The inconspicuous penis in children.

REVIEWS The inconspicuous penis in children Marcello Cimador, Pieralba Catalano, Rita Ortolano and Mario Giuffrè Abstract | The term ‘inconspicuous penis’ refers to a group of anatomical abnormalities in which the penis looks smaller than is expected. Micropenis can be defined as ‘true micropenis’—which results from a defect in the hypothalamic–pituitary–gonadal axis—and ‘micropenis secondary to congenital anatomical anomalies of the surrounding and overlying structures’—also known as ‘concealed penis’. The different forms of concealed penis include webbed penis, congenital megaprepuce and partially hidden penis caused by prepubic adiposity. This disorder can also have iatrogenic causes resulting from adhesions that are secondary to circumcision —this type of concealed penis is known as ‘trapped penis’. However, in both groups, micropenis is defined as a stretched penile length that is at least 2.5 SD below the mean for the patient’s age, but without any other penile defects. Patients with true micropenis can be managed with testosterone, which has demonstrated good penile elongation results in the long term. Surgery also has a pivotal role in reconstruction for elongating the penis and for correction of anatomical abnormalities in concealed penis. Cimador, M. et al. Nat. Rev. Urol. 12, 205–215 (2015); published online 7 April 2015; doi:10.1038/nrurol.2015.49

Introduction

Department of Science for Health Promotion and Mother and Child Care, University of Palermo, Via Alfonso Giordano 3, 90127 Palermo, Italy (M.C., P.C., R.O., M.G.). Correspondence to: M.C. marcello.cimador@ unipa.it

The term ‘inconspicuous penis’ refers to a group of anato mical abnormalities in which the penis appears small for the age of the patient. This term was first used in the lit erature by Bergeson et al.1 in 1993 and it comprises all of the urological entities that Maizels et al.2 described in 1986, including buried penis secondary to poor penile skin suspension in children and secondary to localized adiposity in adolescents, webbed penis, trapped penis, diminutive penis and micropenis (where the penis is small but not malformed). According to Maizels and col leagues’ classification, the inconspicuous penis can be secondary to a short penile shaft—the true micropenis —or, more commonly, results from abnormalities in the surrounding and overlying structures, which can have congenital, developmental or iatrogenic causes. This latter group of abnormalities—which is also defined as ‘con cealed penis’—can be further divided into buried penis, webbed penis and trapped penis. The true incidence of inconspicuous penis in chil dren is not known, but it has been reported that 9% of patients presenting for an initial circumcision, and 63% of patients referred for circumcision revision had evi dence of this condition.3 With regards to the psycho logical aspects of inconspicuous penis, an inconspicuous penis can result in considerable concern for both parents and children, as they believe that the small appearance of the penis is always caused by a short penile shaft.4 Young boys might develop depression and anxiety related to the fear of being ridiculed by their peers. Parents might worry about issues concerning the future sexual activity and fertility of their son. Medical counselling by primary care providers and paediatricians is often required. However, Competing interests The authors declare no competing interests.

the term ‘micropenis’ is frequently misapplied in paedi atric practice and can cause unwarranted stress if wrongly used. Thus, it is important that paediatricians have a good understanding of these conditions and can differentiate the true micropenis from the concealed penis, in order to reassure parents and patients and also to refer patients for urological evaluation as appropriate.5 Adequate knowl edge of the inconspicuous penile disorders is also impor tant as circumcision is contraindicated in some cases and some cases might also be associated with symptoms such as abnormalities of the urinary stream, pain during micturition and sexual dysfunction.1 When discussing micropenis, it is important to stress that available data come from nonrandomized and noncontrolled studies. In this Review, we define the different conditions associ ated with inconspicuous penis and describe appropriate medical and surgical methods by which these conditions can be managed.

Penile development

To better understand the aetiopathogenesis of the different forms of inconspicuous penis and the required treatments, it is necessary to be familiar with penile development.

Embryology of the penis Until about 7 weeks’ gestation, the human embryo remains sexually indifferent. From the eighth week of gestation, male and female developmental paths diverge and during male development the foetal testicular Leydig cells, stimulated by maternal chorionic gonadotropins from the placenta, produce testosterone. Male external genital development is dependent on the conversion of testosterone to the more active dihydrotestosterone (DHT) by 5α-reductase, which is present in genital tissues, and its subsequent action via tissue receptors.

NATURE REVIEWS | UROLOGY

VOLUME 12 | APRIL 2015 | 205 © 2015 Macmillan Publishers Limited. All rights reserved

REVIEWS Key points ■■ An inconspicuous penis can result in considerable concern for both parents and children ■■ 9% of patients presenting for initial circumcision have evidence of an inconspicuous penis ■■ Micropenis is defined as stretched penile length that is at least 2.5 SD below the mean for the patient’s age, without any other abnormalities, such as hypospadias ■■ ‘True micropenis’, caused by deficient secretion and action of testosterone, should be distinguished from ‘concealed micropenis’ ■■ Medical and surgical treatments for inconspicuous penis disorders aim to restore normal penis size, standing micturition and enable future sexual activity ■■ Surgical correction of concealed penis is currently the gold-standard treatment

Skin

Glans penis Corona of glans penis

Superficial fascia

Superficial fascia

Skin

Areolar tissue

Deep fascia

Levator ani muscle in ischioanal fossa

Deep fascia Corpora cavernosa

Tunica albuginea

Corpus spongiosum

Figure 1 | Diagram of the anatomy of the penis.

