Ciliopathies

Question 1

Alstrom syndrome

Answer 1

Inheritance: Autosomal recessive
Gene: ALMS1

●Clinically similar to Bardet-Biedl
●Exceedingly rare (<500 known cases)
●Visual pathology – nystagmus, photophobia, diminished visual acuity, cone-rod dystrophy, blindness
●Obesity
●DCM with CHF
●Hearing loss
●Hepatic and renal dysfunction
●Advanced bone age
●Can differentiation from BBS by absence of polydactyly

Question 2

Bardet-Biedl

Answer 2

Inheritance: Autosomal recessive, Digenic recessive
Gene: BBS1-BBS12, CCDC28B, CEP290, TMEM67, MKS1, MKKS

●Retinitis pigmentosa
●Postaxial polydactyly
●Syndactyly
●Renal anomalies
●Intellectual disability
●Developmental delay
●Speech disorders
●Dilated cardiomyopathy
●Left ventricular hypertrophy
●GI problems and feeding difficulties
●Truncal obesity
●Genitourinary abnormalities
       oPersistent urogenital sinus
       oHypogonadism
       oHypoplasia of female reproductive organs
       oSeptate vagina
       oUterus duplex

Question 3

Joubert syndrome

Answer 3

Inheritance: X-linked, Autosomal recessive
Gene: OFD1, NPHP1, CEP290, AHI1, TMEM67 (MKS3), RPGRIP1L, CC2D2A, ARL13B, INPP5E, TMEM216, KIF7, TCTN1, TCTN2, TMEM237, CEP41, TMEM138, C5orf42, TMEM231, TCTN3

●Moderate intellectual disability
●Developmental delay
●Molar tooth sign on MRI
    oAbnormally deep interpenduncular fossa with cerebellar hypoplasia and brain stem anomalies
●Episodic tachypnea or apnea
●Atypical eye movements
     oNystagmus/Oculomotor apraxia
●Seizures
●Speech apraxia
●Autism
●Behavioral problems

Question 4

Meckel-Gruber syndrome

Answer 4

Inheritance: Autosomal recessive
Gene: MKS1, TMEM216, TMEM67, CEP290, RPGRIP1L, CC2D2A, NPHP3, TCTN2, B9D1, B9D2
●Embryonic lethal
●Renal cystic dysplasia
●CNS malformations
●Polydactyly
●Hepatic malformations
●Oligohydramnios
●Pulmonary hypoplasia

Question 5

Orofacuidigital syndrome 1 (OFD1)

Answer 5

Inheritance:X-linked dominant
Gene: OFD1
●Typically embryonic male lethal (some males have been reported surviving to post-natal period)
●Oral anomalies
oHamartomas/lipomas of tongue, cleft palate, hypodontia, dental anomalies
●Facial anomalies
oHypertelorism/telecanthus, nasal hypoplasia, cleft lip, micrognathia
●Digital anomalies
oBrachydacytly, syndactyly, 5th clino, duplicated large toe, pre- or postaxial polydactyly
●Brain anomalies
oIntracerebral cysts, agenesis of the corpus callosum, cerebellar agenesis w/ or w/o Dandy Walker malformation
●Polycystic kidney disease
●Mild ID (some have normal cognition)

Question 6

Polycystic Kidney disease (AD)

Answer 6

Inheritance: Autosomal dominant (more common), autosomal recessive
Gene: KD1, PKD2, PKD3 (AD), FCYT, PKHD1
Major features (AD):
●Late-onset
●Cysts develop in utero, but grow over time
oCompress kidneys and affect function
o50% of PKD patients have end-stage renal disease by age 60
●Bilateral renal cysts
●Cysts may develop on other organs
oLiver, pancreas, seminal vesicles, arachnoid membrane
●Intracranial aneurysm
●Aortic root dilatation/dissection
●Mitral valve pro

Question 7

Primary Cilliary Dyskinesia (PCD)

Answer 7

Inheritance: Autosomal recessive
Gene: DNA1, DNAH5, DNAH11, DNAI2, KTU, RSPH4A, RSPH9, LRRC50, TXNDC3

●Impaired ciliary motility
●Leads to frequent upper and lower respiratory infections due to poor clearance of mucus from the lungs
●Also causes heterotaxy (irregular placement of organs within the body)
oCiliary motility effects the proper distribution of sonic hedgehog protein, but when ciliary motility is impaired, Shh may be randomly distributed
oSitus inversus is a common form of heterotaxy – all major organs are reversed within the body – “Mirror image”

Question 8

Joubert syndrome: genotype/phenotype correlations

Answer 8

●Retinal dystrophy
●Cystic kidney disease
●Coloboma
●Congenital hepatic fibrosis
●Polydactyly
●Cleft/lip palate, orofacial anomalies

Question 9

Polycystic Kidney disease (AR)

Answer 9

Gene: ARPKD
Major features (AR):
●Renal cysts
●Typically identified in first few weeks of life
●Renal underdevelopment is common
     o30% death rate in newborns