Perineal hypospadias repair with preservation of a coincidental vagina or perineal utricle in boys with disorders of sex development.

INTRODUCTION: An enlarged utricle in patients with proximal hypospadias or disorders of sex development (DSD) is common. The utricle orifice is usually in the posterior urethra near the verumontanum, but in exceptional cases located on the perineum. Concurrence of a perineal hypospadias and perineal utricle or vagina is also known as male vagina, pseudovagina, or blind vaginal pouch. The utricle in such cases is usually excised either before or concomitant with hypospadias repair. The authors developed an alternative approach in which the vagina or perineal utricle is retained during hypospadias repair and report on the results in four patients. OBJECTIVE: To report a novel technique for perineal hypospadias repair while retaining a concurrent vagina or perineal utricle. PATIENTS AND METHODS: Between 1999 and 2014, four neonates presented with perineal hypospadias. In all patients, a second perineal opening providing access to either an enlarged utricle or a vagina was identified. Karyotype in peripheral blood was in two patients 46,XY and in the other two 45,X/46,XY of which one showed a complex mosaicism in gonadal tissue. No genetic cause was identified on DNA evaluation in the two patients with 46,XY DSD. All patients were raised as boys. Hypospadias repair was performed in two stages at prepubertal age. During the second stage of surgery, performed between the age of 1.5 and 5 years, the vagina or utricle orifice was incorporated into the neo-urethra, resulting in a retained 'built-in' vagina or utricle. RESULTS: Surgical procedures were uneventful, and patients remained asymptomatic during a mean postoperative follow-up of 8.5 (range 2-13.5) years. One patient was lost to follow-up after the age of 8 years. At their last visit, the remaining patients, at the age of 4, 15, and 17 years, were able to void in standing position without dribbling. Both adolescent patients reported erections without ejaculations and identified themselves as males without signs of gender dysphoria. CONCLUSION: Hypospadias repair in boys with perineal hypospadias while leaving a male vagina or perineal utricle in situ has not been reported previously, and the study's preliminary results are favorable. One of the benefits of this approach is that inadvertent injury to adjacent anatomic structures such as urethral sphincter, neurovascular bundles, ureters, vas deferens, and rectum is avoided. The main rationale for adopting this conservative approach however is to minimize genital tissue removal in children with a not yet definite gender identity, which will certainly facilitate unforeseen future gender reassignment surgery.

Deletion of Brg1 causes stereocilia bundle fusion and cuticular plate loss in vestibular hair cells.

Brg1 is an ATPase subunit of the SWI/SNF chromatin-remodeling complex, and it is indispensable for the development and homeostasis of various organs. Conditional deletion of Brg1 in cochlea hair cells (HCs) leads to multiple structural defects and profound deafness. However, the premature death of Brg1-deficient cochlea HCs hindered further study of the role of Brg1. In contrast to cochlea HCs, Brg1-deficient vestibular HCs survived for a long time. Therefore, HC apical structure and vestibular function were examined in inner HC-specific conditional Brg1 knockout mice. Vestibular HCs exhibited fused and elongated stereocilia bundles after deletion of Brg1, and the cuticular plate was absent in most HCs with fused stereocilia bundles. HC loss was observed in conditional Brg1 knockout mice at the age of 12 months. Morphological defects and HC loss were primarily restricted in the striolar region of the utricle and saccule and in the central region of ampulla. The behavioral tests revealed that Brg1 deletion in HCs caused vestibular dysfunction in older adult mice. These results suggest that Brg1 may play specific roles in the maintenance of the HC stereocilia bundle and the cuticular plate.

Acoustically evoked short latency negative responses in hearing loss patients with enlarged vestibular aqueduct.

This study aims to assess the diagnostic value of the acoustically evoked short latency negative response (ASNR) during the auditory brainstem response (ABR) test for enlarged vestibular aqueduct (EVA). The ABR test was performed on 175 subjects with severe and profound hearing loss from July 2008 to August 2011. Patients were submitted to high-resolution computed tomography scans for the temporal bone of the inner ear, and were diagnosed with EVA (EVA group; n = 24 cases, 46 ears), no inner ear deformity (no deformity group; n = 136 cases, 272 ears), or other inner ear deformity (other deformities group; n = 15 cases, 29 ears). The prevalence of ASNR was 26/46 ears (56.52 %) in the EVA group, 10/272 ears (3.67 %) in the no deformity group, and 3/29 ears (10.34 %) in the other deformities group. The rate of ASNR in the EVA group was higher than that in other groups (p < 0.05). The rate of ASNR is positively correlated with EVA. Therefore, the recording of ASNRs could be a valuable method for discovering EVA.

