The role of substance P release in the lung with esophageal acid.

To investigate whether tachykinins are released in the airways by stimulating the esophagus, airway plasma extravasation induced by intraesophageal hydrochloric acid (HCl) in the presence or absence of the neutral endopeptidase (NEP) inhibitor phosphoramidon and the neurokinin-1-receptor antagonist FK888 was studied in anesthetized guinea pigs. Airway plasma extravasation also was studied in the presence of the NEP inhibitor in guinea pigs pretreated with capsaicin or bilateral vagotomy. Propranolol and atropine were used in all animals to block adrenergic and cholinergic nerve effects. Airway plasma leakage was evaluated by measuring extravasated Evans blue dye. One normal HCl infusion into the esophagus significantly increased plasma extravasation in the trachea. Phosphoramidon significantly potentiated plasma extravasation induced by HCl infusion into the esophagus in the trachea and main bronchi, and FK888 significantly inhibited extravasation in a dose-related manner. In capsaicin-treated animals, airway plasma extravasation was completely inhibited even in the presence of phosphoramidon. Tracheal plasma extravasation potentiated by phosphoramidon was significantly inhibited in the bilaterally vagotomized animals. These results suggest that locally acting substances are released by intraesophageal HCl stimulation that cause airway plasma extravasation. These substances are generated through activation of neural pathways, including some that traffic through the vagus nerves that link the esophagus or airways.

Human bronchial intraepithelial T lymphocytes as a distinct T-cell subset: their long-term survival in SCID-Hu chimeras.

Intestinal intraepithelial T lymphocytes (i-IELs) show features different from those of conventional T cells and play specific roles in the mucosal immunity. To investigate whether human bronchial intraepithelial T lymphocytes (IELs) are a distinct entity, we examined T cells in human bronchial xenografts transplanted on mice with severe combined immune deficiency (SCID). We transplanted human bronchi subcutaneously into mice with SCID, resected the xenografts after various incubation periods (7-174 d), and examined them for CD3(+), CD4(+), CD8(+), and CD45(+) cells by immunohistochemistry. The number of CD3(+) cells in the lamina propria decreased significantly in the first month (from 308.7 +/- 60.2 to 70.9 +/- 49. 4/mm(2); P < 0.05), and xenografts more than 5 mo of age had scant T cells in the lamina propria (5.2 +/- 2.0/mm(2)). However, there was no significant difference between the number of CD3(+) IELs in freshly isolated bronchi and in xenografts maintained for more than 5 mo. In freshly isolated bronchi, the number of CD4(+) IELs was significantly lower than that of CD8(+) cells (2.35 +/- 0.62 versus 4.56 +/- 1.32/mm basement membrane; P < 0.01). After transplantation, the mean CD4-to-CD8 ratio of all xenografts was significantly higher than that of freshly isolated bronchi (5.2 +/- 0.9 versus 0.6 +/- 0.2; P < 0.005). The IELs were positive for CD45, which is specific for human leukocytes, and they were eliminated by irradiation before the transplantation. Almost all IELs (99.5%) in the xenografts expressed alphabeta T-cell receptor, and 35.8% of IELs expressed alpha(e)beta7 integrin. Bronchial epithelial cells in the xenografts expressed interleukin (IL)-7, stem cell factor, intercellular adhesion molecule (ICAM)-1, and human leukocyte antigen-DR (HLA-DR). We conclude that in the SCID-Hu chimera model, human bronchial IELs survive for more than 5 mo, unlike the T cells in the lamina propria, and we suggest that human bronchial IELs may be stimulated by bronchial epithelial cells expressing IL-7, stem cell factor, ICAM-1, and HLA-DR.

The role of cysteinyl leukotrienes in the pathogenesis of asthma: clinical study of leukotriene antagonist pranlukast for 1 year in moderate and severe asthma.

