Hearing and vision disorders

Question 1

BLEPHAROPHIMOSIS, PTOSIS, and EPICANTHUS INVERSUS

Responsible gene:
Protein:
Cytogenetic locus:
Inheritance:
Clinical Features and Diagnostic Criteria:
Clinical Tests:
Molecular Tests:
Disease Mechanism:

Answer 1

Responsible gene: FOXL2
Protein: ForkheadBox Protein L2
Cytogenetic locus: 3q23
Inheritance: AD (50% de novo)
Clinical Features and Diagnostic Criteria: blepharophimosis, ptosis, epicanthus inversus, and telecanthus. BPES type Iincludes the four major features and premature ovarian failure (POF); BPES type II includes only the four major features. Can also see: lacrimal duct anomalies, amblyopia, strabismus, and refractive errors. Minor features: broad nasal bridge, low-set ears, and a short philtrum.
Clinical Tests: FOXL2 sequencing, deletion/duplication analysis
Molecular Tests:Combination of seqanalysis and deletion testing
Disease Mechanism: FOXL2is a transcriptional repressor of granulosa cell differentiation; mutations cause accelerated differentiation of granulosa cells and secondary depletion of the primordial follicle pool
Treatment/Prognosis: Surgical correction of eye anomalies, ovum donation if POF

Question 2

CONGENITAL HEARING LOSS -Connexin 26 and 30

Responsible genes:
Proteins:
Cytogenetic loci:
Inheritance:
Clinical Features and Diagnostic Criteria:
Clinical Tests:
Molecular Tests:
Disease Mechanism:
Treatment/Prognosis:

Answer 2

Responsible genes: GJB2 (Cx26), GJB6 (Cx30)
Proteins: Gap junction proteins 2 and 6
Cytogenetic loci: 13q11-12
Inheritance: AR
Clinical Features and Diagnostic Criteria: Congenital mild-profound SNHL. Rare patients can have AD Cx26 HL which can include skin findings: palmar-planter keratoderma, KID syndrome (keratitis-ichthyosis-deafness)
Clinical Tests: Newborn hearing screen, ABR diagnostic, monitor with standard audiometry.
Molecular Tests:GJB2: sequencing of exon 2 and exon 1 for splice site mutation (4thmost common mutation). 35delG common in Caucasians, 235delC in Asians, 167delT, del35Gand Cx30 gene deletion in Ashkenazi Jewish. GJB6-D13S1830 deletion: deletion that includes Cx30, causes HL if homozygous or combined with single Cn26 mutation.
Disease Mechanism: Loss of gap junction prevents recycling of toxic ions and metabolites away from hair cells leading to their death
Treatment/Prognosis: No treatment. Some have progressive HL. Habilitation with hearing aids or cochlear implants.

Question 3

HERMANSY-PUDLAK SYNDROME

Responsible gene :
Inheritance:
Clinical Features and Diagnostic Criteria:
Molecular Tests:
Disease Mechanism:
Treatment/Prognosis:

Answer 3

Responsible gene (protein, cytogenetic locus): HPS1(10q23.1, HPS 1 protein), AP3B1(5q14.1, AP-3 complex subunit beta), HPS3,4,5,6,7and 8(3q24, 22q11.2-q12.2, 11p15-p13, 10q24.3, 6p22.3, 19q13, HPS 3,4,5,and 6 proteins, dysbindin, and biogenesis of lysosome-related organelles complex -1sununit2), HPS9(BLOC1S6)(15q21.1)
Inheritance: AR
Clinical Features and Diagnostic Criteria: Findings of oculocutaneousalbanismand a bleeding diathesis: hypopigmentation of the skin and the hair, nystagmus, reduced iris pigment, reduced retinal pigment, foveal hypoplasia, increased crossing of optic nerve fibers. Can develop skin cancer, pulmonary fibrosis, colitis
Clinical Tests: Absent platelet dense bodies (sine qua non) on platelet EM. Prolonged bleeding time.
Molecular Tests:Del/Dup analysis HPS1 (~75% Puerto Rican HPS), HPS3(~25% Puerto Rican HPS). Targeted mutation analysis HPS3(~5% non Puerto Rican HPS)
Disease Mechanism: The HPS genes protein products have unknown fcn
Treatment/Prognosis: DDAVP prior to dental work, thrombin-soaked gel foam for minor cuts, skin protection, annual eye exam, skin exam, and in adulthood PFT’s.

