Genital Abnormality - Hypospadias

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Introduction

Classification of Hypospadias[1]

Hypospadias are the most common penis abnormality (1 in 300) and result from a failure of male urogenital folds to fuse in various regions, the normal process is described as virilization of the external genitalia. This in turn leads to resulting in a proximally displaced urethral meatus or opening.


The cause is unknown, but suggested to involve many factors either indivdually or in combination including: familial inheritance, low birth weight, assisted reproductive technology, advanced maternal age, paternal subfertility and endocrine-disrupting chemicals.[1] Infants with hypospadias should not undergo circumcision.


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Some Recent Findings

  • Somatically Acquired Isodicentric Y and Mosaic Loss of Chromosome Y in a Boy with Hypospadias[2] "Isodicentric Y chromosome [idic(Y)] represents a relatively common subtype of Y chromosomal rearrangements in the germline; however, limited evidence supports the postzygotic occurrence of idic(Y). Here, we report a boy with hypospadias and somatically acquired idic(Y). The 3.5-year-old boy has been identified in our previous study for patients with hypospadias. In the present study, cytogenetic analysis including FISH revealed a 45,X[5]/46,X,idic(Y)[7]/46,XY[8] karyotype. MLPA showed a mosaic deletion involving PPP1R12BP1 and RBMY2DP. The idic(Y) was likely to have been formed through aberrant recombination between P1 palindromes and subsequently underwent mosaic loss. The patient's phenotype was attributable to deletion of some Y chromosomal genes and/or mosaic loss of chromosome Y (mLOY). The results suggest that idic(Y) can originate in postzygotic cells via palindrome-mediated crossovers. Moreover, our data indicate that somatically acquired idic(Y) can trigger mLOY, which usually appears as an aging-related phenomenon in elderly men."
  • Review - Genetic and environmental factors in the aetiology of hypospadias[3] "This article reviews the current evidence and knowledge of the aetiology of hypospadias. Hypospadias remains a fascinating anomaly of the male phallus. It may be an isolated occurrence or part of a syndrome or field defect. The increasing use of assisted reproductive techniques and hormonal manipulation during pregnancy may have been associated with an apparent rise in the incidence of hypospadias. Genetic studies and gene analysis have suggested some defects that could result in hypospadias. New light has also been thrown on environmental factors that could modulate candidate genes, causing altered development of the male external genitalia."
  • Placental insufficiency in early gestation is associated with hypospadias[4] "Of the 104 extremely to very low-birth-weight male infants, 16 (15.3%) had hypospadias, and 10 (62.5%) of those had severe proximal hypospadias. Sixty-two controls who did not have hypospadias and whose body weight was less than 1500 g were identified. The incidence of hypospadias in full-term male birth in the hospital was 12 (0.30%) in 3959 births. Birth body weight and their SD for gestational age were lower in patients with hypospadias compared with those for controls (824 +/- 160 vs 1255 +/- 145 g). Placenta-to-fetal ratio (0.323 +/- 0.07 vs 0.229 +/- 0.03) and gestational age were significantly higher in the patients with hypospadias. Histopathologic study of the maternal placenta obtained from the patients with hypospadias revealed pronounced degenerative changes, infarction, and calcification, whereas these abnormalities were rare in controls. The significant association between the occurrence of hypospadias and early growth retardation with higher placenta-to-fetal ratio and placental abnormalities suggest that placental dysfunction in early gestation may play an important role in the development of hypospadias."
  • Correction of Distal Penile Hypospadias[5]
    • "The major aims of correction of hypospadias include construction of a neourethra, removal of the chordee, and reduction of the probability of postoperative fistulization. Here, we describe a new technique that can be easily used in cases with subcoronal distal penile hypospadias (even those with chordee) for the construction of the urethra using meatus-based transverse flaps."
    • "Meatal mobilization (MEMO) by distal urethral preparation has been demonstrated to be an efficient surgical technique for the correction of distal hypospadias offering excellent short-term success rates."[6]
More recent papers  
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Search term: Hypospadias

Tariq O Abbas, Mansour Ali Urethral Meatus and Glanular Closure Line: Normal Biometrics and Clinical Significance. Urol J: 2018; PubMed 30221335

Charline Warembourg, Luc Multigner, Ronan Garlantézec ##Title## Occup Environ Med: 2018; PubMed 30217926

Karen Smet, Jeffrey Kelsey ##Title## Occup Environ Med: 2018; PubMed 30217925

Laura Bessiène, Marc Lombès, Claire Bouvattier [Differences of Sex Development (DSD): Controversies and Challenges]. [Controverses et challenges sur le développement sexuel différent (DSD).] Ann. Endocrinol. (Paris): 2018, 79 Suppl 1;S22-S30 PubMed 30213302

Zhang Zhao, Ning Sun, Xiangming Mao Vascularization of vessel pedicle in hypospadias and its relationship to near-period complications. Exp Ther Med: 2018, 16(3);2408-2412 PubMed 30210593

Hypospadias Classification

Classification of Hypospadias[1]

The condition is classified by the general location of the relocated opening (meatus) and lack of fusion.

Hypospadias Classification

Classification ICD-10 Meatus Opening Image  Hypospadia classifications.jpg
Anterior Q54.1 on inferior surface of glans penis A
Coronal Q54.0 in balanopenile furrow B
Distal Q54.0 on distal third of shaft C
Penoscrotal Q54.2 at base of shaft in front of scrotum D
Scrotal on scrotum or between the genital swellings E
Perineal Q54.3 behind scrotum or genital swellings F
Table reference[1] Links: hypospadias

Ultrasound

Hypospadia 3D ultrasound 01.jpg

Penoscrotal Hypospadias 3D Ultrasound[7]

Ultrasonography in rendering mode, at GA 33 weeks, with short penis and with evidence of testicles inside a bifid scrotum.