Clinical studies have shown that pranlukast (Ono Pharmaceutical Co., Osaka, Japan) is effective for mild and moderate asthma. However, it is not well known that pranlukast is also effective on moderate and severe persistent asthma in the long term. We studied the effect of pranlukast on moderate and severe asthmatics by evaluating the change of peak expiratory flow (PEF) and therapeutic scores for 1 year before and during pranlukast therapy. We gave pranlukast 225 mg twice daily orally to 25 patients who were receiving more than 400 micrograms/day beclomethasone inhalation and beta 2 stimulant inhalation with or without oral corticosteroid. Pranlukast increased PEF more than 10 L/min in 14 patients in the first 4 weeks. In these 14 patients, 10 patients continued to monitor PEF and kept asthma diaries for 1 year. We compared the data for 1 year before and during the pranlukast therapy. During the pranlukast therapy, PEF significantly increased, puffs of beta 2 stimulant inhalation significantly decreased. The incidence of oral corticosteroid rescue therapy reduced, and the mean daily dose of oral corticosteroid decreased; however, they were not statistically significant. During treatment with pranlukast, no side effect was observed. From these results, we suggest that pranlukast is effective for more than half of the moderate and severe persistent asthmatics, and that the effectiveness continues for more than 1 year.

Allergen exposure induces the expression of endothelial adhesion molecules in passively sensitized human bronchus: time course and the role of cytokines.

To study the mechanisms contributing to the recruitment of a selective leukocyte subset in allergic inflammation involving the airways as may occur in asthma, we examined whether allergic exposure induces the expression of cell adhesion molecules (CAMs) on the bronchial endothelium of passively sensitized human bronchi. Human bronchial tissue obtained from patients undergoing lung cancer surgery was passively sensitized with serum from patients with atopic asthma who were sensitive to house dust mite. We incubated the tissues for 30, 120, 240, and 480 min in the presence or absence of the dust mite allergen. The tissues were stained immunohistochemically for intercellular adhesion molecule 1 (ICAM-1), E-selectin, and vascular cell adhesion molecule 1 (VCAM-1). ICAM-1 was constitutively expressed in both the epithelium and endothelium in all tissues but after allergen stimulation significantly increased at 240 and 480 min. E-selectin expression also existed constitutively and increased significantly at 120 and 240 min with allergen exposure. The constitutive expression of VCAM-1 was less than that of ICAM-1 and E-selectin. Following allergen exposure, VCAM-1 expression increased significantly at 30, 120, 240, and 480 min, and at 480 min reached an almost 3.5-fold increase from baseline expression. The TNF-alpha level in the supernatants significantly increased at 120 min after allergen stimulation, and the interleukin (IL)-1beta level increased in 4 of 15 samples. We also examined the induction of CAMs by TNF-alpha, IL-1beta, and IL-4 on human bronchial tissue. TNF-alpha and IL-1beta increased the expression of ICAM-1, E-selectin, and VCAM-1, whereas IL-4 induced only that of VCAM-1. In addition, neutralizing antibody against TNF-alpha and IL-1beta partially blocked the upregulation of CAMs on passively sensitized bronchial tissue after allergen exposure. Thus, both an IgE-dependent allergic response and selected cytokines are able to upregulate endothelial CAMs in human bronchial tissue. These observations provide further evidence that leukocyte infiltration into the site of allergic inflammation as occurs in atopic asthma is in part regulated by the expression of ICAM-1, VCAM-1, and E-selectin.

Novel phosphodiesterase 4 inhibitor T-440 reverses and prevents human bronchial contraction induced by allergen.

To study the roles of phosphodiesterase (PDE) 4 in the human airways, we examined the effect of the novel PDE4 inhibitor T-440 in the isolated human bronchus. T-440 inhibited PDE4 extracted from human bronchial smooth muscle. IC50 values for the effect of T-440, rolipram (a PDE4 inhibitor) and theophylline on PDE4 activity of the bronchial tissues were 0.08 microM, 2 microM and > 100 microM, respectively. T-440 (10(-6) M to 10(-5) M) and aminophylline (3.3 x 10(-5) M) significantly reversed the 10(-5) M histamine-induced contraction, the efficacy of 10(-6) M T-440 being almost the same as that of 3.3 x 10(-5) M aminophylline. T-440 (10(-6) M to 10(-5) M) and aminophylline (3.3 x 10(-5) M) significantly reversed the 10(-4) M ACh-induced contraction. But their reversal effects on the ACh-induced contraction were weaker than those on the histamine-induced contraction. T-440 (10(-5) M) significantly reversed the contraction induced by allergen in passively sensitized bronchi. The efficacy of the reversal effect of T-440 (10(-5) M) was significantly higher than that of aminophylline (10(-5) M). T-440 and aminophylline significantly relaxed the basal tension, but pretreatment with T-440 or aminophylline did not significantly prevent histamine- or ACh-induced contraction. In contrast, both T-440 (10(-5) M) and aminophylline (3.3 x 10(-5) M) prevented the contraction induced by allergen, which suggests that PDE4 inhibitor inhibits the release of chemical mediators probably from bronchial mast cells in the allergic response. T-440 (10(-6) M to 10(-5) M) caused the accumulation of cAMP at the concentration that relaxed histamine-induced contraction. Thus selective PDE4 inhibitor is a candidate for the treatment of asthma.

