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Current perspectives in hypospadias research: A scoping review of articles published in 2021 (Review)

  • Authors:
    • Horea Gozar
    • Zsolt Bara
    • Emilia Dicu
    • Zoltán Derzsi

  • View Affiliations

  • Published online on: March 23, 2023     https://doi.org/10.3892/etm.2023.11910
  • Article Number: 211

  • Copyright: © Gozar et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Hundreds of papers are written about hypospadias every year referring to all aspects of the pathology, being one of the most common congenital malformations. The present study conducted a scoping review of articles published in 2021 to present the main issues and summarize current perspectives and achievements in the field. It searched for the keyword ‘hypospadias’ in the three most popular databases (PubMed, Scopus and Web of Science). After the analysis of the publications, they were categorized into different domains. The present review was performed respecting the Preferred Reporting Items for Systematic reviews and Meta‑Analyses extension for Scoping Reviews (PRISMA ScR) guidelines. A total of 284 articles were included. These were published in 142 different journals. The most accessed was the Journal of Paediatric Urology with 54 articles. The main identified domains were related to surgical techniques, postoperative care, complications, anesthesia, anatomical factors, genetics, environmental factors, endocrinology, associated malformations, questionnaires and recommendations, management, biological materials, animal models, retrospective studies of centers, social media, bibliometrics, small gestational age, neoplasm, or fertility. Promising modifications of existing surgical techniques were presented with improved outcomes for both the proximal and distal types of hypospadias. Relevant anatomical and etiological, and also genetic factors were clarified. Aspects of the peri‑ and postoperative management referring to the antibiotherapy, analgesia, dressing techniques, and the future use of novel bioengineering agents to prevent, reduce or treat the occurring complications were discussed.

1. Introduction

Hypospadias is a congenital malformation, in which the meatus is opening on the ventral aspect of the penis, at different possible levels. Usually, the malformation is more complex and may be associated with penile curvature, glans deformation, narrow meatus or megameatus, and anomalies of the skin. Severe cases can present other urogenital or chromosomal anomalies. There are a number of unknown aspects of this malformation's etiology and development (1,2). Hypospadias repair may be a routine operation in distal cases and can be very challenging in proximal cases, even for a trained surgeon. There is no consensus on the treatment options for hypospadias and the development of treatment guidelines remains an unsolved file in medicine.

Furthermore, how the penis look is an important somatic and psychological facet of every boy or every family. In these conditions, it is obvious it became a subject of interest in medicine and a number of doctors from different specialties (especially pediatric surgeons or urologists) have tried to solve the problem (3-5).

In the last 10 years, according to the PubMed platform, an average of 313 (±38) studies were published each year (based on a search for the keyword ‘hypospadias’), the number of papers increasing each year. This pathology represents one of the most debated problems and not only among pediatric surgeons (6). For every pediatric surgeon, urologist, and specialist in this field, it is essential to know what is new about hypospadias and be up to date. The present study aims to present this pathology's current perspectives and the most important achievements in hypospadias research during 2021.

2. Materials and methods

The present study protocol was registered with the International Platform of Registered Systematic Review and Meta-Analysis Protocols (INPLASY) on 23 November 2022 and was last updated on 23 November 2022 (registration number INPLASY2022110117). It was performed in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA ScR) guidelines.

The present study chose the three most popular platforms (PubMed, Scopus and Web of Science) and searched for the keyword ‘hypospadias’. All the publications were restricted to 2021. All the results were downloaded in CVS format (or directly as xls format in the case of the Web of Science platform) and processed using Microsoft Excel software. The articles from PubMed were used as a base of the research, PubMed being considered the most accessible and most frequently used database. The duplicate records were removed compared to the results from the other two platforms. The remaining articles were analyzed individually and manually by the three reviewers.

The present study included all the articles which were published in 2021 in the research field of hypospadias with valuable information relating to surgical techniques, postoperative care, complications, anesthesia, anatomical factors, genetics, environmental factors, endocrinology, associated malformations, questionnaires and recommendations, management, biological materials, animal models, retrospective studies of centers, social media, bibliometrics, small gestational age, neoplasm, or fertility. Articles which were written in English were accepted. Papers in other languages were accepted if they had an English abstract with valorous information. Papers which were published in a year other than 2021, were outside of the research field, or were referring to other pathologies were excluded. However, those articles which were published in print format in 2022 and online in 2021 were considered as 2021 articles. Books, commentaries, responses to other papers, errata and withdrawn articles were excluded.

Source selection (both at title/abstract screening and full-text screening) was performed by the three reviewers independently (HG, ZB and ED). Any disagreements were solved by consensus or by the decision of the fourth reviewer (ZD). The process was accompanied by a flowchart detailing the flow from the search, through source selection, duplicates, retrievals, and any additions. The workflow is shown in Fig. 1.

The present study extracted from every qualified paper the essential ideas and conclusions. Then, this information was arranged and grouped into categories, some of them even into subcategories. The main information of the papers on the same topic with similar conclusions was merged, reformulated, and included in the corresponding table. The databases were accessed for the last time on the 20 November 2022. The number of references and the number of included articles differ as in the introduction some papers were cited to describe hypospadias in general.

The conclusions from the included articles relating to hypospadias research were categorized into 18 chapters: Surgical techniques (Subgroups: proximal hypospadias repair, distal hypospadias repair, covering tissue, curvature, fistula and stenosis, reoperative techniques, others), Postoperative care, Complications, Anesthesia, Anatomical factors, Genetics (reviews, genetical research on a population or on hospitalized patients, genetic counseling, genetic syndromes and malformations, genetical and histological analyses), Environmental factors, Endocrinology, Associated malformations, Questionnaires and recommendations, Management, Biological materials, Animal models, Retrospective studies of centers, Social media, Bibliometrics, Small gestational age, Neoplasm, and fertility.

3. Results

A total of 284 articles were included. These were published in 142 different journals in 2021. The most accessed journal on this topic was the Journal of Paediatric Urology with 54 articles (37.75% of the analyzed publications), followed by the World Journal of Urology (nine articles), the African Journal of Urology (eight articles), Journal of Paediatric Surgery (eight articles), Urology (seven articles), Research and Reports in Urology (seven articles), Journal of Urology (seven articles), Frontiers in Pediatrics (seven articles), Andrologia (six articles), Cureus (five articles). All the other publications had fewer than five papers.

The studies were classified in the described manner and 71 referring to surgical techniques (Subgroups: 27, proximal hypospadias repair; 18, distal hypospadias repair; seven, covering tissue; four, curvature; nine, fistula and stenosis; three, reoperative techniques; and three, others), 18 to postoperative care, 16 to complications, 13 to anesthesia, 22 to anatomical factors, 41 to genetics (three, reviews; 21, genetical factors; six, genetical research on a population or on hospitalized patients; four, genetic counseling; five, genetic syndromes and malformations; and two, genetical and histological analyses), 19 to environmental factors, 11 to endocrinology, nine to associated malformations, 20 to questionnaires and recommendations, six to management, six to biological materials, 11 to animal models, 11 to retrospective studies of centers, three to social media, three to bibliometrics, two to small gestational age and two to neoplasm and fertility.

4. Surgical techniques in hypospadias repair

Surgical techniques represents the most important chapter. A number of them refer to proximal hypospadias repair, which is considered the most challenging among surgeons. There were no new techniques described, but modifications were mentioned by different authors in hope of an improved outcome and reducing the complication rate (7-9). The majority of studies concluded that two-stage surgery leads to improved results compared with one stage (9-12). The options described are modified Koyanagi technique (13-15), transverse preputial island flap urethroplasty (10,12,16), inlay (17-19), or buccal mucosa graft (20,21). Tunica vaginalis represents a good coverage material (22-24). Scrotal raphe may be considered as a reserved option in cases of lack of skin (25). The urethroplasty in proximal hypospadias has improved results when stops at the balanic sulcus. There is only one study that proposes a three-stage urethroplasty (26).

Referring to distal hypospadias, tubularized incised urethroplasty remains the most common and indicated operation (27-31). Dorsal inlay graft urethroplasty (17,19), onlay preputial flap (19) and hybrid Mathieu urethroplasty are mentioned techniques (32,33). A number of authors in the last years prefer the simple advancement of the meatus instead of a proper urethroplasty.

