anemia

Coats Plus Syndrome

Clinical Characteristics
Ocular Features: 

Retinal telangiectasia and exudates (Coats disease) occur in association with intracranial cysts, calcifications and extraneurologic manifestations in this condition.  Coats disease lesions may also occur in Labrune syndrome (614561) and, of course, in isolation.

Whereas simple Coats disease almost exclusively occurs unilaterally and in males, both sexes and both eyes may have Coats retinal lesions in this syndrome.

Systemic Features: 

As a result of intracranial calcifications, leukodystrophy and brain cysts, patients have a variety of neurologic signs including spasticity, ataxia, dystonia, cognitive decline, and seizures.  Vascular ectasias may also occur throughout the body such as the intestines, stomach, and in the liver increasing the risk of GI bleeding and portal hypertension with anemia and thrombocytopenia.  Some individuals have sparse hair, abnormal pigmentation of the skin, and dysplastic nails as well. 

Some extraretinal features are also found in patients with dyskeratosis congenita (127550), and in Labrune syndrome (614561).

Genetics

This autosomal recessive pleotropic disorder results from compound heterozygous mutations in the CTC1 gene (17p13.1).  Several patients with mutations in STN1 have also been reported.

Most cases of simple Coats disease occur sporadically.  No associated locus or mutation has been found.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment for the general condition has been reported.  Specific treatment for the retinal vascular and brain lesions might be of benefit.  Physical therapy and special education should be considered in selected patients.

References
Article Title: 

Mutations in STN1 cause Coats plus syndrome and are associated with genomic and telomere defects. J Exp Med. 2016 Jul 25;213(8):1429-40

Simon AJ, Lev A, Zhang Y, Weiss B, Rylova A, Eyal E, Kol N, Barel O, Cesarkas K, Soudack M, Greenberg-Kushnir N, Rhodes M, Wiest DL, Schiby G, Barshack I, Katz S, Pras E, Poran H, Reznik-Wolf H, Ribakovsky E, Simon C, Hazou W, Sidi Y, Lahad A, Katzir H, Sagie S, Aqeilan HA, Glousker G, Amariglio N, Tzfati Y, Selig S, Rechavi G, Somech R. Mutations in STN1 cause Coats plus syndrome and are associated with genomic and telomere defects. J Exp Med. 2016 Jul 25;213(8):1429-40.

PubMed ID: 
27432940

Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus

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, Bonafe 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, Lourenco 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. Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus. Nat Genet. 2012 Jan 22;44(3):338-42.

PubMed ID: 
22267198

Hoyeraal-Hreidarsson Syndrome

Clinical Characteristics
Ocular Features: 

Little is known about the ocular signs in this rare disorder.  As many patients have systemic features of dyskeratosis congenita, however, it is possible that some of the ocular findings such as conjunctival and corneal scarring and lid margin distortion might be similar.  Hoyeraal-Hreidarsson syndrome, though, is a more severe disease and many infants may die before the mucocutaneous manifestations appear.  At least one patient has had an exudative retinopathy similar to that seen in Revesz syndrome (268130).  Epiphora and a preretinal hemorrhage have also been reported.

Systemic Features: 

Features of pancytopenia usually appear after 5 months of age while growth retardation and microcephaly are evident soon after birth.  The marrow may show progression to myelodysplasia.  Birth weight is usually low.  Truncal ataxia and axial hypotonia have been reported and MRI imaging reveals cerebellar hypoplasia.  Global developmental delay is a common feature and a few patients have seizures.  Susceptibility to infection has been noted but the basis for an immunodeficiency remains elusive.  Some patients have signs of dyskeratosis congenita such as sparse hair, nail dysplasia, and a reticular pattern of skin pigmentation.

Genetics

This is an X-linked disorder resulting from mutations in the DKC1 gene (Xq28) active in telomere maintainence.  As expected, the vast majority of affected individuals are male but at least 3 females have been reported. The same gene is also mutated in the X-linked form of dyskeratosis congenita (305000) suggesting that the two are allelic or that both are the same disease.  There are clear clinical differences, however, as severe developmental delay, immunodeficiency, cerebellar hypoplasia, and microcephaly are generally not present in the latter disorder.

