Tsutomu Ogata, Tomonobu Hasegawa, Tomohiro Ishii, Seiji Sato, Kenjiro Kosaki, Keiko Homma, Takao Takahashi, Nobutake MatsuoAbstract:The 5alpha-reductase-2 encoded by the SRD5A2 gene plays a critical role in male sex differentiation by converting testosterone into 5alpha dihydrotestosterone in the peripheral target tissues. In this study, we examined the SRD5A2 gene in 81 Japanese patients with Micropenis (age, 0-14 yr; median, 7 yr) whose stretched penile lengths were between -2.5 SD and -2.0 SD in 39 patients (age, 0-13 yr; median, 8 yr) and below -2.5 SD in 42 patients (age, 0-14 yr; median, 6 yr), together with 100 control males (50 boys and 50 fertile adult males). Mutation analysis was performed for exons 1-5 and their flanking introns by denaturing HPLC and direct sequencing, revealing Y26X/R227Q in an 11-yr-old boy with a penile length of -2.6 SD, G34R/R227Q in a 9-yr-old boy with a penile length of -3.6 SD, and R227Q/R227Q in a 3-yr-old boy with a penile length of -2.4 SD, together with heterozygous R227Q in a control boy and a fertile adult male. Polymorphism analysis was carried out for the most frequent V89L known to reduce the enzyme activity by approximately 30% in 78 patients, except for the three patients with SRD5A2 mutations, and in the 100 control males by direct sequencing, showing that allele and genotype frequencies were similar between 78 patients with Micropenis below -2.0 SD or 40 patients with Micropenis below -2.5 SD and the 100 control males, the 50 boys, or the 50 fertile adult males, with no statistically significant differences. The results suggest that, in Japanese patients, Micropenis can be caused by SRD5A2 gene mutations, especially by R227Q which has been shown to retain approximately 3.2% of normal enzyme activity and appears relatively frequent in Asian populations, and that V89L polymorphism is unlikely to raise the susceptibility to the development of Micropenis.
Charles Sultan - One of the best experts on this subject based on the ideXlab platform.
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Isolated Micropenis reveals partial androgen insensitivity syndrome confirmed by molecular analysis
2020Co-Authors: Amrit Bhangoo, Françoise Paris, Françoise Audran, Pascal Philibert, Svetlana Ten, Charles SultanAbstract:Abstract Partial androgen insensitivity syndrome (PAIS) is the milder variant of androgen receptor (AR) defects. The subtle effects of AR mutations present in a patient with Micropenis, peno-scrotal hypospadias, infertility, clitoromegaly and posterior labial fusion. We studied the association of isolated Micropenis with the genetic defects resulting in androgen resistance, that is, AR gene defects and 5-α reductase type 2 (SRD5A2) deficiency. We describe two cases of isolated Micropenis: one in a 14-year-old boy and the other in a 3-year-old boy who was followed until he was 10 years old. There were no findings of hypospadias, cryptorchidism or gynecomastia in either of these patients. Serum gonadotrophin and androgen levels were obtained and karyotyping was done. Human chorionic gonadotropin (hCG) stimulation testing assessed the functional capacity of the testes. DNA was extracted from peripheral leukocytes, and all exons of the SRD5A2 and AR genes were amplified by polymerase chain reaction and sequenced. In both patients, baseline testosterone (T) level was low and the values were elevated after hCG testing. The sequence of the SRD5A2 gene was normal in patient 1, and a heterozygous polymorphism, V89L, was found in patient 2. Two known mutations, P390S and A870V, were identified in patients 1 and 2, respectively. Mutations in the AR gene can be associated with isolated Micropenis without other features of PAIS, such as hypospadias or gynecomastia. This underlines the importance of including AR gene analysis in the evaluation of isolated Micropenis with normal plasma T to ensure proper management of the patient and appropriate genetic counseling for the family
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High prevalence of Micropenis in 2710 male newborns from an intensive-use pesticide area of Northeastern Brazil
