Week 7: Psych, MF, auditory, ocular, ciliopathies

Question 1

Tell me about GJB2-related hearing loss

Answer 1

-Most common cause of SNHL in most populations
-AR
-Congenital, generally non-progressive, mild to profound, intrafamilial variability

-Most variants are sequence variants but there are three recurring deletions, up to 1/50 Europeans are carriers of 35delG variant

Question 2

Tell me about Usher syndrome

Answer 2

-AR, possible digenic inheritance
-Several types and subtypes

-Features: hearing loss, retinitis pigmentosa, possible vestibular anomalies
-Children typically born with or develop vision loss in late childhood to early adulthood

-Most common genetic cause of deaf-blindness

-Type 1: AR, digenic, congenital bilateral profound SNHL, adolescent onset RP, vestibular ataxia, children usually delayed in walking
-Type 2: AR, digenic, congenital bilateral SNHL ranges from mild to severe, adolescent to adult onset RP, normal vestibular function
-Type 3: AR, postlingual progressive SNHL, late onset RP, variable impairment of vestibular function

Question 3

Tell me about Pendred syndrome/Nonsyndromic enlarged vestibular aqueduct (NSEVA)

Answer 3

-Causes hearing loss, temporal bone anomalies, and thyroid disease
-AR: biallelic variants in SLC26A4 OR one path variant in SLC26A4 and one path variant in FOXI1 or KCNJ10
-Inter and intrafamilial variability
-Can be difficult to differentiate between Pendred and NSEVA

-SNHL: typically congenital, non-progressive and severe to profound, more variable in NSEVA which may be later onset and progressive
-Vestibular dysfunction
-Temporal bone abnormalities on temporal bone CT scan, unilateral or bilateral
-Cochlear abnormalities in Pendred, not NSEVA
-Goiter in late childhood or adulthood on US or clinical exam in 50-70% of Pendred but not NSEVA

Question 4

Tell me about Waardenburg syndrome

Answer 4

-Four subtypes with multiple subtypes
-Features: hearing loss, dysmorphic features (heterochromia, pigmentation anomalies, dystopia canthorum)
-Inter and intrafamilial variability

Type 1:
-AD, PAX3
-Congenital uni/bilateral non-progressive SNHL (typically bilateral and profound)
-White forelock or early graying of scalp
-Iris pigmentation abnormalities
-Dystopia canthorum

Type 2:
-AD or AR: MITF, SOX10, SNAI2
-Same features as WS1
-Absence of dystopia canthorum

Type 3:
-AD or AR: PAX3
-Same features as WS1
-Presence of upper limb abnormalities
-AKA Klein-Waardenburg syndrome

Type 4:
-AD or AR: EDNRB, EDN3, SOX10
-Same features as WS2 (absence of dystopia canthorum)
-Presence of Hirschsprung disease
-AKA Waardenburg-Shah syndrome

-Affected individuals not actually hyperteloric!
-Have skin on outside of eyes makes it look that way, pupils are actually normal distance apart with a large inner canthal distance

Question 5

What type of hearing loss do we typically consider genetic testing for?

Answer 5

Typically considered for bilateral SNHL or mixed hearing loss

NOT for unilateral or bilateral conductive hearing loss

Diagnostic yield highest for congenital, bilateral hearing loss

Question 6

What is aniridia? How is it caused?

Answer 6

-Absence of the iris tissue
-Classic aniridia is panocular with cataract, glaucoma, foveal hypoplasia, nystagmus, and/or keratopathy
-Rare

-Can be caused by single gene mutations or chromosomal defects, primarily affecting PAX6 (90% of cases), AD
-Other genes as well, some cases remain unexplained

PAX6 genotype/phenotype:
-Truncating/del variant typically result in classic aniridia phenotype
-Missense phenotype is much more variable: isolated cataract, foveal hypoplasia, ASD, MAC spectrum

Question 7

Tell me about WAGR syndrome

Answer 7

-Wilms tumor, Aniridia, Genitourinary anomalies, and ID
-Deletion of PAX6 and WT1 on 11p13