Neourethral covering tissues are effective to prevent complications: tunica vaginalis, dartos, or Buck's fascia are well-known, they can be used in one or two layers. Dorsal plication remains the most used and simple approach to ventral curvature (34).

Table I presents the summaries of the articles about surgical techniques in hypospadias repair.

Table I

Summary of the articles about surgical techniques in hypospadias repair.

Table I

Summary of the articles about surgical techniques in hypospadias repair.

Proximal hypospadias
Author, yearConclusions(Refs.)
Wang et al, 2021Proximal hypospadias operated with transverse preputial island flap urethroplasty: those who benefit from incised urethral diversion had improved outcomes compared with those with transurethral diversion.(8)
Ali MM et al, 2021Staged (two-stage) transverse preputial island flap urethroplasty has improved results compared with one-stage surgery.(10)
Zhu X et al, 2021 (12)
Lin et al, 2021 (16)
Zhu XJ et al, 2021 (35)
Ali and Anwar, 2022 (36)
Chan et al, 2021Proximal hypospadias repairs in two stages: Pedicled preputial flaps and inlay grafts are superior choices compared with Byars' flaps.(11)
Zhu et al, 2021Transected urethral plate and transverse preputial island flap are good techniques in severe hypospadias.(12)
Madec et al, 2022A two stage procedure Koyanagi urethroplasty allows good final results.(13)
Aziz Tamer et al, 2021 (37)
Vu et al, 2021Results of the one-stage proximal hypospadias repair with modified Koyanagi technique in a single Vietnam center.(14)
Acimi et al, 2021Despite the modifications added by Snow and Hayashi to Koyanagi urethroplasty in so-called Koyanagi-Snow-Hayashi urethroplasty, the rate of complications. remains high(15)
Silay et al, 2021Inlay graft is a good choice, but it is not superior to classic repair.(17)
Chen et al, 2021Urethroplasty with buccal mucosa graft, in the first stage, facilitates the second-stage neourethral coverage and is a good technique.(20)
Shandilya et al, 2021 (21)
Radhakrishnan et al, 2021The tunica-vaginalis flap is an excellent buttress in severe hypospadias repair.(24)
Akkary et al, 2021 (39)
Obaidullah et al, 2021Islanded scrotal raphe flap is an option in complicated hypospadias repair with skin. shortage(25)
Chen et al, 2021 (41)
Lu et al, 2021The positioning of the external urethral orifice in the coronary sulcus, and urethroplasty in case of severe hypospadias leads to superior results.(38)
Akkary et al, 2021 (39)
Ding et al, 2021Prefabricated urethra and pre-implanted urethral plate methods are suitable for the correction of severe hypospadias as staging surgery in children.(40)
Lyu et al, 2021Spongiosum-combined glanuloplasty reduces the rate of complications in proximal. hypospadias(42)
Karakuș et al, 2021Vertical plication in penile curvature displaces the urethral plate transection in proximal hypospadias.(43)
Ndiaye et al, 2021Tubed pedicled preputial island flap (DUCKETT procedure) is associated with a high complication rate.(44)
Rawashdeh et al, 2021Foreskin transplantation in a two-stage reconstruction between monozygotic twins.(45)
Blanc et al, 2021Double-face preputial island flap revisited is a reliable one-stage procedure for proximal hypospadias.(46)
Fahiem-Ul-Hassan et al, 2021Single-stage urethroplasty is a versatile approach for different types of hypospadias, with a fistula rate of 12.8%. Posterior hypospadias, pyuria, and longer urethral defect are associated with higher rates of fistula formation.(47)
Keshk et al, 2021The modified Koyanagi one-stage repair of proximal hypospadias uses a dartos muscle flap as a cover for the urethroplasty improves the results and minimizes. complications(48)
Tudu et al, 2021The outcome of pediatric urethroplasty was favourable with routine use of intermediate vascularised flap in proximal hypospadias repair.(49)
Long et al, 2021Masculinizing genitoplasty in children with genital atypia, even if the parents opted for early surgery, is associated with 41% complications in cases of severe hypospadias, in a multicentric study.(50)
Distal hypospadias
Omran et al, 2021Dorsal inlay graft urethroplasty (DIGU) has improved surgical outcome compared with Onlay preputial flap (LOF).(19)
Taneli et al, 2021Tubularized reconstructed plate urethroplasty (TRPU) is an alternative for distal hypospadias repair, without incision or grafting.(27)
Khirallah et al, 2021Hybrid Mathieu urethroplasty: the Mathieu technique associated with incision of the urethral plate.(32)
Fahiem Ul-Hassan et al, 2021Buck's fascia repair with wingless glanuloplasty is a good technique with low fistula rates and glanular dehiscence(47)
Askarpour et al, 2021Meatal advancement glandular with release chordi is superior to Snodgrass methods, regarding the repair of distal hypospadias.(51)
Edan, 2021The urethral mobilization technique is a good choice, especially in the case of circumcised patients, the cosmesis and functional results are good and the. complications are less(52)
Noureldin et al, 2021Predictors of successful outcome of TIP repair are: absence of the chordee, meatus at coronal/subcoronal level, plate width ≥9 mm, AGD >5 cm, patient younger than ≤2 years old, GMS score ≤7, SPL >3.5 cm and grooved glanular shape.(53)
Abdelhalim et al, 2021 (54)
Shoukry et al, 2021Patients with a GMS score >6 have a higher risk of complications. Glans width of ≥14 mm and a penoscrotal length of ≥5 cm is associated with less risk of complication.(55)
Macedo et a, 2021The GUD (glandular urethral disassembly) technique (without urethroplasty): disconnects the spongious and the distal urethra from the corpora and detaching partially the glans. The glans is opened in midline. It is followed by cranial mobilization of the urethra with caudal and medial rotation of glans wings.(56)
Özbey et al, 2021Modeling of the foreskin with the GFC (Glanular-Frenular-Collar) technique to obtain an anatomic aspect.(57)
Permana et al, 2021TIP urethroplasty leads to good cosmetic and functional outcomes for the cases with megameatus intact prepuce.(58)
Ahmed et al, 2021The grafted-TIP urethroplasty has comparable results with the classic-TIP in terms of cosmoses, success rate, and complications; grafted-TIP is associated with significantly longer operative time.(59)
Kızılöz et al, 2021MAGPI under local anesthesia without a catheter is an alternative to the TIP procedure in distal hypospadias repair.(60)
Alshammari et al, 2021Deepithelialized glans reconfiguration (DeGRe) is a good option for distal hypospadias.(61)
Zhang et al, 2021Reconstructing forked corpus spongiosum provides excellent outcomes.(62)
Mohajerzadeh et al, 2021With the exception of the long-term outcomes in cosmetic and functional evaluation, Mathieu incised plate technique is superior to TIP technique.(63)
Benson et al, 2021A review of long-term outcomes of one-stage augmentation anterior urethroplasty shows worse results than expected.(64)
Covering tissue
Tiwari et al, 2021Tunica vaginalis flap or graft is a viable method to repair urethra lesions.(22)
Favorito et al, 2021 (23)
Tessier et al, 2021The more severe the hypospadias, the more effective is the cover the new urethra with flap.(65)
Rudin et al, 2021The augmentation of the urethral plate of the glans and the distal urethra with the implantation of a wide rectangular free flap in to the meatus, represents an advantage over the implantation of diamond-shaped grafts using the GTIP or TIP graft technique.(66)
Verma et al, 2021Dartos Flap as an additional cover to TIP is associated with an acceptable complication and has good cosmesis compared with spongioplasty.(67)
Naumeri et al, 2021The covering of neo-urethra by a double dartos layer (compared with a single layer), significantly reduces complications after tubularized incised plate urethroplasty.(68)
Zhang et al, 2021Buck's fascia with the glans can be used as an integral covering technique in one-stage distal to proximal hypospadias and primary or re-operative hypospadias repair.(69)
Curvature
Akdemir et al, 2021Dorsal plication is a relatively simple method with low risk and a high success rate for the treatment of congenital ventral penile curvatures.(34)
Cetin et al, 2021There are no differences in outcomes between pre-pubertal and post-pubertal boys after correction of penile curvature using corporal plication.(70)
Kozyrev et al, 2021STAGE technique in ventral curvature penile allows to correct ventral curvature of 15-60˚ with minimal complications.(71)
Zhou et al, 2022Interposition urethroplasty for glandular hypospadias is a reliable technique. The staged technique had superior outcomes compared with the single-stage technique.(72)
Fistula and stenosis
Swatesutipun et al, 2021For urethral stenosis: dorsal transurethral incision, (±dilatation), then oral mucosa graft on the defect (±glans preservation) is a feasible technique. Long strictures and thickness skin grafts are associated with lower success(18)
Furr et al, 2021 (73)
Favre et al, 2021 (74)
Mershon et al, 2021Recurrent Anterior Urethral Stricture. Augmentation with genital skin flaps and/or grafts or with buccal mucosa is occasionally required. Urinary diversion and perineal urethrostomy has to be considered.(75)
Sing et al, 2022PATIO technique for small fistulae is more successful compared with standard repair.(76)
Bar-Yosef et al, 2022Concomitant repair of meatal stenosis and urethral fistula does not increase the risk of fistula recurrence.(77)
Chatterjee et al, 2021Epithelium of track of the fistula is ablated with a hypodermic needle.(78)
Shirazi et al, 2021Clamping time for >2 min may prevent bleeding during and after meatotomy.(79)
Shaw et al, 2021Asopa technique represents an option for augmenting urethral caliber for urethral strictures.(80)
Reoperative techniques
Jordan et al, 2022A 3-Stage Approach for the Reoperative Hypospadias. i) Excision and buccal mucosal graft harvest. ii) Dorsal tissue expander placement. iii) The creation of neourethra and skin closure.(26)
Xie et al, 2022The Mathieu combined tunnel technique for repairing glans dehiscence after failed hypospadias repair is a feasible and reliable procedure.(33)
Yadav et al, 2021The best treatment for hypospadic meatal stenosis might be a dorsal midline incision, as it does not lead to a proximal shift of the meatus, and heals by reepithelisation without significant scarring, which decreases fistula formation.(81)
Others
Samir et al, 2021Running sutures groups was associated with a higher complication rate compared to interrupted sutures.(82)
Spinoit et al, 2021Redistribution of the abundant dorsal skin and its hooded prepuce to the ventral side of the penis is an option in a number of situations.(83)
Alaraby et al, 2021Running sutures is a superior suture compare to Vicryl.(84)

