A Rare Case of Penoscrotal Webbing and Extensive Hernias: An Anatomical Report With Genetic Insights

During a routine anatomical dissection of an 81-year-old male cadaver received through the Gift Body Program of Saint Louis University School of Medicine (SLU SOM), a massive bulging in the abdominal area was observed that was consistent with numerous hernia repairs noted in the donor’s self-reported medical history. Gross anatomical dissection of the cadaveric body revealed extensive herniation of portions of the small intestine and peritoneal sac along the costal margin and extending to the left aspect of the abdomen. Additionally, an uncircumcised phallus was buried within the suprapubic fat pad and demonstrated simple, grade III penoscrotal webbing (PSW), creating an impression of micropenis presence. To gain additional insights into the current case, analysis of the coding regions (exomes) of DNA procured from the body for putative genetic variants was performed using next-generation sequencing (NGS) technology. This analysis revealed 110 rare (minor allele frequency (MAF) ≤ 0.01), pathologic/deleterious genetic mutations. The most relevant variants to this case were the ones associated with male sexual development, BMP1 and BMP4; connective tissue development, COL3A1 and COL5A3; cilia morphogenesis and function, DNAH5 and MAPK15; as well as hormonal homeostasis, ESR1. Direct involvement of BMP1 both in male sexual development and hernia genesis makes it a strong candidate for linking the two pathologies, PSW and multiple hernias, observed in the present case. Yet the presence of a group of mutated genes linked to myopathies (ITGA7, NRAP, POLM, SCN5A, XIRP2) and muscular dystrophy (ITGA7) raises a question about the involvement of these muscular pathologies in hernia genesis and unsuccessful hernia repairs associated with the current case.


Introduction
Male sexual development occurs under the intricate control of many genes.Mutations involving these specific genes that play a role in male sexual development can result in genitalia malformations.The condition of penoscrotal webbing (PSW) has been discussed under a variety of names, including webbed penis, penoscrotal fusion, penoscrotal pterygium, and penis palmatus [1].PSW is a condition in which a fold of skin connecting the penile shaft to the scrotum obscures the penoscrotal angle making an otherwise normal-sized penile shaft appear smaller than it actually is [1].The prevalence of PSW is unknown; however, one study of 5,881 newborns found that about 4% had the condition [1].Congenital PSW frequently coexists with other congenital anomalies such as hypospadias, chordee, buried penis, or micropenis [2].Due to the physical and psychological impact that this condition can have on males, many parents elect for surgical correction in infancy.
The anatomical organization of male external genitalia emerges during embryonic and fetal development, and understanding the developmental biology of external genitalia is critical for appreciating pathologies that lead to malformations of the penis and surgical repair of such malformations [3].The exact etiology of PSW is still unknown, but there are two hypotheses that suggest potential causes.A delay or disturbance in the development of the preputial skin could result in a deficiency of the ventral penile skin or abnormal dartos band attachment that could explain the condition [4].Another hypothesis includes an abnormal attachment of the skin due to an embryonic remnant of a cloacal membrane that may contribute to PSW [5].
A classification system of PSW has been proposed by El-Koutby et al. and is the most used method in describing this condition and for planning surgical correction.This classification system first divides the condition into the primary and secondary webbed penis [1].The primary webbed penis is congenital and can be further broken down into simple or compound cases, while the secondary webbed penis is acquired postcircumcision due to an overly aggressive resection of the prepuce.Primary simple webbed penis is further subdivided into grades I-III based on where scrotal skin attaches along the penile shaft [1].Grade I PSW extends to the proximal one-third of the penile shaft, grade II extends to the middle one-third of the penile shaft, and the most extreme grade III PSW extends to the distal one-third of the penile shaft [1].