There is evidence for telomere length variations in this syndrome and in dyskeratosis congenita.  Homozygous mutations in RTEL1 (regulator of telomere length helicase 1) (20q13.33) have also been found in these conditions.

Pedigree: 
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

No effective treatment has been reported.

References
Article Title: 

Révész Syndrome

Clinical Characteristics
Ocular Features: 

This is likely a severe form of dyskeratosis congenita with an exudative retinopathy in addition to the usual lid deformities, corneal opacification, conjunctival scarring.  The exudates are often present in early childhood, and may be of sufficient volume to present as leukocoria mimicking a retrolental mass.  The exudates extend through nearly all layers of the retina and are said to resemble Coats retinopathy. Vitreous hemorrhage and opacification has also been reported.  Severe vision loss and blindness may occur depending on the degree of retinal and vitreous disease.

Systemic Features: 

Patients with Revesz syndrome have cerebral calcifications, and hypoplasia of the cerebellum in addition to mild signs of dyskeratosis congenita such as a reticulated skin pattern, nail dysplasia, and oral leukoplakia.  Ataxia is a prominent sign but is not present in all patients.  Bone marrow failure with pancytopenia and a high risk of malignancies, however, are serious problems.  Aplastic anemia and neutropenia may present in early childhood while other signs may not appear until late childhood.  Sparse hair, intrauterine growth retardation and low birth weight are also features.   

Few patients with Revesz syndrome have been reported and the clinical features have not been fully delineated.  It is important to note that there is a large amount of clinical variation among patients.

Genetics

Heterozygous mutations in the TINF2 gene (14q12) have been found in Revesz syndrome.  Mutations in the same gene have also been found in the autosomal dominant form of dyskeratosis congenita (613990) suggesting that the two disorders, if distinct, are allelic.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Bone marrow failure may respond favorably to hematopoietic stem cell transplantation, at least for some time. Lifelong medical monitoring is required for the systemic and ocular disease.

References
Article Title: 

Pearson Marrow-Pancreas Syndrome

Clinical Characteristics
Ocular Features: 

Although systemic disease is usually evident during infancy, ocular symptoms such as ptosis and ophthalmoplegia may not be apparent until adulthood in those that survive.  The ocular myopathy in adults can resemble Kearns-Sayre syndrome (530000) as the result of a phenotypic shift from a predominantly hematopoietic disorder to a mitochondrial myopathy.  Bilateral zonular cataracts and strabismus have been reported in a 3 year old male.  A midperiphery pigmentary retinopathy has been observed.  Endothelial cell failure leads to corneal edema. 

Systemic Features: 

Low birth weight, failure to thrive, hypoplastic anemia and exocrine pancreatic dysfunction are often seen in infancy.  Precursor cells in the marrow show typical vacuolization. Malabsorption and insulin-dependent diabetes often develop.  The pancreas and bone marrow may become fibrotic.  Patients with the classic syndrome as a child can develop features of the Kearns-Sayre syndrome if they survive childhood.  Progressive muscle weakness in pharyngeal, facial, neck, and limb muscles is sometimes seen in older individuals and muscle biopsy reveals ragged-red fibers characteristic of mitochondrial disease.  Some patients have an organic aciduria and others develop hepatic failure with elevated transaminase, bilirubin and lipid levels.  Kidney damage results in Fanconi syndrome.  Young children may recover from the refractory anemia eventually but metabolic acidosis with life-threatening lactic acidosis is a constant threat and responsible for many childhood deaths.

Genetics

Deletions in mtDNA involving numerous genes are responsible for this condition.  As a result, it is maternally transmitted but somewhat inconsistently due to mitochondrial heteroplasmy.  Both sexes are affected.  The irregular size of the mtDNA deletions and the tissue distribution of affected mitochondria results in considerable variation in clinical expression.  Defective oxidative phosphorylation seems to be the underlying cause of many of the signs and symptoms.

Treatment
Treatment Options: 

This multisystem disease requires careful monitoring throughout life.  Blood transfusions may be required and careful attention needs to be given to nutrition and metabolic dysfunction.  A few patients have required insulin.  In spite of vigorous treatment of electrolyte imbalances, correction of acidosis, and hormonal supplements, many patients do not survive beyond childhood.  Organ failure requires individualized treatment.

