Adult diagnosis of Townes-Brocks syndrome with renal failure: Two related cases and review of literature.

Townes-Brocks syndrome (TBS) is a rare autosomal dominant syndrome, resulting from heterozygous variant in SALL1 gene and initially characterized by the triad of anorectal, thumb, and ear malformations. Essentially described in children, adult case reports are uncommon. Renal involvement has already been reported in adults and children but poorly described. Structural abnormalities such as hypodysplasia, unilateral renal agenesis or multicystic kidneys have been described, as well as functional impairment (with or without structural abnormalities) that may progress to end-stage renal disease (ESRD). We report two adult cases (mother and daughter) which exhibited kidney hypoplasia (focal and segmental glomerulosclerosis for the mother) and ESRD. The mother had unilateral polydactyly. TBS was suggested after physical examination. TBS diagnosis was confirmed by identification of a SALL1 variant. We conducted a literature review to evaluate the renal anomalies in TBS cases diagnosed in adulthood. Among 44 adult cases of TBS with genetic confirmation (including our two cases), 10 had kidney disease. The circumstances of renal failure diagnosis were incidental findings (2/5), gout (2/5), or repeated episodes of pyelonephritis (1/5). The median age of kidney disease diagnosis was 30 years old and of renal transplant 49 years old. The most frequent renal malformation was bilateral kidney hypoplasia. TBS is probably underestimated in adulthood and this report highlights that less obvious elements of morphology such as dysplasic ears can facilitate the diagnosis of TBS. As long-term prognosis of renal involvement in TBS patients remains largely unknown, a regular evaluation is required throughout life for patients.

A novel autosomal recessive GJB2-associated disorder: Ichthyosis follicularis, bilateral severe sensorineural hearing loss, and punctate palmoplantar keratoderma.

Ichthyosis follicularis, a distinct cutaneous entity reported in combination with atrichia, and photophobia has been associated with mutations in MBTPS2. We sought the genetic cause of a novel syndrome of ichthyosis follicularis, bilateral severe sensorineural hearing loss and punctate palmoplantar keratoderma in two families. We performed whole exome sequencing on three patients from two families. The pathogenicity and consequences of mutations were studied in the Xenopus oocyte expression system and by molecular modeling analysis. Compound heterozygous mutations in the GJB2 gene were discovered: a pathogenic c.526A>G; p.Asn176Asp, and a common frameshift mutation, c.35delG; p.Gly12Valfs*2. The p.Asn176Asp missense mutation was demonstrated to significantly reduce the cell-cell gap junction channel activity and increase the nonjunctional hemichannel activity in the Xenopus oocyte expression system. Molecular modeling analyses of the mutant Cx26 protein revealed significant changes in the structural characteristics and electrostatic potential of the Cx26, either in hemichannel or gap junction conformation. Thus, association of a new syndrome of an autosomal recessive disorder of ichthyosis follicularis, bilateral severe sensorineural hearing loss and punctate palmoplantar keratoderma with mutations in GJB2, expands the phenotypic spectrum of the GJB2-associated disorders. The findings attest to the complexity of the clinical consequences of different mutations in GJB2.

Deletion 21pterq22.11: Report of a Patient with Dysmorphic Features, Hypertonia, and Café-au-Lait Macules and Review of the Literature.

Partial monosomy 21 results in a great variability of clinical features that may be associated with the size and location of the deletion. In this study, we report a 22-month-old girl who showed a 45,XX,add(12)(p13)dn,-21 karyotype. The final cytogenomic result was 45,XX,der(12)t(12;21)(p13;q22.11) dn,-21.arr[hg19] 21q11.2q22.11(14824453_33868129)×1 revealing a deletion from 21pter to 21q22.11. Clinical manifestation of the patient included hypertonia, a long philtrum, epicanthic folds, low-set ears, and café-au-lait macules - a phenotype considered as mild despite the relatively large size of the deletion compared to patients from the literature.

Two Cases with Ring Chromosome 13 at either End of the Phenotypic Spectrum.

Ring chromosome 13 is a rare genetic condition with an incidence of 1/58,000 in live births. Major clinical features of patients with ring chromosome 13 include growth and developmental retardation, microcephaly, facial dysmorphism, ambiguous genitalia, anal atresia, eye malformations, retinoblastoma, and hand, foot, and toe abnormalities. The severity of the phenotype depends on the amount of genetic material lost during ring chromosome formation. Here, we report 2 cases with ring chromosome 13 at either end of the phenotypic spectrum.