5. Postoperative care

Post-operatory care was also a debated issue. In some authors' opinion, stented or un-stented repair may lead to a similar outcome, especially in the case of distal hypospadias (28,85). The type of the dressings was not considered as important, although a number of substances were enumerated by different authors to increase their efficacy. Using compound Chamomile and Lidocaine hydrochloride gel, Aloe vera, or autologous platelet gel might decrease pain and edema, reduce inflammation and fibrosis, tubular finger oxygen-enriched oil inside-coated device decrease complications (86,87). Hyperbaric oxygen therapy may help in wound healing (88,89). The number of diapers used is not important for the surgical outcome, but a good washing of genitalia before and after surgery may be effective (90). The use of opioids or perioperative antibiotics is not relevant for surgical success (91-93). Postoperative C-Reactive Protein value (24 h after surgery) is a reliable marker for a possible complication after hypospadias surgery (94).

Table II presents the summaries of the articles about postoperative care.

Table II

Summary of the articles about surgical techniques in hypospadias repair.

Table II

Summary of the articles about surgical techniques in hypospadias repair.

Author, yearConclusions(Refs.)
Abdel-Hamid El-Hawy et al, 2021The outcome after stented and un-stented distal urethroplasty reveals similar results.(28)
Scarpa et al, 2021 (85)
Zhang et al, 2021Compound chamomile and Lidocaine hydrochloride gel relieve pain and reduce edema following hypospadias surgery.(86)
Doluoglu et al, 2022Aloe vera applied to the wound decreases inflammation and fibrosis after the tubularized incised plate urethroplasty model on rats.(87)
Anand et al, 2022Hyperbaric oxygen therapy prevents wound infection and helps in wound healing and decreases graft failure.(89)
Donelly et al, 2021Factors associated with opioid prescriptions in postoperative pediatric urology prescription were increasing age and scrotal surgery.(91)
Basin et al, 2021 (93)
Cornwell et al, 2022Children undergoing hypospadias surgery usually do not require opioid analgesics and are more likely to endorse pain.(92)
Ji F et al, 2021Postoperative C-Reactive Protein value (24 h after surgery) is a reliable marker for a possible complication after hypospadias surgery.(94)
Karakaya et al, 2021Functional and cosmetic results after TIPU are independent of dressing.(95)
Esposito et al, 2021Dressing using a tubular finger oxygen-enriched oil inside-coated device is effective, easy to manage, cheaper and decreases the rate of complications.(96,97)
Anand, 2021Tissue glue-based dressings following hypospadias repair do not represent a major change in postoperative care.(98)
Elsayem et al, 2022Autologous platelet gel improves outcomes in tubularized incised plate repair and limits surgical complications.(99)
Murakami et al, 2021Washing the genitals and groin 2 h preoperatively as well as immediately after the removal of a stent, to prevent infections after hypospadias repair.(100)
Canon et al, 2021The use of perioperative prophylactic antibiotics in hypospadias surgery does not reduce the possibility of infections.(101)

6. Complications after hypospadias repair

The most common complications after hypospadias repair remain fistula or stenosis. In some cases, they are easy to treat, but some of them require special interventions with grafts or dilatations and perineal diversion of the urine (28,102,103). For urethra suturing, interrupted sutures are an improvement on running sutures and PDS an improvement on Vicryl (82,104).

Wound dehiscence also remains a debated problem. Factors affecting glanular dehiscence are anatomical (glans width <14 mm, urethral plate width <7 mm), age (before 6 months of age and after puberty), and anesthesia (caudal block). All of these required reinterventions (42,105). Reoperation rate after distal hypospadias repair ranges from 3.3-6.7% (106,107). Other related complications are penile curvature that appears in 25% of cases (>30˚) (43,102,108-110), hairy urethra (111,112), erectile dysfunctions (113,114) and lower urinary tract symptoms (115). There were similar complications every surgeon is acquainted with.

Table III summarizes the articles on complications.

Table III

Summary of the articles about complications after hypospadias repair.

Table III

Summary of the articles about complications after hypospadias repair.

Author, yearConclusions(Refs.)
Kim et al, 2021Penile curvature appears in 25% (>30 degrees) of patients operated on hypospadias within the first 2 years.(102)
Snodgrass et al, 2021 (108)
Spinoit et al, 2021 (110)
Arslan et al, 2022Unusual case: Combined dorsal and lateral subcoronal urethrocutaneous fistula.(103)
Karabulut et al, 2022Factors affecting glanular dehiscence: anatomical (glans width <14 mm, urethral plate width <7 mm), age (before 6 months of age and after puberty), anesthesia (caudal block).(105)
Nguyen et al, 2021Reoperation rate after distal hypospadias repair: 3.3 to 6.7%. Follow-up at least 6 years is mandatory.(106)
Varea et al, 2021Hairy urethra or diverticulum found after hypospadias surgery using flap.(111)
Kumar et al, 2021 (112)
Husmann, 2021Erectile dysfunction after multiple hypospadias surgery is associated with advancing age, division of the urethral plate, prior ventral corporal grafting and repetitive internal urethrotomy for strictures.(114)
Chapman et al, 2021The consequence after urethroplasty: LUTS (lower urinary tract symptoms) related to detrusor underactivity.(115)
Favre et al, 2021The main etiological factor for urethral stricture is hypospadias.(116)
Faraj et al, 202225% of adults presenting with bulbar strictures have a history of hypospadias repair in childhood.(117)
Ali et al, 2021Failing to correct the deficient corpus spongiosum during hypospadias surgery, may become symptomatic in adolescence.(118)
Tack et al, 2021Hypospadias repair: More reinterventions if the initial repair was performed under 12 months, urinary problems and/or suboptimal sexual functional (52.9%), suboptimal voiding (22.1%).(119)
Godfrey, 2021Patients with hypospadias or complete androgen insensitivity syndrome reported better mental health than patients with other 46, XY (disorders of sexual development) diagnoses.(120)
Sembring et al, 2021Preoperative testosterone administration is accompanied by decreased risk of. glandular dehiscence(121)
Lucas-Herald et al, 2022Hypospadias is associated with vascular dysfunction including hypercontractility and impaired vasodilation. Secondary endothelial dysfunction and vascular injury early in life predispose to hypertension and cardiovascular events in adulthood.(122)

7. Anesthesia

General anesthesia remains the most widely accepted type of anesthesia in hypospadias repair (29,123-125). It is difficult to recommend regional anesthesia for pediatric penoscrotal procedures (127). The usefulness of caudal block-type anesthesia in postoperative pain control and its potential to favor complications represent a common topic. According to Routh (127) caudal block ‘is not a cause of complication-according to the data- and it is not a key to success’. A restrictive regimen is preferred over the conventional intraoperative fluid regimen during hypospadias surgery (128).

