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

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.

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.

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.

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.

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.

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.

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.

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.

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 summarizes the articles about genetical 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 SO 2 ( 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.

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.

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.

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.

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.

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.

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 XIV summarizes the articles about retrospective studies of centers.

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

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.

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.