Familial X/Y Translocation Encompassing ARSE in Two Moroccan Siblings with Sensorineural Deafness.

Unbalanced translocations involving X and Y chromosomes are rare and associated with a contiguous gene syndrome. The clinical phenotype is heterogeneous including mainly short stature, chondrodysplasia punctata, ichthyosis, hypogonadism, and intellectual disability. Here, we report 2 brothers with peculiar gestalt, short stature, and hearing loss, who harbor an X/Y translocation. Physical examination, brainstem acoustic potential evaluation, bone age, hormonal assessment, and X-ray investigations were performed. Because of their dysmorphic features, karyotyping, FISH, and aCGH were carried out. The probands had short stature, hypertelorism, midface hypoplasia, sensorineural hearing loss, normal intelligence as well as slight radial and ulnar bowing with brachytelephalangy. R-banding identified a derivative X chromosome with an abnormally expanded short arm. The mother was detected as a carrier of the same aberrant X chromosome. aCGH disclosed a 3.1-Mb distal deletion of chromosome region Xp22.33pter. This interval encompasses several genes, especially the short stature homeobox (SHOX) and arylsulfatase (ARSE) genes. The final karyotype of the probands was: 46,Y,der(X),t(X;Y)(p22;q12).ish der(X)(DXYS129-,DXYS153-)mat.arr[hg19] Xp22.33(61091_2689408)×1mat,Xp22.33(2701273_3258404)×0mat,Yq11.222q12 (21412851_59310245)×2. Herein, we describe a Moroccan family with a maternally inherited X/Y translocation and discuss the genotype-phenotype correlations according to the deleted genes.

Whole-exome sequencing identified a missense mutation in WFS1 causing low-frequency hearing loss: a case report.

BACKGROUND: Low-frequency nonsyndromic hearing loss (LF-NSHL) is a rare, inherited disorder. Here, we report a family with LF-NSHL in whom a missense mutation was found in the Wolfram syndrome 1 (WFS1) gene. CASE PRESENTATION: Family members underwent audiological and imaging evaluations, including pure tone audiometry and temporal bone computed tomography. Blood samples were collected from two affected and two unaffected subjects. To determine the genetic background of hearing loss in this family, genetic analysis was performed using whole-exome sequencing. Among 553 missense variants, c.2419A → C (p.Ser807Arg) in WFS1 remained after filtering and inspection of whole-exome sequencing data. This missense mutation segregated with affected status and demonstrated an alteration to an evolutionarily conserved amino acid residue. Audiological evaluation of the affected subjects revealed nonprogressive LF-NSHL, with early onset at 10 years of age, but not to a profound level. CONCLUSION: This is the second report to describe a pathological mutation in WFS1 among Korean patients and the second to describe the mutation in a different ethnic background. Given that the mutation was found in independent families, p.S807R possibly appears to be a "hot spot" in WFS1, which is associated with LF-NSHL.

A novel CHST3 allele associated with spondyloepiphyseal dysplasia and hearing loss in Pakistani kindred.

Skeletal dysplasias (SDs) are highly heterogeneous disorders composed of 40 clinical sub-types that are part of 456 well-delineated syndromes in humans. Here, we enrolled consanguineous kindred from a remote area of Sindh province of Pakistan, with 14 affected individuals suffering with short stature, kyphoscoliosis, joint dislocations, clubfoot, heart valve anomalies and progressive bilateral mixed hearing loss. To identify pathogenic variants in this family, whole exome sequencing (WES) was performed in one affected and one normal individual, which revealed a novel transversion mutation (c.802G>T; p.Glu268*) in CHST3 associated with the phenotype. CHST3 encodes a chondroitin 6-O-sulfotransferase-1 (C6ST-1) enzyme that is essential for the sulfation of proteoglycans found in cartilages. Previously, mutations in CHST3 have largely been reported in sporadic cases of SD, primarily with severe spinal abnormalities, joint dislocations, joint contractures, and clubfoot. Clinical and radiological examination of the affected individuals in this family provides new insights into phenotypic spectrum of CHST3 alleles and disease progression with age.

