View source for Medicine:Cerebroretinal microangiopathy with calcifications and cysts

{{Infobox medical condition (new)
| name            = Cerebroretinal microangiopathy with calcifications and cysts
| synonyms        = CRMCC
| image           = Exudative retinopathy and vitreos hemorrhage in cerebroretinal microangiopathy with calcifications and cysts.jpg
| alt             = Exudative retinopathy and vitreous hemorrhage in cerebroretinal microangiopathy with calcifications and cysts
| caption         = Vitreous hemorrhage and exudative retinal detachment resembling Coats' disease in a child with cerebroretinal microangiopathy with calcifications and cysts
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'''Cerebroretinal [[Medicine:Microangiopathy|microangiopathy]] with calcifications and cysts (CRMCC)''' is a rare [[Medicine:Genetic disorder|genetic disorder]], which affects multiple [[Biology:Organ (anatomy)|organs]].<ref name="pmid16943371">{{cite journal |vauthors=Linnankivi T, Valanne L, Paetau A, Alafuzoff I, Hakumäki JM, Kivelä T, Lönnqvist T, Mäkitie O, Pääkkönen L, Vainionpää L, Vanninen R, Herva R, Pihko H | title = Cerebroretinal microangiopathy with calcifications and cysts | journal = Neurology | volume = 67 | issue = 8 | pages = 1347–43 |date=Oct 2006 | pmid = 16943371 | doi = 10.1212/01.wnl.0000236999.63933.b0| s2cid = 28941194 }}</ref><ref name="pmid18076099">{{cite journal | vauthors = 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 | title = Cerebroretinal microangiopathy with calcifications and cysts (CRMCC) | journal = Am J Med Genet A | volume = 146A | issue = 2 | pages = 182–90 |date=Jan 2008 | pmid = 18076099 | doi = 10.1002/ajmg.a.32080| s2cid = 39256035 }}</ref> Its hallmarks are widespread progressive [[Biology:Calcification|calcification]]s, cysts and abnormalities of the [[Biology:White matter|white matter]] of the brain, usually occurring together with abnormalities of the blood vessels of the [[Biology:Retina|retina]]. Additional features include poor prenatal growth, [[Medicine:Preterm birth|preterm birth]], [[Medicine:Anemia|anemia]], [[Unsolved:Osteopenia|osteopenia]] and [[Medicine:Bone fracture|bone fracture]]s,<ref name=pmid15002047>{{cite journal |vauthors=Crow YJ, McMenamin J, Haenggeli CA, Hadley DM, Tirupathi S, Treacy EP, Zuberi SM, Browne BH, Tolmie JL, Stephenson JB | title = Coats' plus: a progressive familial syndrome of bilateral Coats' disease, characteristic cerebral calcification, leukoencephalopathy, slow pre- and post-natal linear growth and defects of bone marrow and integument | journal = Neuropediatrics | volume = 35 | issue = 1 | pages = 10–19|date=Feb 2004 | pmid = 15002047 | doi = 10.1055/s-2003-43552}}</ref><ref name=pmid11992766>{{cite journal |vauthors=Sazgar M, Leonard NJ, Renaud DL, Bhargava R, Sinclair DB | title = Intracranial calcification, retinopathy, and osteopenia: a new