Congenital Hearing Loss

http://emedicine.medscape.com/article/1290083-overview

http://emedicine.medscape.com/article/878218-overview

Bailey’s Chap 137

Luquetti D, et al. Microtia: Epidemiology and Genetics. American Journal of Medical Genetics. 2011. 158(1):124-139.

Breakdown the most common causes of syndromic hearing loss into inheritability types. 

Tell us about syndromes that cause renal problems with hearing loss. Cardiac problems with hearing loss. Vision problems with hearing loss. 

RENAL + hearing loss:

Autosomal Dominant:

• • Branchiootorenal syndrome (BOR) is the second most common type of autosomal dominant syndromic hearing loss. It consists of conductive, sensorineural, or mixed hearing loss in association with branchial cleft cysts or fistulae, malformations of the external ear including preauricular pits, and renal anomalies. Penetrance is high, but expressivity is extremely variable. In approximately 40% of families segregating a BOR phenotype, pathogenic variants in EYA1 can be identified; in a few other families pathogenic variants have been found in SIX1 [Ruf et al 2004] and SIX5 [Hoskins et al 2007]. The BOR phenotype is also caused by mutation of other as-yet-unidentified genes.

Autosomal Recessive: n/a

X-linked:

• Alport syndrome is characterized by progressive sensorineural hearing loss of varying severity, progressive glomerulonephritis leading to end-stage renal disease, and variable ophthalmologic findings (e.g., anterior lenticonus). Hearing loss usually does not manifest before age ten years. Autosomal dominant, autosomal recessive, and X-linked forms are described. X-linked inheritance accounts for approximately 85% of cases, and autosomal recessive inheritance accounts for approximately 15% of cases. Autosomal dominant inheritance has been reported on occasion.

CARDIAC + hearing loss:

Autosomal Dominant: n/a

Autosomal Recessive:

• • Jervell and Lange-Nielsen syndrome is the third most common type of autosomal syndromic hearing loss. The syndrome consists of congenital deafness and prolongation of the QT interval as detected by electrocardiography (abnormal QTc [c=corrected] >440 msec). Affected individuals have syncopal episodes and may have sudden death. Although a screening ECG is not highly sensitive, it may be suitable for screening deaf children. High-risk children (i.e., those with a family history that is positive for sudden death, SIDS, syncopal episodes, or long QT syndrome) should have a thorough cardiac evaluation. Pathogenic variants in two genes have been described in affected persons.

VISION + hearing loss:

Autosomal Dominant:

• Waardenburg syndrome (WS) is the most common type of autosomal dominant syndromic hearing loss. It consists of variable degrees of sensorineural hearing loss and pigmentary abnormalities of the skin, hair (white forelock), and eyes (heterochromia iridis). Because affected persons may dye their hair, the presence of a white forelock should be specifically sought in the history and physical examination. Four types are recognized — WS I, WS II, WS III, and WS IV — based on the presence of other abnormalities. WS I and WS II share many features but have an important phenotypic difference: WS I is characterized by the presence of dystopia canthorum (i.e., lateral displacement of the inner canthus of the eye) while WS II is characterized by its absence. In WS III, upper-limb abnormalities are present, and in WS IV, Hirschsprung disease is present. Mutation of PAX3 causes WS I and WS III. Mutation of MITF causes some cases of WS II. Mutation of EDNRB, EDN3, and SOX10 causes WS IV.

  • Stickler syndrome consists of progressive sensorineural hearing loss, cleft palate, and spondyloepiphyseal dysplasia resulting in osteoarthritis. Three types are recognized, based on the molecular genetic defect: STL1 (COL2A1), STL2(COL11A1), and STL3 (COL11A2). STL1 and STL2 are characterized by severe myopia, which predisposes to retinal detachment; this aspect of the phenotype is absent in STL3 because COL11A2 is not expressed in the eye.

Autosomal Recessive:

• • Usher syndrome is the most common type of autosomal recessive syndromic hearing loss. It consists of dual sensory impairments: affected individuals are born with sensorineural hearing loss and then develop retinitis pigmentosa (RP). Usher syndrome affects over 50% of the deaf-blind in the United States. The vision impairment from RP is usually not apparent in the first decade, making fundoscopic examination before age ten years of limited utility. However, electroretinography (ERG) can identify abnormalities in photoreceptor function in children as young as age two to four years. During the second decade, night blindness and loss of peripheral vision become evident and inexorably progress.