Glomerulopathy in patients with distal duplication of chromosome 6p.

BACKGROUND: Duplication of the distal part of chromosome 6p is a rare genetic syndrome. Renal involvement has been reported in the majority of patients, including a wide range of congenital abnormalities of kidney and urinary tract and, occasionally, a proteinuric glomerulopathy. CASE PRESENTATION: Here, we report a 13-year-old girl with 6p25.3p22.1 duplication who presented with proteinuria in infancy, was later diagnosed as focal segmental glomerulosclerosis, progressed to end-stage renal disease and was successfully transplanted. CONCLUSION: A systematic literature review suggests that 15-20 % of individuals with distal 6p duplication develop progressive proteinuric glomerulopathy. Monitoring of kidney function should be recommended in all cases.

Delineation of EFTUD2 haploinsufficiency-related phenotypes through a series of 36 patients.

Mandibulofacial dysostosis, Guion-Almeida type (MFDGA) is a recently delineated multiple congenital anomalies/mental retardation syndrome characterized by the association of mandibulofacial dysostosis (MFD) with external ear malformations, hearing loss, cleft palate, choanal atresia, microcephaly, intellectual disability, oesophageal atresia (OA), congenital heart defects (CHDs), and radial ray defects. MFDGA emerges as a clinically recognizable entity, long underdiagnosed due to highly variable presentations. The main differential diagnoses are CHARGE and Feingold syndromes, oculoauriculovertebral spectrum, and other MFDs. EFTUD2, located on 17q21.31, encodes a component of the major spliceosome and is disease causing in MFDGA, due to heterozygous loss-of-function (LoF) mutations. Here, we describe a series of 36 cases of MFDGA, including 24 previously unreported cases, and we review the literature in order to delineate the clinical spectrum ascribed to EFTUD2 LoF. MFD, external ear anomalies, and intellectual deficiency occur at a higher frequency than microcephaly. We characterize the evolution of the facial gestalt at different ages and describe novel renal and cerebral malformations. The most frequent extracranial malformation in this series is OA, followed by CHDs and skeletal abnormalities. MFDGA is probably more frequent than other syndromic MFDs such as Nager or Miller syndromes. Although the wide spectrum of malformations complicates diagnosis, characteristic facial features provide a useful handle.

Cochlear implantation for progressive hearing loss caused by an A8296G mutation in mitochondrial DNA.

Mitochondrial DNA mutations such as A3243G or A1555G are widely reported to cause hearing loss, but few reports exist on the A8296G mutation, which can also cause hearing loss. This report presents the case of a patient with the A8296G mutation and severe bilateral sensorineural hearing loss (SNHL) that progressed over two decades. The patient had no history of diabetes, but did have a family history of SNHL in her father and maternal grandmother. She was first diagnosed with SNHL at 45 years of age, and an A8296G mutation was found. The hearing threshold in the low-frequency range of the right ear was preserved at diagnosis, but eventually declined resulting in severe bilateral hearing loss by the age of 66 years, and cochlear implantation (CI) was performed in the left ear. The hearing threshold three months after CI was 25-45 dB HL, and the phoneme speech discrimination score in the left ear improved from 20% without CI to 74% with CI. SNHL patients with the A8295G mutation are good candidates for treatment with CI.

A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome.

The Jervell and Lange-Nielsen (JLN) syndrome (MIM 220400) is an inherited autosomal recessive disease characterized by a congenital bilateral deafness associated with a QT prolongation on the electrocardiogram, syncopal attacks due to ventricular arrhythmias and a high risk of sudden death. JLN syndrome is a rare disease, which seems to affect less than one percent of all deaf children. Linkage to chromosome 11p15.5 markers was found by analysing four consanguinous families. Recombinants allowed us to map the JLN gene between D11S922 and D11S4146, to a 6-cM interval where KVLQT1, a potassium channel gene causing Romano-Ward (RW) syndrome, the dominant form of long QT syndrome, has been previously localized. An homozygous deletion-insertion event (1244, -7 +8) in the C-terminal domain of this gene was detected in three affected children of two families. We found that KVLQT1 is expressed in the stria vascularis of mouse inner ear by in situ hybridization. Taken together, our data indicate that KVLQT1 is responsible for both JLN and RW syndromes and has a key role not only in the ventricular repolarization but also in normal hearing, probably via the control of endolymph homeostasis.