syndrome? | journal = Pediatr Neurol | volume = 26 | issue = 4 | pages = 324–8|date=Apr 2002 | pmid = 11992766 | doi = 10.1016/s0887-8994(01)00398-8}}</ref><ref name="pmid21523908">{{cite journal |vauthors=Toiviainen-Salo S, Linnankivi T, Saarinen A, Mäyränpää MK, Karikoski R, Mäkitie O | title = Cerebroretinal microangiopathy with calcifications and cysts: characterization of the skeletal phenotype | journal = Am J Med Genet A | volume = 155A | issue = 6 | pages = 1322–6 |date=Jun 2011 | pmid = 21523908 | doi = 10.1002/ajmg.a.33994| s2cid = 19482634 }}</ref> and [[Medicine:Gastrointestinal bleeding|gastrointestinal bleeding]].<ref name="pmid21373254">{{cite journal |vauthors=Briggs TA, Hubbard M, Hawkins C, Cole T, Livingston JH, Crow YJ, Pigott A | title = Treatment of gastrointestinal bleeding in a probable case of cerebroretinal microangiopathy with calcifications and cysts | journal = Mol Syndromol | volume = 1 | issue = 4 | pages = 159–62 |date=Jan 2011 | pmid = 21373254 | pmc = 3042118| doi = 10.1159/000321559}}</ref> It is caused by [[Biology:Compound heterozygosity|compound heterozygous]] [[Biology:Mutation|mutation]]s in the '''conserved [[Biology:Telomere|telomere]] maintenance component 1 (''CTC1'') [[Biology:Gene|gene]]''',<ref name="pmid22267198">{{cite journal |vauthors=Anderson BH, Kasher PR, Mayer J, Szynkiewicz M, Jenkinson EM, Bhaskar SS, Urquhart JE, Daly SB, Dickerson JE, O'Sullivan J, Leibundgut EO, Muter J, Abdel-Salem GM, Babul-Hirji R, Baxter P, Berger A, Bonafé L, Brunstom-Hernandez JE, Buckard JA, Chitayat D, Chong WK, Cordelli DM, Ferreira P, Fluss J, Forrest EH, Franzoni E, Garone C, Hammans SR, Houge G, Hughes I, Jacquemont S, Jeannet PY, Jefferson RJ, Kumar R, Kutschke G, Lundberg S, Lourenço CM, Mehta R, Naidu S, Nischal KK, Nunes L, Ounap K, Philippart M, Prabhakar P, Risen SR, Schiffmann R, Soh C, Stephenson JB, Stewart H, Stone J, Tolmie JL, van der Knaap MS, Vieira JP, Vilain CN, Wakeling EL, Wermenbol V, Whitney A, Lovell SC, Meyer S, Livingston JH, Baerlocher GM, Black GC, Rice GI, Crow YJ | title = Mutations in ''CTC1'', encoding conserved telomere maintenance component 1, cause Coats plus | journal = Nat Genet | volume = 44 | issue = 3 | pages = 338–42 |date=Jan 2012 | pmid = 22267198 | doi = 10.1038/ng.1084| hdl = 10400.17/2516 | s2cid = 205343417 | hdl-access = free }}</ref><ref name=PolviA>{{cite journal |vauthors=Polvi A, Linnankivi T, Kivelä T, Herva R, Keating JP, Mäkitie O, Pareyson D, Vainionpää L, Lahtinen J, Hovatta I, Pihko H, Lehesjoki AE | title = Mutations in ''CTC1'', encoding the CTS telomere maintenance complex component 1, cause cerebroretinal microangiopathy with calcifications and cysts | journal = Am J Hum Genet | volume = 90| issue = 3 | pages = 540–549|date=Mar 2012 | pmid = 22387016| pmc = 3309194| doi = 10.1016/j.ajhg.2012.02.002}}</ref> but its exact pathophysiology is still not well understood.

