Cell Tissue Res (2001) 305:379–387
DOI 10.1007/s004410000345
REGULAR ARTICLE
Laurence S. Baskin · Ali Erol · Priya Jegatheesan
Yingwu Li · Wenhui Liu · Gerald R. Cunha
Urethral seam formation and hypospadias
Received: 14 September 2000 / Accepted: 12 December 2000 / Published online: 27 June 2001
© Springer-Verlag 2001
Abstract Knowledge of the formation of the normal
male urethra may elucidate the etiology of hypospadias.
We describe urethral formation in the mouse, show the
similarities and relevance to human urethral develop-
ment, and introduce the concept of the epithelial seam
formation and remodeling during urethral formation.
Three mechanisms may account for epithelial seam for-
mation: (1) epithelial-mesenchymal transformation simi-
lar to that described in the fusion of the palatal shelves,
(2) apoptosis, and/or (3) tissue remodeling via cellular
migration. Urethral development in the embryonic
mouse (14–21 days of gestation) was compared with ure-
thral formation in embryonic human specimens
(8–16 weeks of gestation) by using histology, immuno-
histochemistry, and three-dimensional reconstruction.
The urethra forms by fusion of the epithelial edges of the
urethral folds, giving a midline epithelial seam. The epi-
thelial seam is remodeled via cellular migration into a
centrally located urethra and ventrally displaced remnant
of epithelial cells. The epithelial seam is remodeled by
narrowing approximately at its midpoint, with subse-
quent epithelial migration into the urethra or penile skin.
The epithelial cells are replaced by mesenchymal cells.
This remodeling seam displays a narrow band (approxi-
mately 30 µm wide) of apoptotic activity corresponding
This work was supported by NIH Grants K08 DK02397–04, RO1
DK51397–02, and RO1 DK57246–01
L.S. Baskin (✉) · A. Erol · P. Jegatheesan · Y. Li · W. Liu
G.R. Cunha
Department of Urology,
University of California School of Medicine,
San Francisco, CA 94143-0738, USA
e-mail: lbaskinl@urol.ucsf.edu
Tel.: +1-415-4761612, Fax: +1-415-4768849
L.S. Baskin
Department of Pediatrics,
University of California School of Medicine,
San Francisco, CA 94143, USA
G.R. Cunha
Anatomy, University of California School of Medicine,
San Francisco, CA 94143, USA
to the mesenchymal cells and not to epithelial cells. No
evidence was seen of the co-expression of cytokeratin
and mesenchymal markers (actin or vimentin). Urethral
seam formation occurs in both the mouse and the human.
Our data in the mouse support the hypothesis that seam
transformation occurs via cellular migration and not by
epithelial mesenchymal transformation or epithelial ap-
optosis. We postulate that disruption of epithelial fusion,
remodeling, and cellular migration leads to hypospadias.
Keywords Urethral development · Apoptosis · Genital
abnormalities · Pediatrics · Cellular remodeling ·
Epithelial mesenchymal transformations · Human ·
Mouse
Introduction
Hypospadias is a congenital defect of the penis resulting
in incomplete development of the penile urethra (Duckett
and Baskin 1996). The abnormal urethral opening may
lie anywhere along the shaft of the penis or may open
onto the scrotum or the perineum (Fig. 1). Hypospadias
is one of the most common congenital anomalies occur-
ring in approximately 1:250 to 1:300 live births with
recent evidence suggesting a doubling in incidence
(Paulozzi et al. 1997)
The etiology of hypospadias remains elusive in the
majority of cases. Normal male sexual differentiation is
dependent on testosterone and its metabolites, together
with the presence of a functional androgen receptor
(Conte and Grumbach 1995). Genetic defects in the an-
drogen metabolism pathway, e.g., 5α-II reductase de-
fects or androgen receptor defects, are known to result in
hypospadias (Wilson et al. 1993; Griffin et al. 1995).