Nature Reviews | Urology

In males, the genital tubercle enlarges to form the penis (both the shaft and the glans) and the urogenital folds fuse along the midline to become the penile urethra. The glanular segment of the urethra forms by invagination from the tip of the glans and the labioscrotal folds fuse across the midline to shape and form the scrotum. Penile differentiation is achieved by the thirteenth week of gesta tion, after which a marked increase in penis size occurs, with the penis growing almost 20 mm between the four teenth and thirty-eighth week of gestation.6,7 During this period, development of the penis is completed by foetal androgens, which are produced under the influence of stimulation by the foetal pituitary gonadotropins. Thus, a hormonal abnormality of the hypothalamic–pituitary– testicular axis occurring after the twelfth week of gestation can result in an underdeveloped penis.

Anatomy of the penis The main components of the penis—dorsally the two corpora cavernosa and ventrally the corpus spongiosum with the urethra—are covered by areolar tissue and a layer of skin (Figure 1). The presence of these different layers is important in penile pathophysiology. Skin has a pivotal role in protecting the penis from trauma during sexual inter course and the foreskin is very rich in erogenous recep tors. The underlying structures that surround the corpora 206 | APRIL 2015 | VOLUME 12

cavernosa protect against bacterial infections from strepto cocci, staphylococci and other gram-negative bacteria; however, they can also exacerbate intracavernosal issues such as abscesses or haematomas. The skin of the penis is thin, without any underlying fat tissue, and only loosely connected to the penile shaft; however, the skin is firmly attached to the spongy tissue on the glans. The under lying areolar structures are known as the superficial fascia of the penis (otherwise known as Colles’ fascia) and the deep fascia of the penis (otherwise known as Buck’s fascia) (Figure 1). The deep fascia can sometimes be involved in penile abscesses and necrotising fasciitis. The superficial fascia of the penis, also called the dartos fascia, forms a thin cylindrical sheath loosely attached to the overlying skin and the underlying deeper fascia; it is carried forward into the prepuce and is fixed to the base of the glans penis in the coronal sulcus. Ventrally, at the base of the penis, the dartos fascia combines with more smooth muscle fibres and closely adheres to the skin of the scrotal wall, making a well-defined penoscrotal angle along with the skin. The deep fascia of the penis is thick and elastic and attaches to the tunica albuginea (Figure 1). This loose attach ment between the fascial layers and the skin allows free movement of the skin over the deeper penile structures. At the level of the symphysis pubis, a fat layer known as Camper’s fascia is present over the more membranous inner layer of the superficial fascia (Scarpa’s fascia), which is relatively adherent to the deep fascia. The root of the penis is firmly attached to the pubic rami by the penile ligaments. These ligaments, which are made of connec tive tissue, arise from the external oblique aponeurosis, and comprise a two-unit structure fixed to the front of the symphysis pubis. One unit—the suspensory liga ment of the penis—attaches to the midline of the penile root, rises from the linea alba and contains mostly elastic fibres. This component of the penile ligaments provides dorsal support to the penis and covers the hilum of the penis anteriorly, protecting the neurovascular bundle from repeated trauma, which can impair sensation and activation of erection apparatus. Shortening or section of the suspensory ligament can expose the penis to trauma during walking and can force the penis downward, embedding it within the scrotum. Destabilization of the erect penis can also occur and could cause it to fracture during sexual intercourse. The second unit—known as the fundiform ligament or ligament of Luschka—consists of dartos fascial fibres extending from Scarpa’s fascia of the abdomen onto the penile shaft. This ligament contains mainly fibrous elements and it fans laterally and ven trally to encircle the penile root. The fundiform ligament attaches to the pubis on each side of the symphysis and provides sling-like ventral support to the penis. Anomalies in this anatomical setting can give rise to problems that make the penis look diminutive, especially when the sus pensory ligaments are shorter than normal, owing to a congenital abnormality.

The true micropenis

Micropenis is usually defined as a normally formed penis that has a stretched penile length (SPL) of at least 2.5 SD

www.nature.com/nrurol © 2015 Macmillan Publishers Limited. All rights reserved

REVIEWS Table 1 | Genes known to be involved in sex differentiation Gene

Locus in humans

Suggested function

Loss-of-function phenotype

Gain-of-function phenotype

SRY

Yp11.3

Transcription factor

Female (XY)

Male (XX)

SOX9

17q24


Female (XY) and CMD

Male (XX)

SF1

9p33


Female (XY) and adrenal failure

NR

WT1

11p13


Female (XY) and kidney defects and Wilms’ tumour

NR

DAX1

Xp21.3


Adrenal hypoplasia and hypogonadism

Female (XY)

DMRT1

9p24.3


Female (XY)

NR

ATRX

Xq13.3


Female (XY) and mental retardation and thalassemia

NR

M33 (not validated in humans)

17q25


Female (XY)

NR

FGF9 (not validated in humans)

13q11‑13

Signalling molecule

Female (XY) (variable phenotype)

NR

WNT4

1p35

Signalling molecule

XX with testosterone synthesis and development of Wolffian ducts

Female (XY)

FOXL2

3q23


Premature ovary failure and BPES

NR

Testis-determining

Ovary-determining

Abbreviations: BPES, blepharophimosis, ptosis, and epicanthus inversus syndrome; CMD, campomelic dysplasia; NR, not reported. Adapted from Wiley © Fleming, A. & Vilain, E. Clin. Genet. 67, 15–25 (2004).