Links: Ultrasound

Surgical Repair

Depending on the class of hypospadias there are a number of different surgical repair techniques including: orthoplasty or penile straightening, urethroplasty, meatoplasty and glanuloplasty, scrotoplasty (oscheoplasty) and skin coverage.

Maternal Factors

Data from a case-control study in Sweden and Denmark (2000 - 2005) identified a number of maternal factors that may be associated with hypospadias.[8]

  • Maternal diet during pregnancy lacking both fish and meat - more than 4-fold increased risk
  • Maternal obesity - more than 2-fold increased risk
  • Maternal hypertension - 2.0-fold increased risk
  • Maternal absence of nausea - 1.8-fold increased risk
  • Maternal nausea in late pregnancy - also appeared to be positively associated with increased risk

Molecular Factors

  • chromosomal abnormalities
  • HOX, FGF, Shh - genes of penile development
  • WT1, SRY - testicular determination
  • luteinizing hormone (LH) receptor
  • 5alpha reductase, androgen receptor - action of androgen
  • CXorf6
  • ATF3

Links: OMIM - CXorf6

Related Genetic Conditions

  • X-linked isolated hypospadias-1 HYSP1 OMIM 300633
  • X-linked isolated hypospadias-2 HYSP2 OMIM 300758
  • X-linked isolated hypospadias-3 HYSP3 OMIM 146450
  • Johanson-Blizzard syndrome[9] - hypospadias, failure to thrive, exocrine pancreatic deficiency, short stature and developmental delay, cutis aplasia on the scalp, aplasia of alae nasi, hypothyroidism, myxomatous mitral valve, and patent ductus arteriosus.

References

  1. 1.0 1.1 1.2 1.3 Baskin LS, Himes K & Colborn T. (2001). Hypospadias and endocrine disruption: is there a connection?. Environ. Health Perspect. , 109, 1175-83. PMID: 11713004
  2. Miyado M, Muroya K, Katsumi M, Saito K, Kon M & Fukami M. (2018). Somatically Acquired Isodicentric Y and Mosaic Loss of Chromosome Y in a Boy with Hypospadias. Cytogenet. Genome Res. , , . PMID: 29627832 DOI.
  3. George M, Schneuer FJ, Jamieson SE & Holland AJ. (2015). Genetic and environmental factors in the aetiology of hypospadias. Pediatr. Surg. Int. , 31, 519-27. PMID: 25742936 DOI.
  4. Fujimoto T, Suwa T, Kabe K, Adachi T, Nakabayashi M & Amamiya T. (2008). Placental insufficiency in early gestation is associated with hypospadias. J. Pediatr. Surg. , 43, 358-61. PMID: 18280290 DOI.
  5. Kutlay R, Isik D, Ercel C, Anlatici R & Isik Y. (2010). A new technique for correction of distal penile hypospadias. Ann Plast Surg , 65, 66-9. PMID: 20548222 DOI.
  6. Seibold J, Werther M, Alloussi S, Gakis G, Schilling D, Colleselli D, Stenzl A & Schwentner C. (2010). Objective long-term evaluation after distal hypospadias repair using the meatal mobilization technique. Scand. J. Urol. Nephrol. , 44, 298-303. PMID: 20450394 DOI.
  7. Rios LT, Araujo Júnior E, Nardozza LM, Rolo LC, Hatanaka AR, Moron AF & Martins Mda G. (2012). Prenatal diagnosis of penoscrotal hypospadia in third trimester by two- and three-dimensional ultrasonography: a case report. Case Rep Urol , 2012, 142814. PMID: 23304621 DOI.
  8. Akre O, Boyd HA, Ahlgren M, Wilbrand K, Westergaard T, Hjalgrim H, Nordenskjöld A, Ekbom A & Melbye M. (2008). Maternal and gestational risk factors for hypospadias. Environ. Health Perspect. , 116, 1071-6. PMID: 18709149 DOI.
  9. Fallahi GH, Sabbaghian M, Khalili M, Parvaneh N, Zenker M & Rezaei N. (2011). Novel UBR1 gene mutation in a patient with typical phenotype of Johanson-Blizzard syndrome. Eur. J. Pediatr. , 170, 233-5. PMID: 20556423 DOI.

Reviews

Cunha GR, Sinclair A, Risbridger G, Hutson J & Baskin LS. (2015). Current understanding of hypospadias: relevance of animal models. Nat Rev Urol , 12, 271-80. PMID: 25850792 DOI.

Carmichael SL, Shaw GM & Lammer EJ. (2012). Environmental and genetic contributors to hypospadias: a review of the epidemiologic evidence. Birth Defects Res. Part A Clin. Mol. Teratol. , 94, 499-510. PMID: 22678668 DOI.

van der Zanden LF, van Rooij IA, Feitz WF, Franke B, Knoers NV & Roeleveld N. (2012). Aetiology of hypospadias: a systematic review of genes and environment. Hum. Reprod. Update , 18, 260-83. PMID: 22371315 DOI.

Articles

McNamara ER, Schaeffer AJ, Logvinenko T, Seager C, Rosoklija I, Nelson CP, Retik AB, Diamond DA & Cendron M. (2015). Management of Proximal Hypospadias with 2-Stage Repair: 20-Year Experience. J. Urol. , 194, 1080-5. PMID: 25963188 DOI.

Search Pubmed

June 2010 "Hypospadia" All (4698) Review (377) Free Full Text (413)

Search Pubmed: Hypospadias | Hypospadias Surgical Repair

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Cite this page: Hill, M.A. (2018, September 18) Embryology Genital Abnormality - Hypospadias. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Genital_Abnormality_-_Hypospadias

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