-Need screening for Wilms tumor in all infants with aniridia until WT1 deletion ruled out (renal US every 3-4 months)
-If WT1 deleted screening should continue through 5yo

Question 8

What is microphthalmia

Answer 8

Small eye

Question 9

What is anophthalmia

Answer 9

Missing eye

Question 10

What is a coloboma

Answer 10

Gap in ocular structures

Question 11

What is nystagmnus

Answer 11

Involuntary movement of the eye

Question 12

Tell me about Leber Congenital Amaurosis (LCA)

Answer 12

-Severe congenital or early childhood vision loss, nystagmnus often present
-15 genes, most AR
-CEP290, CRB1, GUCY2D, RPE65 most common

Question 13

What is amblyopia

Answer 13

Lazy eye

Question 14

What are cataracts

Answer 14

A clouding of the eye’s lens that can affect vision caused by proteins in the lens that break down and clump together

Question 15

Name some syndromic causes of retinitis pigmentosa

Answer 15

-Bardet-Biedl
-Joubert
-Primary ciliary dyskinesia
-Refsum disease
-Senior Loken syndrome
-Usher syndrome

Question 16

Tell me about heterotaxy

Answer 16

-May affect all organs, only some, or even be isolated to the heart
-Problems with spleen can lead to increased risk for infection (children need prophylactic antibiotics)

-Most have unknown genetic causes, some rare cases have gene identified (ie NODAL)
-Most are isolated, non-familial cases
-In rare cases can be inherited in AD or AR form even if genetic testing is negative

-Genetic testing has low yield with the exception of primary ciliary dyskinesia (PCD)-big reason why we do genetic testing in children with heterotaxy!

Question 17

Tell me about primary ciliary dyskinesia (PCD)

Answer 17

-All symptoms of PCD stem from the fact that the cilia (motile) do not move as they are supposed to
-In other words, the lung disease caused by PCD is secondary to the primary issue of poor cilia movement
-This is NOT referring to lack of movement of single primary cilia on cell surface!!

-PCD is group of mostly AR disorders that affect motile cilia
-Results in chronic lung disease (like CF), infertility, increased risk for heterotaxy

-Genetic testing for PCD done on kids with heterotaxy or recurrent pulmonary/sinus infection/lung disease
-PCD panels also include CTFR in case kids with CF missed
-If negative, can undergo ciliary biopsy

Question 18

Name some cardinal features of ciliopathies

Answer 18

-Retinal degeneration
-Progressive kidney disease
-Cerebral anomalies
-Skeletal anomalies
-Liver disease
-Truncal obesity
-Laterality defects (heterotaxy)

Question 19

Tell me about Bardet-Biedl syndrome

Answer 19

-The classic ciliopathy, disease of non-motile cilia
-Main features: obesity, post axial polydactyly, cognitive impairment, retinal dystrophy, kidney disease, hypogonadism
-Aggressive diabetes and hypertension treatment so don’t damage vital organs

-At least 26 genes, AR
-Rare cases of digenic inheritance
-Given overlap with other cilipothies, broader panel usually completed

Question 20

Tell me about Alstrom syndrome

Answer 20

-Progressive disorder that affects many (most) body systems
-MAY appear normal at birth, but nystagmus becomes apparent before 1st bday
-Eventually pts become blind and most become deaf as well
-Cardinal features: nystagmus, photodysphoria, low vision/blindness, glue ear, chronic otitis media, sensorineural impairment, cardiomyopathy, obesity, HTN, male hypogonadism, T2DM, enlarged liver, UTIs, incontience, proteinuria, chest congestion, asthma, seizures, muscle weakness, unusual sleep patterns, DD, speech issues, learning disability,
-Other significant organ involvement/damage

-AR: ALMS1

Question 21

If a newborn has heterotaxy, what testing should we order (given insurance will cover it)?

Answer 21

Exome!

If cannot get WES then primary ciliary dyskinesia panel/heterotaxy panel