ciliopathy

Spondylometaphyseal Dysplasia, Axial

Clinical Characteristics
Ocular Features: 

Due to the small number of individuals reported, the ocular phenotype is variable and likely incompletely described.  Optic atrophy and pigmentary retinopathy are the most consistent findings.  The most completely studied individual had evidence of slight bilateral optic nerve atrophy on cerebral MRI imaging as well.  There may be extensive RPE atrophy but the fundus pigmentation is usually described as resembling retinitis pigmentosa.  The ERG in several patients during the second decade of life already shows severe dysfunction of the photoreceptors, with cones the most severely impacted.  In spite of this Goldmann visual fields have been reported to be normal.  The macula and OCT have been reported as normal.  Telecanthus, nystagmus, hypertelorism, proptosis, and photophobia have been reported.  Early onset and progressive visual impairment are characteristic.

Systemic Features: 

Only 5 patients with this condition have been reported most of whom were short in stature.  There may be frontal bossing and the chest is narrow and flattened.  Moderate platyspondyly has been described with enlarged but shortened ribs and an irregular iliac crest.  Rhizomelic shortening of the limbs is common.  The femoral metaphyses are abnormal with their necks shortened and enlarged.  The ribs are enlarged but shortened as well and are flared at the ends.  Mental development and function are normal.

Genetics

This is an autosomal recessive condition due to homozygous or compound heterozygous mutations in C21orf2.

Treatment
Treatment Options: 

No effective treatment is known.

References
Article Title: 

Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations

Wang Z, Iida A, Miyake N, Nishiguchi KM, Fujita K, Nakazawa T, Alswaid A, Albalwi MA, Kim OH, Cho TJ, Lim GY, Isidor B, David A, Rustad CF, Merckoll E, Westvik J, Stattin EL, Grigelioniene G, Kou I, Nakajima M, Ohashi H, Smithson S, Matsumoto N, Nishimura G, Ikegawa S. Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations. PLoS One. 2016 Mar 14;11(13).

PubMed ID: 
26974433

Axial spondylometaphysealdysplasia

Ehara S, Kim OH, Maisawa S, Takasago Y, Nishimura G. Axial spondylometaphysealdysplasia. Eur J Pediatr. 1997 Aug;156(8):627-30.

PubMed ID: 
9266195

Short-Rib Thoracic Dysplasia 9

Clinical Characteristics
Ocular Features: 

A pigmentary retinopathy resembling retinitis pigmentosa is present in the majority of individuals.  Reduced acuity is likely responsible for the associated nystagmus and occasional strabismus.  Night blindness is a feature although the age of onset is unknown.  Visual acuity is decreased in the first decade but at least one patient at age 40 years still had vision of 20/40-20/50.  The ERG shows decreased scotopic and photopic responses as early as 12 years of age.  The retinopathy has been described as an atypical nonpigmented retinal degeneration in the peripheral retina. However, bone-spicule pigmentary deposits have been noted.  The retinal disease is progressive. 

Systemic Features: 

The LFT140 mutation has widespread effects, impacting the kidney, liver and skeletal systems.  The thorax is shortened, while the ribs are abnormally short and may result in respiratory difficulties, recurrent infections, and an early demise.  The middle phalanges of the hands and feet often have cone-shaped epiphyses, especially notable in childhood and leading to brachydactyly.  The long bones are often shortened as well.  The femoral neck can be short while the femoral epiphyses are often flattened.  Microcephaly has been reported in several individuals.

The liver may be enlarged and become fibrotic.  The kidneys often are cystic and histologically may have sclerosing glomerulonephropathy.  Kidney disease has an onset in the first decade and its progression often defines the survival prognosis.  Renal transplantation can be lifesaving when nephronophthisis develops.  Psychomotor delays have been reported but are uncommon. 

Genetics

Homozygous or compound heterozygous mutations in the IFT140 gene (16p13.3) have been identified.  However, there is some genetic heterogeneity since several patients having the typical phenotype have been reported with only heterozygous mutations.

This may be the same condition as Retinitis Pigmentosa 80 (617781) in which the same mutation occurs. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for the general disease.  Renal and pulmonary function needs to be monitored with intervention as needed.  Some patients have benefitted from renal transplantation.