These specific defects in androgen metabolism, however,
do not explain the etiology of the overwhelming majority
of hypospadias cases, specifically moderate and mild
forms of hypospadias (Allen and Griffin 1984; Allera
et al. 1995; Sutherland et al. 1996; Albers et al. 1997;
Silver and Russell 1999)
380
Fig. 1A–F Variations of
hypospadias from mild to se-
vere (arrows opening of the
hypospadiac urethra meatus).
A Mild, with the urethral open-
ing on the glans. B Mild, with
the urethral opening at the co-
ronal margin. C Moderate, with
the urethral opening on the dis-
tal penile shaft. D Moderate,
with the urethral opening on
the mid-penile shaft. E Severe,
with the urethral opening at the
penoscrotal junction. F Severe,
with the urethral opening in the
scrotum. Note that, in hypospa-
dias, the foreskin is absent on
the ventral surface of the penis
and excessive on the dorsal as-
pect. The more severe forms of
hypospadias are associated
with penile curvature

During development of the penile urethra in humans,
the urethral folds fuse and make contact in the midline to
form an epithelial seam (Baskin et al. 1997; Kurzrock et
al. 1999a) Subsequently, the epithelial seam disappears
resulting in the normal tubular urethra. Abnormalities in
urethral seam formation and remodeling may explain hy-
pospadias. The mechanism of urethral seam transforma-
tion has not been described. We propose three possible
mechanisms for removal/remodeling of the epithelial
seam: (1) epithelial-mesenchymal transformation similar
to that occuring during fusion of the palatal shelves, (2)
apoptosis, and/or (3) tissue remodeling via cellular mi-
gration. To test these possibilities, we have studied ure-
thral development in the embryonic mouse genital tuber-
cle. We have shown that urethral development in the
mouse, like that in the human, involves seam formation
and removal. We have also studied the mechanism of
seam formation and remodeling into the completed tubu-
lar urethra.
Material and methods
The protocol was approved by the committee on animal research
at UCSF. Multiple genital tubercles from embryonic male mice
(14–21 days of gestation), and newborn and adult mice were re-
moved, fixed in formalin, and processed to paraffin. Transverse
sections (6 µm thick) were cut on a microtome. Serial sections
were (1) stained to detect apoptosis by using the terminal transfer-
ase nuclear end labeling (TUNEL) method, (2) immunostained
with antibodies to E-cadherin, cytokeratin 8, smooth muscle
α-actin, and vimentin, or (3) stained with hematoxylin and eosin
(Baskin et al. 1997). Briefly, the avidin-biotin-peroxidase proce-
dure was employed by using Vectastatin ABC kits (Vector labora-
tories, Burlingame, Calif.) with cobalt intensification. Primary an-
tibodies to E-cadherin, cytokeratin 8, smooth muscle α-actin, and
vimentin were obtained from Sigma (St Louis, Mo.). Biotinylated
anti-rabbit and anti-mouse IgGs were obtained from Amersham
International (Arlington Heights, Ill.). Peroxidase-linked avi-
din/biotin complex reagents were obtained from Vector Laborato-
ries. Negative controls utilized IgG of the same species in place of
and at the same dilution as the primary antibody. The purified rab-
bit and mouse IgGs were obtained from Zymed (South San Fran-
cisco, Calif.). Human specimens were processed as previously de-
scribed (Baskin et al. 1997, 1998) Dating of the fetal specimens
was based on fetal heel-toe length (Hern 1984).
Slides were imaged by using a Leaf Systems (Southborough,
Mass.) Lumina scanner system attached to a Zeiss microscope.
Images were collected on an Apple Power Macintosh G-4 comput-
er by using Adobe Photoshop software.
Three-dimensional reconstruction of the developing urethra fo-
cusing on seam formation and remodeling was performed by using
Adobe PhotoShop and NIH image software.(Baskin et al. 1998)
Urethral development in the mouse was compared with urethral
formation in embryonic human specimens (Baskin et al. 1997,
1998)
Results
Urethral seam formation in the human is documented in
a 12 week embryonic specimen in Fig. 2. Serial histolog-
ic sections show that the epithelial edges of the urethral
folds touch in the midline and fuse forming the epithelial
seam. The seam is remodeled, in a proximal to distal
fashion, into the tubularized urethra. The three-dimen-
sional reconstruction shows the completed urethra proxi-
mally, the open urethra with the urethral groove and
folds in the middle of the developing penis, and the em-
bryonic glans and epithelial tag distally. The orientation
of the three-dimensional reconstruction is from the bot-
tom or ventral aspect.
Urethal seam formation was also documented in the
developing mouse genital tubercle. Figure 3 shows seam
formation at 18 days of gestation (arrows). In mouse,
urethral development of the urethral folds touch and fuse
 381
Fig. 2A–G Human urethral
development. Histology and
three-dimensional reconstruc-
tion of a embryonic human pe-
nis at 12 weeks gestation. The
orientation of the developing
fetal penis is from the ventral
aspect. The epithelial skin tag
is noted distally (A) together
with the developing glans
(B, C). The urethral folds and
groove are seen along the pe-
nile shaft (D). Slightly proxi-
mal along the penile shaft, the
urethral folds fuse, the two epi-
thelial surfaces forming an epi-
thelial seam (E). The urethral
seam is then remodeled into
the completed urethra (black
arrow) (F). The urethral folds
and groove with subsequent
sections (G) are distal to the
area in which the urethra will
subsequently form. A, B, C,
G ×25; D, E, F ×50

Fig. 3A–F Urethral seam formation. Double immunohistochemi-
cal analysis of urethral seam formation and remodeling in the em-
bryonic mouse genital tubercle at 18 days of gestation (green cyto-
keratin 8 for epithelial cells, orange smooth muscle α actin). In
the developing mouse urethra, the ventral epithelial surfaces fuse
forming a closed urethral groove (asterisk) but not the true urethra
(A). Note that within the closed urethral groove, two epithelial
surfaces touch, fuse, and are remodeled (B–E large arrows). The
epithelial cells lose expression of cytokeratin without undergoing
mesenchymal transformation. F Positive control for smooth mus-
cle showing the mouse rectum. Bar 25 µm
382
Fig. 4A–E Mouse genital development. Histology and three-
dimensional reconstruction of a embryonic male mouse penis at
17 days of gestation. Note that the mouse has an epithelial seam
similar to that of the human (C). Distally, the urethral folds fuse
ventrally to form a closed urethral groove (B, C). The true urethra
develops from the fusion of the epithelial edges within the urethral
groove forming an epithelial seam that is remodeled into the ure-
thra (C, D). E A serial section of D after TUNEL staining; apopto-
sis within the remodeled seam. The three-dimensional reconstruc-
tion (middle) depicts the developing hypospadiac urethra (orange
zone) and the reabsorbing seam or epithelial tail (green and
yellow). The completed proximal tubular urethral is depicted in
green, and the outline of the genital skin is in yellow. The black
and white reconstruction lower left shows the developing urethral
opening from a straight-on perspective. A, B, C, E ×200; D ×100
at the ventral surface (asterisk) essentially turning the
urethra groove into a closed structure (Fig. 3A). Close
inspection of urethral development, however, reveals
that this epithelial fusion does not represent the forma-
tion of the true urethra. In the middle of this closed ure-
thral groove, two epithelial edges touch (Fig. 3C, D),
fuse, and are remodeled into the true urethra centrally.
Ventrally, the excluded epithelial cells are remodeled in-
to the ventral skin of penis. The epithelial cells in Fig. 3
have been immunostained to show cytokeratin 8 stain-
ing. The genital tubercle is also immunostained to show
smooth muscle α actin. When the seam is remodeled, the
epithelial cells do not undergo transformation into cells
with either a smooth-muscle or mesenchymal phenotype,
as revealed by the lack of α actin (Fig. 3E, arrow) or vi-
mentin (data not shown) staining.
