What Problems are Ciliopathies Associated With?

Patient Presentation
A 6-month-old female came to clinic for her health supervision visit. Her mother was worried because she seemed to often turn her head differently or held it in a strange posture. This had not been present at her 4 month visit but was occurring more over the past month. Light didn’t seem to bother her and she seemed to respond to face and voice. Her mother also said that she could roll over but it was rare. She was not sitting by herself, but could with support. Her body didn’t seem to move in strange ways when seated.

The past medical history was non-contributory. The family history was positive for strokes in older family members and heart disease. There was no history of early infant deaths or genetic problems.

The pertinent physical exam showed normal vital signs and growth parameters were 50-75% for age and tracking appropriately. She would look at the examiner but would seem to throw her head in the direction of where she wanted to look. She also seemed to be floppier in her mother’s arms. Neurological examination showed that she had abnormal eye movements that seemed to be more lateral movements, but occasionally there were some strange vertical movements as well. The eyes did not have “roving” movements. Her pupils were equal, round and responsive to light. She did seem to be able to fix on the examiner’s face or an interesting object. She had decreased tone overall. She could push herself up from prone but it was poor and not sustained. She would not roll over and would “clamshell” when put into a seated posture. She did not seem to have abnormal truncal movements when seated. Strength appeared to be intact.

The diagnosis of a 6 month old with new onset of abnormal eye movements and hypotonia was made. She was seen by ophthalmology within 2 days who made the diagnosis of ocular motor apraxia. The ophthalmologist also ordered a head magnetic resonance imaging study because of the risk of a potential syndrome which showed hypoplasia of the corpus callosum. The patient had also been referred to physical therapy and neurology. The ophthalmologist, neurologist and general pediatrician conferred about the potential further evaluation of the patient and agreed to genetic testing for possible causes including nephronophthisis. The patient was doing well in physical therapy and the genetic testing was pending. The family had not gotten other laboratories such as an urinalysis yet.

Nephronophthisis (NPHP) one cause of end-stage renal disease (ESRD) usually occurring before age 30 years. NPHP is a non-motile ciliopathy affecting cellular sensing in the renal tubular epithelium. See To Learn More below.
The incidence varies according to location with 1:1 million in the US but 1:50,000 in Finland.

There are 3 subtypes:

  • Infantile
    • Occurs usually within 1 year of life
    • Enlarged kidneys and severe hypertension
    • In utero can have oligohydramnios problems such as pulmonary hypoplasia, facial dysmorphisms, limb contractures
    • Extra-renal problems include congenital heart disease, liver fibrosis, recurrent pulmonary infections
  • Juvenile
    • Most common
    • Occurs generally by early adolescence (median age 13 years)
    • Normal size or small kidneys, impaired concentrating and electrolyte abnormalities, chronic kidney disease, normal blood pressure
    • Extra-renal problems include brain malformations (cerebellar vermis aplasia), retinal degeneration and gaze problems including ocular motor apraxia, liver fibrosis and skeletal defects
    • Common presentations include poor growth, polydipsia, polyuria, and chronic iron-resistant anemia
  • Adolescent
    • Occurs by later adolescence
    • Manifestations are similar to juvenile type

Genetically there are many different genes associated with NPHP which are of autosomal recessive inheritance.
Up to 80+% of individuals may have no extra-renal problems.

NPHP is associated with other syndromes include Joubert syndrome, Oculomotor Apraxia (Cogen type), Meckel-Gruber syndrome, Senior-Loken syndrome, and various syndromic skeletal defects.

A review of ocular motor apraxia can be found here.

Learning Point
Cilia are found on most vertebrate cells. They can be motile or immotile. Cilia are an important cell membrane structure and most of the genes encoding it are conserved. There are multiple genes that cause ciliopathies. Those that are errant often are associated with the basal structures that integrate into the plasma membrane and the areas adjacent to it (primary ciliopathies). Secondary ciliopathies are caused by mutations not in the cilia itself but help the cilia to function.

Problems associated with ciliopathies include:

  • Motile cilia
    • These can move a cell (such as sperm) or move overlying fluid such as lungs, brain ependymal cells and oviducts
    • Hydrocephalus
    • Infertility
    • Respiratory problems, chronic
  • Non-motile cilia
    • Most sensory cilia are non-mobile but can also be mobile.
    • Hydrocephalus
    • Anosmia
    • Central nervous system including ataxia, epilepsy, intellectual disability, malformations
    • Facial anomalies
    • Genital problems including hypogonadism
    • Hearing problems
    • Liver fibrosis
    • Obesity, central
    • Renal dystrophy
    • Skeletal problems
  • Both
    • Organ laterality problems including the node which is a transient developmental structure important for left-right axis determination
    • Congenital heart disease

Questions for Further Discussion
1. What are indications for dialysis? A review can be found here
2. What are indications for renal transplant?
3. What is in the differential diagnosis of hypotonia? A review can be found here

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Kidney Failure and Eye Diseases.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Deacon BS, Lowery RS, Phillips PH, Schaefer GB. Congenital ocular motor apraxia, the NPHP1 gene, and surveillance for nephronophthisis. J AAPOS. 2013;17(3):332-333. doi:10.1016/j.jaapos.2013.02.003

Stokman M, Lilien M, Knoers N. Nephronophthisis. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®® University of Washington, Seattle; 1993. Accessed April 12, 2021. http://www.ncbi.nlm.nih.gov/books/NBK368475/

Reiter JF, Leroux MR. Genes and molecular pathways underpinning ciliopathies. Nature Reviews Molecular Cell Biology. 2017;18(9):533-547. doi:10.1038/nrm.2017.60

Luo F, Tao Y-H. Nephronophthisis: A review of genotype-phenotype correlation. Nephrology (Carlton). 2018;23(10):904-911. doi:10.1111/nep.13393

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa