Disease relevance of Hypospadias

• Furthermore, somatic heterozygous loss of WT1 is known to lead to cryptorchidism and hypospadias in males [1].
• Homozygous mutants were viable and fertile, but females exhibited pronounced genitourinary abnormalities that included vaginal and uterine defects and hypospadias [2].
• To test this hypothesis we measured estrogen and androgen formation in two brothers with perineoscrotal hypospadias and severe gynecomastia (the Reifenstein phenotype) due to a mutation that impairs androgen receptor function [3].
• Incomplete urethral tubularization (hypospadias) and anorectal abnormalities are two common and poorly understood birth defects that affect the extreme caudal midline of the human embryo [4].
• The clinical features, which include hypertelorism, cleft lip and palate, defects of cardiac septation, hypospadias, and anorectal anomalies, indicate an underlying disturbance of the developing ventral midline of the embryo [5].

Psychiatry related information on Hypospadias

• It is also imperative to establish whether defects in steroid 5 alpha-reductase 2, perhaps in the heterozygous state, are responsible for a portion of cases of sporadic hypospadias, to determine whether 5 alpha-reductase plays a role in progesterone action in women, and to elucidate the relation between androgen action and gender role behavior [6].
• The X-linked form of Opitz syndrome (OS) affects midline structures and produces a characteristic, but heterogeneous, phenotype that may include severe mental retardation, hypertelorism, broad nasal bridge, widow's peak, cleft lip/cleft palate, congenital heart disease, laryngotracheal defects, and hypospadias [7].
• The case control analysis did indicate a greater use of allylestrenol in the hypospadias group, but this difference was not statistically significant in the critical period for induction of hypospadias (ie, the third and fourth months of gestation) [8].

High impact information on Hypospadias

• Opitz syndrome (OS, McKusick 145410) is a well described genetic syndrome affecting multiple organ systems whose cardinal manifestations include widely spaced eyes and hypospadias (Fig. 1). It was first reported as two separate entities, BBB syndrome, and G syndrome [9].
• Affected males from this family also have hypospadias, not previously described in SPD, but consistent with HOXD13 expression in the developing genital tubercle [10].
• We report that mice lacking the IIIb isoform of fibroblast growth factor receptor 2 (Fgfr2) exhibit severe hypospadias [11].
• Loss of Bmp7 and Fgf8 signaling in Hoxa13-mutant mice causes hypospadia [12].
• Mice mutant for Hoxa13 also exhibit changes in androgen receptor expression, providing a developmental link between Hoxa13-associated hypospadias and those produced by antagonists to androgen signaling [12].

Chemical compound and disease context of Hypospadias

• The 3 subjects who changed gender role behavior to male underwent hypospadias repair, and 1 was given supplemental testosterone therapy [13].
• The most frequent anomalies were spinal defects (four) and glandular hypospadias (three), all in association with maternal therapy with valproate, carbamazepine, or both [14].
• In a 5-yr-old 46,XY male pseudohermaphrodite with microphallus, perineal hypospadias, chordee and cryptorchidism, serum C19 steroid levels were abnormally low in the basal state and after adrenal and testicular stimulation [15].
• Serum levels of testosterone, androstenedione and dehydroepiandrosterone were measured before and after 5 days of treatment with hCG (2000 IU/d) in 36 prepubertal boys with cryptorchidism and 11 with hypospadias in order to determine whether a defect in androgen synthesis could be a common cause for these disorders [16].
• These data indicate that enzymatic defects in the steroidogenic steps from cholesterol to DHT are not a common etiology of hypospadias [17].
• There was a significantly reduced risk of hypospadias associated with of folate use during the first 3 months of pregnancy (OR = 0.64; 95% CI, 0.44-0.93) [18].

Biological context of Hypospadias

• Treatment with flutamide on days 14-20 of gestation resulted in hypospadias, the absence or only rudimentary growth of prostate and seminal vesicles, and the presence of a vagina in male offspring [19].
• RESULTS: A missense mutation of exon 2 of the androgen receptor gene was noted in 1 patient with isolated distal penile shaft hypospadias [20].
• Increased exposure to environmental factors (endocrine-disrupting chemicals and smoking) or maternal endogenous estrogen may cause hypospadias because male sexual differentiation is dependent on normal androgen homeostasis [21].
• Characterization of two point mutations in the androgen receptor gene of patients with perineoscrotal hypospadia [22].
• Maternal exposure to ethylene glycol monomethyl ether acetate and hypospadia in offspring: a case report [23].

Anatomical context of Hypospadias

• Mice carrying mutations which disrupt the bidirectional signals that these molecules transduce develop with variably penetrant severe hypospadias and incomplete midline fusion of the primitive cloaca [4].
• PURPOSE: In 1987 we developed distal urethral advancement and glanuloplasty, a surgical technique specifically intended for coronal and subcoronal hypospadias repair that involves moving the distal urethra 0.5 to 1 cm., Y shaped meatoplasty and glanuloplasty [24].
• Abnormality of intracellular 5 alpha-dihydrotestosterone binding in simple hypospadias: studies on equilibrium steroid binding in sonicates of genital skin fibroblasts [25].
• In the 1990s, declining semen quality has been reported from Belgium, Denmark, France, and Great Britain. The incidence of testicular cancer has increased during the same time incidences of hypospadias and cryptorchidism also appear to be increasing [26].
• This midline plate does not appear in finasteride-exposed fetuses destined to have hypospadias as demonstrated in a previous study [27].

Gene context of Hypospadias

• The results suggest that mothers with the CYP1A1 MspI variant allele may have a decreased risk for hypospadias [21].
• CONCLUSIONS: Our results suggest that variations in the ESR2 might influence susceptibility to hypospadias [28].
• In ESR1, no significant gene alteration was found to be associated with hypospadias [28].
• CONCLUSION: Mutant SRD5A1 isoenzyme does not seem to play a crucial role in the development of hypospadias [29].
• Exclusion of WTAP and HOXA13 as candidate genes for isolated hypospadias [30].
• The present study evidences two nonindependent risk factors for hypospadias in the ESR2 gene [31].

Analytical, diagnostic and therapeutic context of Hypospadias

• A variety of 1-stage repairs were applied including those of King, Mathieu, Mustardé and Duckett, and a combined midline and transverse island flap for perineal hypospadias [32].
• We studied 24 boys who were randomized to receive caudal epidural anesthesia with 0.33 ml.kg.-1 0.25% bupivacaine either before (group A) or after (group B) Mathieu repair of distal hypospadias [33].
• Cryptorchidism and hypospadias have been related to prenatal estrogen exposure in animal models [34].
• CONCLUSIONS: Split prepuce in situ onlay hypospadias repair is applicable in virtually all cases of coronal to mid shaft hypospadias [35].
• Midline dorsal plication to repair recurrent chordee at reoperation for hypospadias surgery complication [36].

References