International Journal of Andrology, 2012Co-Authors: Laura Gaspari, Françoise Paris, Mattea Orsini, D. R. Sampaio, Françoise Audran, J. B. Neto, Charles SultanAbstract:Summary Exposure to endocrine-disrupting chemicals (EDCs) has been suggested to contribute to the increasing trends of external genital malformation in male newborns. In Northeastern Brazil, the poor sanitary conditions found in the favelas encourage the widespread use of pesticides. This 2-year study of a total birth cohort of full-term male newborns in the regional hospitals of Campina Grande (Paraiba, Brazil) sought to (1) accurately establish for the first time the incidences of neonatal male genital malformations, (2) investigate the endocrine and genetic aetiologies of these malformations, and (3) evaluate their associations with possible prenatal exposure to EDCs. A total of 2710 male newborns were explored for cryptorchidism, hypospadias and Micropenis. Cases were referred to the Pediatric Endocrine Clinic for endocrine and genetic investigations, and all parents were interviewed about their environmental/occupational exposure to EDCs before/during pregnancy by paediatric endocrinologists using a detailed questionnaire. We observed 56 cases of genital malformation (2.07%), including 23 cryptorchidism (0.85%), 15 hypospadias (0.55%), and 18 Micropenis (0.66%). All cases exhibited normal/subnormal testosterone production and none presented androgen receptor or 5α-reductase gene mutation. More than 92% of these newborns presented foetal contamination by EDCs, as their mothers reported daily domestic use of pesticides (i.e., DDT) and other EDCs. Most of these undervirilized male newborns presented additional EDC contamination, as 80.36% of the mothers and 58.63% of the fathers reported paid or unpaid work that entailed the use of pesticides and other EDCs before/during pregnancy for the mothers and around the time of fertilization for the fathers. The high rate of Micropenis in our population associated with an elevated percentage of parental environmental/occupational exposure to EDCs before/during pregnancy indicates that foetal contamination may be a risk factor for the development of male external genital malformation.
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Isolated 'idiopathic' Micropenis: hidden genetic defects?
International journal of andrology, 2011Co-Authors: Françoise Paris, Françoise Audran, Pascal Philibert, K. De Ferran, Amrit Bhangoo, Svetlana Ten, Najiba Lahlou, Nadège Servant, F. Poulat, Charles SultanAbstract:Micropenis is defined as a stretched penile length of less than 2-2.5SD for age. Aetiologies include hypogonadotropic hypogonadism, testicular dysgenesis, defects in testosterone synthesis, androgen resistance [5α-reductase (5αR) deficiency or partial androgen insensitivity] and other rare causes like growth hormone GH deficiency. Often, the cause remains unknown. The aim of this study was to determine whether isolated Micropenis with normal plasma testosterone could hide a molecular defect in the androgen pathway. Twenty-six boys with isolated Micropenis were included in this study. All of them had 46,XY karyotype, normal luteinizing hormone and follicle-stimulating hormone and a normal plasma testosterone response to human chorionic gonadotropin testing. Androgen receptor (AR), 5αR and steroidogenic factor 1 (SF1) genes were sequenced. A mutation in the AR gene was found in two patients, and a new mutation in the SF1 gene was found in one patient who was the only one to have a low level of inhibin B (InhB). This is the first report of isolated Micropenis as a revealing symptom of AR and SF1 mutations. Anti-Mullerian hormone and InhB should thus be evaluated in patients with isolated Micropenis, even when plasma testosterone is in the normal range. Detection of gene mutations is helpful for diagnosis, treatment and genetic counselling for probands.
Nobutake Matsuo - One of the best experts on this subject based on the ideXlab platform.
