Cerebroretinal microangiopathy with calcifications and cysts

Last updated
Cerebroretinal microangiopathy with calcifications and cysts
Other namesCRMCC
Exudative retinopathy and vitreos hemorrhage in cerebroretinal microangiopathy with calcifications and cysts.jpg
Vitreous hemorrhage and exudative retinal detachment resembling Coats' disease in a child with cerebroretinal microangiopathy with calcifications and cysts
Specialty Medical genetics   OOjs UI icon edit-ltr-progressive.svg

Cerebroretinal microangiopathy with calcifications and cysts (CRMCC) is a rare genetic disorder, which affects multiple organs. [1] [2] Its hallmarks are widespread progressive calcifications, cysts and abnormalities of the white matter of the brain, usually occurring together with abnormalities of the blood vessels of the retina. Additional features include poor prenatal growth, preterm birth, anemia, osteopenia and bone fractures, [3] [4] [5] and gastrointestinal bleeding. [6] It is caused by compound heterozygous mutations in the conserved telomere maintenance component 1 (CTC1) gene , [7] [8] but its exact pathophysiology is still not well understood.

Contents

Cerebroretinal microangiopathy with calcifications and cysts is alternatively known as the Coats plus syndrome, [3] a reference to its most typical ocular phenotype.

Signs and Symptoms

Presentation

Before birth

A child who has inherited this disorder will grow slower than normal in the uterus before birth and typically will be born before term. [1] [2] [3] The pregnancy can be complicated by gestational hypertension and pre-eclampsia.[ citation needed ]

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 retinal detachment and glaucoma. [1] [2] [3] A minority present with seizures or spasticity . The time of onset of symptoms varies from infancy to adolescence. Because a child born before term will need to undergo screening for retinopathy of prematurity, some will have abnormalities in their retinal blood vessels detected when they have no symptoms yet.[ citation needed ]

Brain

Neurologic symptoms and signs vary depending on the site of the brain abnormalities. Common symptoms are partial epilepsy, asymmetric spasticity, ataxia and cognitive impairment. [1] [2] [3] The latter affects visuospatial and visuoconstructive skills first. The intracranial pressure can be elevated if cysts develop in the brain. Migraine-like headaches can occur.[ citation needed ]

Eyes

Smaller blood vessels of the 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. [1] [2] [3] [9] This is known as telangiectasia. The vessel walls are weak and leak blood plasma and lipid within and underneath the retina. This leakage can lead to exudative 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. [9] 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. [1] These can bleed and be attached to the vitreous humour. The attachment can cause traction retinal detachment.

Gastrointestinal tract

Recurrent intestinal bleeding is fairly common. [1] [2] [6] It originates from telangiectatic small blood vessels in the intestinal mucosa. Additional findings in some individuals are portal hypertension and liver failure. [1] [2]

Blood

Many affected children develop anemia, which may be macrocytic in type. [1] [2] [4] Some also develop thrombocytopenia. Bone marrow examinations may show megaloblasts and increased erythropoiesis or bone marrow suppression. [1] [2] [4]

Bones

The long bones show osteopenia and pathologic fractures can occur. [1] [2] [4] [5]

Skin, nails and hair

Some children have sparse and greying hair, café au lait spots and nail dystrophy. [1] [2] [9]

General

Most patients continue to grow poorly after birth. [1] [3]

Genetics

Typical childhood-onset cerebroretinal microangiopathy with calcifications and cysts is caused by compound heterozygous mutations in the conserved telomere maintenance component 1 (CTC1) gene [10] located in chromosome 17p.31. [7] [8] A late-onset phenotype without abnormal eye findings from a CTC1 mutation has been reported. [8] CTC1 [10] is a component of the CST complex, [11] which is additionally composed of oligonucleotide/oligosaccharide-binding fold containing 1 (coded by OBFC1, [12] also known as STN1) and telomerase capping complex subunit homolog 1 (coded by TEN1). [13] CST complex is evolutionarily conserved. [11] It binds to single-stranded DNA and associates with a fraction of telomeres, potentially protecting them.[ citation needed ]

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. [1] [2]

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 endothelial cell, resulting in leakage of blood plasma and lipid. [14] Macrophages then migrate into the retina and subretinal space and digest the lipid. The accumulation of the proteinaceous exudate and macrophages thickens the retina, leading to exudative retinal detachment.[ citation needed ]

Diagnosis

Clinical

The retinal changes are easily identified by ophthalmoscopy, which is performed under general anesthesia if the child is very young. The abnormal vessels are even better seen with fluorescein angiography. In advanced disease, glaucoma is diagnosed by measuring intraocular pressure and cataract by using slit lamp biomicroscopy.[ citation needed ]

Imaging findings

The most consistent finding are widespread calcifications, which involve the white matter of the cerebrum mostly adjacent to the junction with the grey matter, the thalami, the basal ganglia and the brainstem. [1] [2] The white matter of the cerebellum and the dentate nuclei are less often involved. However, the brain may appear normal in the neonatal period. The calcifications are visible both with computed tomography and with magnetic resonance imaging.

Magnetic resonance imaging shows additionally diffuse or patchy white matter changes, especially in the periventricular region, the thalami and the 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 parietal lobe and the frontal lobe.

The long bones may be osteopenic and various skeletal changes are found in several patients, such as metaphyseal sclerosis and mild flaring, which is most pronounced in the femur and tibia. [3] [4] [5]

Laboratory findings

The cerebrospinal fluid and blood tests are typically normal, except for anemia and thrombocytopenia in some children. [1] [2] [4]

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 CTC1is known. [7] [8]

Management

Seizures are managed with anticonvulsive medications.

Laser coagulation or cryoablation (freezing) of the retina can be used to destroy the abnormal blood vessels. Retinal detachment is repaired with a scleral buckle or with vitrectomy. Removal or enucleation of the eye is a last resort option if the eye already has become blind and painful.[ citation needed ]

Repeated blood transfusions may be needed to control anemia, and thrombocytopenia can be managed with splenectomy. [1]

Prognosis

The neurological symptoms are progressive and can lead to severe spasticity, bulbar symptoms and dysarthria within one to two decades. [1] [3] 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 pneumonia, fulminant intestinal bleeding or multiple organ dysfunction. [1]

If not treated, the retinal detachment can lead to ischemia and growth of new blood vessels over the iris and anterior chamber angle. This in turn can cause secondary glaucoma, cataract and, ultimately, blindness of the eye. [1] [2]

Epidemiology

This syndrome is usually sporadic although families with two or more affected siblings of both sexes are known. [1] [3]

History

A child who was eventually diagnosed with cerebroretinal microangiopathy with calcifications and cysts was first described in the literature in 1987. [9] [15] The disorder was suspected of being allelic with either the Revesz syndrome [2] or leukoencephalopathy with calcifications and cysts. [1] [2] However, Revesz syndrome, a severe variant of dyskeratosis congenita, was later shown to result from heterozygous dominant mutations in the TINF2 gene, [16] which encodes TRF1-interacting nuclear factor 2, a major component of the telomere protecting shelterin complex, and individuals with the leukoencephalopathy with calcifications and cysts phenotype have not had mutations in the CTC1 gene. [7] [8]

Before the causative mutation was identified, mutations were sought from the Wnt signalling pathway because its components were known to be responsible for Norrie disease and familial exudative vitreoretinopathy, which share features of the eye phenotype but not the brain or systemic abnormalities. [1] [2]

Coats' disease is named after George Coats. [17] [18]

Related Research Articles

<span class="mw-page-title-main">Retinopathy</span> Medical condition

Retinopathy is any damage to the retina of the eyes, which may cause vision impairment. Retinopathy often refers to retinal vascular disease, or damage to the retina caused by abnormal blood flow. Age-related macular degeneration is technically included under the umbrella term retinopathy but is often discussed as a separate entity. Retinopathy, or retinal vascular disease, can be broadly categorized into proliferative and non-proliferative types. Frequently, retinopathy is an ocular manifestation of systemic disease as seen in diabetes or hypertension. Diabetes is the most common cause of retinopathy in the U.S. as of 2008. Diabetic retinopathy is the leading cause of blindness in working-aged people. It accounts for about 5% of blindness worldwide and is designated a priority eye disease by the World Health Organization.

<span class="mw-page-title-main">Diabetic retinopathy</span> Medical condition

Diabetic retinopathy, is a medical condition in which damage occurs to the retina due to diabetes mellitus. It is a leading cause of blindness in developed countries.

<span class="mw-page-title-main">Microangiopathy</span> Medical condition

Microangiopathy is a disease of the microvessels, small blood vessels in the microcirculation. It can be contrasted to macroangiopathies such as atherosclerosis, where large and medium-sized arteries are primarily affected.