Targeted Next-Generation Sequencing in Children With Bilateral Sensorineural Hearing Loss: Diagnostic Yield and Predictors of a Genetic Cause.

OBJECTIVE: To investigate the diagnostic yield of targeted next-generation sequencing using hearing loss panels and to identify patient-related factors that are associated with a definite genetic cause. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary referral center. PATIENTS: Children with congenital or late-onset, bilateral sensorineural hearing loss. INTERVENTIONS: Diagnostic. MAIN OUTCOME MEASURES: The number of patients with a definite genetic diagnosis. RESULTS: We report on 238 patients with hearing loss: 130 were male and 108 were female. About 55% had congenital hearing loss. A genetic cause was identified in 94 of the patients (39.5%), with 72.3% of these showing nonsyndromic and 27.6% showing syndromic hearing loss. The diagnostic yield was highest among North African patients (66.7%). A multiple linear regression model shows that profound hearing loss, family history of hearing loss, congenital hearing loss, and North African ethnicity are significantly related to identifying a genetic cause. CONCLUSIONS: Targeted next-generation sequencing using a panel of hearing loss genes identified a genetic diagnosis in almost 40% of children with bilateral sensorineural hearing loss. We describe the predictors of a genetic diagnosis, and this information may be used during genetic counseling.

Association of Genetic Diagnoses for Childhood-Onset Hearing Loss With Cochlear Implant Outcomes.

Importance: In the US, most childhood-onset bilateral sensorineural hearing loss is genetic, with more than 120 genes and thousands of different alleles known. Primary treatments are hearing aids and cochlear implants. Genetic diagnosis can inform progression of hearing loss, indicate potential syndromic features, and suggest best timing for individualized treatment. Objective: To identify the genetic causes of childhood-onset hearing loss and characterize severity, progression, and cochlear implant success associated with genotype in a single large clinical cohort. Design, Setting, and Participants: This cross-sectional analysis (genomics) and retrospective cohort analysis (audiological measures) were conducted from 2019 to 2022 at the otolaryngology and audiology clinics of Seattle Children's Hospital and the University of Washington and included 449 children from 406 families with bilateral sensorineural hearing loss with an onset younger than 18 years. Data were analyzed between January and June 2022. Main Outcomes and Measures: Genetic diagnoses based on genomic sequencing and structural variant analysis of the DNA of participants; severity and progression of hearing loss as measured by audiologic testing; and cochlear implant success as measured by pediatric and adult speech perception tests. Hearing thresholds and speech perception scores were evaluated with respect to age at implant, months since implant, and genotype using a multivariate analysis of variance and covariance. Results: Of 406 participants, 208 (51%) were female, 17 (4%) were African/African American, 32 (8%) were East Asian, 219 (54%) were European, 53 (13%) were Latino/Admixed American, and 16 (4%) were South Asian. Genomic analysis yielded genetic diagnoses for 210 of 406 families (52%), including 55 of 82 multiplex families (67%) and 155 of 324 singleton families (48%). Rates of genetic diagnosis were similar for children of all ancestries. Causal variants occurred in 43 different genes, with each child (with 1 exception) having causative variant(s) in only 1 gene. Hearing loss severity, affected frequencies, and progression varied by gene and, for some genes, by genotype within gene. For children with causative mutations in MYO6, OTOA, SLC26A4, TMPRSS3, or severe loss-of-function variants in GJB2, hearing loss was progressive, with losses of more than 10 dB per decade. For all children with cochlear implants, outcomes of adult speech perception tests were greater than preimplanted levels. Yet the degree of success varied substantially by genotype. Adjusting for age at implant and interval since implant, speech perception was highest for children with hearing loss due to MITF or TMPRSS3. Conclusions and Relevance: The results of this cross-sectional study suggest that genetic diagnosis is now sufficiently advanced to enable its integration into precision medical care for childhood-onset hearing loss.

The human deafness-associated connexin 30 T5M mutation causes mild hearing loss and reduces biochemical coupling among cochlear non-sensory cells in knock-in mice.

