Chanarin-Dorfman syndrome

 Chanarin-Dorfman syndrome

Other Names: 

CDS; Chanarin-Dorfman disease; DCS; Disorder of cornification 12 (neutral lipid storage type); Dorfman Chanarin syndrome; Ichthyosiform erythroderma with leukocyte vacuolation; NLSDI; Neutral lipid storage disease with ichthyotic; Triglyceride

Description

Chanarin-Dorfman syndrome is a condition in which fats (lipids) are stored abnormally in the body. Affected individuals cannot break down certain fats called triglycerides, and these fats accumulate in organs and tissues, including skin, liver, muscles, intestine, eyes, and ears. People with this condition also have dry, scaly skin (ichthyosis), which is usually present at birth. Additional features of this condition include an enlarged liver (hepatomegaly), clouding of the lens of the eyes. difficulty with coordinating movements (ataxia), hearing loss, short stature, muscle weakness (myopathy), involuntary movement of the eyes (nystagmus), and mild intellectual disability.

The signs and symptoms vary greatly among individuals with Chanarin-Dorfman syndrome. Some people may have ichthyosis only, while others may have problems affecting many areas of the body.

METHODS

Because CDS is an extremely rare disease, there are only a limited number of articles on this condition in literature. However, a very thorough examination of the literature was made to prepare this systemic review. To this end, articles published between 1974 and 2018 were searched on Medline, Scopus and Google Scholar by using the following keywords singly or in various combinations: ‘Chanarin–Dorfman Syndrome’, ‘Dorfman–Chanarin syndrome’, ‘Ichthyosis’, ‘congenital Ichthyosiform erythroderma’, ‘neutral lipid storage disorder’, ‘adipose triglyceride lipase’, ‘lipid droplets’, ‘ABHD5/CGI-58 mutation’, ‘Jordan's anomaly’. This search included case reports, letters to the editor, original articles, meta-analyses and review articles. Regardless of whether mutation analysis was performed in the ABHD5 gene, patients with ichthyosis and Jordan anomaly were evaluated as CDS, and included in the study.8 Patients who were mentioned repeatedly in several articles were excluded from the study. The patients’ race, age, gender, demographic characteristics, clinical symptoms, diagnosis, laboratory and radiological imaging results, histopathological examination, genetic mutations and treatments were all evaluated. The structure of this systematic review followed the PRISMA guidelines

Synonyms

Chanarin-Dorfman disease

neutral lipid storage disease type I

CGI58 deficiency

disorder of cornification 12 (neutral lipid storage type)

DOC 12 (neutral lipid storage type)

Dorfman Chanarin syndrome

ichthyosiform erythroderma with leukocyte vacuolation

ichthyotic neutral lipid storage disease

triglyceride storage disease impaired long-chain fatty acid oxidation

CDS

Signs & Symptoms

Chanarin-Dorfman syndrome can affect many systems. All patients have skin findings that are usually present at birth: redness, fine scaling, dark pigmentation and severe itching which leads to scratching and skin-picking (excoriation). The skin appearance is referred to “Ichthyosiform nonbullous erythroderma”. Patients also have liver disease with lipid storage which can lead to liver failure. About 60% of patients also have muscle problems. They have slowly progressive weakness of the proximal arms and legs. When the muscles are affected they release their enzymes in the blood, which can be detected by the presence of a CK elevation. Exercise intolerance has never been reported, but many patients reported early fatigability.

Less commonly, other systems can be involved. Around 40% of patients have eye problems consisting mainly in cataracts or eyelids pointing outwards (ectropion). Approximately 25% of patients have progressive hearing loss. Around 25% have cognitive impairment. Short stature and growth retardation have also been reported. Some patients have intestinal problems such as fatty diarrhea (steatorrhea) and enlarged spleen. Some have orthopedic problems and kidney dysfunction.

Causes

Chanarin-Dorfman syndrome is caused by changes (mutations) in the ABHD5 gene located on chromosome 3. This gene produces a protein involved in fat metabolism called CGI-58. This protein is called a co-factor because it helps the activity of the main enzyme, which is adipose triacylglycerol lipase (ATGL). The function of this enzyme is to break down a type of fat called triacylglycerol (TAG). This process is disturbed when either the enzyme or the helper protein doesn’t work properly. When the fat (triacylglycerol) cannot be broken down, it accumulates in various parts of the body as lipid droplets and causes different symptoms. This is what happens in a group of disorders called ‘neutral lipid storage disease’. It comprises two entities:

When the mutation occurs in the gene for the main enzyme (ATGL), the disease is called ‘neutral lipid storage disease with myopathy’.