<span class="mw-page-title-main">Retinoschisis</span> Eye disease involving splitting of the retina

Retinoschisis is an eye disease characterized by the abnormal splitting of the retina's neurosensory layers, usually in the outer plexiform layer. Retinoschisis can be divided into degenerative forms which are very common and almost exclusively involve the peripheral retina and hereditary forms which are rare and involve the central retina and sometimes the peripheral retina. The degenerative forms are asymptomatic and involve the peripheral retina only and do not affect the visual acuity. Some rarer forms result in a loss of vision in the corresponding visual field.

<span class="mw-page-title-main">Retinoblastoma</span> Medical condition

Retinoblastoma (Rb) is a rare form of cancer that rapidly develops from the immature cells of a retina, the light-detecting tissue of the eye. It is the most common primary malignant intraocular cancer in children, and it is almost exclusively found in young children.

Retinopathy of prematurity (ROP), also called retrolental fibroplasia (RLF) and Terry syndrome, is a disease of the eye affecting prematurely born babies generally having received neonatal intensive care, in which oxygen therapy is used because of the premature development of their lungs. It is thought to be caused by disorganized growth of retinal blood vessels and may result in scarring and retinal detachment. ROP can be mild and may resolve spontaneously, but it may lead to blindness in serious cases. Thus, all preterm babies are at risk for ROP, and very low birth-weight is an additional risk factor. Both oxygen toxicity and relative hypoxia can contribute to the development of ROP.

<span class="mw-page-title-main">Retinal detachment</span> Medical condition of the eye

Retinal detachment is a disorder of the eye in which the retina peels away from its underlying layer of support tissue. Initial detachment may be localized, but without rapid treatment the entire retina may detach, leading to vision loss and blindness. It is a surgical emergency.

Norrie disease is a rare disease and genetic disorder that primarily affects the eyes and almost always leads to blindness. It is caused by mutations in the Norrin cystine knot growth factor (NDP) gene, which is located on the X chromosome. In addition to the congenital ocular symptoms, the majority of patients experience a progressive hearing loss starting mostly in their 2nd decade of life, and some may have learning difficulties among other additional characteristics.

Progressive retinal atrophy (PRA) is a group of genetic diseases seen in certain breeds of dogs and, more rarely, cats. Similar to retinitis pigmentosa in humans, it is characterized by the bilateral degeneration of the retina, causing progressive vision loss culminating in blindness. The condition in nearly all breeds is inherited as an autosomal recessive trait, with the exception of the Siberian Husky (inherited as an X chromosome linked trait) and the Bullmastiff (inherited as an autosomal dominant trait). There is no treatment.

Eales disease is a type of obliterative vasculopathy, also known as angiopathia retinae juvenilis, periphlebitis retinae or primary perivasculitis of the retina. It was first described by the British ophthalmologist Henry Eales (1852–1913) in 1880 and is a rare ocular disease characterized by inflammation and possible blockage of retinal blood vessels, abnormal growth of new blood vessels (neovascularization), and recurrent retinal and vitreal hemorrhages.

<span class="mw-page-title-main">Progressive outer retinal necrosis</span> Medical condition

Progressive outer retinal necrosis (PORN) syndrome is a form of chorioretinitis, an infection in the retina, the back of the eye. The disease is most commonly caused by the varicella zoster virus and is found almost exclusively in patients with HIV/AIDS. Progressive outer retinal necrosis is the second most common opportunistic retinal infection in North America among people with AIDS. The reason this disease process is considered opportunistic is precisely because it only presents in patients with AIDS, a disease that attacks and weakens the immune system, making space for other infections, like Varicella zoster virus (VZV) and Herpes simplex virus (HSV), to attack the body.

<span class="mw-page-title-main">Coats' disease</span> Human eye disease causing full or partial blindness

Coats' disease is a rare congenital, nonhereditary eye disorder, causing full or partial blindness, characterized by abnormal development of blood vessels behind the retina. Coats' disease can also fall under glaucoma.

<span class="mw-page-title-main">Papillorenal syndrome</span> Medical condition

Papillorenal syndrome is an autosomal dominant genetic disorder marked by underdevelopment (hypoplasia) of the kidney and colobomas of the optic nerve.