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human chorionic gonadotropin stimulation test in prepubertal children with Micropenis can accurately predict leydig cell function in pubertal or postpubertal adolescents
Hormone Research in Paediatrics, 2015Co-Authors: Tomohiro Ishii, Tsutomu Ogata, Seiji Sato, Goro Sasaki, Nobutake Matsuo, Shinya Tamai, Makoto Anzo, Tsutomu Kamimaki, Mikako Inokuchi, Naoaki HoriAbstract:Background/Aim: To evaluate the accuracy of the human chorionic gonadotropin (hCG) stimulation test in children with Micropenis in predicting later Leydig cell function. Methods: We conducted a retrospective investigation of testosterone response to a 3-day hCG test (3,000 IU/m2/day) in prepuberty to indicate the need for hormone replacement therapy (HRT) in adolescence. Results: Fifty Japanese boys (range, 0.8-15.4 years of age; median, 8.9) with Micropenis were enrolled. Thirty-four spontaneously developed puberty and preserved the ability of testosterone production (group 1), while 16 did not develop any pubertal signs without HRT (group 2). Serum testosterone levels after the hCG test (post-hCG T) in group 2 (range, Conclusions: The hCG test in prepubertal children with Micropenis can be useful for predicting Leydig cell function in pubertal or postpubertal adolescents. The post-hCG T cut-off level of 1.1 ng/ml is recommended to screen for those who will likely require HRT for pubertal development.
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testosterone enanthate therapy is effective and independent of srd5a2 and ar gene polymorphisms in boys with Micropenis
The Journal of Urology, 2004Co-Authors: Tomohiro Ishii, Tomonobu Hasegawa, Seiji Sato, Goro Sasaki, Nobutake Matsuo, Tsutomu OgataAbstract:ABSTRACTPurpose: We report penile length (PL) responses to testosterone enanthate (TE) therapy for Micropenis, and the relevance of the V89L polymorphism of SRD5A2 encoding the 5α-reductase type 2 ...
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Micropenis and the 5α reductase 2 srd5a2 gene mutation and v89l polymorphism analysis in 81 japanese patients
The Journal of Clinical Endocrinology and Metabolism, 2003Co-Authors: Goro Sasaki, Tsutomu Ogata, Tomonobu Hasegawa, Tomohiro Ishii, Seiji Sato, Kenjiro Kosaki, Keiko Homma, Takao Takahashi, Nobutake MatsuoAbstract:The 5alpha-reductase-2 encoded by the SRD5A2 gene plays a critical role in male sex differentiation by converting testosterone into 5alpha dihydrotestosterone in the peripheral target tissues. In this study, we examined the SRD5A2 gene in 81 Japanese patients with Micropenis (age, 0-14 yr; median, 7 yr) whose stretched penile lengths were between -2.5 SD and -2.0 SD in 39 patients (age, 0-13 yr; median, 8 yr) and below -2.5 SD in 42 patients (age, 0-14 yr; median, 6 yr), together with 100 control males (50 boys and 50 fertile adult males). Mutation analysis was performed for exons 1-5 and their flanking introns by denaturing HPLC and direct sequencing, revealing Y26X/R227Q in an 11-yr-old boy with a penile length of -2.6 SD, G34R/R227Q in a 9-yr-old boy with a penile length of -3.6 SD, and R227Q/R227Q in a 3-yr-old boy with a penile length of -2.4 SD, together with heterozygous R227Q in a control boy and a fertile adult male. Polymorphism analysis was carried out for the most frequent V89L known to reduce the enzyme activity by approximately 30% in 78 patients, except for the three patients with SRD5A2 mutations, and in the 100 control males by direct sequencing, showing that allele and genotype frequencies were similar between 78 patients with Micropenis below -2.0 SD or 40 patients with Micropenis below -2.5 SD and the 100 control males, the 50 boys, or the 50 fertile adult males, with no statistically significant differences. The results suggest that, in Japanese patients, Micropenis can be caused by SRD5A2 gene mutations, especially by R227Q which has been shown to retain approximately 3.2% of normal enzyme activity and appears relatively frequent in Asian populations, and that V89L polymorphism is unlikely to raise the susceptibility to the development of Micropenis.