Cerebroretinal microangiopathy with calcifications and cysts is alternatively known as the '''Coats plus''' syndrome,<ref name="pmid15002047"/> a reference to its most typical ocular [[Biology:Phenotype|phenotype]].

==Signs and Symptoms==
===Presentation===

====Before birth====
A child who has inherited this disorder will grow slower than normal in the [[Biology:Uterus|uterus]] before birth and typically will be born [[Medicine:Preterm birth|before term]].<ref name="pmid16943371"/><ref name="pmid18076099"/><ref name="pmid15002047"/> The pregnancy can be complicated by gestational hypertension and [[Medicine:Pre-eclampsia|pre-eclampsia]].{{citation needed|date=September 2020}}

====After birth====
The majority of affected children present with ''symptoms and signs relating to the eyes'' such as leukokoria, redness, irritation and impaired vision, which result from [[Medicine:Retinal detachment|retinal detachment]] and [[Medicine:Glaucoma|glaucoma]].<ref name="pmid16943371"/><ref name="pmid18076099"/><ref name="pmid15002047"/> A minority present with ''seizures or spasticity''. The time of onset of symptoms varies from infancy to [[Social:Adolescence|adolescence]]. Because a child born [[Medicine:Preterm birth|before term]] will need to undergo screening for [[Medicine:Retinopathy of prematurity|retinopathy of prematurity]], some will have abnormalities in their retinal blood vessels detected when they have no symptoms yet.{{citation needed|date=September 2020}}

===Brain===
Neurologic symptoms and signs vary depending on the site of the brain abnormalities. Common symptoms are partial [[Medicine:Epilepsy|epilepsy]], asymmetric spasticity, [[Medicine:Ataxia|ataxia]] and [[Cognition|cognitive]] impairment.<ref name="pmid16943371"/><ref name="pmid18076099"/><ref name="pmid15002047"/> The latter affects visuospatial and visuoconstructive skills first. The [[Medicine:Intracranial pressure|intracranial pressure]] can be elevated if cysts develop in the brain. Migraine-like headaches can occur.{{citation needed|date=September 2020}}

===Eyes===
Smaller [[Biology:Blood vessel|blood vessel]]s of the [[Biology:Retina|retina]] are abnormally developed and appear tortuous and dilated to a variable extent, typically in one sector and mainly in the peripheral and temporal portions of the retina.<ref name="pmid16943371"/><ref name="pmid18076099"/><ref name="pmid15002047"/><ref name="pmid3402627">{{cite journal |vauthors=Tolmie JL, Browne BH, McGettrick PM, Stephenson JB | title = A familial syndrome with Coats' reaction retinal angiomas, hair and nail defects and intracranial calcification | journal = Eye (Lond) | volume = 2 | issue = Pt 3 | pages = 297–303 | year = 1988 | pmid = 3402627 | doi = 10.1038/eye.1988.56| doi-access = free }}</ref> This is known as telangiectasia. The vessel walls are weak and leak [[Biology:Blood plasma|blood plasma]] and [[Chemistry:Blood lipids|lipid]] within and underneath the retina. This leakage can lead to exudative [[Medicine:Retinal detachment|retinal detachment]], also known as exudative retinopathy in this context. The detachment typically has a yellowish tint because the fluid under the retina contains lipid. These findings mimic Coats disease.<ref name="pmid3402627"/> Characteristically, the abnormal vessels are localized and the retinal blood vessels peripheral to the abnormal ones seemingly have failed to develop and are thus not seen.

In some eyes, retinal vessels form small nodules on the surface of the retina, known as angiomas.<ref name="pmid16943371"/> These can bleed and be attached to the vitreous humour. The attachment can cause traction [[Medicine:Retinal detachment|retinal detachment]].

===Gastrointestinal tract===
Recurrent [[Chemistry:Intestine|intestinal]] bleeding is fairly common.<ref name="pmid16943371"/><ref name="pmid18076099"/><ref name="pmid21373254"/> It originates from telangiectatic small blood vessels in the intestinal mucosa. Additional findings in some individuals are [[Medicine:Portal hypertension|portal hypertension]] and liver failure.<ref name="pmid16943371"/><ref name="pmid18076099"/>

===Blood===
Many affected children develop [[Medicine:Anemia|anemia]], which may be macrocytic in type.<ref name="pmid16943371"/><ref name="pmid18076099"/><ref name="pmid11992766"/> Some also develop [[Medicine:Thrombocytopenia|thrombocytopenia]]. Bone marrow examinations may show megaloblasts and increased erythropoiesis or [[Medicine:Bone marrow suppression|bone marrow suppression]].<ref name="pmid16943371"/><ref name="pmid18076099"/><ref name="pmid11992766"/>

===Bones===
The long bones show [[Unsolved:Osteopenia|osteopenia]] and [[Medicine:Pathologic fracture|pathologic fracture]]s can occur.<ref name="pmid16943371"/><ref name="pmid18076099"/><ref name="pmid11992766"/><ref name="pmid21523908"/>

