Cerebroretinal microangiopathy with calcifications and cysts (CRMCC) is a rare genetic disorder, which affects multiple organs. 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 fracture A bone fracture (abbreviated FRX or Fx, Fx, or #) is a medical condition in which there is a partial or complete break in the continuity of any bone in the body. In more severe cases, the bone may be broken into several fragments, known as a '' ...

s, and gastrointestinal bleeding. It is caused by compound heterozygous mutations in the conserved telomere maintenance component 1 (''CTC1'') gene, but its exact pathophysiology is still not well understood. Cerebroretinal microangiopathy with calcifications and cysts is alternatively known as the Coats plus syndrome, 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. The pregnancy can be complicated by gestational hypertension and

pre-eclampsia Pre-eclampsia is a disorder of pregnancy characterized by the onset of high blood pressure and often a significant amount of protein in the urine. When it arises, the condition begins after 20 weeks of pregnancy. In severe cases of the disease ...

After birth

The majority of affected children present with ''symptoms and signs relating to the eyes'' such as

leukokoria Leukocoria (also white pupillary reflex) is an abnormal white reflection from the retina of the eye. Leukocoria resembles eyeshine, but leukocoria can also occur in animals that lack eyeshine because their retina lacks a '' tapetum lucidum''. Leu ...

, redness, irritation and impaired vision, which result from

retinal detachment 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 blin ...

and glaucoma. A minority present with '' seizures or spasticity''. The time of onset of symptoms varies from

infancy An infant or baby is the very young offspring of human beings. ''Infant'' (from the Latin word ''infans'', meaning 'unable to speak' or 'speechless') is a formal or specialised synonym for the common term ''baby''. The terms may also be used to ...

adolescence Adolescence () is a transitional stage of physical and psychological development that generally occurs during the period from puberty to adulthood (typically corresponding to the age of majority). Adolescence is usually associated with the t ...

. 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.

Brain

Neurologic symptoms and signs vary depending on the site of the brain abnormalities. Common symptoms are partial epilepsy, asymmetric spasticity, ataxia and

cognitive Cognition refers to "the mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought, ...

impairment. The latter affects visuospatial and visuoconstructive skills first. The intracranial pressure can be elevated if cysts develop in the brain.

Migraine Migraine (, ) is a common neurological disorder characterized by recurrent headaches. Typically, the associated headache affects one side of the head, is pulsating in nature, may be moderate to severe in intensity, and could last from a few hou ...

-like headaches can occur.

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. 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

, 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 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. It can have a similar pre ...

. 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. These can bleed and be attached to the vitreous humour. The attachment can cause traction

Gastrointestinal tract

Recurrent intestinal bleeding is fairly common. It originates from telangiectatic small blood vessels in the intestinal mucosa. Additional findings in some individuals are

portal hypertension Portal hypertension is abnormally increased portal venous pressure – blood pressure in the portal vein and its branches, that drain from most of the intestine to the liver. Portal hypertension is defined as a hepatic venous pressure gradient gr ...

and liver failure.

Blood

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

Bones

The long bones show osteopenia and pathologic fractures can occur.

Skin, nails and hair

Some children have sparse and greying hair,

café au lait spot ''Café au lait'' spots, or ''café au lait'' macules, are flat, hyperpigmented birthmarks. The name ''café au lait'' is French for "coffee with milk" and refers to their light-brown color. Café au lait lesions with rough borders (" coast of Mai ...

s and

nail dystrophy A nail disease or onychosis is a disease or deformity of the nail. Although the nail is a structure produced by the skin and is a skin appendage, nail diseases have a distinct classification as they have their own signs and symptoms which may r ...

General

Most patients continue to grow poorly after birth.

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 located in chromosome 17p.31. A late-onset phenotype without abnormal eye findings from a ''CTC1'' mutation has been reported.CTC1 is a component of the CST complex, which is additionally composed of oligonucleotide/oligosaccharide-binding fold containing 1 (coded by ''OBFC1'', also known as STN1) and telomerase capping complex subunit homolog 1 (coded by ''TEN1''). CST complex is evolutionarily conserved. It binds to single-stranded DNA and associates with a fraction of telomeres, potentially protecting them.

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. By analogy to

, the exudative retinopathy is thought to result from breakdown of the blood-retinal barrier at the level of the vascular

endothelial cell The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...

, resulting in leakage of blood plasma and lipid.

Macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...

s 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

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.

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 thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all directions, ...

, the basal ganglia and the

brainstem The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is cont ...

. The white matter of the

cerebellum The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cerebel ...

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 A computed tomography scan (CT scan; formerly called computed axial tomography scan or CAT scan) is a medical imaging technique used to obtain detailed internal images of the body. The personnel that perform CT scans are called radiographers ...

and with

magnetic resonance imaging Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio wave ...

. 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.

Laboratory findings

The cerebrospinal fluid and blood tests are typically normal, except for anemia and thrombocytopenia in some children.

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.

Management

Seizures are managed with anticonvulsive medications.

Laser coagulation Laser coagulation or laser photocoagulation surgery is used to treat a number of eye diseases and has become widely used in recent decades. During the procedure, a laser is used to finely cauterize ocular blood vessels to attempt to bring about var ...

or cryoablation (freezing) of the retina can be used to destroy the abnormal blood vessels.

Retinal detachment 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 blin ...

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

Prognosis

The neurological symptoms are progressive and can lead to severe spasticity, bulbar symptoms and dysarthria within one to two decades. 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. If not treated, the retinal detachment can lead to

ischemia Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems wi ...

and growth of new blood vessels over the iris and

anterior chamber angle The anterior chamber angle is a part of the eye located between the cornea and Iris (anatomy), iris which contains the trabecular meshwork. The size of this angle is an important determinant of the rate aqueous humour flows out of the eye, and thu ...

. This in turn can cause secondary glaucoma, cataract and, ultimately, blindness of the eye.

Epidemiology

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

History

A child who was eventually diagnosed with cerebroretinal microangiopathy with calcifications and cysts was first described in the literature in 1987. The disorder was suspected of being allelic with either the Revesz syndrome or leukoencephalopathy with calcifications and cysts. However, Revesz syndrome, a severe variant of dyskeratosis congenita, was later shown to result from heterozygous dominant mutations in the ''TINF2'' gene, 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. 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. Coats' disease is named after George Coats.

References

External links

{{Medical resources , DiseasesDB = , ICD10 = {{ICD10, Q, 87, 8, q, 87 , ICD9 = {{ICD9, 759.89 , ICDO = , OMIM = 612199 , OMIM_mult = , MedlinePlus = , eMedicineSubj = , eMedicineTopic = , MeshID = , GeneReviewsName = , SNOMED CT = 711482008 Genetic diseases and disorders Rare diseases Telomeres