<span class="mw-page-title-main">Revesz syndrome</span> Medical condition

Revesz syndrome is a fatal disease that causes exudative retinopathy and bone marrow failure. Other symptoms include severe aplastic anemia, intrauterine growth retardation, fine sparse hair, fine reticulate skin pigmentation, ataxia due to cerebellar hypoplasia, and cerebral calcifications. Its effects are similar to that of Hoyeraal-Hreidarsson syndrome. It is a variant of dyskeratosis congenita.

<span class="mw-page-title-main">Macular telangiectasia</span> Disease of the retina affecting central vision

Macular telangiectasia is a condition of the retina, the light-sensing tissue at the back of the eye that causes gradual deterioration of central vision, interfering with tasks such as reading and driving.

<span class="mw-page-title-main">Persistent fetal vasculature</span> Medical condition

Persistent fetal vasculature(PFV), also known as persistent fetal vasculature syndrome (PFSV), and until 1997 known primarily as persistent hyperplastic primary vitreous (PHPV), is a rare congenital anomaly which occurs when blood vessels within the developing eye, known as the embryonic hyaloid vasculature network, fail to regress as they normally would in-utero after the eye is fully developed. Defects which arise from this lack of vascular regression are diverse; as a result, the presentation, symptoms, and prognosis of affected patients vary widely, ranging from clinical insignificance to irreversible blindness. The underlying structural causes of PFV are considered to be relatively common, and the vast majority of cases do not warrant additional intervention. When symptoms do manifest, however, they are often significant, causing detrimental and irreversible visual impairment. Persistent fetal vasculature heightens the lifelong risk of glaucoma, cataracts, intraocular hemorrhages, and Retinal detachments, accounting for the visual loss of nearly 5% of the blind community in the developed world. In diagnosed cases of PFV, approximately 90% of patients with a unilateral disease have associated poor vision in the affected eye.

<span class="mw-page-title-main">Familial exudative vitreoretinopathy</span> Retinal vascular disease

Familial exudative vitreoretinopathy is a genetic disorder affecting the growth and development of blood vessels in the retina of the eye. This disease can lead to visual impairment and sometimes complete blindness in one or both eyes. FEVR is characterized by incomplete vascularization of the peripheral retina. This can lead to the growth of new blood vessels which are prone to leakage and hemorrhage and can cause retinal folds, tears, and detachments. Treatment involves laser photocoagulation of the avascular portions of the retina to reduce new blood vessel growth and risk of complications including leakage of retinal blood vessels and retinal detachments.

Autoimmune retinopathy (AIR) is a rare disease in which the patient's immune system attacks proteins in the retina, leading to loss of eyesight. The disease is poorly understood, but may be the result of cancer or cancer chemotherapy. The disease is an autoimmune condition characterized by vision loss, blind spots, and visual field abnormalities. It can be divided into cancer-associated retinopathy (CAR) and melanoma-associated retinopathy (MAR). The condition is associated with retinal degeneration caused by autoimmune antibodies recognizing retinal proteins as antigens and targeting them. AIR's prevalence is extremely rare, with CAR being more common than MAR. It is more commonly diagnosed in females in the age range of 50–60.

Sickle cell retinopathy can be defined as retinal changes due to blood vessel damage in the eye of a person with a background of sickle cell disease. It can likely progress to loss of vision in late stages due to vitreous hemorrhage or retinal detachment. Sickle cell disease is a structural red blood cell disorder leading to consequences in multiple systems. It is characterized by chronic red blood cell destruction, vascular injury, and tissue ischemia causing damage to the brain, eyes, heart, lungs, kidneys, spleen, and musculoskeletal system.

<span class="mw-page-title-main">Goldmann–Favre syndrome</span> Medical condition