Cochleosaccular dysplasia associated with a connexin 26 mutation in keratitis-ichthyosis-deafness syndrome.

OBJECTIVE: The objective of this study was to characterize the temporal bone phenotype associated with a mutation of GJB2 (encoding connexin 26). STUDY DESIGN: The authors conducted correlative clinical, molecular genetic, and postmortem histopathologic analysis. METHODS: The study subject was a male infant with keratitis-ichthyosis-deafness (KID) syndrome. We performed a nucleotide sequence analysis of GJB2 and a histopathologic analysis of the temporal bones. RESULTS: The subject was heterozygous for G45E, a previously reported KID syndrome mutation of GJB2. The primary inner ear abnormality was dysplasia of the cochlear and saccular neuroepithelium. CONCLUSIONS: GJB2 mutations can cause deafness in KID syndrome, and possibly in other GJB2 mutant phenotypes, by disrupting cochlear differentiation.

Quantitative study of the vestibular sensory epithelium in cochleosaccular dysplasia.

BACKGROUND: Cochleosaccular dysplasia is the most common pathologic finding seen in children with profound congenital sensorineural hearing loss. There has been no quantitative study on the peripheral vestibular system in cochleosaccular dysplasia. OBJECTIVE: To investigate quantitatively the extent of pathologic changes of the vestibular sensory epithelium in cochleosaccular dysplasia. SUBJECTS AND METHODS: Thirteen temporal bones with congenital deafness from 10 individuals were selected for this study from the temporal bone collection of University of Minnesota that showed suitable pathologic findings for the histopathologic criteria of cochleosaccular dysplasia. Age-matched normal control temporal bones were also selected. The vestibular hair cells including types I and II hair cells were counted separately in the saccular macula, utricular macula, and three cristae of the semicircular canals using Nomarski microscopy. RESULTS: The hair cell densities of types I and II hair cells in the macula of the saccule in cochleosaccular dysplasia were significantly decreased compared with the data of normal subjects. Both types I and II hair cells in the utricular macula and the cristae of the three semicircular canals in cochleosaccular dysplasia were well preserved, and no significant difference was observed between findings of cochleosaccular dysplasia and normal controls in the utricle and the three semicircular canals. CONCLUSIONS: In cases with cochleosaccular dysplasia, the neurosensorial hair cells of the saccule were affected; however, the osseous labyrinth, the membranous utricle, and the semicircular canals were normal. Further studies should be performed to establish the pathogenesis of cochleosaccular dysplasia in humans.

Neurovestibular modulation of circadian and homeostatic regulation: vestibulohypothalamic connection?

Chronic exposure to increased force environments (+G) has pronounced effects on the circadian and homeostatic regulation of body temperature (T(b)), ambulatory activity (Act), heart rate, feeding, and adiposity. By using the Brn 3.1 knockout mouse, which lacks vestibular hair cells, we recently described a major role of the vestibular system in mediating some of these adaptive responses. The present study used the C57BL6JEi-het mouse strain (het), which lacks macular otoconia, to elucidate the contribution of specific vestibular receptors. In this study, eight het and eight WT mice were exposed to 2G for 8 weeks by means of chronic centrifugation. In addition, eight het and eight WT mice were maintained as 1G controls in similar conditions. Upon 2G exposure, the WT exhibited a decrease in T(b) and an attenuated T(b) circadian rhythm. Act means and rhythms also were attenuated. Body mass and food intake were significantly lower than the 1G controls. After 8 weeks, percent body fat was significantly lower in the WT mice (P < 0.0001). In contrast, the het mice did not exhibit a decrease in mean T(b) and only a slight decrease in T(b) circadian amplitude. het Act levels were attenuated similarly to the WT mice. Body mass and food intake were only slightly attenuated in the het mice, and percent body fat, after 8 weeks, was not different in the 2G het group. These results link the vestibular macular receptors with specific alterations in homeostatic and circadian regulation.

A new mouse model with cochleo-saccular type inner ear defects.

We found a new inner ear mutant exhibiting abnormal behavior, such as circling and head shaking, in a breeding stock of SJL/J mice. The traits are inherited in a simple autosomal-recessive fashion. Animals homozygous for the responsible gene, designated cosa, show no startle response to sounds and an inability to swim. In the inner ears of cosa/cosa homozygous, but not +/cosa heterozygous adults, histopathological features of severe damage that are typical for 'cochleo-saccular' or 'spotting' mutants have been demonstrated. We suggest here that the abnormal mice carry a mutation of a gene that is developmentally switched on in the early stages of development and is involved in endolymph homeostasis.

Behavioural changes in hamsters with otoconial malformations.

