Chanarin–Dorfman syndrome in three siblings in a non-consanguineous family

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The Chanarin–Dorfman syndrome (CDS, OMIM: 275630) is a rare, inherited disorder of lipid metabolism characterized by ichthyosis, lipid vacuoles in leukocytes (Jordan anomaly), and involvement of several internal organs (liver, eyes, ears, skeletal muscle and central nervous system).This autosomal recessive lipid storage disease was first described in 1974 by Dorfman and Chanarin.[1] Mutations in ABHD5/CGI58 gene are associated with CDS and triacylglycerols accumulate in cytosolic droplets in multiple organs.[2] To date approximately 58 cases of CDS were detected, and most of which are reported from the Mediterranean and Middle-East countries.[3]

We present three siblings with Chanarin–Dorfman disease born to non-consanguineous parents, and they are the oldest cases of CDS reported to date (Table 1, Figs. 1, 2).

Table 1. Summary of patients' clinical and laboratory data
 Patient 1Patient 2Patient 3
Age/sex40/M39/M35/F
Age of onsetBirthBirthBirth
Collodion membraneAbsentAbsentPresent
Parental consanguinityAbsentAbsentAbsent
Dermatological examinationFine scaling on an erythematous background involving face, abdomen, arms and legsMild erythema and desquamation Scaling and dryness are more pronounced in the skin of the extremity than the skin of his face or trunkNonbullous congenital ichtyosiform erythroderma. She presented with bilateral ectropion The palms and soles were spared and the nails and teeth were normal.
Abdominal examinationHepatoesteatosisLiver cirrhosisHepatoesteatosis
Neurologic examinationNormalMuscle biopsy also reveals marked neutral lipid accumulation.Myopathy and mild bilateral sensorineural type hearing loss
Oftalmological examinationAstigmatism and cataractNormalBilateral extropion
Laboratory parametresGOT 65 U/L (limits 10-37U/L); GPT 78 U/L (limits 10–65U/L); cholesterol 114 mg/dL (limits 125–220 mg/dL); HDL 34 mg/dL (limits 39–96 mg/dL); LDL 62.4 (limits 80–180 mg/dL)GOT 105 U/L; GPT 153 U/L; CK 770 U/L; LDH 883 U/L.GOT 65 U/L; GPT 63 U/L; CK 840; LDH 890; cholesterol 117 mg/dL (limits 125–220 mg/dL); HDL 36 mg/dL (limits 39–96 mg/dL); LDL 63 (limits 80–180 mg/dL.
Peripheral smear90% granulocytes and monocytes showing lipid vacuoles80% granulocytes and monocytes showing lipid vacuoles90% granulocytes and monocytes showing lipid vacuoles (Figure 3)
MutationMutation in CGI 58 N209 X geneMutation in CGI 58 N209 X geneMutation in CGI 58 N209 X gene
Treatment

Low fat diet

Local application of emollients containing urea

Waiting for liver transplantation, and taking a diet diet rich in carbohydrates and short-medium chained fatty acids, propranolol, ursodeoxycolic acid (15 mg/kg/day) and Vitamin E (100 IU/day). Local application of emollients containing urea was continued.Diet low in long-chain fatty acids. Supplements of medium chain fatty acids were started. Local application of emollients containing urea was continued
Figure 1.

(a) Generalized erythrodermic congenital ichtyosis with fine and white scales in three siblings. (b) and (c) White fine scaling on an erythematous background (patient 2 and 3, respectively). (d) Fine and white scales producing tautness 6 and ectropion (patient 3).

Figure 2.

Prominent intracytoplasmic vacuoles within peripheral blood polymorphonuclear neutrophils (Giemsa staining, 1000x).

The degree of systemic involvement and the pattern and severity of dermatological involvement is quite variable in this syndrome.[4] This phenotypic variation may range from isolated cutaneous manifestations to multisystemic involvement, including hepato-splenomegaly, cirrhosis, double-side cataracts, growth or mental retardation, myopathy, ataxia, bilateral sensorineural hearing loss and horizontal nistagmus.[5-7] Cutaneous involvement in CDS is a constant feature, and the clinical presentation corresponds to non-bullous congenital ichthyosiform erythroderma with fine, white scales involving the flexures, scalp and face, producing tautness or ectropion, but in several cases has been described as nonerythrodermic ichthyosis. Clinical presentation as Erythrokeratoderma variabilis-like icthyosis[8] and progressive symemetric erythrokeratoderma-like[9] has been reported. Hyperkeratosis in palms and soles, focal or diffuse alopecia, tranverse leuconychia, dystrophic or thickened nails, ungual pitting and onychoschizia are other dermatological manifestations occasionally reported in this disorder.[1, 7, 10]

Lipid droplets are found in most of the affected tissues, such as in keratinocytes, nerve cells, hepatocytes, or granulocytes. Important lipid accumulation and muscle injury may occur very early in the absence of patent clinical and imaging muscle involvement. The severity of the skin condition is not correlated with the presence of lipid drops in the epidermis.[10] Lipid droplets observed in the cytoplasm of granulocytes are described as Jordan′s anomaly and this is a pathognomonic sign for CDS. The diagnosis with simple peripheral blood examination helps in prompt diagnosis and avoids further investigations in the differentiation of fatty liver in patients with ichthyosis. Therefore, it is recommended that every case of congenital ichthyosis should have an analysis of a fresh peripheral blood smear examined with special attention to detect lipid droplets in granulocytes or monocytes. Peripheral blood smear examination of clinically unaffected members for Jordan′s anomaly to help in the detection of heterozygous carriers.[10]

There is no effective treatment of CDS, but a low fat diet is reported to improve skin and liver findings, although there is no evidence that diet alters the course of the disease. Retinoids can improve the skin, but cannot be given in patients with liver disease. Parents should be counselled regarding the high risk of recurrence in future pregnancy.

In conclusion, the present case series highlights the importance of simple peripheral smear in the diagnosis of CDS. Observation of lipid vacuoles in neutrophils in peripheral blood smears in patients with ichthyosiform erythroderma is diagnostic of Chanarin–Dorfman Syndrome.

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