splenomegaly

Mitochondrial DNA Depletion Syndrome 3

Clinical Characteristics
Ocular Features: 

Nystagmus, disconjugate eye movements, and "optic dysplasia" have been noted.

Systemic Features: 

Infants feed poorly which is frequently associated with vomiting, failure to thrive, and growth delay.  They are hypothermic, hypoglycemic, and often jaundiced with signs of liver failure noted between birth and 6 months of age and death by approximately 1 year of age.  Hepatosplenomegaly is present early with abnormal liver enzymes, cholestasis, steatosis, and hepatocellular loss followed by cirrhosis with portal hypertension.  Metabolic acidosis, hyperbilirubinemia, hypoalbuminemia, and hypoglycemia are often present.  Mitochondrial DNA depletion in the liver approaches 84-90%.

All patients have encephalopathic signs with evidence of cerebral atrophy, microcephaly, hypotonia.  Hyperreflexia may be present and some infants have seizures.  Muscle tissue, however, has normal histology and respiratory chain activity.

Genetics

This disorder results from homozygous or compound heterozygous mutations in the DGUOK gene (2p13).

The same gene is mutated in PEOB4 (617070).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no effective treatment.  Liver transplantation in one infant was unsuccessful.  

References
Article Title: 

Optic Nerve Edema, Splenomegaly, Cytopenias

Clinical Characteristics
Ocular Features: 

Persistent optic nerve edema is eventually followed by some degree of optic atrophy.  The nerve edema may be seen early in the first decade of life and is not associated with increased lumbar puncture pressure.  Peripapillary hemorrhages may be seen.  Visual acuity may decrease somewhat by the end of the first decade of life and becomes functionally significant in early adolescence and may be reduced to counting fingers.  The ERG, which shows minimal dysfunction early, eventually appears nearly flat without photopic or scotopic responses.  The retinal vessels become markedly attenuated and the macula may be mildly edematous and show pigmentary changes.  Pigment clumping is not seen.  Visual fields show a central or cecocentral scotoma, enlargement of the blind spot, and eventually severe peripheral constriction.  The vitreous and aqueous humor sometimes have an increased number of cells.   Lenticular opacities requiring cataract surgery has been reported.  One patient developed a phacomorphic angle closure attack at the age of 19 years.

Systemic Features: 

Splenomegaly is a consistent sign and is usually present in the first decade of life but histology shows primarily cellular congestion of the red pulp cords.  Bone marrow biopsies show mild erythroid hyperplasia. Peripheral blood counts show mild neutropenia and thrombocytopenia.  Occasional atypical lymphocytes may be seen.  Patients often complain of mildly to moderately severe migraine headaches.  Urticaria and anhidrosis are common features.

Genetics

Only a single report of this condition has been published.  A mother and two daughters (half sisters) had the symptoms described here and this is the basis for consideration of autosomal dominant inheritance.  Nothing is known regarding the etiology or the mechanism of disease.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Topical, intravitreal, oral, and subtenon application of steroids apparently have no impact on the progression of the intraocular disease.  Cataracts may need to be removed.

References
Article Title: 

An inherited disorder with splenomegaly, cytopenias, and vision loss

Tantravahi SK, Williams LB, Digre KB, Creel DJ, Smock KJ, Deangelis MM, Clayton FC, Vitale AT, Rodgers GM. An inherited disorder with splenomegaly, cytopenias, and vision loss. Am J Med Genet A. 2012 Mar;158A(3):475-81. doi: 10.1002/ajmg.a.34437. Epub 2012 Feb 3.

PubMed ID: 
22307799

Tangier Disease

Clinical Characteristics
Ocular Features: 

This disorder of lipoprotein metabolism is associated in many cases with corneal infiltrates, cicatricial ectropion, poor lid closure, and exposure keratopathy.  The corneal clouding alone generally cause little reduction of acuity but those with poor lid function and exposure keratopathy may have severe vision loss.  There may be weakness in the periorbital and lid muscles.  The corneal infiltration occurs late in life but is progressive with older individuals having the greatest visual impairment.  The corneal infiltrates are described as a “dot-like haze”, more prominent centrally and located in the stroma.  On electron microscopy, deposits in the conjunctiva are described as birefringent lipid particles located in pericytes and fibrocytes.  Lipid deposition occurs throughout the body including the conjunctiva.  Corneal hypesthesia has been reported.

In a series of 13 patients, ectropion and corneal scarring were reported in 3 and corneal infiltrates in 9.  Four had orbicular muscle weakness.  The latter together with corneal hypesthesia may be the earliest ocular signs of Tangier disease and should suggest the diagnosis even before the corneal clouding occurs.

Systemic Features: 

Patients with Tangier disease have significant enlargement of the liver, spleen and lymph nodes.  The tonsils are also frequently enlarged and have a characteristic yellow-orange  coloration.  The enlargement of these organs is due to lipid infiltration.  Plasma levels of cholesterol and HDL are characteristically slightly low while triglycerides are mildly elevated.  Peripheral neuropathy and muscle atrophy can be debilitating.  Severe coronary artery disease is common with onset sometime in the 5th decade.

Genetics

Tangier disease is an autosomal recessive disorder resulting from mutations in the ATP-binding cassette-1 gene ABCA1 (9p31.1) located in exon 22.  Parental consanguinity is common.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for this disorder beyond local organ treatment as indicated.
 

References
Article Title: 

Ocular complications of Tangier disease

Pressly, T. A.; Scott, W. J.; Ide, C. H.; Winkler, A.; Reams, G. P. : Ocular complications of Tangier disease. Am. J. Med. 83: 991-994, 1987.

PubMed ID: 
3314502
Subscribe to RSS - splenomegaly