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characterization of the aryl hydrocarbon receptor repressor gene and association of its pro185ala polymorphism with Micropenis
Teratology, 2002Co-Authors: Hideki Fujita, Tsutomu Ogata, Tomonobu Hasegawa, Nobutake Matsuo, Takao Takahashi, Rika Kosaki, Hiroshi Yoshihashi, Masaru Tomita, Kenjiro KosakiAbstract:Background Genetic background of a fetus contributes to the abnormal development after teratogen exposure. In rodents, in utero exposure to dioxins affects male external genital development. The effects of dioxins are mediated via the aryl hydrocarbon receptor (AHR) and its binding protein, aryl hydrocarbon receptor nuclear translocator (ARNT). In mice, aryl hydrocarbon receptor repressor (AHRR), which binds to ARNT in competition with AHR, plays a critical negative regulatory role in AHR signaling. We attempt to characterize the human AHRR gene and investigate the relationship between AHRR polymorphisms and the incidence of Micropenis, a phenotype of undermasculinization. Methods We identified and characterized the human homolog of mouse AHRR, taking advantage of the publicly available draft version of the human genome sequence. After detecting an AHRR protein polymorphism by the direct sequencing of pooled human genomic DNA, we evaluated the association between the polymorphism and the presence or absence of Micropenis (<−2.5 SD) in patients with Micropenis and control subjects. Results The deduced sequence for human AHRR (715 residues) and the mouse AHRR protein exhibited 81% sequence homology to each other. The Pro185Ala polymorphism was identified between the PAS-A region and the highly conserved arginine/cysteine-rich RCFRCRL/VRC region. Forty-six percent (27/59) of patients with Micropenis and 27% (22/80) of the controls were homozygous for 185Pro; this difference in frequencies was significant (P = 0.03). Conclusions Homozygosity for the 185Pro allele of AHRR may increase the susceptibility of a fetus to the undermasculinizing effects of dioxin exposure in utero, presumably through the diminished inhibition of AHR-mediated signaling. Teratology 65:10–18, 2002. © 2002 Wiley-Liss, Inc.
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Micropenis and the ar gene mutation and cag repeat length analysis
The Journal of Clinical Endocrinology and Metabolism, 2001Co-Authors: Tomohiro Ishii, Tsutomu Ogata, Seiji Sato, Kenjiro Kosaki, Goro Sasaki, Koji Muroya, Nobutake MatsuoAbstract:Various mutations of the AR gene and expanded CAG repeats at exon 1 of that gene have been reported in patients with hypospadias or genital ambiguity. However, the role of the AR gene has not been systemically studied in those with isolated Micropenis lacking hypospadias or genital ambiguity. We studied 64 Japanese boys with isolated Micropenis (age, 0-14 yr; median, 7 yr), whose stretched penile lengths were between -2.5 and -2.0 SD (borderline Micropenis) in 31 patients (age, 0-13 yr; median, 8 yr) and below -2.5 SD (definite Micropenis) in 33 patients (age, 0-14 yr; median, 6 yr). Mutation analysis of the AR gene was performed for exons 1-8 and their flanking introns, except for the CAG and GGC repeat regions at exon 1, by denaturing HPLC and direct sequencing, identifying a substitution of cytosine to thymine at a position -3 in the 3' splice site of intron 1 in a patient with definite Micropenis. CAG repeat length at exon 1 was determined by electrophoresis with internal size markers and direct sequencing, revealing no statistically significant difference in the distribution of CAG repeat lengths [median (range) and mean +/- SE: total patients with isolated Micropenis, 24 (14-34) and 23.5 +/- 0.38; patients with borderline Micropenis, 24 (15-29) and 23.5 +/- 0.53; patients with definite Micropenis, 23 (14-34) and 23.5 +/- 0.56; and 100 control males, 23 (16-32) and 23.5 +/- 0.29] or in the frequency of long CAG repeats (percentage of CAG repeats > or =26 and > or =28: total patients with isolated Micropenis, 17.2 and 4.7%; patients with borderline Micropenis, 19.4 and 6.5%; patients with definite Micropenis, 15.2 and 3.0%; and 100 control males, 21.0 and 10.0%). These results suggest that an AR gene mutation is rare and that CAG repeat length is not expanded in children with isolated Micropenis.