Bronchial hyperreactivity in patients with familial amyloidotic polyneuropathy and autonomic neuropathy.

To investigate the role of autonomic regulation on airway reactivity, we performed bronchial inhalation tests of methacholine (MCh) and histamine (Hist) in Japanese patients with familial amyloidotic polyneuropathy (FAP) and autonomic neuropathy. First we examined the FEV1 and Raw in seven patients with FAP and in six normal subjects, then we administered aerosols of increasing concentrations of MCh (0.075 to 25 mg/ml) at about 5-min intervals via a nebulizer controlled by a dosimeter. We measured the FEV1 until either the concentration of MCh producing a 20% reduction from the basal value (PD20) or the maximal concentration was reached. Five of the seven patients with FAP showed bronchial hyperreactivity to MCh, and PD20 to MCh was significantly lower than that of the normal subjects (p < 0.01). Furthermore the PD20 tended to correlate inversely with the severity of autonomic neuropathy (p = 0.052). The bronchial hyperreactivity to MCh was completely blocked by pretreatment inhalation of ipratropium bromide, suggesting the muscarinic receptor-mediated mechanism. Of these five patients with hyperreactivity to MCh, three with low PD20 to MCh (< 50 units) did not respond to Hist, but two with high PD20 (> 50 units) to MCh did, suggesting different mechanisms of hyperreactivity to MCh and Hist in FAP. The PD20 to Hist significantly correlated inversely to the PD20 to MCh (p < 0.05). Histochemical examination revealed marked amyloid deposition in the vagus nerves and tracheal wall in an autopsied patient with FAP and severe autonomic symptoms. These data suggest that patients with FAP and advanced autonomic neuropathy have bronchial hyperreactivity to MCh and/or Hist, probably because of denervation supersensitivity resulting from amyloid deposition in the peripheral autonomic nerves of the airways.

Esophageal stimulation by hydrochloric acid causes neurogenic inflammation in the airways in guinea pigs.

To investigate whether tachykinins are released in the airways in response to stimulation of the esophagus, we studied the airway plasma extravasation induced by intraesophageal HCl in the presence or absence of neutral endopeptidase inhibitor phosphoramidon and NK1-receptor antagonist FK-888 in anesthetized guinea pigs. The airway plasma leakage was evaluated by measuring extravasated Evans blue dye in the animals pretreated with propranolol and atropine. Infusion of 1 N HCl into the esophagus significantly increased plasma extravasation in the trachea. Phosphoramidon significantly potentiated plasma extravasation in the trachea and main bronchi, whereas FK-888 significantly inhibited that extravasation in a dose-related manner. In the capsaicin-treated animals, airway plasma extravasation was completely inhibited even in the presence of phosphoramidon. Tracheal plasma extravasation potentiated by phosphoramidon was significantly inhibited in the bilateral vagotomized animals. These results suggest that 1) tachykinin-like substances are released to cause plasma extravasation in the airways as a result of intraesophageal HCl stimulation and 2) there are neural pathways communicating between the esophagus and airways, including the vagus nerve.

Evidence that allergen-induced contraction of guinea pig bronchi is mediated in part by the release of tachykinins.