Mutations in the GJB2 and GJB6 genes, respectively, coding for connexin26 (Cx26) and connexin30 (Cx30) proteins, are the most common cause for prelingual non-syndromic deafness in humans. In the inner ear, Cx26 and Cx30 are expressed in different non-sensory cell types, where they largely co-localize and may form heteromeric gap junction channels. Here, we describe the generation and characterization of a mouse model for human bilateral middle/high-frequency hearing loss based on the substitution of an evolutionarily conserved threonine by a methionine residue at position 5 near the N-terminus of Cx30 (Cx30T5M). The mutation was inserted in the mouse genome by homologous recombination in mouse embryonic stem cells. Expression of the mutated Cx30T5M protein in these transgenic mice is under the control of the endogenous Cx30 promoter and was analysed via activation of the lacZ reporter gene. When probed by auditory brainstem recordings, Cx30(T5M/T5M) mice exhibited a mild, but significant increase in their hearing thresholds of about 15 dB at all frequencies. Immunolabelling with antibodies to Cx26 or Cx30 suggested normal location of these proteins in the adult inner ear, but western blot analysis showed significantly down-regulated the expression levels of Cx26 and Cx30. In the developing cochlea, electrical coupling, probed by dual patch-clamp recordings, was normal. However, transfer of the fluorescent tracer calcein between cochlear non-sensory cells was reduced, as was intercellular Ca(2+) signalling due to spontaneous ATP release from connexin hemichannels. Our findings link hearing loss to decreased biochemical coupling due to the point-mutated Cx30 in mice.

Genome-wide SNP genotyping identifies the Stereocilin (STRC) gene as a major contributor to pediatric bilateral sensorineural hearing impairment.

Hearing loss is the most prevalent sensory perception deficit in humans, affecting 1/500 newborns, can be syndromic or nonsyndromic and is genetically heterogeneous. Nearly 80% of inherited nonsyndromic bilateral sensorineural hearing loss (NBSNHI) is autosomal recessive. Although many causal genes have been identified, most are minor contributors, except for GJB2, which accounts for nearly 50% of all recessive cases of severe to profound congenital NBSNHI in some populations. More than 60% of children with a NBSNHI do not have an identifiable genetic cause. To identify genetic contributors, we genotyped 659 GJB2 mutation negative pediatric probands with NBSNHI and assayed for copy number variants (CNVs). After identifying 8 mild-moderate NBSNHI probands with a Chr15q15.3 deletion encompassing the Stereocilin (STRC) gene amongst this cohort, sequencing of STRC was undertaken in these probands as well as 50 probands and 14 siblings with mild-moderate NBSNHI and 40 probands with moderately severe-profound NBSNHI who were GJB2 mutation negative. The existence of a STRC pseudogene that is 99.6% homologous to the STRC coding region has made the sequencing interpretation complicated. We identified 7/50 probands in the mild-moderate cohort to have biallelic alterations in STRC, not including the 8 previously identified deletions. We also identified 2/40 probands to have biallelic alterations in the moderately severe-profound NBSNHI cohort, notably no large deletions in combination with another variant were found in this cohort. The data suggest that STRC may be a common contributor to NBSNHI among GJB2 mutation negative probands, especially in those with mild to moderate hearing impairment.

Congenital cytomegalovirus infection - a common cause of hearing loss of unknown aetiology.

AIM: The aim of this study was to investigate the role of congenital cytomegalovirus (CMV) infection as a cause of various types of sensorineural hearing loss (SNHL) in a group of nonsyndromic children with otherwise unknown aetiology of hearing loss. Furthermore, the occurrence of combined congenital CMV infection and connexin 26 (Cx26) mutations was investigated. METHODS: The dried blood spot (DBS) cards of 45 children with various degrees of hearing deficits and 46 children with severe/profound hearing loss were tested for CMV DNA with polymerase chain reaction (PCR) technique. The DBS cards of the 46 children with severe/profound hearing loss were also analysed for Cx26 mutations. RESULTS: Of the 45 children with various degrees of hearing loss, nine were positive for CMV DNA (20%). The nine children represented severe/profound, mild and unilateral hearing loss. From the 46 children with severe/profound hearing loss, nine of 46 (20%) were positive for CMV DNA. In addition, three of the CMV DNA-positive children were carriers of mutations of Cx26. CONCLUSION: Congenital CMV infection is a high risk factor in hearing impairment among children.

A mutation in HOXA2 is responsible for autosomal-recessive microtia in an Iranian family.

