Panel testing recommended at Breda Genetics for this condition:
If negative:
If negative again:
Aicardi-Goutières syndrome (ADAR, IFIH1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, TREX1)
Summary
Cerebroretinal microangiopathy with calcifications and cysts (CRMCC), also known as Coats plus syndrome, is a rare disorder caused by mutations in the CTC1, SNORD118 or POT1 gene. It shows consistent clinical overlap with Labrune syndrome (also known as leukoencephalopathy, brain calcifications, and cysts – LCC) and may resemble dyskeratosis congenital or Aicardi-Goutières syndrome in some patients.
Detailed clinical description
Cerebroretinal microangiopathy with calcifications and cysts is an autosomal recessive disorder characterized primarily by extensive intracranial calcifications, leukodystrophy, and brain cysts. The primary pathogenesis of the disorder moves from a small vessel obliterative microangiopathy.
The disorder is pleomorphic (pleiotropic), as it can affect several different organs and apparatuses, and shows broad clinical expressivity from patient to patient. Onset can be at any age, from early childhood to late adulthood. Symptoms include spasticity, ataxia, dystonia, seizures, and cognitive decline. Typically, patients also show bilateral retinal signs such as telangiectasia and exudates (Coats disease), hence the name Coats plus syndrome. Extraneurologic manifestations can also be observed: osteopenia with predisposition to fractures, poor bone healing, skeletal demineralization; bone marrow suppression; and portal hypertension leading to esophageal varices, which may rupture and give gastrointestinal bleeding. Some patients also show hair, skin, and nail changes, as well as anemia and thrombocytopenia. Intrauterine growth retardation has been reported.
Molecular genetics
The disorder can be caused by biallelic mutations in the CTC1, SNORD118 or POT1 gene. The transmission is autosomal recessive.
Prenatal diagnosis
No cases of prenatal diagnosis of cerebroretinal microangiopathy with calcifications and cysts have been so far reported. However, if the causative mutations are known, early molecular diagnosis on fetal DNA is possible.
Differential diagnosis
Leukoencephalopathy, brain calcifications, and cysts (LCC), also known as Labrune syndrome, is a clinically similar but genetically different disorder, showing central nervous system features as CRMCC in the absence of extraneurologic or systemic manifestations.
Some features of CRMCC resemble those observed in dyskeratosis congenital, which is actually an allelic disorder (some patients with dyskeratosis congenital have mutations in the CTC1 gene).
Primary familial brain calcification is a neurodegenerative disorder with characteristic calcium deposits in the basal ganglia and other brain areas visualized on neuroimaging. Most affected individuals are in good health during childhood and young adulthood and typically present in the fourth to fifth decade with gradually progressive neuropsychiatric and movement disorders. Mutations in SLC20A2 (previously known as IBGC3), PDGFRB, and PDGFB have been reported to cause primary familial brain calcification.
A number of children with cerebroretinal microangiopathy with calcifications and cysts have been misdiagnosed as having a later-onset form of Aicardi-Goutières syndrome. Aicardi-Goutières syndrome can be caused by TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, or ADAR mutations.
Genetic testing strategy
Cerebroretinal microangiopathy with calcifications and cysts present very significant overlap with Labrune syndrome and some similarities with other conditions such as dikeratosis congenital (which is also an allelic disorder) and primary familial brain calcification. Hence next generation sequencing panel testing based on clinical exome sequencing (6,000 genes) is recommended.
Panel testing recommended at Breda Genetics for this condition:
If negative:
If negative again:
Aicardi-Goutières syndrome (ADAR, IFIH1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, TREX1)
References:
Cerebroretinal microangiopathy with calcifications and cysts (CRMCC). Briggs TA, Abdel-Salam GM, Balicki M, Baxter P, Bertini E, Bishop N, Browne BH, Chitayat D, Chong WK, Eid MM, Halliday W, Hughes I, Klusmann-Koy A, Kurian M, Nischal KK, Rice GI, Stephenson JB, Surtees R, Talbot JF, Tehrani NN, Tolmie JL, Toomes C, van der Knaap MS, Crow YJ. Am J Med Genet A. 2008 Jan 15;146A(2):182-90. PMID: 18076099
A POT1 mutation implicates defective telomere end fill-in and telomere truncations in Coats plus. Takai H, Jenkinson E, Kabir S, Babul-Hirji R, Najm-Tehrani N, Chitayat DA, Crow YJ, de Lange T. Genes Dev. 2016 Apr 1;30(7):812-26. PMID: 27013236
Mutations in SNORD118 cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts. Jenkinson EM, Rodero MP, Kasher PR, Uggenti C, Oojageer A, Goosey LC, Rose Y, Kershaw CJ, Urquhart JE, Williams SG, Bhaskar SS, O’Sullivan J, Baerlocher GM, Haubitz M, Aubert G, Barañano KW, Barnicoat AJ, Battini R, Berger A, Blair EM, Brunstrom-Hernandez JE, Buckard JA, Cassiman DM, Caumes R, Cordelli DM, De Waele LM, Fay AJ, Ferreira P, Fletcher NA, Fryer AE, Goel H, Hemingway CA, Henneke M, Hughes I, Jefferson RJ, Kumar R, Lagae L, Landrieu PG, Lourenço CM, Malpas TJ, Mehta SG, Metz I, Naidu S, Õunap K, Panzer A, Prabhakar P, Quaghebeur G, Schiffmann R, Sherr EH, Sinnathuray KR, Soh C, Stewart HS, Stone J, Van Esch H, Van Mol CE, Vanderver A, Wakeling EL, Whitney A, Pavitt GD, Griffiths-Jones S, Rice GI, Revy P, van der Knaap MS, Livingston JH, O’Keefe RT, Crow YJ. Nat Genet. 2016 Oct;48(10):1185-92. PMID: 27571260
Cerebro-retinal microangiopathy with calcifications and cysts due to recessive mutations in the CTC1 gene. Bisserbe A, Tertian G, Buffet C, Turhan A, Lambotte O, Nasser G, Alvin P, Tardieu M, Riant F, Bergametti F, Tournier-Lasserve E, Denier C. Rev Neurol (Paris). 2015 May;171(5):445-9. PMID: 25843205
Dyskeratosis Congenita. Savage SA. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. SourceGeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2009 Nov 12 [updated 2016 May 26]. PMID: 20301779
Primary Familial Brain Calcification. Ramos EM, Oliveira J, Sobrido MJ, Coppola G. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. SourceGeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2004 Apr 18 [updated 2017 Aug 24]. PMID: 20301594
OMIM: 612199