To study the role of tachykinins in allergic responses in the airways of guinea pigs sensitized to ovalbumin (OVA), we examined the bronchial contractile response to allergen in the presence or absence of the tachykinin antagonist FK224 in vitro. Because neutral endopeptidase (NEP) effectively cleaves tachykinins, we incubated bronchial tissues with the NEP inhibitor phosphoramidon (10(-5) M) to maintain the activity of endogenously released tachykinins. Then we added 10(-5)% (10 microns/ml) OVA in the presence or absence of FK224 (10(-5) M). FK224 significantly inhibited OVA-induced contraction plateaued and began to relax, we added 10(-5) M phosphoramidon. In the tissue without FK224, phosphoramidon blocked the relaxation and enhanced the contraction. In contrast, in the tissues treated with FK224, phosphoramidon did not enhance the OVA-induced contraction. The enhancement of the contraction induced by phosphoramidon was not inhibited by the sodium channel blocker tetrodotoxin. These results suggest that (1) allergic response causes release of tachykinin-like substances to induce bronchial contraction in part, (2) these responses are blocked by tachykinin antagonist FK224 and (3) nerve conduction is not necessary for the release of tachykinin-like substances induced by allergic response in the guinea pig bronchus.

Tachykinin antagonist FK224 inhibits neurokinin A-, substance P- and capsaicin-induced human bronchial contraction.

To determine the roles of endogenously released tachykinins (substance P [SP] and neurokinin A [NKA]) in the human bronchial tissues, we studied the effects of tachykinin antagonist FK224 on bronchial smooth muscle contraction induced by SP, NKA and capsaicin in an organ bath. FK224 (10(-6) M and 10(-5) M, respectively) significantly inhibited NKA-induced contraction and 10(-5) M FK224 shifted the dose-response curve to more than one log unit higher concentration. Because SP- and capsaicin-induced contractions were small, we pretreated the tissues with the neutral endopeptidase inhibitor phosphoramidon (10(-5) M), which inhibits degradation of exogenous tachykinins in order to potentiate the contractions. FK224 (10(-5) M) significantly inhibited SP-induced contraction and it shifted the dose-response curves to about one log unit higher concentration. FK224 (10(-5) M) also significantly inhibited capsaicin-induced contraction and it shifted the dose-response curves to more than one log unit higher concentration. In contrast, FK224 (10(-5) M) did not affect on acetylcholine-, histamine-, and leukotriene D4-induced contraction. These results suggest that FK224 is a tachykinin receptor antagonist in the human bronchial smooth muscle, and that capsaicin-induced contraction is due to endogenously released tachykinin-like substances in the human bronchus.

Inhibitory effect of tyrosine kinase inhibitors on antigen-induced tracheal contraction and histamine release in guinea pigs.

We examined the effect of two different types of tyrosine kinase inhibitor, herbimycin A and genistein, on antigen-induced tracheal contraction and antigen-induced histamine release from the trachea in sensitized guinea pigs in vitro. Herbimycin A (1-10 microM) and genistein (1-10 microM) significantly inhibited antigen-induced tracheal contraction, compared with control. Additionally, herbimycin A (1-10 microM) and genistein (3-10 microM) significantly inhibited antigen-induced histamine release from the trachea in a concentration-dependent manner, compared with control. On the contrary, herbimycin A and genistein did not suppress acetylcholine- and histamine-induced tracheal contraction. We concluded that herbimycin A and genistein inhibit antigen-induced tracheal contraction without inhibiting smooth muscle contractility, and these inhibitory effects are due to, at least partially, inhibiting histamine release from tracheal mast cells.

Transfer characteristics of lateral geniculate nucleus X neurons in the cat: effects of spatial frequency and contrast.

1. The dependence of signal transfer in the lateral geniculate nucleus (LGN) on stimulus spatial frequency and contrast was investigated by comparing responses of individual X cells with their direct retinal inputs. 2. We used extracellular single-cell recording methods to isolate action potentials (LGN) and S potentials (SPs) from individual neurons in layers A and A1 of anesthetized and paralyzed cats. The stimuli were drifting sinusoidal gratings that were presented at each neuron's preferred orientation. The effects of stimulus spatial frequency and contrast on retinogeniculate signal transfer were determined by comparing the amplitude of the fundamental Fourier responses measured for a cell's action potentials (LGN) and its retinal input (SP) and calculating the transfer ratio (LGN amplitude/SP amplitude) for each stimulus condition. 3. In all units, the LGN response amplitude was lower than that of its retinal input regardless of stimulus spatial frequency. The mean transfer ratio measured at the peak spatial frequency for individual units was 0.56 +/- 0.03 (SE). For the majority of X LGN neurons, however, the efficiency of signal transfer varied considerably with stimulus spatial frequency. The average transfer ratio increased monotonically from 0.08 cycle/deg to near the high cutoff spatial frequency. 4. The effects of stimulus contrast on geniculate signal transfer were far more complex than previously reported and varied substantially between individual neurons. At low stimulus contrasts (< 10%), where all units exhibited linear response characteristics, only one third of our sample showed a monotonic decrease in transfer ratio with increasing stimulus contrast. The remaining two thirds either exhibited proportionately greater signal transfer for higher stimulus contrasts, or signal transfer remained relatively unchanged with increasing stimulus contrasts. When stimulus contrasts exceeded 10%, where response amplitude began to saturate, the transfer ratio was relatively constant in all units and independent of stimulus contrast. 5. Our results demonstrate that signal transfer from retina to visual cortex is regulated by LGN neurons in a stimulus-dependent manner, which appears to reflect the complex interactions between local membrane mechanisms and extraretinal inputs.