below the mean for the patient’s age.8 The coexistence of SPL of at least 2.5 SD below the mean and hypospadias is defined as ‘microphallus’. SPL is defined as the maximum length of the penis when stretched and is determined by measuring the distance from the base of the penis under the pubic symphysis to the tip of the glans. For adult patients, measuring the penis from pubic bone to the midpoint of the glans penis (the erect length of the penis) is the best practice. Normal values of SPL for newborn full-term infants have been reported by Wigul and Palmer.5 Normal values for Caucasian preterm infants born at 24–36 weeks’ gestation can be calculated using the following formula: (0.16 × weeks of gestation) – 2.27.9 Standard SPL values differ between studies; variations in sample size and ethnic differences can cause signifi cant discrepancies in penile measurements but ethnicity might not be of relevance for SPL values of newborns. Schonfeld and Beebe,10 Flatan et al.11 and Feldman and Smith12 reported the mean SPLs of newborns of differ ent ethnicities that have been amalgamated and accepted as the standard SPL values in many studies10,13,14 and are referred to by clinicians in the diagnosis of micropenis. Micropenis that is confirmed at birth is usually a result of a hormonal disorder during gestation and the con dition can be isolated or be part of a disorder of sexual development (DSD).15

Sexual differentiation Sex development is a genetically and hormonally con trolled process that starts immediately at conception with the establishment of the chromosomal sex (XX or XY) and, through the expression of specific genes, contin ues with the formation of the gonads (testes or ovaries). A number of different genes are known to be involved (Table 1).

In the presence of testis-determining genes such as SRY (sex-determining region Y), which encodes a tran scription factor called testis determining factor, bipoten tial gonads become testes. Four major cell types are present in the undifferentiated gonads: steroidogenetic cells, supporting cells, germ lineage cells and connec tive cells. In the presence of SRY, supporting cells and steroidogenetic cells become Sertoli cells and Leydig cells, respectively. Sertoli cells are essential for the nutrition of germline cells and produce anti-Müllerian hormone (AMH) and inhibin B (InB), which induce the regres sion of the Müllerian structures and inhibit follicle- stimulating hormone (FSH). At 9 weeks’ gestation, human chorionic gonadotropin (hCG) stimulates Leydig cells to produce testosterone by binding to the luteinizing hormone (LH) receptor; this production of testosterone leads to male foetal development by binding to the andro gen receptor (AR). At 14 weeks’ gestation, testosterone production falls under the control of the foetal hypo thalamic–pituitary–gonadal axis and induces the differ entiation of Wolffian duct derivatives in internal male genitalia. DHT, derived from the peripheral conversion of testosterone by 5α-reductase 2, induces the viriliza tion of the external genitalia. Both testosterone and DHT act by binding ARs. In the absence of SRY and as a result of the actions of other genes (such as WNT4, DAX1, FOXL2 and RSPO1), the primordial gonads differenti ate into the ovaries, with regression of the Wolffian duct structures and development of Müllerian duct derivatives occurring owing to the lack of testosterone and AMH.16 Sex development is the result of complex and sequen tial events controlled by various hormones, receptors, transcription factors and genes. Any perturbation in this system can result in DSDs of different types and degrees of severity.



REVIEWS Penile growth Testosterone and DHT are necessary for the normal development of male external genitalia. As mentioned above, at 9 weeks’ gestation, foetal production of testoster one by the gonads is under the control of hCG; at 14 weeks’ gestation, testosterone production falls under the control of the foetal hypothalamic–pituitary–gonadal axis and it is converted to DHT by 5α-reductase 2. After the first trimester (weeks 1–12), penile growth depends on DHT binding to the AR.17,18 After an initial surge of LH and tes tosterone at birth, lasting about 12 h and causing the penis to grow, the levels of gonadotropins (LH and FSH) and testosterone drop and remain low during the first few days of life. Approximately 1 week after birth, gonadotropin and testosterone levels begin to rise, peaking at levels similar to those seen during puberty (a phase known known as ‘minipuberty’) and cause the penis to grow again. These hormone levels then decrease to prepubertal levels by 6 months but growth of the penis continues after mini puberty has ended, with general somatic growth owing to the action of growth hormone.19,20 At puberty (defined as aged 10–14 years), penile growth increases again with the activation of the hypothalamic–pituitary–gonadal axis, which stimulates testicular testosterone production. Aetiology True micropenis is a result of a hormonal abnormality occurring during gestation and it can present in isola tion or as part of a DSD.15 The absence of palpable testes indicates a high probability of a DSD, which requires a specialized evaluation by an expert endocrinologist to distinguish an undervirilized patient with 46, XY karyo type (46, XY DSD) from a virilized patient with 46, XX karyotype (46, XX DSD). In addition, a true micropenis is possible in patients with a sex chromosome DSD such as Klinefelter syndrome (47, XXY karyotype). New nomenclature for different types of DSD was suggested in the 2006 consensus statement on the management of intersex disorders.21 True micropenis might be caused by a defect of the hypothalamic–pituitary–gonadal axis, a defect in andro gen secretion (caused by abnormal hypothalamic or pituitary function, LH-receptor defects or 17-β hydroxy steroid dehydrogenase deficiency),19 a defect in andro gen action (caused by 5α-reductase 2 deficiency or partial androgen insensitivity syndrome), growth hormone defi ciency, a primary structural anomaly or a genetic syn drome. External genitalia can present various different degrees of ambiguity (for example, labioscrotal fusion and hypospadias), from an apparently normal female phenotype to an isolated micropenis in an otherwise normal male phenotype.22,23 Maternal progesterone use in pregnancy is another possible cause of micropenis as progesterone can interfere with foetal androgen receptors. Many genetic syndromes have been described that include micropenis in their phenotypical spectrum and are associated with deficient testosterone secre tion and/or action including hypogonadotropic hypo gonadism, Prader–Willi syndrome and growth hormone/ insulin-like growth factor I deficiency, amongst others. 208 | APRIL 2015 | VOLUME 12