  • Three types of Usher syndrome are recognized based on the degree of hearing impairment and result of vestibular function testing.

    • Usher syndrome type I is characterized by congenital severe-to-profound sensorineural hearing loss and abnormal vestibular dysfunction. Affected persons find traditional amplification ineffective and usually communicate manually. Because of the vestibular deficit, developmental motor milestones for sitting and walking are always reached at later-than-normal ages.

    • Usher syndrome type II is characterized by congenital mild-to-severe sensorineural hearing loss and normal vestibular function. Hearing aids provide effective amplification for these persons and their communication is usually oral.  

    • Usher syndrome type III is characterized by progressive hearing loss and progressive deterioration of vestibular function.

• Biotinidase deficiency is caused by a deficiency in biotin, a water-soluble B-complex vitamin that covalently attaches to four carboxylases essential for gluconeogenesis (pyruvate carboxylase), fatty acid synthesis (acetyl CoA carboxylase), and catabolism of several branched-chain amino acids (propionyl-CoA carboxylase and beta methylcrotonoyl-CoA carboxylase). If biotinidase deficiency is not recognized and corrected by daily addition of biotin to the diet, affected persons develop neurologic features such as seizures, hypertonia, developmental delay, and ataxia, as well as visual problems. Some degree of sensorineural hearing loss is present in at least 75% of children who become symptomatic. Cutaneous features are also present and include a skin rash, alopecia, and conjunctivitis. With biotin treatment, neurologic and cutaneous manifestations resolve; however, the hearing loss and optic atrophy are usually irreversible. Therefore, whenever a child presents with episodic or progressive ataxia and progressive sensorineural deafness, with or without neurologic or cutaneous symptoms, biotinidase deficiency should be considered. To prevent metabolic coma, diet and treatment should be initiated as soon as possible [Heller et al 2002, Wolf et al 2002].

• Refsum disease consists of severe progressive sensorineural hearing loss and retinitis pigmentosa caused by faulty phytanic acid metabolism. Although extremely rare, it is important that Refsum disease be considered in the evaluation of a deaf person because it can be treated with dietary modification and plasmapharesis. The diagnosis is established by determining the serum concentration of phytanic acid.

X-linked:

• • Alport syndrome is characterized by progressive sensorineural hearing loss of varying severity, progressive glomerulonephritis leading to end-stage renal disease, and variable ophthalmologic findings (e.g., anterior lenticonus). Hearing loss usually does not manifest before age ten years. Autosomal dominant, autosomal recessive, and X-linked forms are described. X-linked inheritance accounts for approximately 85% of cases, and autosomal recessive inheritance accounts for approximately 15% of cases. Autosomal dominant inheritance has been reported on occasion.  TYPE 4 COLLAGEN

  • Mohr-Tranebjaerg syndrome (deafness-dystonia-optic atrophy syndrome) was first described in a large Norwegian family with progressive, postlingual, nonsyndromic hearing impairment. Reevaluation of this family has revealed additional findings, including visual disability, dystonia, fractures, and intellectual disability, indicating that this form of hearing impairment is syndromic rather than nonsyndromic. TIMM8A, the gene in which mutation occurs to cause this syndrome, is involved in the translocation of proteins from the cytosol across the inner mitochondrial membrane (TIM system) and into the mitochondrial matrix.

OTHERS:

Autosomal Dominant:

• • Neurofibromatosis 2 (NF2) is associated with a rare, potentially treatable type of deafness. The hallmark of NF2 is hearing loss secondary to bilateral vestibular schwannomas. The hearing loss usually begins in the third decade, concomitant with the growth of a vestibular schwannoma, and is generally unilateral and gradual, but can be bilateral and sudden. A retrocochlear lesion can often be diagnosed by audiologic evaluation, although the definitive diagnosis requires magnetic resonance imaging (MRI) with gadolinium contrast. Affected persons are at risk for a variety of other tumors including meningiomas, astrocytomas, ependymomas, and meningioangiomatosis. Mutation of NF2 is causative. Molecular genetic testing of presymptomatic at-risk family members facilitates early diagnosis and treatment.