Goldmann–Favre syndrome is a rare genetic disorder characterized by early-onset nyctalopia, decreased visual acuity, and abnormal findings of the fundus. It is a type of progressive vitreotapetoretinal degeneration.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 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 (Oct 2006). "Cerebroretinal microangiopathy with calcifications and cysts". Neurology. 67 (8): 1347–43. doi:10.1212/01.wnl.0000236999.63933.b0. PMID   16943371. S2CID   28941194.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 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 (Jan 2008). "Cerebroretinal microangiopathy with calcifications and cysts (CRMCC)". Am J Med Genet A. 146A (2): 182–90. doi: 10.1002/ajmg.a.32080 . PMID   18076099. S2CID   39256035.
  3. 1 2 3 4 5 6 7 8 9 10 Crow YJ, McMenamin J, Haenggeli CA, Hadley DM, Tirupathi S, Treacy EP, Zuberi SM, Browne BH, Tolmie JL, Stephenson JB (Feb 2004). "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". Neuropediatrics. 35 (1): 10–19. doi:10.1055/s-2003-43552. PMID   15002047.
  4. 1 2 3 4 5 6 Sazgar M, Leonard NJ, Renaud DL, Bhargava R, Sinclair DB (Apr 2002). "Intracranial calcification, retinopathy, and osteopenia: a new syndrome?". Pediatr Neurol. 26 (4): 324–8. doi:10.1016/s0887-8994(01)00398-8. PMID   11992766.
  5. 1 2 3 Toiviainen-Salo S, Linnankivi T, Saarinen A, Mäyränpää MK, Karikoski R, Mäkitie O (Jun 2011). "Cerebroretinal microangiopathy with calcifications and cysts: characterization of the skeletal phenotype". Am J Med Genet A. 155A (6): 1322–6. doi:10.1002/ajmg.a.33994. PMID   21523908. S2CID   19482634.
  6. 1 2 Briggs TA, Hubbard M, Hawkins C, Cole T, Livingston JH, Crow YJ, Pigott A (Jan 2011). "Treatment of gastrointestinal bleeding in a probable case of cerebroretinal microangiopathy with calcifications and cysts". Mol Syndromol. 1 (4): 159–62. doi:10.1159/000321559. PMC   3042118 . PMID   21373254.
  7. 1 2 3 4 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 (Jan 2012). "Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus". Nat Genet. 44 (3): 338–42. doi:10.1038/ng.1084. hdl: 10400.17/2516 . PMID   22267198. S2CID   205343417.
  8. 1 2 3 4 5 Polvi A, Linnankivi T, Kivelä T, Herva R, Keating JP, Mäkitie O, Pareyson D, Vainionpää L, Lahtinen J, Hovatta I, Pihko H, Lehesjoki AE (Mar 2012). "Mutations in CTC1, encoding the CTS telomere maintenance complex component 1, cause cerebroretinal microangiopathy with calcifications and cysts". Am J Hum Genet. 90 (3): 540–549. doi:10.1016/j.ajhg.2012.02.002. PMC   3309194 . PMID   22387016.
  9. 1 2 3 4 Tolmie JL, Browne BH, McGettrick PM, Stephenson JB (1988). "A familial syndrome with Coats' reaction retinal angiomas, hair and nail defects and intracranial calcification". Eye (Lond). 2 (Pt 3): 297–303. doi: 10.1038/eye.1988.56 . PMID   3402627.
  10. 1 2 "Entrez Gene: CTC1".
  11. 1 2 Surovtseva YV, Churikov D, Boltz KA, Song X, Lamb JC, Warrington R, Leehy K, Heacock M, Price CM, Shippen DE (Oct 2009). "Conserved telomere maintenance component 1 interacts with STN1 and maintains chromosome ends in higher eukaryotes". Mol Cell. 36 (2): 207–18. doi:10.1016/j.molcel.2009.09.017. PMC   2768651 . PMID   19854131.
  12. ↑ "Entrez Gene: OBFC1".
  13. ↑ "Entrez Gene: TEN1".
  14. ↑ Chang MM, McLean IW, Merritt JC (Sep 1984). "Coats' disease: a study of 62 histologically confirmed cases". J Pediatr Ophthalmol Strabismus. 21 (5): 163–8. doi:10.3928/0191-3913-19840901-03. PMID   6502405.
  15. ↑ McGettrick PM, Loeffler KU (1988). "Bilateral Coats' disease in an infant (a clinical, angiographic, light and electron microscopic study)". Eye (Lond). 1 (Pt 1): 136–45. doi: 10.1038/eye.1987.20 . PMID   3556653.
  16. ↑ Savage SA, Giri N, Baerlocher GM, Orr N, Lansdorp PM, Alter BP (Feb 2008). "TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita". Am J Hum Genet. 82 (2): 501–9. doi:10.1016/j.ajhg.2007.10.004. PMC   2427222 . PMID   18252230.
  17. ↑ doctor/1926 at Who Named It?
  18. ↑ Coats G (Nov 1908). "Forms of retinal disease with massive exudation". R Lond Ophthalmol Hosp Rep. 17 (3): 440–525.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.