Micropenis associated with intrauterine growth restric tion, severe neonatal hypotonia, central nervous system malformations, limb defects, facial dysmorphisms and other congenital malformations are seen in Smith–Lemli– Opitz syndrome. This syndrome is caused by mutations in DHCR7, which encodes 7‑dehydrocholesterol reductase, the enzyme responsible for the final step of cholesterol production. Testosterone is a derivative of cholesterol and, therefore, impairment of cholesterol production can affect testosterone production and penile growth, leading to micropenis. Hypogonadotropic hypogonadism occurs in Kallman syndrome (a disorder characterized by hypo gonadism and anosmia) and Prader–Willi syndrome (where patients present with neonatal hypotonia, hypo gonadism, hyperphagia and mild mental retardation). In hypergonadotropic hypogonadism or primary testicular failure, micropenis can be a result of gonadal dysgenesis or might be associated with Robinow syndrome24 or poly‑X syndromes, such as Klinefelter syndrome. Partial gonadal dysgenesis (46, XY karyotype and testicular tissues in dysgenetic gonads) is distinguishable from mixed gonadal dysgenesis (chromosomal mosaic 45, X/46, XY karyotype and a streak gonad on one side and dysgenetic testis on the other side). Micropenis has been described in many genetic syndromes, including those caused by chromosomal abnormalities (for example, tri somies 8, 13, 18 and 21), gene mutations and epigenetic alterations (for example, alterations in gene methylation, as occurs in Prader–Willi syndrome).9 Finally, bladder exstrophy in newborn boys is typically associated with epispadias and a reduced penile length.

Diagnosis Patients with evidence of micropenis should undergo a genetic and endocrinological consultation and clini cal investigations in order to identify the cause of the disorder and possible associated life-threatening conditions associated. Micropenis is an exclusively male condition; however, distinguishing between a male with micropenis and bilateral cryptorchidism and a female with clitoromegaly and scrotalization of the labia can be difficult and mis diagnosis can occur. The external masculinization score (EMS)25 might be useful for improving the initial assess ment of ambiguous genitalia in infants. This scoring system is based on the presence of scrotal fusion, the length of the penis, the location of the urethral meatus and the position of the gonads; a score of >11 is consid ered as normal virilization, a score between 7 and 11 is considered as mild hypovirilization and a score of 150% during therapy,36 and this treatment option might be a good alternative for patients who do not respond to testosterone.37 Two reports have described the administration of LH and FSH in patients with hypogonadotropic hypo gonadism and micropenis. 38,39 One of these studies reported only a minimal increase in penile length despite a significant increase in testicular volume38 and the other study reported a significant increase in SPL in both patients.39 The latter evidence is in agreement with the gonadotropin-releasing hormone increase seen immedi ately after birth in normal infants. The effect of the administration of LH and FSH in patients is similar to the effect of the increase of LH and FSH during minipuberty; they promote testicular and penis growth in patients with hypogonadotropic hypogonadism,20 with a subsequent rise in Sertoli cell populations.40 Recombinant human LH–FSH treatment is only useful for treating micropenis in patients with hypogonadotropic hypogonadism. Researchers have found that the administration of exogenous testosterone in childhood does not com promise ultimate penile length increase in adulthood.41 Nevertheless, the effects of testosterone administration in childhood on masculinization during puberty are still not fully understood and further long-term data are needed. If medical treatment of micropenis yields unsatisfac tory results, surgery should be considered in order to obtain a more appropriate penile length. Sex reassign ment is also suggested by some authors, especially in cases where testicular tissue is lacking,42,43 but might only be ethically appropriate in a minority of cases.



REVIEWS The first experience of reconstructive surgery in the treatment of micropenis was reported in 1970 by Hinman. 44 In 1980, the first description of a fascio cutaneous neophallus using the blood supply of the radial artery of the forearm was described, representing an important advance in penile reconstruction surgery.45 Researchers have also reported the successful release of the suspensory ligament in order to elongate the penis in cases of epispadias, exstrophy and retracted phallus resulting from spinal cord injuries.46 Detachment of this ligament from the symphysis pubis enables forward movement of corpora cavernosa, thereby enabling the penis to extend closer to its erect length while flaccid, although care must be taken to avoid damage to the dorsal neurovascular bundle.47 Unfortunately, a maximum increase in length of only 2.5 cm is obtained and the satisfaction rate is low (29%).48 Many other methods of penile reconstruction have been reported, including the sensate osteoc utaneous fibula flap, the free scapular flap, the suprapubic abdomi nal wall flap and the vertical rectus abdominis flap. Nevertheless, the radial forearm free flap is still the most popular technique for penile reconstruction,49 where a free skin flap is harvested from the forearm, preserv ing radial artery blood supply and the cephalic vein. The free flap is then moved to the pubic area to form a cylindrical phallus and, after performing the urethral anastomosis, the radial artery is microsurgically anasto mosed end-to-side to the femoral artery. Venous drain age is achieved by anastomosis between the cephalic vein and the greater saphenous vein. The lateral cuta neous nerve of the forearm is then linked to the ilio inguinal nerve to protect nerve sensation and the medial cutaneous nerve of the forearm is anastomosed to the dorsal penile nerve for erogenous sensation. The radial forearm flap has been widely accepted as the best donor site for penile reconstruction and is currently the gold standard in phalloplasty for female-to-male gender reassignment. This same technique can also be applied for severe penile insufficiency.50 Use of a radial-artery-based flap for penile recon struction seems to be associated with the best results;51 however, the complication rate remains high, even in those who do not present with any associated anoma lies (for example, transsexual patients), and when experienced surgeons perform the procedure. 51,52 Complications at the donor site (such as radius fracture, considerable decrease of pinch and grip power, limita tions in range of wrist motion, cold intolerance and para esthesia in the first dorsal web)53 are uncommon when the surgery is undertaken by an experienced reconstruc tive urologist. However, complications associated with the flap remain a problem, particularly in cases requiring an urethral anastomosis where a vascular blood supply is needed. Monstrey et al. 51 reported a flap revision rate of 12% and another study showed that a mean of six surgical procedures were needed to obtain a lasting neophallus. However, no comprehensive controlled studies have been carried out in a paediatric population. Although acceptable short-term results are offered by 210 | APRIL 2015 | VOLUME 12