Table IV summarizes the articles on anesthesia.

Table IV

Summary of the articles about anesthesia.

Table IV

Summary of the articles about anesthesia.

Author, yearConclusions(Refs.)
Zhang et al, 2021There are similar rates of complications between groups receiving caudal block and general anesthesia vs general anesthesia in hypospadias surgery.(29)
Alizadeh et al, 2022 (123)
Koul et al, 2022 (124)
Adler et al, 2021 (125)
Osmani et al, 2021It is difficult to recommend regional anesthesia for ambulatory pediatric penoscrotal procedures. It depends on the patient, anatomy, medical history, duration of surgery.(126)
Elsonbaty et al, 2021A restrictive regimen is preferred over the conventional intraoperative fluid regimen during hypospadias surgery, in terms of respiratory function and recovery.(128)
Kandirici et al, 2021Caudal block administration does not contributes to urethral fistula formation.(129)
Sisay et al, 2021A rare case report: total spinal anesthesia following caudal block.(130)
Ponde et al, 2021No difference between the success rate of the caudal block techniques: landmark guided, stimulation-guided, and ultrasound-guided; US-guided pudendal block gives more postoperative pain control.(131)
Abdalla et al, 2021 (132)
Wang et al, 2021Administration of 1.5 µg kg-1 of dexmedetomidine in the caudal block is most adequate to reduce anesthesia, and operation associated adverse events.(133)
Hassan et al, 2021Adding nalbuphine to levobupivacaine in caudal block had a longer duration for postoperative analgesia and showed more sedation time than fentanyl and dexamethasone with more stability in hemodynamics.(134)
Karami et al, 2021Caudal block can provide longer postoperative analgesia compared to penile block using rectal acetaminophen.(135)

8. Anatomical factors

There are some anatomical factors associated with hypospadias and the severity of the malformation. Glans width, urethral plate width and shape and history of previous surgery are the most important factors in hypospadias (136). In addition, the anogenital distance and penile length are diminished in children having this malformation (137). Small glans are associated with the severity of hypospadias (138). Penile curvature accompanies almost all cases of hypospadias. To objectively measure the penile curvature different degrees were defined, but it is difficult to standardize them (139,140). A paper proposes a 3D-printed penile model from a set of five pictures obtained from a lateral view (141).

Microvascular density in the prepuce is not clear which is correlated with the severity of the malformation (142). Magnetic resonance imaging is a solution to a improved view of anatomical components of the penis, even from the intrauterine stage, but we cannot imagine this procedure performed on every child presenting hypospadias (143,144). Artificial intelligence is not advanced enough to recognize and classify hypospadias (145). As another observation, 2/3 of the patients having prostatic utricle cysts present hypospadias (146).

The appetite for quantification is present in hypospadias. The Hypospadias Objective Penile Evaluation (HOPE) score, the Plate Objective Scoring Tool (POST), or the Glans-Meatus-Shaft score are proposed for an improved evaluation of hypospadias (30,147,148). Risk factors associated with complications were severe ventral curvature (the main factor), followed by urethral stricture, dehiscence, and reoperation (107).

Table V summarizes the articles about anatomical factors.

Table V

Summary of the articles about anatomical factors.

Table V

Summary of the articles about anatomical factors.

Author, yearConclusions(Refs.)
Zhang et al, 2021Urethral plate quality is an independent factor influencing postoperative outcomes of hypospadias surgery. Urethral plate width has to be ≥6 mm in tubularized incised plate urethroplasty.(29)
Abbas, 2021 (140)
Galal et al, 2021The urethral plate width and glandular width are not correlated with the TIP outcome. HOPE score is correlated with a wide urethral plate.(30)
Ru et al, 2021Risk factors associated with numerous reoperations: severe ventral curvature (the main factor), followed by urethral stricture, dehiscence, and primary staged repair.(107)
Ben-David et al, 2021Dorsal penile curvature associated with megameatus intact prepuce hypospadias required ventral plication.(109)
Goel et al, 2021Anatomical factors affecting the outcome of hypospadias repair: glans width (most important), urethral plate width and shape, and history of previous surgery.(136)
Sennert et al, 2022A small glans is found in about a third of distal, two-thirds in proximal, and more than 90% of perineal hypospadias.(138)
Abbas, 2022Patients having hypospadias had the lower scrotal base distance, anogenital distance, and penile length compared with a group of full-term healthy boys; a number of methods measure and make a degree of curvature, with strong and weak points, but no one became a standard. It is very important to have a preoperative objective quantification of curvature.(139)
Fernandez et al, 2021Standardization of penile angle with a set of 5 pictures obtained from a lateral view (00, 150, 300, 450, 600) at a standard distance of 75 cm results in a 3-D printed penile model with a curvature angle ranging from 10 to 90˚.(141)
Zhao et al, 2021The lower preputial microvessel density is correlated with the severity of hypospadias and early postoperative complications.(142)
Li et al, 2021Magnetic resonance imaging studies in hypospadias can present more accurate anatomical structures and the vascularization of the penis. This conduces to better preparation of surgery. This method can diagnose fetal hypospadias and evaluate the severity.(143)
Chaudhary et al, 2022 (144)
Fernandez et al, 2021Artificial intelligence with digital pattern recognition used for the diagnosis and classification of hypospadias is less accurate than an experienced pediatric urologist. With an increasing number of images, the accuracy of diagnosis becomes better.(145)
Dai et al, 20212/3 of the patients having prostatic utricle cysts present hypospadias.(146)
Abbas, 2021Plate Objective Scoring Tool (POST) proposes some important anatomical landmarks on the urethral plate to have an objective and accurate evaluation of this.(147)
D'Oro et al, 2021The pre-operative Glans-Meatus-Shaft Score can be altered after penile degloving and meatal displacement, resulting in a ‘meatal mismatch’ (20% of patients). This mismatch increase (3 times) the risk of fistula.(148)
Gopal et al, 2021Patients with and short anoscrotal distance have more chance to present severe chordee.(149)
Yeşildal et al, 2021Microvascular density in the prepuce with hypospadias is increased (also inflammation), compared to the healthy prepuce. The density of androgen and estrogen receptors are. similar(150)
Seleim et al, 2021Topographic labeling of glans and corpus spongiosum can lead to better planning of the. surgery(151)
Abdullaev et al, 2021The type of hypospadias and the length of the urethral defect are the main risk factors for recurrent fistula after primary urethrocutaneous fistulectomy.(152)
Özbey et al, 2021Long-term urethral catheterization can lead to disruption in a tear in the septum glandis and produce iatrogenic hypospadias.(153)

9. Genetics

Gene mutation is a proven cause for a part of these penile malformations. Table VI presents a number of cases of patients with hypospadias who had a novel mutation or a formerly mentioned one, syndromes, or complex malformations. Some genes can be associated with hypospadias in some geographical regions (such as, Algeria and China). There are only a few reviews (three) about gene complexes or syndromes that are associated with hypospadias (154-156). Genetic counseling for patients with hypospadias is mandatory, especially when hypospadias is associated with other malformations, is the conclusion of one study (157). Future studies will appear with more information and predictability and easier and more organized systems for managing genetic issues.

Table VI

Summary of the articles about genetical factors.

Table VI

Summary of the articles about genetical factors.