When the mutation occurs in the gene for the helper protein (CGI-58), the disease is called ‘neutral lipid storage disease with ichthyosis’, or Chanarin-Dorfman syndrome.

It is important to distinguish between the two because the clinical presentations are very different. In the first one, patients usually present in early adulthood with muscle abnormalities caused by the accumulation of fat. In Chanarin-Dorfman syndrome, patients primarily have skin abnormalities that are apparent at birth. For this reason, Chanarin-Dorfman syndrome is also part of a group of diseases called ‘ichthyoses’, which are characterized by skin abnormalities. Another difference is the absence of heart problems (cardiomyopathy) in Chanarin-Dorfman syndrome, whereas they are present in first one.

The genetic mutation in Chanarin-Dorfman syndrome leads to abnormal accumulation of fat (lipid droplets) in many cells, especially in the skin, liver and white blood cells. The effect on the skin is an abnormal permeability, which leads to a characteristic rash and intense itching. In the liver, the lipid droplet accumulation leads to fatty change called “steatosis” that can eventually progress to cirrhosis and liver failure.

Chanarin-Dorfman syndrome is inherited in an autosomal recessive pattern, which means the individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

Disorders with Similar Symptoms

There are a few disorders other than Chanarin-Dorfman syndrome that have similar skin changes at birth and involve many systems. Among those, there is Neherton syndrome, Sjögren-Larsson syndrome, Conradi-Heunermann-Happle syndrome, Ichthyosis follicularis, atrichia and photophobia (IFAP) syndrome and Refsum syndrome.

Neherton syndrome is characterized by congenital ichthyosis and predisposition to allergic features such as chronic hives, asthma, rhinitis and hay fever (referred to as atopy). A unique feature is “bamboo hair”, which are short, sparse, dry and not lustrous.

Sjögren-Larsson syndrome is characterized by congenital ichthyosis, paralysis of lower limbs and severe intellectual disability.

Conradi-Heunermann-Happle syndrome manifests as skin changes at birth, in addition to skeletal abnormalities (asymmetrical shortening of limbs, kyphoscoliosis), short stature and cataracts.

IFAP is characterized by ichthyotic skin changes and loss of hair on the entire scalp (alopecia totalis). There is also extreme sensitivity to light, short stature, intellectual disability and convulsions.

Refsum syndrome develops during childhood and adolescence. In addition to the skin findings, there is functional disorder of the nervous system with ataxia, inflammation of the nerves (peripheral neuritis) and inflammation of the retina in the eyes (retinitis pigmentosa).

Diagnosis

Newborns usually have characteristic skin changes (Ichthyosiform changes), but the combination of skin appearance, liver abnormalities and other system involvement is what raises the suspicion for Chanarin-Dorfman syndrome. The suspected diagnosis is made with a peripheral blood smear test, where fat deposits (lipid droplets) are seen in white blood cells (called Jordan’s anomaly). Molecular genetic testing for mutations in the ABHD5 gene is available to confirm the diagnosis.

Treatment

There is no effective treatment for Chanarin-Dorfman syndrome. However, it is recommended to have a low fat diet (specifically low long-chain fatty acid and minimal saturated fat), enriched with medium-chain triglycerides, ursodiol (a bile acid) and vitamin E. This would decrease the liver size and normalize the liver enzymes. This diet has no effect on skin symptoms. To alleviate itching and other skin symptoms, it is recommended to apply moisturizers on the skin. Vitamin A derivatives like acitretin are useful for skin and muscle manifestations, but are often considered contraindicated if the liver enzymes are impaired, which is commonly the case. However, improvement in skin symptoms without deleterious effect on liver function has been reported with the use of acitretin. There is no consensus about the use of retinoid in Chanarin-Dorfman syndrome with abnormal liver function. One case of liver transplant followed by the usual dietary modifications has been reported with stabilisation of the skin and intellectual disability deterioration after 1 year, but there are insufficient studies to conclude the effectiveness and the long-term effects of liver transplantation.