penile corpora cavernosum augmentation procedures (for example, implantation of autogenous saphenous vein grafts or expanded polytetrafluoroethylene vessel patches) long‑term data are required.54 The main problem related to the management of micropenis is, in fact, the lack of long-term data. In 1989, Reilly and Woodhouse55 described their results in a population investigated for long-term sexual func tion and gender identity. All 20 study participants had a male gender identity and were aged 10–43 years, with micropenis that was unresponsive to hormonal admin istration during childhood. All patients reported normal erection and orgasm. Among the 12 adult patients, nine were sexually active and six had experienced teasing due to genital appearance.55 Similar results were also reported in 2004 by Lee and Houk.56 Long-term data also suggest that satisfaction with genital appearance is still an issue for patients with micropenis.57 The majority of patients with micropenis have a normal male gender and sexual identity, even when the condition is untreated.5

Concealed penis

A penis of normal size can be concealed by being buried in the prepubic tissues, enclosed in the scrotal wall owing to penoscrotal webbing, trapped by a scar caused by circumcision or trauma, or hidden by a large hernia or hydrocele.58 Most of these cases of concealed penis are associated with phimosis, as inadequate fixation of penile skin and poor basal attachment of the shaft result in a pile of narrowed skin on the tip of the penis, prevent ing the exposure of the glans. However, in contrast to the situation in straightforward phimosis surgery, the prepuce should not be excised in patients with concealed penis, as it is the only cutaneous coverage of the penis and might be needed to cover the penile shaft during reconstructive surgery.59

Buried penis Buried penis was defined by Maizels et al.2 as a congeni tal anomaly in which a normal-sized penis is hidden below the surface of prepubic skin. The penis might be partially visible with a ‘stumpy-looking’ appearance or can be completely invisible, with only the glans covered by prepuce protruding. The classification into ‘partial’ and ‘complete’ subtypes of buried penis was proposed in 1977 by Crawford,60 who distinguished a buried penis secondary to excessive suprapubic fat, which could improve with age, from a penis that was buried as a result of superficial fascial laxity, which commonly needs sur gical correction. Usually, in obese adolescents, buried penis occurs because localized suprapubic adiposity conceals the penis. In infants and toddlers, buried penis is secondary to incorrect or complete lack of anchoring of the superficial fascia and skin to the deep fascia at the base of the penis, which is consequently concealed within the prepubic tissue. More recently, buried penis has been described as a phallus of normal girth and short length associated with a paucity of shaft skin, which seems to be a contributing factor to the short appearance of the penis.61


REVIEWS a

b

c

d

Figure 2 | Surgical correction of buried penis with congenital megaprepuce. Nature Reviews | Urology a | Buried penis with congenital megaprepuce. b | Incision on penoscrotal angle exposes the penis hidden in the overlying structures. c | Degloving of the shaft shows the normal length of penis. d | Excess tissue is removed and final cosmetic outcome is good.

The aetiology of buried penis is not completely clear. Different causes have been suggested including the following: abnormal fibrous bands between the dartos fascia and deep fascia,62–67 deficiency of shaft skin,68–70 lack of attachment of skin to the penile shaft,65,66 exces sive prepubic fat 66–68,70 and abnormal displacement of the penis in a ventral direction.64 Buried penis probably has a multifactorial aetiology, in which tethering of the shaft skin and nonadherent skin are the main contrib uting factors.67 The most widely accepted hypothesis is that abnormally thick and fibrous bands of dartos fascia, extending from Scarpa’s fascia of the abdomen, attach to the middle or distal dorsal shaft of the penis and tether the cavernosal bodies proximally.68 Liu et al.71 speculated that these dysgenetic bands correspond to an abnormal attachment of the fundiform ligament, which is consistent with Crawford’s description. In line with this anatomical abnormality, penile skin develop ment is also abnormal. The skin (which is inadequately attached to the deep fascia at the penis root) is not suffi cient to cover the whole shaft, especially in the erected state, when a dorsal curve appears in completely buried penises. In this state, the dorsal skin is fixed to the pre pubic skin with no opportunity to extend, whereas the scrotal skin ascends to the middle shaft, thereby com pensating for the paucity of cutaneous coverage.71 Other clinical entities, such as large scrotal masses (for example, hernias or hydroceles) and an excessive inner prepuce (such as megaprepuce) can also bury the penis. In such cases, the excessive redundancy or abnormal anchor ing of the surrounding tissues make the penis look relatively diminutive. Congenital anomalies resulting in buried penis observable from birth are distinguishable from