Genetics-Reviews
Author, yearConclusions(Refs.)
Gao et al, 2021There is a significant association between patients carrying MAMLD1 gene variants and micropenis, hypospadias, cryptorchidism, or split scrotum.(154)
Ibba et al, 2021DSD may be very different, with clinical variants and genetic or molecular alterations.(155)
Nassau et al, 2021Classic Klinefelter syndrome (46XXY) or mosaicism can be associated with a decrease of testosterone ambiguous genitalia, cryptorchidism, and/or hypospadias.(156)
Genetical factors
Fendereski et al, 2021A prenatally diagnosed 46, XY DSD with a typical female phenotype caused by two heterozygous variants in LHCGR including a novel c.29_55 alteration.(158)
Alfei et al, 2022A child with BCL11B missense mutation. Hypospadias and neurologic disorders.(159)
Li et al, 2021A novel variant of SRD5A2 gene in a child featuring steroid 5α-reductase type 2 deficiency in a boy with hypospadias.(160)
Strong et al, 2022A novel MBTPS2 variant (c.766 G>A; (p.Val256Leu) is associated with Bresheck syndrome (with genotypic and phenotypic manifestation) and hypospadias.(161)
Arsov et al, 2021A novel variant in NR2F2 is associated with asplenia, immune deficiency, glandular hypospadias, and cryptorchidism.(162)
Thomas et al, 2021Two patients with Desbuquois dysplasia due to homozygous CANT1 mutations presented hypoplastic scrotum and hypospadias.(163)
Bouhouche et al, 2021A new mutation c.461G>A (p.Arg154Gln) in the short-chain dehydrogenase/reductase family 42E member 1 (SDR42E1) gene in a boy with hypospadias and ocular. malformation(164)
Luo et al, 2021A novel mutation in the HRAS gene (c.38G>T; p.Gly13Val) was detected in a patient with Schimmelpenning-Feuerstein-Mims syndrome and hypospadias.(165)
Akramov et al, 2021The WT1 gene (chr11: 32417947G>A), leads to translation termination site in the 369 codons (p.Arg369Ter, NM_024426.4) in a boy with bilateral Wilms' tumor and. scrotal hypospadias(166)
Elghezal et al, 2021HSD17B3 variants (c.239 G>A, p.R80Q) are rare causes of 46, XY DSD. Whole exome sequencing can increase diagnostic and identify genomic variants; Ring X syndrome, hypospadias with 923 Kb terminal deletion on the pseudoautosomal region 1 (PAR1) including SHOX gene followed by a duplication of 2.4 Mb.(167)
Ravirajendran et al, 2021A young adult with 45X0/46XY mixed gonadal dysgenesis who had Mullerian remnants that tend to enlarge in size over time.(168)
Correya et al, 2021Two patients presenting DSD, ambiguous genitalia with a 45XO/46XY mosaic chromosome pattern, hypospadias, Mullerian remnants, gonadal dysgenesis, streak gonad.(169)
Chen et al, 2021Mutations c.154_162delinsTCCTGTT and c.674T>A leads to3β-HSD deficiency with adrenal insufficiency and sex hormone synthesis dysfunction and hypospadias.(170)
Saida et al, 2021X-linked intellectual disability with OTUD5 gene variants: c.878A>T, p.Asn293Ile [NM_017602.4], c.1210 C>T, p.Arg404Trp and p.Arg404Trp.(171)
Çiftci et al, 2022A case of 46XY patient with female phenotype who had a variation in the HSD17B3 gene: c.673_1G>C homozygous class 2 (splice site) variation in intron 9.(172)
Laan et al, 2021Partial gonadal dysgenesis in 46XY patients with NR5A1 c.991-1G > C splice-site variants: OTX2 p.P134R or PROP1 c.301_302delAG.(173)
Gerber et al, 2021Robinow syndrome is a rare, genetic disorder. Boys may have genitourinary atypicality, among them hypospadias in 5/8 patients.(174)
Sheppard et al, 2021Heterozygous recurrent HNF4A variant p.Arg85Trp causes Fanconi renotubular syndrome 4, diabetes, Fanconi Bickel syndrome with colobomas and hypospadias.(175)
Tripolszki et al, 2021X-linked syndrome in 13 males of a family with a missense variant in the OTUD5 gene. Neurodevelopmental problems, congenital heart defects, and hypospadias were noted.(176)
Hage et al, 2021A novel androgen receptor gene mutation in two patients with mild insensitivity syndrome. It was found a novel missense mutation, Ala699Thr, in exon 4 within the ligand-binding domain.(177)
Basa et al, 2021Pathogenic Aristaless novel gene-variant C1010_1013dupGCTA; p.Tyr338 in a lissen cephaly boy with ambiguous genitalia.(178)
Genetic research on a population or on hospitalized patients
Li et al, 2021SRD5A2 and AR genes are two top candidate genes associated with 46, XY hypospadias in Chinese patients.(160)
Kherouatou-Chaoui et al, 2021It was found the absence of SRY and NR5A1 gene mutation in Algerian children. with DSD(179)
Chen et al, 2021An important link was found between rs12458 (3'-UTR of GATA4) and susceptibility to hypospadias.(180)
Wong et al, 2022Children affected by 45, X/46, XY mosaicism have a wide spectrum in their phenotypes.(181)
Deng et al, 2021GREM1 is associated with susceptibility to hypospadias in the European population. GREM1 risk allele rs3743104[G] increases hypospadias susceptibility among the southern Han population.(182)
Siregar et al, 2021ESR1 gene polymorphisms (PvuII, XbaI, and SNP 12) were found in hypospadias patients and there are correlate with the severity of hypospadias.(183)
Genetic counseling
Nordenskjöld et al, 2021Genetic counseling for patients with hypospadias is mandatory, especially when hypospadias is associated with other malformations. The risk of low fertility is a reality.(157)
Saraç et al, 2021Genes involved in the sonic hedgehog homolog pathway might play a role in the etiology of hypospadias.(184)
Tenenbaum-Rakover et al, 2021In DSD, 78% of our patients indicate a major role for whole-exome sequencing and its role in the diagnosis and management of the cases.(185)
Ea et al, 2021Next-generation sequencing reveals different forms of DSD (including hypospadias). It is important to have a follow-up and medical counseling in future.(186)
Genetical syndromes and malformations
Schmidt et al, 2022Variants in the transcription of the factor TP63 have been linked to several autosomal dominantly inherited malformations. Hypospadias is one of these malformations.(187)
Ding et al, 2021Noonan syndrome (frequently with hypospadias and cryptorchidism), is associated with PTPN11 variation, and SOS2 gene variation more often than previously reported.(188)
Lourenço et al, 2021An aberrant right subclavian artery may be associated with mosaicism 45, X [13]/46, X,e(X) (p22.1q22.1) and in some cases with hypospadias.(189)
Konishi et al, 20215α-reductase type 2 deficiency may lead to ambiguous phenotypes.(190)
Rjiba et al, 2021In Wolf-Hirschhorn syndrome we find a partial deletion of the short arm of chromosome 4. MSX1 gene absence might be responsible for the hypospadias phenotype in these children.(191)
Genetical and histological analyses
Yuri et al, 2021The expression of mRNA vascular endothelial growth factor in hypospadias patients does not affect the severity of hypospadias (dartos).(192)
Kong et al, 2021The expression of the Mafb gene and protein in the foreskin of children with hypospa dias is lower than that in the normal foreskin.(193)

Table VI summarizes the articles about genetical factors.

10. Environmental factors

Maternal exposure to different chemicals can induce malformation of the penis. The most incriminated chemicals in this process are bisphenol, inorganic solvents, alkyl phenolic compounds, phthalates, benzophenones, parabens, siloxanes, pesticides or herbicides, diethylstilbestrol, cadmium, DDT, vinclozolin (fungicide), petroleum solvents and SO2 (194-201). Some studies are more general and incriminate the air pollution, heat, or the proximity of a vineyard in the development of hypospadias (202-204).

Table VII summarizes the articles on environmental factors.

Table VII

Summary of the articles about environmental factors.

Table VII

Summary of the articles about environmental factors.

