Chediak-Higashi syndrome

Chediak-Higashi syndrome is inherited as an autosomal recessive disease. It was described over 50 years ago. Clinical reports have identified mutations throughout the CHS1/LYST lysosomal trafficking gene.¹ The nature of the mutation can be a predictor of the severity of the disease.² There are a number of animal models including mouse, cat, cattle, mink and killer whale.¹

Chediak-Higashi syndrome epidemiology

The disease is exceptionally rare with fewer than 500 cases reported in the literature.³

Chediak-Higashi syndrome is characterised by partial oculocutaneous albinism, immunodeficiency, and a mild bleeding tendency.

In 85% of cases, Chediak-Higashi Syndrome develops into an accelerated phase characterised by pancytopenia, high fever, and lymphohistiocytic infiltration of the liver, spleen, and lymph nodes.⁵

Clinical features of Chediak-Higashi syndrome include:

• Impaired vision, photophobia.

• Albinism of the OCA2 type, giving a lighter complexion than unaffected family members.⁶

• Silvery sheen to hair which may be fair in colour.

• Frequent infections (skin, mucous membranes, respiratory).

• Epilessia.

• Mental retardation.

• Enlarged liver and spleen, jaundice.

• Ataxia causing incoordination and a typical ataxic gait; tremor.

Initially the condition may present as one of the varieties of albinism but the recurrent infections should make one suspect the diagnosis. The Hermansky-Pudlak syndrome and Griscelli's syndrome are similar but distinct conditions.³

The diagnosis is established in a proband with giant inclusions within leukocytes on peripheral blood smear and/or by the identification of biallelic pathogenic variants in LYST on molecular genetic testing.

• Blood smear shows giant granules in the neutrophils that stain for peroxidases.

• Bone marrow smears show giant inclusion bodies in leukocyte precursor cells.

• Giant granules are also found in cells from biopsy of skin, muscle and nervous system.

• Platelet or leukocyte levels are abnormally low.

• Genetic testing may show mutations in the CHS1 gene.

• Light or polarised light examination of hair shafts can help to diagnose Chediak-Higashi syndrome but cannot differentiate it from the appearance seen in Griscelli's syndrome.⁷

• Fluorescence cytometric analysis of cellular granularity and surface molecules offer useful diagnostic information.

• EEG may be abnormal.

• Brain MRI or CT scan may show small brain due to atrophy.

• Oral radiographs may reveal extensive loss of alveolar bone, often resulting in tooth exfoliation. .

• EMG or nerve conduction velocity testing may show delayed nerve conduction.

• A red light reflex is present in the eye (this is frequently seen in albinism).

• There are abnormalities of immune function including reduced level of CD4 lymphocytes.

• Infection is a constant problem.

• For a better understanding of the visual defects and the problems related to the OCA2, see the separate record on Albinismo.

• Initial chemoimmunotherapy followed by transition to continuation therapy for the accelerated phase.

• Allogenic stem cell transplant as soon as possible to cure haematological and immunological defects.

• L-dopa may be considered for those with parkinsonism.

• Home modifications and intensive rehabilitation for those with ataxia and other neurological complications.

• Corrective lenses to improve visual acuity, sunglasses to protect sensitive eyes from UV light.

• Sunscreen to prevent sun damage and skin cancer.

• Management of other presenting features, eg, epilepsy.

Consulenza genetica

Chediak-Higashi Syndrome is inherited in an autosomal recessive manner. When both parents are heterozygous, each sibling of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

Prenatal testing of CHS is possible if the pathogenic variants have been identified in the family.

Frequent infections lead to ipertrofia splenica which in turn causes trombocitopenia and haemorrhage.

About 85% of patients develop an unusual linfoma. This is called the accelerated phase and is characterised by generalised lymphohistiocytic infiltrates, fever, jaundice, hepato-splenomegaly, lymphadenopathy, pancytopenia and bleeding.¹

Without stem cell transplant, death before the age of 10 is common.¹

The prognosis for the accelerated phase is poor and the only treatment is allogenic haematopoietic stem cell transplantation (HSCT).⁸

All affected individuals including adolescents and adults with atypical Chediak-Higashi syndrome and children with classic Chediak-Higashi syndrome who have successfully undergone allogenic haematopoietic stem cell transplantation develop neurological findings during early adulthood (peripheral neuropathy causing motor and sensory changes and weakness).⁴