FIGURE 1: The abdominal appearance.
A: An anterior view of the abdomen demonstrating a large midline scar and a large bulge off to the left aspect of the abdomen.B: A lateral view of the abdomen demonstrating a bulge above the pubic region.
The phallus was uncircumcised (Figure 2A) with a penile length measured at 5.33 cm (2.10 inches) (Figure 2B).Due to the large hernia and fat deposits above the pubic symphysis, it was not possible to measure beginning at the pubic symphysis.Rather, the measurement was obtained by placing a ruler lateral to the penis to determine the length of the penile shaft that was exposed.The proximal portion of the penile shaft was palpated through the large bulge, but the entirety of the penile shaft was not visible or measured until after dissection.Anatomical dissection of the abdomen revealed extensive herniation of the small intestine within the peritoneal sac (Figure 3).These hernias traced the costal margin and extended to the left aspect of the abdomen.Due to the extent of the herniated abdominal contents and prior surgeries, it was difficult to determine the specific types of hernias present.Consultation with a general surgeon confirmed the presence of numerous incisional hernias along a large midline scar.Other hernias such as epigastric hernia and left primary Spigelian hernia could not be ruled out.Evidence of a previous umbilical hernia repair and left femoral hernia repair were observed.

FIGURE 3: Abdominal hernias.
A: Left lateral aspect of the abdomen demonstrating extensive hernias outlined in red.B: Right lateral aspect of the abdomen demonstrating extensive hernias outlined in red.
As removal of the skin continued inferiorly towards the region of the pubic symphysis, a large loop of small intestine was located within the suprapubic fat pad (Figure 4).

FIGURE 4: Suprapubic region.
Herniation of a loop of small intestines through the hypogastric region of the anterior body wall outlined in red.The herniation was located superomedial to the inguinal ligament.
We believe that the presence of this hernia in addition to a large amount of suprapubic fat obscured the length of the shaft of the penis giving it a much smaller appearance than was present.
The anterior abdominal wall was removed and hernias that were incarcerated in the anterior abdominal wall were carefully freed.The entirety of the bowel was examined and revealed multiple stitches on the small intestine suggesting previous surgical procedures.Evidence of a left femoral hernia repair, including sutures and mesh, were observed and appeared to compress the left spermatic cord.The spermatic cord was dissected to reveal a normal ductus deferens that was traced into the pelvic cavity.Once in the pelvic cavity, the following structures were identified: ampulla of ductus deferens, seminal vesicles, ureters, prostate, urethra, and the related vasculature.The prostate was also intact and was located inferior to the bladder.All internal genital organs appeared normal.The testes were palpated within the scrotum to ensure that two were present, descended into the scrotum, and were of normal size measuring to be approximately 15.3 cm 3 compared to the mean volume of 12-30 cm 3 in normal males [6,7].
Lastly, a dissection of the perineum was conducted.A flap of tissue that appeared to be the scrotal septum was observed fusing the entire ventral length of the penile shaft to the scrotum (Figure 5).

FIGURE 5: Dissection of penoscrotal webbing (PSW).
Left lateral view of the PSW with the red arrow pointing to the webbing.
Dissection of the scrotum revealed the uncircumcised phallus was buried within the suprapubic fat pad and accompanied by a simple, grade III PSW.All other male anatomical structures were observed to be normal.

Genetic screen
Given the uniqueness of this case of extensive abdominal hernias and penoscrotal webbing, a screen for the putative genetic variants was performed using next-generation sequencing (NGS) on the Illumina platform.The exome sequencing of DNA extracted from the embalmed cadaveric tissue revealed 110 rare (minor allele frequency (MAF) ≤ 0.01), pathologic/deleterious genetic variants (Table 1).

Gene
Protein Function ABCA10 ATP Binding Cassette Subfamily A Member 10.The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters.

ADAM18
ADAM Metallopeptidase Domain 18.This gene encodes a member of the ADAM family that has been implicated in a variety of biological processes involving cell-cell and cell-matrix interactions such as fertilization, muscle development, and neurogenesis.

COL5A3
Collagen Type V Alpha 3 Chain.This gene encodes an alpha chain for one of the low abundance fibrillar collagens.Type V collagen is found in tissues containing type I collagen and appears to regulate the assembly of heterotypic fibers composed of both type I and type V collagen.Mutations in this gene are responsible for the symptoms of a subset of patients with Ehlers-Danlos syndrome type III.Seven genetic variants, BMP1, BMP4, COL3A1, COL5A3, MAPK15, DNAH5, and ESR1, could be linked directly to this case (Table 2) due to their involvement in wound healing and male sex organ development.