References
Article Title: 

Pearson Syndrome

Farruggia P, Di Marco F, Dufour C. Pearson Syndrome. Expert Rev Hematol. 2018 Jan 16. doi: 10.1080/17474086.2018.1426454. [Epub ahead of print].

PubMed ID: 
29337599

Wolfram Syndrome 2

Clinical Characteristics
Ocular Features: 

As in Wolfram syndrome 1, only insulin dependent diabetes mellitus and optic atrophy are essential to the diagnosis. The optic atrophy is progressive over a period of years and can be the presenting sign.  Its onset, however, is highly variable and may begin in infancy but almost always before the third decade of life.  The majority (77%) of patients are legally blind within a decade of onset.  The visual field may show paracentral scotomas and peripheral constriction.  Both VEPs and ERGs can be abnormal.  Diabetic retinopathy is uncommon and usually mild.

Systemic Features: 

The clinical features of this disorder are many and highly variable.  Sensorineural hearing loss, anemia, seizures, ataxia, and autonomic neuropathy are usually present. Respiratory failure secondary to brain stem atrophy may have fatal consequences by the age of 30 years.  A variety of mental disturbances including mental retardation, dementia, depression, and behavioral disorders have been reported.  The diabetes mellitus is insulin dependent with childhood onset.  Hydroureter is often present.

Diabetes insipidus may be present in patients with Wolfram syndrome 1 (222300) but has not been reported in patients reported with Wolfram syndrome 2.   Upper GI ulceration and bleeding were present in several individuals.

Genetics

This is an autosomal recessive disorder similar to Wolfram syndrome 1 (WFS1; 222300) but caused by mutations in the CISD2 gene (4q22-q24).  The gene codes for a small protein (ERIS) localized to the endoplasmic reticulum. It seems to occur less commonly than WFS1.

Some patients have mutations in mitochondrial DNA as the basis for their disease (598500).  Combined with evidence that point mutations at the 4p16.1 locus predisposes deletions in mtDNA, this suggests that at least some patients with Wolfram syndrome have a recessive disease caused by mutations in both nuclear and mitochondrial genes.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is supportive for specific organ disease.  Low vision aids may be helpful in selected individuals.

References
Article Title: 

Wolfram Syndrome 1

Clinical Characteristics
Ocular Features: 

Optic atrophy in association with diabetes mellitus is considered necessary to the diagnosis of Wolfram syndrome.  The optic atrophy is progressive over a period of years and can be the presenting symptom.  Its onset, however, is highly variable and may begin in infancy but almost always before the third decade of life.  The majority (77%) of patients are legally blind within a decade of onset.  The visual field may show paracentral scotomas and peripheral constriction.  Both VEPs and ERGs can be abnormal.  Diabetic retinopathy is uncommon and usually mild.

Two sibs with confirmed WFS1 have been reported with microspherophakia, congenital cataracts, and glaucoma in addition to optic atrophy .

Systemic Features: 

The clinical features of this disorder are many and highly variable.  Sensorineural hearing loss, diabetes insipidus, anemia, seizures, vasopressin deficiency, ataxia, and autonomic neuropathy are usually present. Respiratory failure secondary to brain stem atrophy may have fatal consequences by the age of 30 years.  A variety of mental disturbances including mental retardation, dementia, depression, and behavioral disorders have been reported.  The diabetes mellitus is insulin dependent with childhood onset.  Dilated ureters and neurogenic bladder are frequently seen, especially in older patients..

Genetics

Wolfram syndrome 1 is an autosomal recessive disorder that can be caused by mutations in the WFS1 gene (4p16.1) encoding wolframin, a small protein important to maintenance of the endoplasmic reticulum.  However, a minority of individuals also have deletion mutations in mitochondrial DNA (598500).  Some evidence suggests that point mutations at 4p16.1 predispose deletions in mtDNA, and, if so, this recessive disorder may owe its appearance to combined mutations in both nuclear and mitochondrial DNA.  In addition, rare families with the Wolfram syndrome phenotype and mutations in the WFS1 gene show transmission patterns consistent with autosomal dominant inheritance.