secondary forms of buried penis that occur in older, obese boys. Congenital anomalies can be divided into two subgroups—buried penis without megaprepuce and buried penis with megaprepuce (also termed congenital megaprepuce).69 Congenital buried penis without megaprepuce and secondary buried penis are generally asymptomatic but are sometimes associated with functional problems, such as recurrent balanitis,70 and voiding difficulties, including ballooning of the prepuce, urine spraying and urine dribbling.2 On physical examination, the penis is not visible above the skin level, but can be exposed by applying finger pressure on opposite sides of the shaft base, retracting the prepuce and penile skin. When com pression is released, the shaft disappears beneath the prepubic tissues. The most common reasons for referral of patients with congenital buried penis without megaprepuce or secondary buried penis to the surgeon are for correction of the cosmetic problem or, erroneously, for circum cision revision, as a circumcised buried penis will still look uncircumcised after surgery.72 Many prepubertal children with buried penis secondary to excessive supra pubic or prepubic fat do not need surgical correction. Most children will lose their excessive fat pad as they grow and by puberty their penis will look normal. In excessively obese postpubertal boys with secondary buried penis, surgical treatment might be necessary to ensure psychological confidence. By contrast, congenital buried penis with or without megaprepuce in patients who are not obese should be surgically corrected in most cases. Although not all patients with buried penis need sur gical correction, there is no consensus on patient eligibil ity for surgery. In fact, in some boys the shaft protrudes well after erection and in others only circumcision is necessary.56 Use of liposuction and suprapubic lipec tomy have been reported in the paediatric literature in extremely severe cases, but their use is rare.2,65 The most commonly described surgical techniques for correct ing buried penis include the following steps: complete degloving of the shaft in order to mobilize the penis, release of the anomalous dartos attachments with sub sequent correction of the fixing of the skin and dartos fascia to the deep fascia, reconstruction of the normal penopubic and penoscrotal angle and use of the pre putial skin to cover the penis, especially the ventral side (Figure 2). Congenital megaprepuce is a specific form of buried penis, the first case of which was reported by O’Brien et al. 73 in 1994. Only a few papers have reported experience of the treatment of this malfor mation in children.68, 69,71,74–78 Congenital mega prepuce is characterized by poor fixation of the skin at the base of the penis (as is the case in buried penis without megaprepuce) and phimosis and a swollen inner prepuce, with major ballooning of the prepuce and dysuria during voiding, which also occurs from the first months of life. 69 Visually, the penis looks short, the glans is located beneath the penoscrotal angle and



REVIEWS

Figure 3 | Severe webbed penis with complete fusion Nature Reviews | Urology of penoscrotal skin.

the penis has a dome-shaped base that exhibits hemi spheric ballooning during micturition. This swelling, caused by urine retention in the preputial space, deflates when the urine slowly exits through the narrow pre putial orifice. Children with congenital megaprepuce usually suffer from discomfort during voiding, which is the main indication for early surgical correction. The exact aetiology of buried penis with congenital mega prepuce is not defined; however, the condition seems to originate from a proximal and stenotic preputial meatus that induces resistance to voiding and leads to progres sive distension caused by urine retention in the inner prepuce and the dissociation of basal shaft skin from the deep fascia. 76 This penile malformation is often misdiagnosed by physicians, but diagnosis is possible as early as birth: manual compression of the peno scrotal swelling results in urine spillage and reduction of the tumefaction. Surgery for congenital megaprepuce does not differ from correction of buried penis without megaprepuce in the basic steps (such as reconstruction of penopubic and penoscrotal angles and fixing of the skin and dartos fascia to the deep fascia). Additional steps in this surgery involve the cosmetic reduction of redundant skin, which should be adapted to the smaller corpora cavernosa. A Z‑plasty on the ventral side of shaft is a good option in cases such as these, but a ventral midline suture of skin is preferable.

Webbed penis Webbed penis (also known as penis palmatus or peno scrotal fusion) was first reported as ‘virga palmata’ in Italian in 1953,79 and described as a penile deformity in the English language in 1968.80 In 1986, Maizels et al.2 defined webbed penis as a congenital condition in which a skin fold or web obscures the penoscrotal angle, meaning that an otherwise normal-sized penis looks small. This description is still the accepted definition of webbed penis.81 Generally, this condition is the result of abnormal dartos bands, which anchor the penile skin to the scrotum. The aetiology of this malformation is 212 | APRIL 2015 | VOLUME 12