Author, yearConclusions(Refs.)
Spinder et al, 2021Maternal exposure to Bisphenol A, organic solvents/alkyl phenolic compounds and phthalates/benzophenones/parabens/siloxanes, pesticides in early pregnancy is associated with urogenital anomalies in the offspring.(194)
Rodprasert et al, 2021 (195)
Mesquita et al, 2021 (205)
Mattiske et al, 2021Genistein, Bisphenol A (BPA), Phthalates, Parabens, flame retardants, solvents, agricultural chemicals, Atrazine (herbicide), DDT, and Vinclozolin (fungicide) can interfere with androgen and estrogen levels during the development and result hypospadias.(196)
Laws et al, 2021Plasticizers (bisphenols and phthalates), personal care products (parabens), environmental contaminants (polychlorinated biphenyls), herbicides or pesticides, cadmium, conduct to male disorders: infertility, cryptorchidism, hypospadias, and testicular cancer.(197)
Stukenborg et al, 2021 (198)
Giovanni et al, 2022 (199)
 We have to focus on prenatal exposure to mild analgesics: acetaminophen (more involved) and Ibuprofen (less involved). 
Wu et al, 2022Maternal exposure to pesticides, phthalates, bisphenol A, and polychlorinated biphenyls are associated with hypospadias and micropenis in offspring. They have transgenerational effects with long-term effect.(200)
Gaspari et al, 2021 (201)
Huang et al, 2021Air pollution during pregnancy was associated with the occurrence of hypospadias, but conclusions have been inconsistent. Some ethnic groups may present a type of such malformation.(202)
Xing et al, 2021Air pollution and risk of hypospadias in offspring: there is an effect of PM2.5 exposure on hypospadias risk.(203)
Bougnères et al, 2021The residence of pregnant mothers close to vineyards was statistically linked with the risk of hypospadias in children.(204)
Soyer-Gobillard et al, 2021Prenatal exposure to Diethylstilbestrol produced multigenerational phenotypic (hypospadias endometriosis) and psychiatric disorders.(206)
Zhang ZC et al, 2021Dibutyl phthalate is an endocrine disruptor. It has anti-androgenic effects and a weak estrogenic effects. Lower doses cause more adverse effects than the highest dose.(207)
Zhang S et al, 2021Maternal exposure to SO2 during the 3 months before and the first and second months after conception may increase the risk of hypospadias in offspring.(208)
Rouget et al, 2021An association between petroleum solvents and hypospadias has been observed.(209)
Haghighi et al, 2021The appearance of hypospadias is linked to heat exposure. Effects increased with the duration and intensity of heat exposure.(210)
Gadagbui et al, 2021Procymidone as an endocrine disrupting chemical can produce hypospadias but is not very suggestive for other malformations.(211)
Lin et al, 2021There is a modest association between prenatal PM2.5 (fine particulate matter) exposure during 1 month before pregnancy or within the first trimester and the risk of hypospadias in offspring.(212)

11. Endocrinological factors

In regard to endocrinological factors, two main hypotheses were identified. One is that prenatal factors: diabetes, intake of progestins, estrogens, β-blockers, assisted reproductive technology, and diethylstilbestrol (treatment in grandmothers can lead to a greater risk for hypospadias in offspring and grandsons) (207,213-217). The other is that in some penile malformations, preoperatory testosterone treatment is conducted for improved results (218-220).

Table VIII summarizes the articles about endocrinological factors.

Table VIII

Summary of the articles about endocrinological factors.

Table VIII

Summary of the articles about endocrinological factors.

Author, yearConclusions(Refs.)
Zhan ZC, 2021Prenatal and/or gestational factors (diabetes), intake of different treatments during pregnancy (progestins, estrogens, β-blockers), assisted reproductive technology and diethylstilbestrol treatment in grandmothers can lead to a greater risk for hypospadias in offspring and grandsons.(207)
Akay et al, 2021 (213)
Chung et al, 2021 (214)
Baskin et al, 2021 (215)
Wu et al, 2021 (216)
Schraw et al, 2021 (217)
Liu et al, 2021Testosterone treatment in children with hypospadias, especially those with a 5α-reductase deficiency, can alter its degree and lead to a greater success for the operation.(218)
Khokar et al, 2021 (221)
Li et al, 2021Preoperative androgen stimulation is used in proximal hypospadias or small glans size. It appears it does not affect the operative outcome, but it is not certain.(219)
Chukwubuike et al, 2021 (222)
Concepción et al, 2021Boy with partial androgen insensitivity syndrome (having hypospadias and cryptorchidy), required testosterone therapy and genitoplasty.(220)

12. Associated malformations

The best-known associated malformation with proximal hypospadias is cryptorchidism (223). Hypospadias is frequently associated with cardiac, renal and skeletal malformations (224). There is also a correlation between anorectal malformation complexity and associated urologic abnormalities (225). In addition, a number of genetic syndromes are associated with hypospadias, some of which are described in the Genetics section (section 9). A peculiarity is cases of hypospadias with disorders of sex development. Severe genital ambiguity requires complex genetic and anatomic investigation to declare the patient as a male (226-228). Other observations note that talipes, hypospadias and septal heart defects are more frequent mild defects associated with prematurity and gonadal neoplastic lesions appearing frequently together with hypospadias (229).

Table IX summarizes the articles on associated malformations.

Table IX

Summary of the articles about associated malformations.

Table IX

Summary of the articles about associated malformations.

Author, yearConclusions(Refs.)
D'Oro et al, 2021Patients with proximal hypospadias present a higher risk of acquired. cryptorchidism(223)
Ludorf et al, 2021Hypospadias is most frequently associated with cardiac, renal, and skeletal malformations. Hypospadias in combination with eye defects did not include defects in other organ systems.(224)
Fuchs et al, 2021There is a correlation between anorectal malformation complexity and associated urologic abnormalities.(225)
De Jesus et al, 2021Cases of hypospadias in the disorder of sex development (DSD) associated with ovotestis, severe genital ambiguity, and the child was declared male after elaborate analysis or an apparent male with infertility who presented 46 XX karyotype.(226)
Nelwan et al, 2021 (227)
Ashfaq et al, 2021 (228)
Álvarez-Álvarez et al, 2021Cases of hypospadias associated with Dandy-Walker malformation (75), bifid phallus (77), dorsal penile curvature with megameatus (136), Wolf-Hirschhorn syndrome (262).(230)
Viet Nguyen et al, 2021 (231)
Çelik et al, 2021 (232)

13. Questionnaires and malformations

Some papers refer to the outcome following hypospadias surgery. Some authors call for standardization of penile appearance. The Penile Perception Score-PPS, Hypospadias Objective Score Evaluation-HOSE, International Index of Erectile Function-5-IIEF5, or Health-related quality of life (HRQoL) were conceived for that purpose (6,233). These scores are different from the point of view of patients, parents, or surgeons so there is no standard yet. Curvature and shortening are the anatomical modifications most perceived by the patients (234). Voiding, erectile problems, social interaction and psychological issues are the functional problems after surgery (233,235).

Table X summarizes the articles about questionnaires and malformations.

Table X

Summary of the articles about questionnaires and malformations.

Table X

Summary of the articles about questionnaires and malformations.