Autosomal Recessive:

• • Pendred syndrome is the second most common type of autosomal recessive syndromic hearing loss. The syndrome is characterized by congenital sensorineural hearing loss that is usually (though not invariably) severe-to-profound and euthyroid goiter. Goiter is not present at birth and develops in early puberty (40%) or adulthood (60%). Delayed organification of iodine by the thyroid can be documented by a perchlorate discharge test. The deafness is associated with an abnormality of the bony labyrinth (Mondini dysplasia or dilated vestibular aqueduct) that can be diagnosed by CT examination of the temporal bones. Vestibular function is abnormal in the majority of affected persons. Pathogenic variants in SLC26A4 are identified in approximately 50% of multiplex families. Such genetic testing is appropriate for persons with Mondini dysplasia or an enlarged vestibular aqueduct and progressive hearing loss.

Deafness and Hereditary Hearing Loss Overview; Richard JH Smith, MD, A Eliot Shearer, Michael S Hildebrand, PhD, and Guy Van Camp, PhD.

What intrauterine infectious diseases cause hearing loss? Tell us about each. 

Toxoplasmosis:

• Causative Organism – Toxoplasma gondii

• Transmission

  • Transplacental

  • Fecal-oral route

  • Oocysts excreted in cat feces

  • Found in undercooked meat, contaminated water/soil, and unpasteurized goat milk

  • Risk of fetal infection increases with gestational age

  • Severity of fetal infection decreases with gestational age

• Clinical Manifestations

  • First Trimester – often results in death

  • Second Trimester – classic triad

    • Hydrocephalus

    • Intracranial calcifications

• • Third Trimester – often asymptomatic at birth

  • Symptoms may also include fever, IUGR, microcephaly, seizure, hearing loss, maculopapular rash, jaundice, hepatosplenomegaly, anemia, and lymphadenopathy

• Diagnosis

  • Definitive – Isolating organism from placenta, serum, or CSF

  • Also available – PCR & IgM titer (IgG will be elevated if mother is infected regardless of transmission)

• Treatment

  • Pyrimethamine 2 mg/kg (maximum 50 mg/dose) once daily for two days; then 1 mg/kg (maximum 25 mg/dose) once daily for six months; then 1 mg/kg (maximum 25 mg/dose) every other day to complete one year of therapy, plus

Syphilis:

• Causative Organism – Treponema pallidum

• Transmission

  • Transplacental

  • Sexual activity

• Clinical Manifestations

  • Majority are symptomatic at birth

  • Early Congenital Syphilis (symptoms at 1-2 months of age)

  • Maculopapular rash, “snuffles,” maculopapular rash, lymphadenopathy, hepatomegaly, thrombocytopenia, anemia, meningitis, chorioretinitis, osteochondritis

  • Late congenital Syphilis (symptoms after 2 years of age)

    • Hutchinson Teeth 

• • • Mulberry Molars 

• • • Rhagades (cracks or fissures in the skin around the mouth)

• • • Saber Shins 

• • • Sensorineural hearing loss (CN VIII)

    • Interstitial Keratitis

• • Diagnosis

    • Dark field microscopy

    • FTA-Abs, RPR, VDRL

  • Treatment

    • Penicillin

Rubella

• Causative Organism - Togavirus

• Transmission

  • Transplacental

  • Respiratory secretions

• Clinical Manifestations

  • “Blueberry Muffin” rash due to extramedullary hematopoiesis 

• • Cataracts

• • “Salt and Pepper” retinopathy 

• • Radiolucent bone disease (long bones) 

  • IUGR, glaucoma, hearing loss, pulmonic stenosis, patent ductus arteriosus, lymphadenopathy, jaundice, hepatosplenomegaly, thrombocytopenia, interstitial pneumonitis, diabetes mellitus

• Diagnosis

  • Culture from blood, urine, CSF, oral/nasal secretions

  • IgM titer

• Treatment

  • Supportive care

Cytomegalovirus

• Causative Organism – Human herpesvirus 5

• Most common intrauterine infection and infectious cause of hearing loss

• Transmission

  • Transplacental

  • Perinatal (contact with vagina during delivery or breast milk after delivery)

  • Contact with bodily fluids (urine/saliva)

  • Transmission is possible through reactivation of latent virus (decreased risk of transmission)

• Clinical Manifestations

  • Majority are asymptomatic at birth

  • Periventricular calcifications