uncertain, although some authors have proposed that it is secondary to aberrant preputial development, where there is insufficient ventral skin coverage of the penis and, instead, the penis is covered by adjacent scrotal tissue.82 This condition can be isolated or can be associ ated with other malformations such as hypospadias, chordee and true micropenis.1,34,82 Diagnosis of webbed penis is made by physical exam ination: when the shaft is lifted up, obliteration of the penoscrotal angle by a cutaneous fold—which extends from the ventral penile skin to the scrotal wall—is clearly evident. In some cases, penoscrotal fusion can involve the entire length of the penis up to the preputial skin (Figure 3). Hypospadias and chordee should always be ruled out in boys with webbed penis so that appropri ate treatment can be given. Surgical correction as soon as possible after diagnosis is advised, in order to mini mize psychological problems caused by the cosmetic appearance of the penis.1,79,83,84 Early descriptions of treatment for webbed penis have included simple incisions to mobilize skin flaps and/ or excise redundant skin, tailored incisions and exci sions and multiple Z‑plasties (whereby skin flaps are mobilized to elongate skin and tissue).64,82–86 However, some disadvantages have been reported with these techniques. The procedures that are characterized by a vertical suture line crossing the penoscrotal angle can be associated with scar contracture, which interferes with penile erection;87 skin flaps that are excessively manipulated or stitched are at risk of ne crosis—with functional and cosmetic consequences—while multi ple Z‑plasties are unnecessary as webbed penis can be fixed using simple surgery and the skin web is easy to manipul ate. Moreover, the undesirability of transferring hair‑bearing skin to the penis has been pointed out.31 Dilley and Currie88 described a simple method for reconstructing the penoscrotal angle, which avoids a vertical suture line by using a diamond-shaped marking. This diamond is subdivided into four triangles and two triangles on opposite sides are excised. The remain ing two triangles are mobilized as simple skin flaps so that the horizontal suture line becomes the new penoscrotal angle. On the basis of the concept that patients with webbed penis have inadequate scrotal migration, Radhakrishnan et al.58 proposed a V–Y plasty along the ventral midline, this surgery results in the scrotum dropping downwards and the creation of a penoscrotal junction. The first classification system for webbed penis, based on the severity of webbing, was proposed in 2010 by Montasser and Gohary.89 According to these authors, webbed penis can be broadly classified into primary and secondary types. The primary—or congenital—type is further subdivided into simple (if the malformation is isolated) and compound (if it presents together with prepenile scrotum [type 1], penile curvature [type 2] or a broad web [type 3]). Simple webbing is also divided into grades 1–3, on the basis of how far the web extends from the proximal to the distal sites. Secondary webbed


REVIEWS penis is observed after circumcision in obese children or in those with concealed penis. This classification system aims to streamline the appropriate operative procedure for babies who are referred for circumcision but present with a webbed penis. In fact, circumcision might be contraindicated in some of these cases and, if abso lutely necessary, it should be performed along with a webbing correction technique. In more complex cases (such as primary simple grade 3, primary compound and secondary types of webbed penis) the ventral skin defect might require the use of a rotational flap of fore skin or even Byar’s transposition flaps (sagittal division of dorsal prepuce, splitting ventrally).89 In patients with associated chordee and/or hypospadias, more extensive urethral reconstruction after chordee correction might be necessary.

Trapped penis Children are not born with trapped penis. This con dition is generally caused by inappropriate circumci sion. In fact, overexuberant circumcision (especially in newborns) or the routine circumcision of a mis diagnosed concealed penis (buried or webbed) can result in trapped penis. Furthermore, if circumcision is performed in a child with significant scrotal swell ing secondary to hydrocele or hernia, trapped penis can occur soon after circumcision when the redundant scrotal wall develops adhesions with the dorsal penile skin. The reported incidence of trapped penis in boys who presented for circumcision revision was 26% (nine of 35 patients aged 2 months to 9 years); in all of these nine cases, an inconspicuous penis was found on physical examination.90 Blalock et al.91 reported that 2.9% of neonatal circum cisions result in a trapped penis. Another study dem onstrated that this condition, which is mostly evident during infancy after circumcision, might not be perma nent and in some cases could spontaneously resolve as infants get older.92 These findings led the authors to rec ommend that surgery is not performed for buried penis that occurs after circumcision (that is, trapped penis) in children aged younger than 3 years.92 Patients with an inconspicuous penis caused by abnormalities of surroundi ng structures seem to be at increased risk of penile entrapment after circumcision 66 and are also predisposed to keloid formation on the penis. 93 Thus, contrai ndications to newborn circumcision should include concealed penis as well as hypospadias, epispadias and micropenis.91 A trapped penis is of normal size but is partially stuck in the prepubic fat or scrotum owing to a circumferential scar of the penile skin that traps it after circumcision and causes it to withdraw. Physical examination reveals entrapment of the penile shaft in scarred prepubic skin that is associated with deforming adhesions that entirely or partially prevent glans exposure.94 Trapped penis is characterized by a secondary phimosis, which can predispose affected children to recurrent urinary tract infections, ballooning during urination or even urinary retention. Treatment is, therefore, necessary.31

Previously, the management of trapped penis was primarily surgical, as it was believed that this condi tion would not improve on its own. However, surgi cal treatment is no longer necessary as topical steroids have been found to be effective: the combination of topical betamethasone and manual retraction has been found to result in complete resolution in the major ity of patients, reducing the need for formal operative repair.96 Thus, surgical correction is reserved for cases where topical therapy fails. The surgery chosen depends on the extent of the scar and the amount of skin that has been removed. In simple cases, adhesiolysis with vertical incision of the constricting phimotic ring or recircum cision might be all that is required. More complex cases that show total deficiency of penile skin due to a wide scar or previous excessive removal of skin might need extensive reconstruction to be carried out. These recon struction techniques include the use of vascularized flaps,53,96 split-thickness skin grafts,97,98 and two-stage repair after burying the shaft under the middle scrotal wall during reconstruction.99 However, there are dis advantages associated with these techniques: vascular ized flaps are associated with multiple scars at the level of the hypogastrium and on the penile skin, split-thickness skin grafts are associated with a significant risk of com plications and two-stage repair is associated with puber tal onset of hairy skin around the shaft (although this issue can be easily solved with permanent depilation).