Microtia, a congenital deformity manifesting as an abnormally shaped or absent external ear, occurs in one out of 8,000-10,000 births. We ascertained a consanguineous Iranian family segregating with autosomal-recessive bilateral microtia, mixed symmetrical severe to profound hearing impairment, and partial cleft palate. Genome-wide linkage analysis localized the responsible gene to chromosome 7p14.3-p15.3 with a maximum multi-point LOD score of 4.17. In this region, homeobox genes from the HOXA cluster were the most interesting candidates. Subsequent DNA sequence analysis of the HOXA1 and HOXA2 homeobox genes from the candidate region identified an interesting HOXA2 homeodomain variant: a change in a highly conserved amino acid (p.Q186K). The variant was not found in 231 Iranian and 109 Belgian control samples. The critical contribution of HoxA2 for auditory-system development has already been shown in mouse models. We built a homology model to predict the effect of this mutation on the structure and DNA-binding activity of the homeodomain by using the program Modeler 8v2. In the model of the mutant homeodomain, the position of the mutant lysine side chain is consistently farther away from a nearby phosphate group; this altered position results in the loss of a hydrogen bond and affects the DNA-binding activity.

[The results of audiological examination of children presenting with sensorineural loss of hearing due to GJB2 gene mutations during the first year of life].

One of the topical problems of modern pediatric audiology is early diagnostics of congenital sensorineural loss of hearing in children and their timely rehabilitation. The objective of the present study was to obtain audiological characteristics of sensorineural hearing impairment associated with GJB2 gene mutations in children during the first year of life. The methods used were registration of short-latency auditory evoked potentials (slAEP) and the otoacoustic emission (OAE) techniques. The study included 66 children at the age of several months presenting with bilateral sensorineural loss of hearing who were available for the examination by an otorhinolaryngologist, tympanometry, slAEP recording, delayed EOAE (dEOAE) and distortion-product frequency OAE (dpOAE) techniques, and genetic counseling. The examination was carried out in duplicate, with an interval of 3 months. The genotype containing GJB2 gene mutations was identified in 47 (71.2%) children. The 35delG mutation was found in 41; in 31 of them it occurred in the homozygous state and in 10 in the heterozygous state. In the latter group, 8 children had the 35delG mutation in the compound heterozygous state together with one more mutation. Six children turned out to carry a pathological genotype with other GJB2 gene mutations. It was shown that OAE fails to be recorded in most patients with hearing impairment due to GJB2 gene mutations during the first months of life. The authors conclude that these mutations usually lead to the development of persistent bilateral symmetric sensorineural loss of hearing.

Delayed-Onset NOG Gene-Related Syndromic Conductive Deafness: A Case Report.

We report a 6-year-old girl with progressive bilateral conductive hearing loss for 2 years. She passed the newborn hearing screening conducted with otoacoustic emissions testing and had a normal development of speech and language, which indicated that her deafness was delayed-onset. She also had congenital proximal interphalangeal joints. Proximal symphalangism was confirmed by genetic testing (NOG gene: c.406C > T, p.R136C). Bilateral stapes ankyloses were proved by surgery and her hearing was improved after stapedotomy by over 30 dB. Besides, this case should remind clinicians to carefully distinguish NOG gene-related deafness from congenital ossicular malformation and pediatric otosclerosis.

[Genetic screening for hearing disorders in newborn infants in combination with audiological screening].

Congenital deafness has the heterogeneous nature and can be underlain by both acquired and genetically determined causes. It has been estimated that the prevalence of clinically manifest forms of congenital deafness amounts to 1 case per 700 births. Half of these patients present with the deafness of genetic origin. One of the most common forms of congenital deafness is the hereditary one associated with mutations of the GJB2 gene. The most frequent mutation documented in this country is 35delG leading to congenital and prelingual bilateral deafness in 52% of the cases. The number of carriers of the 35delG mutation among healthy populations in the majority of regions of the Russian Federation is estimated at 2-4%. At present, identification of a child with bilateral loss of hearing in the course of detailed audiological screening dictates the necessity of genetic testing. It is believed that combined audiological and molecular genetic screening may be helpful for the early detection of children with a pathological genotype including those with only slightly manifest hearing loss at birth. Families having such a child should be in due time counseled about the risk of giving life to another child with the above disorder by the same couple or other relatives of the childbearing age.