References
Article Title: 

Combined NGS approaches identify mutations in the intraflagellar transport gene IFT140 in skeletal ciliopathies with early progressive kidney Disease

Schmidts M, Frank V, Eisenberger T, Al Turki S, Bizet AA, Antony D, Rix S, Decker C, Bachmann N, Bald M, Vinke T, Toenshoff B, Di Donato N, Neuhann T, Hartley JL, Maher ER, Bogdanovic R, Peco-Antic A, Mache C, Hurles ME, Joksic I, Guc-Scekic M, Dobricic J, Brankovic-Magic M, Bolz HJ, Pazour GJ, Beales PL, Scambler PJ, Saunier S, Mitchison HM, Bergmann C. Combined NGS approaches identify mutations in the intraflagellar transport gene IFT140 in skeletal ciliopathies with early progressive kidney Disease. Hum Mutat. 2013 May;34(5):714-24.

PubMed ID: 
23418020

Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations

Perrault I, Saunier S, Hanein S, Filhol E, Bizet AA, Collins F, Salih MA, Gerber S, Delphin N, Bigot K, Orssaud C, Silva E, Baudouin V, Oud MM, Shannon N, Le Merrer M, Roche O, Pietrement C, Goumid J, Baumann C, Bole-Feysot C, Nitschke P, Zahrate M, Beales P, Arts HH, Munnich A, Kaplan J, Antignac C, Cormier-Daire V, Rozet JM. Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations. Am J Hum Genet. 2012 May 4;90(5):864-70.

PubMed ID: 
22503633

Chorioretinopathy with Microcephaly 2

Clinical Characteristics
Ocular Features: 

Microphthalmia and microcornea are seen in most individuals and one patient had unilateral clinical anophthalmia. Hyperopia and cataracts may be present. Nystagmus is common.  One patient had a corneal opacity.  The chorioretinopathy has not been described beyond evidence of the maculopathy, attenuated retinal vessels, and occasionally hyperpigmented zones.  The ERG is either not recordable or consistent with a severe rod-cone dystrophy.  Vitreous inclusions and a 'vitreoretinal dystrophy' with falciform retinal folds were noted in several patients.  A traction detachment was present in one and bilateral serous detachments were noted in another.

Systemic Features: 

Patients have mild to severe microcephaly (up to -15 SD) with psychomotor delays.  Profound intellectual disability is a consistent feature.  Physical growth is retarded and patients have shortness of stature.  Most patients are unable to sit, stand, or walk unassisted.  One patient died at 5.5 years of age while another was alive at 20 years of age.  Rare patients may have hearing loss and seizures.

Scoliosis, kyphosis, and lordosis may be seen while  other skeletal malformations seem to occur sporadically e.g., triphalangeal thumbs, brachydactyly, postaxial polydactyly, and restricted large joint motion.  

The forehead slopes markedly.  Neuroimaging shows a consistent reduction in cortex size with simple gyral folding while the cerebellum and the brain stem are also small.  Subarachnoid cysts have been noted in several patients and the corpus callosum may be short or otherwise malformed.

Genetics

Homozygous mutations in the PLK4 gene (4q28.2) segregate with this condition.  Its product localizes to centrioles and plays a central role in centriole duplication.

For a somewhat similar condition but without the sloping forhead see Chorioretinoapathy with Microcephaly 1 (251270) but resulting from homozygous mutations in TUBGCP6.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is know.

References
Article Title: 

Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy

Martin CA, Ahmad I, Klingseisen A, Hussain MS, Bicknell LS, Leitch A, Nurnberg G, Toliat MR, Murray JE, Hunt D, Khan F, Ali Z, Tinschert S, Ding J, Keith C, Harley ME, Heyn P, Muller R, Hoffmann I, Daire VC, Dollfus H, Dupuis L, Bashamboo A, McElreavey K, Kariminejad A, Mendoza-Londono R, Moore AT, Saggar A, Schlechter C, Weleber R, Thiele H, Altmuller J, Hohne W, Hurles ME, Noegel AA, Baig SM, Nurnberg P, Jackson AP. Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy. Nat Genet. 2014 Dec;46(12):1283-92.

PubMed ID: 
25344692
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