Urethral development in three-dimensional recon-
struction and cross-sectional histology at gestational
days 17 and 20 and in an adult male mouse are shown in
Figs. 4, 5, and 6. During mouse genital development, as
in the human, the urethral opening progresses from a
proximal location on the genital tubercle to the distal
glandular location in the adult. In the 17- and 20-day em-
bryonic specimens, urethral seam formation and remod-
eling is clearly seen in the histologic cross-sections. The
three-dimensional reconstructions show movement of
the urethral opening to a more distal aspect on the geni-
tal tubercle. In the 17-, 18-, and 20-day gestation speci-
mens (Figs. 3, 4, and 5), the epithelial edges within the
closed urethral groove touch and fuse; the seam is re-
modeled by migration of the epithelial cells into the cen-
trally located tubular urethra, and ventrally, the excluded
epithelial cells are remodeled into the penile skin. Loss
of the epithelial seam markers (E-cadherin and cytokera-
tin 8) is not associated with co-expression of epithelial or
mesenchymal markers (smooth muscle α actin and vi-
mentin). The seam is remodeled into the tubularized ure-
thra without connection to the epidermis. Ventral to the
finished urethra are the excluded epithelial cells that are
seen in the three-dimensional reconstructions as a long
epithelial tail that eventually is remodeled into the penile
skin as the urethral opening progresses to the tip of the
genital tubercle. In the three-dimensional reconstruction
of the genital tubercle of the adult mouse (Fig. 6), the
epithelial tail and urethral seam are not visible, since
they have been remodeled into the mature urethra and
penile skin. Moreover, the extensive bone and cartilage

Fig. 5A–G Mouse genital development. Histology and three-
dimensional reconstruction of a embryonic male mouse penis at
20 days of gestation. Note that urethral formation has progressed
compared with that at 17 days (black and white reconstruction
lower left). The histologic sections show the closed urethral
groove distally (A, B), the formation of the true urethra via the
epithelial seam (arrows) and subsequent remodeling (C–E), and
the completed urethra proximally with reabsorption of the epithe-
lial tail (F, G). The three-dimensional reconstruction (top middle)
depicts the hypospadiac urethra (gray zone) and the reabsorbing
seam or epithelial tail (green and yellow). The completed proximal
tubular urethral is depicted in yellow, and the outline of the genital
skin is in orange. A, B, F, G ×100; C, D, E ×50
formation in the adult mouse is divergent from the adult
human penis.
Remodeling of the epithelial seam at 14 days of ges-
tation and throughout the newborn period is demonstrat-
ed in Fig. 7 following use of the TUNEL stain to identify
apoptosis. The TUNEL stain is localized to a narrow
band of approximately 30 m. Figure 8 shows the remod-
eling epithelial seam in a genital tubercle at 17 days of
gestation (with corresponding hematoxylin and eosin se-
rial sections). Close inspection of Fig. 8 shows that the
apoptosis is localized to the mesenchymal cells and not
the epithelial cells; this is also true for the TUNEL stain-
ing in Fig. 7 corresponding to gestational days 14, 15,
16, 17, 18, 19, and 20 and the newborn mouse genital tu-
bercle. The mesenchymal cells that have replaced the
midline epithelial seam have a polarity with the long axis
of the cells 90° to the new mesenchymal seam. Pyknotic
nuclei characteristic of apoptosis are found in the mid-
line.
383
Discussion
An understanding of normal urethral development is ger-
mane to defining the etiology of hypospadias. Focusing
on novel ideas that might explain the etiology of hypos-
padias are timely, based on the increasing incidence and
base line prevalence of this common congenital anomaly
(Paulozzi et al. 1997).