Conclusions

Inconspicuous penis is more common than is usually appreciated and often requires evaluation by a paedi atric urologist. It is important to distinguish a true micropenis (where the underlying problem is the size of the penis itself) from a concealed penis such as a buried penis, webbed penis or trapped penis (which result from abnormalities of the covering tissue and underlying and overlying structures). True micropenis has an SPL that is at least 2.5 SD below the mean for the age of the patient, whereas SPL is normal in buried, webbed and trapped penis. True micropenis is usually caused by a defect of the hypothalamic–pituitary–gonadal axis. Primary treat ment of true micropenis is exogenous testosterone administration (for example, intramuscular testoster one enanthate). Other hormonal treatments include topical transdermal DHT and gonadotropin. If response to hormonal treatment is poor or absent, elongation of the phallus can be achieved by reconstructive surgery performed by an experienced paediatric urologist. If the inconspicuous penis is caused by abnormalities of the surrounding structures, it is essential to identify the primary anatomical issue. Diagnosis should be made on the basis of penile appearance while considering the anatomy of the penis. Treatment should be individual ized to each patient on the basis of residual anatomy, type of deformity and the amount of covering skin available. Reconstruction is warranted in some cases in order to avoid future psychosexual issues and provide the child with normal functional anatomy. Buried penis secondary



REVIEWS to excessive suprapubic or prepubic fat does not require surgical correction, but if this condition is secondary to lax penile skin or abnormal dartos bands, surgery might be required. Repair of webbed penis depends on associ ated abnormalities such as hypospadias or chordee and surgery should be performed as early as possible in the child’s life. In the case of trapped penis, which can occur after circumcision, use of topical steroids has reduced the need for further surgery but, in some cases, a new circumcision is necessary. An inconspicuous penis can be a source of concern for both parents and children. Young boys might fear discovery and teasing by classmates, which could result in depression and anxiety. Parents might worry about the future sexual and reproductive function of their child. 1.

2.

3.

4.

5. 6.

7.

8. 9.

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13.

14.

15.

16.

Bergeson, P. S., Hopkin, R. J., Bailey, R. B., McGill, L. C. & Piattt, J. P. The inconspicuous penis. Pediatrics 92, 794–799 (1993). Maizels, M., Zaontz, M., Donovan, J., Bushnik, P. N. & Firlit, C. F. Surgical correction of the buried penis: description of a classification system and a technique to correct the disorder. J. Urol. 136, 268–271 (1986). Williams, C. P., Richardson, B. G. & Bukowski, T. P. Importance of identifying the inconspicuous penis: prevention of circumcision complications. Urology 56, 140–143 (2000). Cytryn, L., Cytryn, E. & Rieger, R. E. Psychological implications of cryptorchidism. J. Am. Acad. Child. Psychiatry 6, 131–165 (1967). Wiygul, J. & Palmer, L. S. Micropenis. ScientificWorldJournal 11, 1462–1469 (2011). Johnson, P. & Maxwell, D. Fetal penile length. Ultrasound Obstet. Gynecol. 15, 308–310 (2000). Zalel, Y., Pinhas-Hamiel, O., Lipitz, S., Mashiach, S. & Achiron, R. The development of the fetal penis—an in utero sonographic evaluation. Ultrasound Obstet. Gynecol. 17, 129–131 (2001). Aaronson, I. A. Micropenis: medical and surgical implications. J. Urol. 152, 4–14 (1994). Tuladhar, R., Davis, P. G. & Batch, J. Establishment of a normal range of penile length in preterm infants. J. Paediatr. Child Health 34, 471–473 (1998). Schonfeld, W. A. & Beebe, G. W. Normal growth and variation in the male genitalia from birth to maturity. J. Urol. 48, 759–777 (1942). Tuladhar, R., Davis, P. G. & Batch, J. Establishment of a normal range of penile length in preterm infants. J. Paediatr. Child Health 34, 471–473 (1998). Feldman, K. W. & Smith. D. W. Fetal phallic growth and penile standards for newborn male infants. J. Pediatr. 86, 395–398 (1975). Camurdan, A. D. et al. Current stretched penile length cross-sectional study of 1040 healthy Turkish children aged 0 to 5 years. Urology 70, 572–575 (2007). Kulkarni, M. L. & Rajendran, N. K. Normal values for penile standards in newborns. Indian Pediatr. 39, 183–186 (1989). Callen, N. et al. Sexual quality of life after hormonal and surgical treatment, including phalloplasty, in men with micropenis: a review. J. Sex. Med. 10, 2890–2903 (2013). Kayes, O. et al. Therapeutic strategies for patients with micropenis or penile dysmorphic disorder. Nat. Rev. Urol. 9, 499–507 (2012).

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Hence this condition commonly results in medical con sultation. Paediatric primary care providers should have an adequate knowledge of all of these conditions so that they can reassure parents or refer them for surgical or endocrine evaluation. Data in the scientific literature indicate that patients with inconspicuous penis are dissatisfied with the appearance of their penis in adulthood, but data on satisfaction of sexual function and quality of life are conflicting. Psychological support should be an impor tant part of management of patients with inconspicu ous penis to alleviate problems and address concerns. However, further publications of series with large numbers of pa rticipants and long-term follow-up are needed.17

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Abnormally long penis in children with vesical calculus.

[An inconspicuous contribution in the "Klinische Monatsblätter" 1944].

Inconspicuous Nasoethmoidal Encephalocele Might Be Wrongly Diagnosed.

Amputation of the Penis.

Nerve block of the penis for postoperative pain relief in children.

Amputation of the Penis.

Carcinoma of the penis.

Subluxation of the Penis.

Fracture of the penis.

Lymphedema of the penis.

The "eggplant penis" sign.

Amputation of the Penis.

Carcinoma of the penis.

Leiomyosarcoma of the penis.

Pityriasis versicolor of the penis.

Granuloma annulare of the penis.

Carcinoma penis.

Tuberculous ulceration of the penis.

[Penis disorders].

"Zip injury" to the penis.

Granuloma annulare of the penis.

Staging carcinoma of the penis.

Pilonidal sinus of the penis.

Care of the uncircumcised penis.