Transfer characteristics of X LGN neurons in cats reared with early discordant binocular vision.

1. The effects of early discordant binocular vision on the functional development of the cat lateral geniculate nucleus (LGN) were investigated by quantitatively comparing responses of individual LGN neurons with their direct retinal inputs. 2. Unilateral convergent strabismus (esotropia) was surgically induced in 11 kittens at the age of 3 wk. After the animals had reached 9 mo of age, extracellular microelectrode recordings were made from individual X LGN units in lamina A and A1 of anesthetized and paralyzed cats. Responses were measured for drifting sinusoidal gratings. Within-unit comparisons of LGN action potentials (LGN output) and S potentials (retinal input) were performed to determine the nature of signal transfer in the units driven by the deviating (N = 42) or nondeviating eyes (N = 29) of strabismic cats. The results were compared with similar data (N = 29) obtained from nine normal control cats. 3. The spatial resolution of many individual LGN units in strabismic cats was abnormally reduced relative to their retinal inputs. These differences were more pronounced in units that received inputs from the nasal retina of the contralateral eye. The resolution loss was closely associated with a dramatic decrease in the strength of the receptive field center mechanism of LGN units relative to their retinal inputs. Moreover, the efficiency of signal transfer for high-spatial-frequency stimuli, determined by the transfer ratio (response amplitude of LGN action potentials/amplitude of S potentials), was significantly lower in strabismic cats compared with normal controls. 4. In strabismic cats, contrast thresholds for the action potentials of individual LGN units were significantly higher than those determined for the S potentials. In normal cats, the input-output differences in contrast threshold were negligible. The observed contrast sensitivity loss was more pronounced for high-spatial-frequency stimuli. 5. The speed of signal transfer was significantly decreased in the LGNs of strabismic animals. The visual response latencies of many, but not all, X LGN cells in the strabismic cats were abnormally long when compared with those in normal control units, whereas SP latencies were virtually the same for strabismic and normal cats. Abnormal latencies were prevalent in units that exhibited contrast threshold deficits, and were more severe among the units receiving input from the contralateral nasal retina. 6. The deficits in strabismic cats were found in the LGN units innervated by the deviating and nondeviating eyes. However, for the majority of response measures, the units innervated by the deviating eyes showed notably larger deficits. 7. We conclude that the fidelity of signal transfer from the retina to the LGN is significantly reduced in cats reared with discordant binocular visual experience. Thus the adverse effects of early strabismus are not confined, at least in cats, to the visual cortex.

Evidence that PGF2 alpha-induced contraction of isolated guinea pig bronchi is mediated in part by release of tachykinins.

To investigate whether prostaglandin F2 alpha (PGF2 alpha) stimulates the release of tachykinins and whether the tachykinins play a role in the PGF2 alpha-induced bronchial contraction, we examined the contractile response to PGF2 alpha in the presence or absence of a neutral endopeptidase (NEP) inhibitor phosphoramidon in the guinea pig main bronchus in vitro. Because NEP effectively cleaves tachykinins, we hypothesized that the inhibition of NEP would enhance a PGF2 alpha-induced bronchial contraction if PGF2 alpha stimulates the release of tachykinins. Phosphoramidon significantly enhanced the concentration-response curve to PGF2 alpha. And it also significantly enhanced 10(-5) M PGF2 alpha-induced contraction. The enhancement was significantly attenuated in tissues where the tachykinins had been depleted by treatment with capsaicin. Furthermore, the enhancement of contraction was also significantly attenuated in the presence of tachykinin antagonist FK-224 (10(-5) M). Tetrodotoxin, a sodium-channel blocker that blocks nerve conduction, did not affect the enhancement. From these results we conclude that 1) PGF2 alpha causes the release of tachykinin-like substances, 2) these substances play a role in bronchial contraction in tissues where NEP activity is inhibited, and 3) nerve conduction is not necessary for the release of these substances in the guinea pig bronchus.