Discussion
The uniqueness and significance of the present case is severalfold.First, the abnormality of the external genitalia in the current case can be categorized as primary simple, grade III PSW according to the classification system proposed in El-Koutby et al. [1].This condition is rare and surgical correction is typically performed in infancy [1].Given the age of the individual's body examined in this report (81 years) and the observation that no other major genitalia abnormalities developed, this could define the current case as isolated PSW thereby providing a unique opportunity to gain insights into the respective molecular mechanisms.
The results presented in this case support clinical observations pointing toward PSW being polygenic in nature and provide important insights into its etiology.Indeed, the respective genetic screen identified mutations in four genes that could be closely linked to the development of human external genitalia: BMP4, DNAH5, MAPK15, and ESR1 (Table 2).There are numerous molecular mechanisms that govern the development of the external male genitalia including the penis and scrotum.In mice, the Sonic hedgehog (SHH) signaling pathway has been identified as a key regulator during initiation of morphologic differentiation of the genital tubercle and its outgrowth [8].The differentiation of the genital tubercle after the initiation of SHH signaling leads to the upregulation of BMP4, HOXA13, and HOXD13, which would work to provide a delicate balance between apoptosis and proliferation.This balance is necessary for the proper differentiation of the genital tubercle and its dysregulation can result in abnormalities involving genital tubercle elongation and the spatiotemporal balance between apoptosis and proliferation [9].
DNAH5 and MAPK15 are involved in the formation and maintenance of cilia, including the primary cilia [10,11], which serves as a platform shared by SHH [12], FGF receptor [13], and WNT signaling pathways [14].Therefore, in this case, the spatiotemporal dysregulation of the primary cilia formation and function may result in the aberrant SHH, FGF, and WNT signaling.This, along with the mutation in BMP4, which might negatively affect its proapoptotic function, could disrupt a dynamic equilibrium between cell proliferation and apoptosis [9], thereby skewing the developmental process of human male external genitalia resulting in PSW.There is no evidence to suggest that PSW affects a male's fertility, though PSW can make penetrative intercourse more difficult or painful.Also, during prenatal and postnatal periods, the development of external genitalia is influenced by steroid hormones [15].Specifically relevant to the current case, the expression of ESR1 at the penoscrotal junction is suggested to play a role in the etiology of penile webbing [16].The detected mutation in ESR1 in this individual supports this notion.
Second, the present case is unique because there have been no previous reports of an individual with PSW also displaying such extensive abdominal hernias.PSW is considered to fit within the spectrum of penoscrotal transposition (PST) [17].Depending on the severity of the PST, associated anomalies can be expected, especially of the gastrointestinal tract [18].Though previously reported associated anomalies involving the gastrointestinal tract include omphalocele and gastroschisis, the extensive hernias seen in the current case cannot be overlooked.Though the etiology of hernias is multi-factorial, it is prevalent that alterations in the ratio of collagen type I to III can impact the likelihood of an individual developing various types of hernias including direct inguinal, recurrent inguinal, incisional, and recurrent incisional hernias [19][20][21].Mutations specifically in COL3A1 have also been linked to both hiatal hernias and bilateral inguinal hernias [22,23].Patients with an inguinal hernia demonstrated a systemic and persistent type V collagen turnover alteration.This imbalance of collagen metabolism may be involved in the development of inguinal hernias.Unfortunately, the quality of the cadaveric tissue in the present case was incompatible with immunohistochemical staining.However, the study subject had a mutation in COL5A3, a gene coding for type V collagen in addition to bilateral inguinal hernia repair [24], which would be consistent with the impairment of type V collagen function and turnover.Individuals with mutations in BMP1 have also been found to have large umbilical hernias [25].With PSW typically corrected surgically in childhood, it is possible that these two anomalies, PSW and extensive abdominal hernias, are linked but have not been previously reported.
Third, the current case is unique because of the presence of numerous hernia repairs that resulted in extensive incisional hernias, primarily due to an aberrant wound-healing process.The latter is supported by the detected mutations in three genes: COL3A1, COL5A3, and BMP1.COL3A1 encodes collagen type III alpha 1 chain while COL5A3 encodes type V collagen, which is found in tissues containing type I collagen and regulates the assembly of heterotypic fibers composed of both type I and type V collagen.Because an aberrant collagen I to collagen III ratio can compromise skin repair and make it more vulnerable to wound recurrence, it is possible that these COL3A1 and COL5A3 mutations are responsible for the extensiveness of the incisional hernias in this individual.Also, given the importance of the extracellular matrix (ECM) in wound repair, the reported mutation in BMP1 is also of significant interest.Indeed, mutations in this gene have been reported to result in impaired production of type I collagen, which in this case would also compromise the integrity of the ECM [25].
Fourth, the presence of a group of mutated genes linked to myopathies (ITGA7, NRAP, POLM, SCN5A, XIRP2) and muscular dystrophy (ITGA7) (Table 2) raises an important question regarding their involvement in the hernia development and the incomplete hernia repair in the present case.Indeed, a close association between myopathy and hernias including inguinal [26,27], hiatal [28], diaphragmatic [29], and experimental incisional [30] types have been previously reported.Additionally, either pre-existing [31] or developed local muscular dystrophy in patients with hernias [32,33] could complicate surgical procedures for hernia repair.More importantly, the pre-existing muscular dystrophy could contribute to hernia genesis as it has been previously shown for double ipsilateral inguinal hernia [34].Therefore, the genetic and physiological testing of patients for pre-existing myopathies and muscular dystrophy should be considered prior to surgical hernia repairs, particularly for individuals with multiple hernias and/or a history of previous unsuccessful repair attempts.