===Skin, nails and hair===
Some children have sparse and greying hair, [[Medicine:Café au lait spot|café au lait spot]]s and nail dystrophy.<ref name="pmid16943371"/><ref name="pmid18076099"/><ref name="pmid3402627"/>

===General===
Most patients continue to grow poorly after birth.<ref name="pmid16943371"/><ref name="pmid15002047"/>

==Genetics==

Typical childhood-onset cerebroretinal microangiopathy with calcifications and cysts is caused by [[Biology:Compound heterozygosity|compound heterozygous]] [[Biology:Mutation|mutation]]s in the conserved [[Biology:Telomere|telomere]] maintenance component 1 (''CTC1'') [[Biology:Gene|gene]]<ref name=CTC1gene>{{cite web | title = Entrez Gene: ''CTC1'' | url=https://www.ncbi.nlm.nih.gov/gene/80169}}</ref> located in chromosome 17p.31.<ref name="pmid22267198"/><ref name="PolviA"/> A late-onset [[Biology:Phenotype|phenotype]] without abnormal eye findings from a ''CTC1'' mutation has been reported.<ref name="PolviA"/>CTC1<ref name="CTC1gene"/> is a component of the CST complex,<ref name=pmid19854131>{{cite journal |vauthors=Surovtseva YV, Churikov D, Boltz KA, Song X, Lamb JC, Warrington R, Leehy K, Heacock M, Price CM, Shippen DE | title = Conserved telomere maintenance component 1 interacts with STN1 and maintains chromosome ends in higher eukaryotes | journal = Mol Cell | volume = 36 | issue = 2 | pages = 207–18|date=Oct 2009 | pmid = 19854131 | pmc = 2768651| doi =10.1016/j.molcel.2009.09.017}}</ref> which is additionally composed of oligonucleotide/oligosaccharide-binding fold containing 1 (coded by ''OBFC1'',<ref>{{cite web | title = Entrez Gene: OBFC1 | url=https://www.ncbi.nlm.nih.gov/gene/79991}}</ref> also known as STN1) and [[Biology:Telomerase|telomerase]] capping complex subunit homolog 1 (coded by ''TEN1'').<ref>{{cite web | title = Entrez Gene: TEN1 | url=https://www.ncbi.nlm.nih.gov/gene/100134934}}</ref> CST complex is evolutionarily conserved.<ref name="pmid19854131"/> It binds to single-stranded DNA and associates with a fraction of [[Biology:Telomere|telomere]]s, potentially protecting them.{{citation needed|date=September 2020}}

==Pathophysiology==
Angiomas and numerous abnormal, small, dilated telangiectatic vessels with thickened, sclerotic and calcified walls have been found in those brain areas which also show calcifications.<ref name="pmid16943371"/><ref name="pmid18076099"/>

By analogy to Coats disease, the exudative retinopathy is thought to result from breakdown of the blood-retinal barrier at the level of the vascular [[Biology:Endothelium|endothelial cell]], resulting in leakage of blood plasma and lipid.<ref name="pmid6502405">{{cite journal |vauthors=Chang MM, McLean IW, Merritt JC | title = Coats' disease: a study of 62 histologically confirmed cases | journal = J Pediatr Ophthalmol Strabismus | volume = 21 | issue = 5 | pages = 163–8 |date=Sep 1984 | doi = 10.3928/0191-3913-19840901-03 | pmid = 6502405 }}</ref> [[Biology:Macrophage|Macrophage]]s then migrate into the retina and subretinal space and digest the lipid. The accumulation of the proteinaceous exudate and macrophages thickens the [[Biology:Retina|retina]], leading to exudative [[Medicine:Retinal detachment|retinal detachment]].{{citation needed|date=September 2020}}