For a period of 10 months, the perceptive-motor skills of golden hamsters were tested as part of an experiment to investigate vestibular controlled behaviour. We found that four out of 40 hamsters had more difficulties with swimming and equilibrium maintenance than the rest of the group. These disturbances either were apparent during the first months of testing or developed at a later period. In three hamsters the disturbances persisted over time while in one hamster performance in perceptive-motor skills increased. Histological examination with scanning electron microscopy revealed otoconial abnormalities in the saccule and/or the utricle. The otoconia were either malformed or replaced by spherulites. We conclude that the observed behavioural disturbances were caused by a defective peripheral vestibular organ. The results show similarities with data from pathology in other animals as well as in the human inner ear.

Minute findings of inner ear anomalies by three-dimensional CT scanning.

In actual clinical situations, inner ear anomalies must be diagnosed by image diagnosis such as high resolution CT-scanning of the temporal bone before three dimensional (3D) CT-scanning was introduced. In this paper, the usefulness of 3D-CT was investigated in some anomaly cases. It was found that 3D-CT was useful in observing the minute structure of the inner ear in that it could ascertain spatial relationships and minute constrictions and protrusions that could not be detected by 2D analysis. This CT was also capable of assessing the stage of embryological injuries and evaluating anomalies in cochlear turning that are the hidden factors of hearing impairment.

Inherited hearing defects in mice.

Mouse mutants with hearing impairment are useful for elucidating the pathological processes underlying auditory system defects, as well as for understanding the normal process of auditory development and sensory transduction. Deaf mouse mutants are also valuable for identifying the responsible genes by positional cloning, and are used to expedite the search for genes involved in human deafness. The distribution of candidate genes for deafness across the mouse genome is presented, together with a summary of the key features of the mutants involved. Genetic defects affecting hearing can be grouped into broad categories according to their pathological features. These categories include middle ear defects, morphogenetic inner ear defects, central auditory system defects, peripheral neural defects, neuroepithelial defects, cochleo-saccular defects, and late onset hearing loss. The biological features and molecular basis of each type of hearing impairment are described. Finally, the effects of mutations in orthologous genes involved in the auditory system in humans and mice are compared.

Genes and deafness.

Many different genes appear to be involved in the development and function of the mammalian inner ear. Some of the genes involved during early inner ear morphogenesis have been identified using mutations or targetted transgenic interruption, while a handful of genes involved in pigmentation anomalies associated with hearing impairment have been cloned. Several genes involved in syndromic late-onset hearing loss have also been identified. However, the majority of cases of hereditary hearing impairment from childhood probably involve genes expressed in the sensory neuroepithelia of the inner ear, and none of the genes or mutations causing this type of deafness have yet been identified. Here, we review the progress that has been made in finding genes for deafness and in using mouse mutants to elucidate the biological basis of the hearing deficit.

Temporal bone findings in keratitis, ichthyosis, and deafness syndrome. Case report.

In 1981, the term KID syndrome was suggested for patients with congenital ichthyosis associated with deafness and keratitis. We had a chance to examine the temporal bone of an infant with this syndrome. This patient showed no auditory brain stem response in either ear. Temporal bone studies revealed cochleosaccular abnormality. These findings are offered as a possible explanation for the patient's deafness. The pathologic inner ear findings of congenital deafness syndromes associated with ichthyosis have been heretofore reported in Refsum's syndrome and in a case with universal alopecia. In these cases, the temporal bone pathologic findings were a result of cochleosaccular abnormality. From our case and previous reports, it is suggested that the deafness associated with congenital ichthyosis might be the result of cochleosaccular abnormality.

Prenatal dinocap exposure alters swimming behavior in mice due to complete otolith agenesis in the inner ear.

Exposure to the fungicide dinocap during gestation produces behavioral abnormalities in the house mouse that are not apparent at birth but become obvious at weaning. Pregnant mice (CD-1) were exposed on Days 7 to 16 of gestation to dinocap at 0, 6, 12, or 25 mg/kg/day and the postnatal behavioral development of the offspring was assessed. Torticollis (head-tilting) appears in the treated offspring at 3 weeks of age (4.4% at 12 and 25.3% at 25 mg/kg/day) and, during a test of swimming ability, many of the mice (6.8% at 12 and 47.2% at 25 mg/kg/day) sink below the surface or are unstable and swim on their side in the water. These behavioral abnormalities are the result of agenesis of the otoliths in the inner ears. These were the only developmental defects noted in the 12 mg/kg/day dosage group. In this group 4.4% of the mice displayed torticollis, 9.2% did not swim normally, 19% were missing one or more whole otoliths (7.7% were missing all four otoliths), and partial agenesis of the crystalline material was seen in an additional 11.6% of the mice. The frequency of behavioral and inner ear defects increased in the higher dosage group, but the order of sensitivity of the effects did not change.