Binocular interactions in striate cortical neurons of cats reared with discordant visual inputs.

The postnatal development of cortical binocularity is known to be adversely affected by early abnormal visual experience. However, little information exists on how the signals from the two eyes are combined in individual cortical neurons of animals reared with early discordant binocular visual experience. Since this is a fundamental issue in understanding visual cortical development, we used extracellular single-unit recording methods to study binocular integration in striate cortical neurons of strabismic cats. Specifically, we measured the sensitivity of individual cells to the relative interocular spatial phase of dichoptically presented drifting sinusoidal gratings (i.e., to binocular retinal image disparity). Clear alterations in ocular dominance were observed in all strabismic subjects. Nevertheless, the majority of cortical neurons exhibited some form of binocular interactions when both eyes were stimulated together. The most prominent aspect of cortical physiology in the strabismic animals was the relatively high prevalence of suppressive binocular interactions. Suppression was most frequently found in kittens reared with 2 weeks of early optical dissociation and among adult cats that received 2 weeks of early optical dissociation and a prolonged recovery period. However, substantial excitatory binocular interactions were also maintained in these animals. With an extended period of interocular misalignment (3 or 8 months), all forms of binocular interactions, excitatory and suppressive, were drastically reduced and a greater number of neurons were truly monocular. Although the reduction in the strength of binocular interactions occurred in all units irrespective of their monocular spatial properties, the effect was more pronounced among those units tuned to higher spatial frequencies and this spatial-frequency-dependent effect was larger in the subjects receiving longer periods of binocular dissociation. The results suggest that the "breakdown" of cortical binocular properties in strabismic subjects is not an all-or-none process, and that suppressive binocular interactions may be closely associated with the abnormal binocular interactions exhibited by strabismic humans. Furthermore, our findings are consistent with the notion that cortical disparity-detecting mechanisms are spatial-frequency dependent and, thus, can be selectively altered depending on an animal's early visual experience.

Transfer characteristics of lateral geniculate nucleus X-neurons in the cat: effects of temporal frequency.

The dependency of intrageniculate signal transfer on stimulus temporal frequency was investigated by comparing responses of individual X-relay cells with their direct retinal inputs in anesthetized and paralyzed cats. Temporal frequency response functions of lateral geniculate nucleus (LGN) X-cells were more narrowly tuned than those of their retinal inputs. The efficiency of signal transfer was consistently highest at or around the geniculate cells' optimal temporal frequency, and the degree of signal transfer, which was more closely related to the LGN cells' firing rate than to the firing rate of their retinal input, decreased for both lower and higher temporal frequencies. The high temporal frequency cut-offs were significantly lower in geniculate cell responses than those of their direct retinal inputs. This reduction in temporal resolution was exaggerated for relatively low stimulus spatial frequencies. The present results provide clear evidence for the notion that LGN cells function as nonlinear temporal filters and that this stimulus-dependent signal transmission appears to be regulated by complex local mechanisms.

Bilateral cleft lip repair.

From 1970 to 1987 we treated 213 patients with bilateral cleft lip at Hokkaido University Hospital and its several branch hospitals. The patients were grouped into 3 types according to the shape of the clefting prolabium. Group 1: complete clefts bilaterally, group 2: incomplete clefts bilaterally, group 3: combination of complete and incomplete clefts. From 1974 to 1987 we treated 176 bilateral cleft lip patients by the Manchester method using several modifications. Presurgical oral orthopaedics, using head cap and orthodontic appliance devised by Dr Peat, was applied to 110 of the 176 cases. Surgical results were satisfactory and the Manchester method is our preferred procedure for bilateral cleft lip repair.

A case of facio-genito-popliteal syndrome.

Facio-genito-popliteal syndrome, or popliteal pterygium syndrome, is a very rare anomaly consisting of various combinations of facial deformities (cleft lip/palate, lip pits, syngnathia), popliteal pterygia, and genital deformities. We have found 56 cases previously recorded in the literature.