Author, yearConclusions(Refs.)
Snodgrass et al, 2021Parents of boys with hypospadias: the majority never previously heard of it, wondered if they are to blame for it and are concerned about future boys. A part of the report is that doctors did not spend enough time discussing these problems.(3)
van Engelen et al, 2021A substantial number of parents report some form of decisional regret regarding the elective surgery for hypospadias in their child.(4)
Costa et al, 2021Surgeons seem more concerned about the cosmetic part of hypospadias surgery than parents. Photography appears to be suitable for documenting corrections of hypospadias regarding penile curvature, and postoperative cosmetic results.(5)
Ceccarelli et al, 2021Three questionnaires: The Penile Perception Score-PPS, the Hypospadias Objective Score Evaluation-HOSE, and the International Index of Erectile Function-5-IIEF5 to patients, parents, and surgeons. The results are different, so there is a need for standardization.(6)
Hismatsu et al, 2021The learning curve in proximal hypospadias repair appears after 50 cases, supervised by an experienced surgeon.(7)
Ludovica et al, 2021Self-reported outcomes in adolescent patients who had TIP repair are similar to the control group. Preputial reconstruction or circumcision did not affect the outcome.(31)
Bhatia et al, 2021Health-related quality of life (HRQoL): penile appearance, voiding, social interaction, sexual health and psychological or behavioral function, have to serve as a guide for future assessments. Patients are usually focused on penile appearance.(233)
Hoare et al, 2021Penile modifications after urethroplasty is perceived by individuals, especially in curvature and shortening.(234)
Chang et al, 2021A significant percentage of adolescents or young adults operated in childhood with hypospadias, present aesthetic complaints (majority) or functional problems (fistula, spaying).(236)
Sinatti et al, 2021Psychosexual satisfaction of adults who had hypospadias surgery demonstrates equal satisfaction rates to those in control group. Interventions on the penile urethra, long panurethral urethroplasties, and reinterventions are associated with greater risks. The functional benefit of non-transecting approaches and grafting techniques on bulbar urethra remains controversial.(237)
Hermosa et al, 2021 (238)
Mallenahalli et al, 2021 (239)
Zhang et al, 2021Delayed surgery in children with hypospadias is determined by the economy of the area where the family lives, the educational level of the parents, and the location of the urethral opening.(240)
Bennecke et al, 2021From patients' perspective, early genital surgery in DSD is more accepted, but every case has its complexity, so it cannot be applied as a rule.(241)
Bangalore et al, 2021The patient's family is encouraged to make individualized treatment guided by shared decision.(242)
Cakmak et al, 2022Hypospadias and neurologic impairment may share common etiologic factors, thus every patient with hypospadias should be evaluated for neurodevelopmental status.(243)
van de Grift et al, 2022The majority of patients with DSD, who had a history of surgery were neutral to satisfied with the appearance and function after masculinizing operations.(244)
Gul et al, 2021Sexual functions and fertility outcomes after hypospadias repair may be affected in some patients.(245)
Guner et al, 2021Hypospadias was one of the early reported malformations in the history of medicine, but very little specific urogenital disease information is mentioned in ancient age sanctuary medicine. Surgical techniques used now were elaborated in the 20th century.(246)
Buyukunal et al, 2021 (247)

14. Management

For most families, a boy having hypospadias is a psychological trauma. Usually, parents do not know about this malformation and have to be informed, and this is not always, in terms of time and explanation, what they expect. The need for reintervention is perceived in the majority of cases as a trauma for patients and parents (3,38). An article claims that hypospadias and neurologic impairment may share common etiologic factors, thus every patient with hypospadias should be evaluated for neurodevelopmental status (243). Timing for complex malformations has to be considered individually in every case. Delayed surgery in children with hypospadias is also determined by the economy of the area where the family lives and the educational level of the parents (240).

In a hospital register, it is not easy to classify hypospadias properly, although there are algorithms for identification (248). Another question is: ‘What are the specialties of the surgeons who are managing these cases?’ Usually, they are pediatric surgeons or pediatric urologists (depending on the country) (249). Regardless of the specialty, the repair of hypospadias requires an experienced doctor. The learning curve seems quite long; surgeons are considered experienced in the field after treating a minimum of 50 cases, supervised by an experienced surgeon (7). When the child becomes an adult, it is better to be managed by urologists trained in genitourinary reconstructive surgery (250). It is important to inform general practitioners, and pediatricians about the management of hypospadias, as it seems that a number of them do have not adequate knowledge about the condition (251).

Table XI summarizes the articles on hypospadias management.

Table XI

Summary of the articles about hypospadias management.

Table XI

Summary of the articles about hypospadias management.

Author, yearConclusions(Refs.)
Baker et al, 2021Methods for classifying distal hypospadias and other urologic problems in registers, present a high risk for misclassification.(248)
Maier et al, 2021In Germany, hypospadias surgery has shown a relevant shift towards pediatric surgery, from pediatric urology.(249)
Scarberry et al, 2021Patients who become adults are better managed by urologists trained in genitourinary reconstruction.(250)
Mahalik et al, 2021Indian questionary among pediatricians: about half of them know what to do and recommend to a patient with hypospadias.(251)
Kharbanda et al, 2021Algorithms can identify infants with selected birth defects using automated health care data with reasonable accuracy.(252)

15. Biological materials

Biological engineering materials and products are becoming increasingly popular in hypospadias repair and the present study enumerated some of them which were used in urethroplasties. Acellular dermal matrix grafts (with Collagen-Binding VEGF), harvested from the bladder or derm were successfully used in the urethral reconstruction and authors claim that the results were comparable with tunica vaginalis (253). Tissue sealants such as fibrin glue, cyanoacrylate glue, Bio Glue, and cryocalcium glue were used to reduce fistula-related complications (254).

Table XII summarizes the articles about biological materials in hypospadias repair.

Table XII

Summary of the articles about biological materials in hypospadias repair.

Table XII

Summary of the articles about biological materials in hypospadias repair.

Author, yearConclusions(Refs.)
Wu et al, 2021Acellular dermal matrix graft is a good material for ventral lengthening of the penis, comparable with tunica vaginalis.(253)
Singh et al, 2021A review of tissue sealants: fibrin glue, cyanoacrylate glue, Bio Glue, and cryocalcium glue. They can reduce complications (fistula, cutaneous lesions), but they remain inconclusive.(254)
Wang et al, 2021Acellular dermal matrix modified with Collagen-Binding VEGF was successfully used in the urethral reconstruction of a dog without severe inflammation.(255)
Morgante et al, 2021Two acellular matrix grafts for tissue bed for surgical repair were compared: full-thickness porcine acellular bladder matrix and commercially-sourced cross-linked acellular matrix from the porcine dermis (Permacol™). The two were conducive to good results.(256)
Tawfeek et al, 2021The application of cyanoacrylate during fistula repair is feasible and safe.(257)
Shenoy et al, 2021Fibrin sealant, applied over the urethroplasty suture represents a good cover and improves the outcome in patients with hypospadias.(258)

16. Animal models

Experiments on animals are rare, poorly reported, less detailed and not reproducible (as a review found) (259). A single urethral reconstruction is reported in a rabbit model. It used a decellularized intestinal submucosa, seeded with urothelial cells (260). Specific genes were discovered and involved in hypospadias formation in rats and mice (261-264). Prenatal atrazine and vinclozolin exposure can affect penile and testicular development (265).

Table XIII summarizes the articles about animal models.

Table XIII

Summary of the articles about animal models.

Table XIII

Summary of the articles about animal models.

Author, yearConclusions(Refs.)
Abbas et al, 2021Urethral repair experiments on animals are poorly reported, less detailed and are not reproducible.(259,266)
Amesty et al, 2021Rabbit urethral defect: neourethra is created by seeding autologous urothelial cells by bladder washing on a decellularized intestinal submucosa matrix (Biodesign® Cook-Biotech®).(260)
 Cell-seeded transplants are superior to nonseeded. 
Palermo et al, 2021A putative pathway network for a male rat, sustained expression of Coup-tfII and hypospadias.(261)
Alcantara et al, 2021Wnt5a contributes to urethral tube formation in mice.(262)
Xiang et al, 2021c-Fos overexpression might contribute to hypospadias (rats and humans) and(263)
Feng et al, 2021NONRATT008453.2 may have an influence on autophagy in the fibroblasts of the genital tubercle in dibutyl phthalate-induced hypospadias in rats.(264)
Yu et al, 2021Maternal vinclozolin exposure can lead to penile and testicular damage (via miR132, miR195a) in the offspring. Prenatal atrazine exposure can induce hypospadias and cryptorchidism in mice.(265)
Tan et al, 2021 (267)
Tokat et al, 2021Intraurethral erythropoietin administration facilitates wound healing after hypospadias correction in rats.(268)
Gulburun et al, 2021Hydrogen-rich saline solution reduces inflammation on the flap tissue in the hypospadias model in rats.(269)

17. Retrospective studies of centers

Table XIV summarizes the articles about retrospective studies of centers.

Table XIV

Summary of the articles about retrospective studies of centers.

Table XIV

Summary of the articles about retrospective studies of centers.