Wolfram syndrome 2 (WFS2) (604928) results from mutations in CISD2 at 4q22-q24.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for Wolfram syndrome but the administration of thiamin can correct the anemia.  Low vision aids may be helpful in early stages of disease.

References
Article Title: 

Gaucher Disease

Clinical Characteristics
Ocular Features: 

Gaucher disease is often divided into three clinical types, I, II, and III although all are caused by mutations in the same gene.  Type I, sometimes called nonneuronopathic type I, has ocular features including white deposits in anterior chamber structures such as the corneal endothelium, pupillary margin, and the angle, as well as in the ciliary body.  Pingueculae can be prominent.  The perimacular retina often appears grayish and also can show some white spots.  These may also be seen in the posterior vitreous in at least some patients with type III  There may be pigmentary changes in the macula and uveitis occurs rarely.  Macular atrophy has been reported and the retinal vasculature may be abnormally permeable. Corneal opacities have been seen in some patients.  Oculomotor apraxia and abnormal opticokinetic responses are common in types II and III.  Visual acuity may be in the range of 20/200.

Other conditions with ataxia and oculomotor apraxia are: ataxia with oculomotor apraxia 1 (208920), ataxia with oculomotor apraxia 2 (602600), ataxia-telangiectasia (208900) and Cogan-type oculomotor apraxia (257550) which lacks other neurologic signs.

Systemic Features: 

This is a severe systemic disease with perinatal lethality in some patients.  The range of clinical heterogeneity is wide, however, and minimally affected adult patients have also been described.  Individuals with nonneuropathic type I lack central nervous system involvement.  They often do have hepatosplenomegaly and pancytopenia with bone marrow involvement which are common to all types.  The latter may be responsible for frequent bone fractures and other orthopedic complications such as vertebral compression.  Thrombocytopenia with bleeding complications contributes to the primary anemia which is also present.  Interstitial lung disease can be seen in type I disease but occurs in less than 5% of patients. This is the most common of the three types. 

Patients with type I Gaucher disease have an increased risk of cancer, especially those of the hematological system.  For example, the risk for multiple myeloma has been estimated to be 37 times higher than in the general population.  There is also evidence of an increased incidence of multiple consecutive cancers in this condition.  Enzyme replacement therapy may reduce the risk of malignancies.

Patient with types II (acute neuronopathic [230900]) and III (subacute neuronopathic [231000]) are more likely to have neurologic disease with bulbar and pyramidal signs and sometimes seizures.  In type II, onset is in infancy and lifespan is about 2 years.   They have hepatosplenomegaly with growth arrest and developmental delays after a few months.  The clinical signs in type III or subacute neuronopathic type the onset is later (2.5 years to adulthood) than in type II and progression of neurologic disease is slower.  Early childhood development may appear normal for several years until abnormal extraocular movements or seizures are observed.  Type III is sometimes called Norrbottnian type.

Genetics

All three types of Gaucher disease are caused by mutations in the GBA (glucocerebrosidase) gene (1q21) and are inherited in an autosomal recessive pattern.

Evidence indicates that SCARB2, which codes for lysosomal integral membrane protein type 2 (LIMP-2), is a modifier of the phenotype in Gaucher disease.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Supportive care is required for all patients.  Splenectomy may be required for thrombocytopenia and blood transfusion can be helpful in severe anemia and excessive bleeding.  The course of disease is highly variable in all types, ranging from neonatal mortality to mild disease into adulthood, especially for individuals with type III.  Testing for deficiency in glucosylceramidase enzyme activity in leukocytes can be diagnostic.   Enzyme replacement or substrate reduction therapies can reduce the severity of clinical disease especially in type I disease but less so in types II and III.

References
Article Title: 

The clinical management of type 2 Gaucher disease

Weiss K, Gonzalez AN, Lopez G, Pedoeim L, Groden C, Sidransky E. The clinical management of type 2 Gaucher disease. Mol Genet Metab. 2014 Nov 14.  [Epub ahead of print] Review.