The first goal of this investigation was to define the
concept of an epithelial seam in the development of the
urethra. Historically, anatomical studies have described
the development of the urethra as an extension of the
urogenital sinus with fusion of the urethral folds in a
proximal to distal fashion (Jones 1914; Hunter 1935;
Glenister 1954). The distal glandular urethra has been
explained by the theory of ectodermal ingrowth (Hart
1908). This dual mode of urethral development is found
in present-day embryology textbooks (Moore 1988)
Our anatomical and immunohistochemical studies ad-
vocate an alternative theory of endodermal differentia-
tion (Kurzrock et al. 1999a). The epithelium of the entire
urethra is of urogenital sinus origin. The entire male ure-
thra, including the glandular urethra, is formed by dorsal
growth of the urethral plate into the genital tubercle, and
ventral growth and fusion of the urethral folds. Under
proper mesenchymal induction, urothelium has the abili-
ty to differentiate into a stratified squamous phenotype
with characteristic keratin staining, thereby explaining
the cell type of the glans penis (Kurzrock et al. 1999b).
There is no evidence of an ectodermal ingrowth or a sol-
id ectodermal cord filling the glans.
384
Fig. 6 Adult mouse penile development. Histology and three-
dimensional reconstruction of the penis of an adult male mouse.
Similarity to human urethral development is lost in that the penis
now has bone (red) and cartilage (blue) in the lower left recon-
struction. In the lower right reconstruction, the bone is depicted in
red and the cartilage in green. The urethral meatus is distal com-
pared with the embryonic specimens (white arrows, light orange
lower left, orange upper right, yellow upper left). Note that the
epithelial seam and epithelial tail have been completely remodeled
In the process of analyzing multiple human fetal spec-
imens for urethral development studies, we observed the
classically described proximal to distal fusion of the ure-
thral folds (Baskin et al. 1997, 1998). As the two epithe-
lial surfaces of the urethral folds fuse, an epithelial seam
is formed that is subsequently remodeled into the ure-
thra. This seam is seen during human fetal development
as illustrated by the white arrow in Fig. 2. We propose
that normal seam formation will result in normal urethral
development. In contrast, if the seam were not to fuse or
be properly remodeled, than the urethra would be open,
consistent with hypospadias as illustrated in Fig. 1. Since
the urethral seam forms in a proximal to distal fashion
along the genital tubercle, any arrest in seam formation
or remodeling anywhere along the tubercle would be
consistent with the spectrum of abnormal urethral open-
ings that are found in hypospadias (Fig. 1).
To study urethral seam formation, we have defined an
experimental model in the mouse. Initially, we had reser-
vations about the mouse model because the adult mouse
has a bone in the penis (Fig. 6), a feature that is not seen
in human development. Embryonic studies, however,
have proved more fruitful in that a seam does occur in
the developing mouse penis, with bone and cartilage for-
mation occurring only in the postnatal period. Figure 3
shows the mouse epithelial seam with two epithelial sur-
faces fusing and remodeling into a mature urethra. Histo-
logically, this resembles the folding of the urethra in the
human with fusion and subsequent seam remodeling.
Like the human, the embryonic mouse goes through a
natural state of hypospadias with the urethral opening on
the ventral aspect of the genital tubercle. With time, the
urethral opening migrates to a terminal position, as is

Fig. 7A–H Apoptosis and urethral seam remodeling from 14 days
of gestation to the newborn period. TUNEL staining showing the
site of apoptosis in the developing urethra in the embryonic
mouse. Note the localization of a narrow band of apoptotic
TUNEL stain (green) next to the remodeling seam. Close inspec-
tion reveals that the apoptosis is localized to the narrow band.
×200
also seen in the human (Figs. 4, 5, and 6). The three-
dimensional reconstructions of the developing mouse
urethra document the remodeling of the epithelial seam.
The urethral folds and groove in the mouse are not exact-
ly analogous to the human, however. In the human, the
tips of the urethral folds fuse to form the completed ure-
thra. In the mouse, the tips of the folds touch and fuse
forming a closed groove, but this is not the seam that
will form the true urethra. In the mouse, the true seam
forms half way down the closed groove (Fig. 3). This
seam is subsequently remodeled with a forward progres-
sion of the urethral opening. The epithelial cells that are
ventral to the seam are excluded from the true urethra.
The excluded epithelial cells can be seen as a tail of re-
modeling cells in Figs. 4 and 5.