Author, yearConclusions(Refs.)
Kaefer et al, 2021A great lesson and the experience of a top surgeon regarding hypospadias.(2)
Fruntelată et al, 2021Overview of center regarding hypospadias from Romania, Afghanistan, Kenya, Pakistan or Saudi Arabia in time of COVID.(270)
Raheem et al, 2021 (271)
Jurat et al, 2021, 2021 (272)
Irene et al, 2021 (273)
Khan et al, 2021 (274)
Ashwin et al, 2021A lifelong view and review of staged and multiple urological surgeries or the treatment of strictures(275)
Wiener et al, 2021 (276)
Ács et al, 2021A database of the Hungarian congenital abnormalities. Hypospadias is number four.(277)
Benavides et al, 2022Birth defects prevalence in Texas, where hypospadias is less prevalent in rural counties compared with urban counties.(278)
Arulanandam et al, 2021In Quebec, the compliance rates, regarding hypospadias are inadequate and need improvement.(279)

18. Social media

On social media (Facebook, Twitter and others), the problem of hypospadias is debated, but much of the shared content does not have supporting evidence and is not affiliated with medical journals, hospitals, or academic institutions. For parents with insufficient medical knowledge, it could be difficult to identify whether the articles shared on social media are a reliable resource for health. YouTube videos present different surgical treatments for this malformation, but the majority of the content is non-medical and may lead to health misinformation (280-282).

Table XV summarizes the articles about social media.

Table XV

Summary of the articles about social media.

Table XV

Summary of the articles about social media.

Author, yearConclusions(Refs.)
Karabay et al, 2021There is a scarcity of high-quality videos on YouTube describing distal hypospadias repair techniques and, further, their quality regarding educational content seems to be unsatisfactory.(280)
Jones et al, 2022 (281)
Cheng et al, 2022Most interesting pediatric urologic issues (including hypospadias), debated on social media (Facebook, Twitter) are debated strongly, but not very relevant.(282)

19. Others

Table XVI summarizes the articles about bibliometrics, small gestational age, neoplasm and fertility.

Table XVI

Others.

Table XVI

Others.

Bibliometrics
Author, yearConclusions(Refs.)
Ghidini et al, 2022The top-cited articles were dispersed among 27 journals of different areas with a median impact factor of 2.676. Current scientific literature deals with congenital anomalies, more specifically with obstructive uropathies and hypospadias. In the last decade, one of the most relevant innovations in pediatric urology was the introduction of robotic surgery.(283)
Matta et al, 2021The list of top 100 most cited articles in pediatric urology is an important resource for clinicians and trainees to understand the body of knowledge and trajectory of this field, charting the evolution of the field and highlighting areas of a potential investigation.(284)
Dogan et al, 2021Between 1980 and 2018, there were 1940 articles about hypospadias, the USA was the top country that contributed to the literature and the top active 3 journals were the Journal of Urology, Journal of Pediatric Urology, and Urology.(285)
Small gestational age
Rittler et al, 2021Talipes, hypospadias, and septal heart defects are more frequent mild defects significantly associated with prematurity.(229)
Braga et al, 2022Children born small for gestational age present a high frequency of hypospadias. Cases were studied genetically, but it was not identified the cause. They conclude that multifactorial causes or unidentified epigenetic defects produce the malformation.(286)
Neoplasm, fertility
Huilin et al, 2021A series of cases with gonadal neoplastic lesions associated with hypospadias Men with hypospadias do not present impaired semen quality using dizygotic twinning as an epidemiological indicator.(287)
Philips et al, 2021 (288)

20. Discussion

As can be seen, hundreds of papers are written every year about hypospadias, referring to all aspects of the pathology. 2021 was mostly a year of accumulation, with a number of papers comparing and hoping for new surgical techniques with improved outcomes, clarifying the relevant anatomical, etiological and genetic factors, assuming the complications, and describing solutions to prevent or treat them. As a limitation of the present study, quality assessment of the included articles was not performed.

According to the findings of the present study, it is possible to highlight the following ideas considering that these might have direct clinical significance: Promising modifications in proximal hypospadias repair were presented and transverse preputial island flap urethroplasty with incised urethral diversion appeared a superior option compared with transurethral diversion (8). Two-stage urethroplasty had improved results compared with one-stage surgery (10,12,16,35,36). Tubed pedicled preputial island flap, Duckett's procedure, was associated with a high complication rate (44). Predictors of a successful outcome of tubularized incised plate (TIP) repair in cases of distal hypospadias were described by different authors (53,86). Dorsal inlay graft urethroplasty was considered a superior technique compared with onlay preputial flap (LOF) (19). With the exception of the long-term outcomes in cosmetic and functional evaluation, Mathieu incised plate technique had improved outcomes compared with the TIP technique (63). For the treatment of congenital ventral penile curvatures, dorsal plication was defined as a relatively simple and successful method with low risks (34). There were no differences in outcomes between pre-pubertal and post-pubertal boys after the correction of penile curvature using corporal plication (70). In order to decrease the rate of complications new dressing techniques, and topical agents were mentioned along the hyperbaric oxygen therapy (88,89,96,97,99). Perioperative prophylactic antibiotics appeared not to reduce the possibility of infections (101). A total of 25% of adults presenting with bulbar strictures had a hypospadias surgery in childhood (117). Penile curvature could appear in 25% of patients within the first 2 years (102,108,110). According to postoperative care, surgeons appear more concerned about the cosmesis than do the parents. Photo documentation of cosmesis (and to evaluate penile curvature) is appropriate at present (5). Self-reported outcomes in adolescent patients with TIP repair were similar to those in a control group (31). Delayed surgery could be determined by the region's economy, the parent's educational level and the urethral opening site (29). There were noteworthy pediatric urologic issues, including hypospadias, on social media and they are debated, but most of them are not very relevant. There is a scarcity of high-quality videos on YouTube describing hypospadias repair techniques, and their quality regarding educational content appears unsatisfactory (280-282).

The novelty of the present study consisted of the lack of similar analyses. To the best of the authors' knowledge, no similarly conceptualized studies have been previously performed in this research field. As a scoping review, the present study represented a well-structured and reproducible mapping of the literature. It aimed to define and clarify key concepts, theories, the most important results and achievements, and to present them in a transparent way, highlighting areas where researchers could identify gaps in the current literature that may require further inquiry. The present study presented sources of evidence that inform practice in the field, eases further investigations and saves time and resources. Hypospadias research in 2021 represents a very complex field. A comprehensive scoping review such as the present constitutes essential information for every pediatric surgeon, urologist, and specialist in this field.

21. Conclusion

According to the papers published in 2021, promising modifications of existing surgical techniques were presented with improved outcomes for the proximal and distal types of hypospadias forms. The present study highlighted and clarified the presented relevant anatomical, etiological and genetic factors. For an improved understanding of the aspects of peri- and postoperative management of hypospadias the antibiotherapy, analgesia, dressing techniques and the future use of novel bioengineering agents to prevent, reduce or treat the occurring complications, were also discussed.

Acknowledgements

Not applicable.

Funding

Funding: No funding was received.

Availability of data and materials

Data sharing is not applicable to this article, as no data sets were generated or analyzed during the current study.

Authors' contributions

HG and ZB were responsible for conceptualization and methodology. ZB was responsible for software. HG, ZB, ED and ZD were responsible for validation. ZB was responsible for formal analysis. HG was responsible for investigation. ED and ZD were responsible for data curation. HG wrote the original draft. HG, ZB, ED and ZD wrote, reviewed and edited the manuscript. ZB was responsible for visualization and supervision. HG was responsible for project administration. All authors read and approved the final manuscript. Data authentication is not applicable.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Spandidos Publications style
Gozar H, Bara Z, Dicu E and Derzsi Z: Current perspectives in hypospadias research: A scoping review of articles published in 2021 (Review). Exp Ther Med 25: 211, 2023.
APA
Gozar, H., Bara, Z., Dicu, E., & Derzsi, Z. (2023). Current perspectives in hypospadias research: A scoping review of articles published in 2021 (Review). Experimental and Therapeutic Medicine, 25, 211. https://doi.org/10.3892/etm.2023.11910
MLA
Gozar, H., Bara, Z., Dicu, E., Derzsi, Z."Current perspectives in hypospadias research: A scoping review of articles published in 2021 (Review)". Experimental and Therapeutic Medicine 25.5 (2023): 211.
Chicago
Gozar, H., Bara, Z., Dicu, E., Derzsi, Z."Current perspectives in hypospadias research: A scoping review of articles published in 2021 (Review)". Experimental and Therapeutic Medicine 25, no. 5 (2023): 211. https://doi.org/10.3892/etm.2023.11910