==Diagnosis==

===Clinical===
The retinal changes are easily identified by [[Physics:Ophthalmoscopy|ophthalmoscopy]], which is performed under general anesthesia if the child is very young. The abnormal vessels are even better seen with [[Medicine:Fluorescein angiography|fluorescein angiography]]. In advanced disease, [[Medicine:Glaucoma|glaucoma]] is diagnosed by measuring [[Biology:Intraocular pressure|intraocular pressure]] and cataract by using [[Physics:Slit lamp|slit lamp]] biomicroscopy.{{citation needed|date=September 2020}}

===Imaging findings===
The most consistent finding are widespread calcifications, which involve
the [[Biology:White matter|white matter]] of the [[Biology:Cerebrum|cerebrum]] mostly adjacent to the junction with the [[Biology:Grey matter|grey matter]], the [[Biology:Thalamus|thalami]], the [[Biology:Basal ganglia|basal ganglia]] and the [[Biology:Brainstem|brainstem]].<ref name="pmid16943371"/><ref name="pmid18076099"/> The white matter of the [[Biology:Cerebellum|cerebellum]] and the [[Biology:Dentate nucleus|dentate nuclei]] are less often involved. However, the brain may appear normal in the neonatal period. The calcifications are visible both with [[Astronomy:X-ray computed tomography|computed tomography]] and with [[Physics:Magnetic resonance imaging|magnetic resonance imaging]].

Magnetic resonance imaging shows additionally diffuse or patchy [[Biology:White matter|white matter]] changes, especially in the periventricular region, the thalami and the [[Biology:Internal capsule|internal capsule]]. Cerebellar and brainstem lesions are less common. Imaging also uncovers parenchymal cysts situated mainly in the thalamic region and more rarely in the brainstem, the [[Biology:Parietal lobe|parietal lobe]] and the [[Biology:Frontal lobe|frontal lobe]].

The long bones may be [[Unsolved:Osteopenia|osteopenic]] and various skeletal changes are found in several patients, such as metaphyseal sclerosis and mild flaring, which is most pronounced in the [[Biology:Femur|femur]] and  [[Biology:Tibia|tibia]].<ref name="pmid15002047"/><ref name="pmid11992766"/><ref name="pmid21523908"/>

===Laboratory findings===
The [[Biology:Cerebrospinal fluid|cerebrospinal fluid]] and blood tests are typically normal, except for [[Medicine:Anemia|anemia]] and [[Medicine:Thrombocytopenia|thrombocytopenia]] in some children.<ref name="pmid16943371"/><ref name="pmid18076099"/><ref name="pmid11992766"/>

==Screening==

Because of the rarity of the syndrome, it is not routinely screened before birth. Prenatal diagnosis is possible in families in which a prior child has been diagnosed, because the responsible gene ''CTC1''is known.<ref name="pmid22267198"/><ref name="PolviA"/>

==Management==

Seizures are managed with anticonvulsive medications.

[[Physics:Laser coagulation|Laser coagulation]] or [[Physics:Cryoablation|cryoablation]] (freezing) of the retina can be used to destroy the abnormal blood vessels. [[Medicine:Retinal detachment|Retinal detachment]] is repaired with a scleral buckle or with [[Medicine:Vitrectomy|vitrectomy]]. Removal or enucleation of the eye is a last resort option if the eye already has become blind and painful.{{citation needed|date=September 2020}}

Repeated [[Medicine:Blood transfusion|blood transfusion]]s may be needed to control [[Medicine:Anemia|anemia]], and [[Medicine:Thrombocytopenia|thrombocytopenia]] can be managed with [[Medicine:Splenectomy|splenectomy]].<ref name="pmid16943371"/>

==Prognosis==
The neurological symptoms are progressive and can lead to severe spasticity, [[Medicine:Corticobulbar tract|bulbar symptoms]] and [[Medicine:Dysarthria|dysarthria]] within one to two decades.<ref name="pmid16943371"/><ref name="pmid15002047"/> The life span is shorter than normal. Death occurs between 2 and 30 years of age, depending on the severity of the syndrome. The immediate cause of death is [[Medicine:Pneumonia|pneumonia]], fulminant intestinal bleeding or [[Medicine:Multiple organ dysfunction syndrome|multiple organ dysfunction]].<ref name="pmid16943371"/>