PubMed ID: 
25435509

A Mutation in SCARB2 is a Modifier in Gaucher Disease

Velayati A, Depaolo J, Gupta N, Choi JH, Moaven N, Westbroek W, Goker-Alpan O, Goldin E, Stubblefield BK, Kolodny E, Tayebi N, Sidransky E. A Mutation in SCARB2 is a Modifier in Gaucher Disease. Hum Mutat. 2011 Jul 27. doi: 10.1002/humu.21566. [Epub ahead of print]

PubMed ID: 
21796727

LCAT Deficiency

Clinical Characteristics
Ocular Features: 

Norum disease and fish-eye disease are discussed as a single entry in this database because they are both caused by mutations in the same gene (LCAT).  Most patients are diagnosed as young adults.  Corneal opacities are may be the only clinically significant abnormality in fish-eye disease whereas anemia and renal complications are more significant in Norum disease.   Lipid deposition in the cornea is responsible for the corneal opacities and may cause significant reduction in vision.  However, opacities are concentrated near the limbus.  The cornea in fish-eye disease has twice the normal amount of cholesterol and vacuoles in the stroma and Bowman's.  Vision ranges from 20/40 to hand motions, with onset in the first two decades and progression throughout life.  The opacities form a mosaic pattern of small dot-like grey-white-yellow opacities.  The fish-eye designation comes from the corneal clouding resembling boiled fish eyes.

Systemic Features: 

Lecithin:cholesterol acyltransferase (LCAT) is a disorder of lipoprotein metabolism resulting in reduced plasma cholesterol esterifying activity.  The mutation leading to Norum disease causes normocytic hemolytic anemia with significant proteinuria secondary to renal failure.  However, patients with fish-eye disease do not have anemia or renal disease.  Red blood cells may have increased cholesterol content and foam cells are found in bone marrow and in the glomerular tufts of the kidney.  Peripheral neuropathy is sometimes present.   Circulating cholesterol, triglycerides and phospholipids are elevated whereas high-density lipoprotein (HDL), apoA-I and apoA-II are reduced.  However, premature atherosclerosis is not a feature contrary to expectations.  

LCAT deficiency does not have hepatomegaly, splenomegaly or enlarged lymph glands as found in another disorder of lipoprotein metabolism with low HDL levels known as Tangier disease (205400).

Genetics

Complete LCAT deficiency (Norum) disease and partial deficiency (fish-eye disease) are autosomal recessive disorders secondary to mutations in the LCAT gene located on chromosome 16 (16q22.1).  The mutation is located in codon 123 in fish-eye disease and in codon 4 of Norum disease.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Severe visual impairment secondary to corneal clouding is an indication for corneal transplantation.  Renal failure may require renal transplantation.
 

References
Article Title: 

Markedly accelerated catabolism of apolipoprotein A-II (ApoA-II) and high density lipoproteins containing ApoA-II in classic lecithin:cholesterol acyltransferase deficiency and fish-eye disease.

Rader, D. J.; Ikewaki, K.; Duverger, N.; Schmidt, H.; Pritchard, H.; Frohlich, J.; Clerc, M.; Dumon, M.-F.; Fairwell, T.; Zech, L.; Santamarina-Fojo, S.; Brewer, H. B., Jr. : Markedly accelerated catabolism of apolipoprotein A-II (ApoA-II) and high density lipoproteins containing ApoA-II in classic lecithin:cholesterol acyltransferase deficiency and fish-eye disease. J. Clin. Invest. 93: 321-330, 1994.

PubMed ID: 
8282802

A molecular defect causing fish eye disease: an amino acid exchange in lecithin-cholesterol acyltransferase (LCAT) leads to the selective loss of alpha-LCAT activity.

Funke, H.; von Eckardstein, A.; Pritchard, P. H.; Albers, J. J.; Kastelein, J. J. P.; Droste, C.; Assmann, G. : A molecular defect causing fish eye disease: an amino acid exchange in lecithin-cholesterol acyltransferase (LCAT) leads to the selective loss of alpha-LCAT activity.  Proc. Nat. Acad. Sci. 88: 4855-4859, 1991.

PubMed ID: 
2052566
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