Strial dysfunction in mice with cochleo-saccular abnormalities.

Most viable dominant spotting (Wv/Wv) mutant mice, which show cochleo-saccular degeneration, were found to have an endocochlear potential (EP) around zero together with a structurally abnormal stria vascularis. Inner hair cells were well preserved, but outer hair cells in the basal half of the cochlea were degenerating, possibly as a result of primary strial dysfunction. Thresholds for the detection of a compound action potential were raised to around 100 dB SPL in the mutants with no EP, and there was little if any cochlear microphonic at the round window. Of the 20 Wv/Wv mice studied, five partially escaped the effects of the mutation and had measurable positive potentials (15-86 mV) in scala media in the basal turn; responses in these animals were intermediate between control responses and those of mutants with no EP. These findings confirm that the pathological processes in this mutant, with cochleo-saccular abnormalities, are fundamentally different from the pathological processes in animals with neuroepithelial abnormalities reported previously [see Steel and Bock (1983) Arch. Otolaryngol. 109, 22-29, for references].

Studies of otoconial development in a "giant-crystal" strain of chicks using scanning electron microscopy, polarized light microscopy, and X-ray crystallography.

Otolith formation was studied in a mutant strain of low-fertility Delaware chicks which exhibit an otolithic defect. In all chicks of this strain, otoliths were present as a fused crystal mass which contained abnormally large (giant) otoconia. Studies of the formation of such otoliths during embryonic development revealed that from the very earliest stages the otoconia were much larger than normal, and in the saccular and utricular otoliths formed a fused mass. These results are interpreted as supporting a hypothesis of the de novo formation of giant otoconia in this giant-crystal strain as opposed to the recrystallization hypothesis proposed for other, dissimilar mutant mammals and birds which also produce giant otoconia.

Inner ear anomalies in two cases of trisomy 18.

Two cases of trisomy 18 in which temporal bone defects were limited to the inner ears are described. Several abnormalities were present that have not been described previously in this syndrome. The first case involved a 1-month-old female infant who died of congenital heart defects. Cochlear nerve fibers were absent on the left side, with near-normal innervation on the right. Although the organ of Corti was present bilaterally, some of the outer hair cells were deformed, having small rounded cell bodies unsupported by Deiters' cells. On the right, similar abnormal cells were found in the tunnel of Corti. Vestibular defects in this case included reduced nerve supply of the left saccular macula, cysts in the superior and posterior cristae, and absence of the utriculoendolymphatic valve. The second case involved a newborn male infant with multiple congenital anomalies. The major cochlear defect was a deformity of the stria vascularis. In the lower apical turn, the stria was adherent to Reissner's membrane and extended beneath it into scala media. Large capillaries, which ran freely suspended in scala vestibuli, entered the upper portion of the stria. Severe atresia of the lateral and posterior semicircular ducts was found in the vestibular apparatus.

Genetic factors affecting hearing development.

Both genetic background and single gene mutations may affect the development of the auditory system. A classification system is presented for those single gene mutations causing hearing impairment. The new feature of this classification is the inclusion of a category for hereditary deafness of central origin. The other categories involve peripheral abnormalities and are: morphogenetic defects, in which the overall structure of the labyrinth is deformed; neuroepithelial degeneration, in which the primary defect appears to occur in the organ of Corti; and cochleo-saccular degeneration, where the stria vascularis is abnormal and Reissner's membrane collapses, leading to further degeneration.

Zinc metabolism in lethal-milk mice. Otolith, lactation, and aging effects.

Lethal-milk (lm), a recessive mutation, occurred in the C57BL/6J inbred strain of mice. Lactating lm dams produce a zinc-deficient milk that is lethal to all nursing pups. If foster-nursed on normal dams, lm pups survive and become reproductively mature. Injection of zinc-glycinate into the pups or zinc supplementation of the water of the lactating dams reduces lethality. Other pleiotropic effects in lm mice include congenital otolith defects with delayed righting, "tail-spinning," and abnormal swimming. These effects are diagnostic criteria for segregation of lm mice among backcross progeny. About 40 percent of the expected number of lm pups survive to weaning. Zinc supplementation of the dam improves development of saccular but not of utricular otoliths; zinc does not improve survival of the lm pups among backcross progenies. The lm mice over eight months of age also exhibit extensive hair loss, dermatitis, and skin lesions. Possible roles of metallothionein in zinc and copper metabolism are discussed in regard to the pleiotropic effects of the lethal-milk mutation.