Conclusions
The increasing trend in the incidence of genital malformations and the decline in human male reproductive health have attracted much concern in recent years.Though the knowledge of the impact that genetics has on the development of external and internal genitalia has improved in recent decades, the exact genetic underpinning is yet to be identified.However, direct involvement of BMP1 both in male sexual development and hernia genesis makes it a strong candidate for linking the two pathologies together, PSW and multiple hernias, observed in the present case.
In summary, the current case has a high clinical and educational value because it not only describes the coexistence of two unique anatomical abnormalities, PSW and multiple hernias, but also provides important insights into their potential common genetic underpinnings.

FIGURE 2 :
FIGURE 2: The external genitalia appearance.A: An anterior view of the pelvic region demonstrating an uncircumcised and diminished phallus.B: The phallus was measured at 5.33 cm (2.10 inches).
DMRTA1Doublesex-And Mab-3-Related Transcription Factor A1.Enables sequence-specific double-stranded DNA binding activity.Predicted to be involved in germ cell development, regulation of transcription by RNA polymerase II, and sex differentiation.DNAH5 Dynein Axonemal Heavy Chain 5. Cilium assembly, cilium movement, determination of left/right asymmetry.ESR1 Estrogen Receptor 1. Plays a role in growth, metabolism, sexual development, gestation, and other reproductive functions.Estrogen controls many cellular processes including growth, differentiation and function of the reproductive system.FN1 Fibronectin 1.This gene encodes fibronectin, a glycoprotein presents in a soluble dimeric form in plasma, and in a dimeric or multimeric form at the cell surface and extracellular matrix.Involved in cell adhesion and migration processes including embryogenesis, wound healing, blood coagulation, host defense, and metastasis.Participates in the regulation of type I collagen deposition by osteoblasts.KRTAP26-1 Keratin Associated Protein 26-1.2023 Olson et al.Cureus 15(10): e47375.DOI 10.7759/cureus.473756 of 12 LRIG2 Leucine Rich Repeats And Immunoglobulin Like Domains 2. LZTS2 NRAP Nebulin Related Anchoring Protein.Located in fascia adherens, muscle tendon junction, and myofibril.Predicted to enable actin filament binding activity and muscle alpha-actinin binding activity.SCN5A Sodium Voltage-Gated Channel Alpha Subunit 5.The protein encoded by this gene is an integral membrane protein and is responsible for the initial upstroke of the action potential.XIRP2 Xin Actin Binding Repeat Containing 2. Enables actin filament binding activity.Predicted to be involved in actin cytoskeleton organization and predicted to act upstream of or within muscle tissue morphogenesis.