Question 4

JERVELL and LANGE-NIELSEN SYNDROME

Responsible gene:
Protein:
Cytogenetic loci:
Inheritance:
Clinical Features and Diagnostic Criteria:
Clinical Tests:
Molecular Tests:
Disease Mechanism:
Treatment/Prognosis:

Answer 4

Responsible gene: KCNQ1 andKCNE1
Protein: Voltage-gated K+ channel protein KvLQT1; K+ voltage-gated channel subfamily E member 1
Cytogenetic loci: 11p15.5, 21q22.1-q22.2
Inheritance: AR (Heterozygotes at risk for AD long QT a.k.a. Romano Ward syndrome)
Clinical Features and Diagnostic Criteria: Congenital severe-profound bilateral SNHL and prolonged QT interval. At risk for arrhythmia, syncope, and sudden death
Clinical Tests: Hearing tests (ABR, audiogram)
Molecular Tests:KCNQ1sequencing (90%), KCNE1(10%)
Disease Mechanism: In cardiac cells: abnormal repolarization of the ventricular action potential. In cochlear cells: abnormal depolarization of the auditory nerve
Treatment/Prognosis: Cochlear implants for HL, beta blockers, cardiac pacemakers, and/or implantable defibrillators. Avoid QT prolonging drugs (http://www.arizonacert.org/). If left untreated, over ½ of children with JLNS die prior to age 15 yrs

Question 5

USHER SYNDROME

Responsible genes:
Proteins:
Inheritance:
Clinical Features and Diagnostic Criteria:
Clinical Tests:
Molecular Tests:
Disease Mechanism:
Treatment/Prognosis:

Answer 5

Responsible genes: multiple genes, majority of cases due to MYO7A,USH2A
Proteins: Myosin-VIIa, UsherinCytogenetic loci: 11q13.5, 1q41I
nheritance: AR
Clinical Features and Diagnostic Criteria: Type Icongenital profound HL, congenital balance problems, retinitis pigmentosa(RP) onset pre-puberty. Type IIcongenital mild-severe HL, normal balance, RP onset in teens-20’s, Type IIIprogressive later onset HL, progressive balance problems, variable onset RP.
Clinical Tests: hearing tests, ERG, eye exam for pigment changes
Molecular Tests:Type IMYO7A sequence analysis (40-50%) Type IIUSH2A sequencing (65%)
Disease Mechanism: RP is caused by degeneration of rod and cone functions of the retina. For at least some gene, inner hair cell function and structure are affected in the ear.
Treatment/Prognosis: RP is progressive, bilateral, and symmetric resulting in progressively constricted visual fields though not complete blindness. Vitamin A may slow progression. HL is complete in Usher Type I and progressive in types II and III. Cochlear implants and hearing aids for HL
USHERSYNDROME

Question 6

WAARDENBURG SYNDROME

Responsible gene:
Protein:
Cytogenetic locus:
Inheritance:
Clinical Features and Diagnostic Criteria:
Clinical Tests:
Molecular Tests:
Disease Mechanism:
Treatment/Prognosis:

Answer 6

Responsible gene: PAX3
Protein: Paired box protein Pax-3
Cytogenetic locus: 2q35
Inheritance: AD
Clinical Features and Diagnostic Criteria: WS1: SNHL, heterochromicirides, white forelock, early graying, leukoderma, dystrophiacanthorum, neural tube defect. WS2:WS1 without dystrophiacanthorumWS3:WS1 features and limb hypoplasia or contracture, carpal bone fusion, or syndactyly WS4:WS1 with Hirschprungdisease
Clinical Tests: ABR, audiogram, calculation of W-index to identify dystopia canthorum
Molecular Tests:PAX3gene sequencing (90% WS1)
Disease Mechanism: Haploinsufficiency. PAX3 is a homeobox transcription factor involved in melanocyte development.
Treatment/Prognosis: Hearing aids or cochlear implants. Folic acid supplementation of pregnancies at risk for WS1 related neural tube defect