If not treated, the retinal detachment can lead to [[Medicine:Ischemia|ischemia]] and growth of new blood vessels over the [[Medicine:Iris (anatomy)|iris]] and [[Medicine:Anterior chamber of eyeball|anterior chamber angle]]. This in turn can cause secondary glaucoma, [[Medicine:Cataract|cataract]] and, ultimately, [[Medicine:Blindness|blindness]] of the eye.<ref name="pmid16943371"/><ref name="pmid18076099"/>

==Epidemiology==

This syndrome is usually sporadic although families with two or more affected siblings of both sexes are known.<ref name="pmid16943371"/><ref name="pmid15002047"/>

==History==

A child who was eventually diagnosed with cerebroretinal microangiopathy with calcifications and cysts was first described in the literature in 1987.<ref name="pmid3402627"/><ref name="pmid3556653">{{cite journal |vauthors=McGettrick PM, Loeffler KU | title = Bilateral Coats' disease in an infant (a clinical, angiographic, light and electron microscopic study) | journal = Eye (Lond) | volume = 1 | issue = Pt 1 | pages = 136–45 | year = 1988 | pmid = 3556653 | doi = 10.1038/eye.1987.20| doi-access = free }}</ref> The disorder was suspected of being allelic with either the [[Medicine:Revesz syndrome|Revesz syndrome]]<ref name="pmid18076099"/> or leukoencephalopathy with calcifications and cysts.<ref name="pmid16943371"/><ref name="pmid18076099"/> However, [[Medicine:Revesz syndrome|Revesz syndrome]], a severe variant of [[Medicine:Dyskeratosis congenita|dyskeratosis congenita]], was later shown to result from heterozygous dominant mutations in the ''TINF2'' gene,<ref name="pmid18252230">{{cite journal |vauthors=Savage SA, Giri N, Baerlocher GM, Orr N, Lansdorp PM, Alter BP | title = TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita | journal = Am J Hum Genet | volume = 82 | issue = 2 | pages = 501–9 |date=Feb 2008 | pmid = 18252230 | pmc = 2427222| doi = 10.1016/j.ajhg.2007.10.004}}</ref> which encodes TRF1-interacting nuclear factor 2, a major component of the [[Biology:Telomere|telomere]] protecting shelterin complex, and individuals with the leukoencephalopathy with calcifications and cysts [[Biology:Phenotype|phenotype]] have not had mutations in the ''CTC1'' gene.<ref name="pmid22267198"/><ref name="PolviA"/>

Before the causative mutation was identified, mutations were sought from the Wnt signalling pathway because its components were known to be responsible for [[Medicine:Norrie disease|Norrie disease]] and [[Medicine:Familial exudative vitreoretinopathy|familial exudative vitreoretinopathy]], which share features of the eye phenotype but not the brain or systemic abnormalities.<ref name="pmid16943371"/><ref name="pmid18076099"/>

[[Medicine:Coats' disease|Coats' disease]] is named after George Coats.<ref>{{WhoNamedIt|doctor|1926}}</ref><ref>{{cite journal | author = Coats G | title = Forms of retinal disease with massive exudation | journal = R Lond Ophthalmol Hosp Rep | volume = 17 | issue = 3 | pages = 440–525 |date=Nov 1908 }}</ref>

==References==
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== External links ==
{{Medical resources
| DiseasesDB      =
| ICD10           = {{ICD10|Q|87|8|q|87}}
| ICD9            = {{ICD9|759.89}}
| ICDO            =
| OMIM            = 612199
| OMIM_mult       =
| MedlinePlus     =
| eMedicineSubj   =
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| MeshID          =
| GeneReviewsName =
| SNOMED CT       = 711482008
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[[Category:Genetic diseases and disorders]]
[[Category:Rare diseases]]

{{Sourceattribution|Cerebroretinal microangiopathy with calcifications and cysts}}