We hypothesize that the mechanism of seam remodel-
ing is attributable to epithelial mesenchymal transforma-
tion (Hay 1995). For example, the palate forms by trans-
formation of two epithelial surfaces into mesenchymal
385
cells (Fitchett and Hay 1989). During palate formation,
the epithelium covering the medial edge of the palatal
shelves fuses to form an epithelial seam in the midline.
Subsequently, the seam thins to one layer of cells and
then breaks into small islands. The epithelial basal lami-
na of the seam cells disappears, and the elongating epi-
thelial cells extend filopodia into the adjacent connective
tissue. Electron microscopy has revealed transitional
steps in the loss of epithelial characteristics and the gain
of fibroblast-like features. Immunostaining has demon-
strated the gradual expression of vimentin and the loss of
keratin in the newly transformed cells of the regressing
seam (Griffith and Hay 1992)
Immunohistochemical analysis of the urethral seam,
however, with epithelial and mesenchymal markers has
not revealed a simultaneous loss of cytokeratin expres-
sion and gain of either smooth muscle α actin or vimen-
tin. High-power histologic analysis of the seam has
shown pyknotic nuclei in the epithelial cells consistent
with a different method of cellular remodeling apoptosis
(Fig. 8).
Close inspection has revealed that the apoptotic cells
are not among the epithelial cells but lie among the mes-
enchymal cells that had migrated into the seam. Analysis
of the embryonic seam from 14 days of gestation to the
newborn period with TUNEL staining has confirmed
that the apoptosis occurs within the mesenchymal cells,
386
Fig. 8A–D Apoptosis and urethral seam remodeling. Apoptotic
staining in a 17-day embryonic mouse with corresponding hema-
toxylin-eosin-stained serial sections (bottom an enlargement corre-
sponding to the boxed areas). Note the pyknotic nuclei corre-
sponding to the apoptotic staining of the urethral seam, and the
polarity of the mesenchymal cells that line up at right angles to the
urethral seam undergoing remodeling
with the epithelial cells having previously migrated to ei-
ther the completed urethra or the excluded epithelial tail
(Figs. 7 and 8). Apoptosis can be seen as a wave of ac-
tivity from proximal to distal along the genital tubercle.
The height of apoptotic activity is at embryonic days 16
and 17. Apoptosis has the advantage of removing un-
wanted cells without disturbing the surrounding cells,
such as occurs during necrosis or inflammatory process-
es (Majno and Joris 1995; Thompson 1995). Once the
epithelial cells have migrated into the urethra or the epi-
thelial tail, the remaining mesenchymal cells seem to ori-
ent at 90° to the remodeled seam. Further ultrastructure
analysis may help to explain this consistent cellular ori-
entation. It may be secondary to the tissue strength nec-
essary to support the urethra and corporal bodies during
voiding and reproductive activity.
In summary, the normal urethra in the human and
mouse forms by fusion of an epithelial seam. The middle
of the epithelial seam narrows and subsequently pinches
into two distinct structures: (1) the centrally located ure-
thra and (2) the ventrally discarded excess epithelial
seam cells that are remodeled into the ventral skin of the
penis. The disappearance of the epithelial seam occurs
concurrently with a highly focalized wave of apoptotic
activity suggestive of a band of epithelial apoptosis.
However, the apoptosis arises in the mesenchymal cells
that had replaced the migrating epithelial seam cells.
Epithelial seam remodeling could also be achieved by an
epithelial to mesenchymal transformation as occurs in
the palate. No evidence of cells co-expressing epithelial
and mesenchymal markers has however been seen, indi-
cating that such a cellular transformation does not occur
in penile development. Based on this study, we conclude
that the epithelial seam in the mouse is similar to that of
the human. Furthermore, the epithelial seam is remod-
eled via epithelial cell migration into the true urethra and
the subsequently reabsorbed epithelial tail. We propose
that hypospadias results from an arrest in urethral seam
formation or seam remodeling.
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