Chediak-Higashi Syndrome Clinical Presentation

Updated: Aug 23, 2016
  • Author: Roman Janusz Nowicki, MD, PhD; Chief Editor: Dirk M Elston, MD  more...
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Presentation

History

Infants born with Chédiak-Higashi syndrome (CHS) have nonpigmented skin (similar to albinos but in patchy distribution), blonde hair, and blue eyes. Signs and symptoms that usually appear soon after birth include the following:

  • Adenopathy
  • Aphthae
  • Gingivitis
  • Hyperhidrosis
  • Miliaria
  • Jaundice
  • Severe and extensive pyoderma
  • Recurrent sinopulmonary infections
  • Fever unrelated to recognizable infection
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Physical

The clinical features of Chédiak-Higashi syndrome (CHS) include partial albinism, photosensitivity, severe recurrent bacterial infections, bleeding diatheses, and late-onset neurological manifestations (central and peripheral neuropathies, sensory loss, muscle weakness, parkinsonism, cerebellar ataxia, and cognitive impairment). [3]

Most patients are diagnosed during the first decade of life, and, while the disease affects multiple organs and systems, death often occurs early because of infection, bleeding, or development of hemophagocytic lymphohistiocytosis (HLH). The accelerated phase is the most life-threatening clinical feature of CHS, affecting about 85% of CHS patients within the first decade. This manifestation defines the characteristic childhood form of the disease and is characterized by massive HLH. It often occurs following initial exposure to Epstein-Barr virus (EBV), when it may resemble lymphoma. HLH manifests as fever, lymphadenopathy, and hepatosplenomegaly with signs of liver dysfunction, cytopenia, and bleeding. Massive lymphohistiocytic infiltration of virtually all organ systems may also be observed. Most patients with a history suggestive of CHS undergo a variable period of recurrent infections before entering the accelerated phase, but primary presentation in the accelerated phase has also been reported. [10, 9]

About 10-15% of patients follow a less severe clinical course of CHS—the adolescent and adult forms. These children present with mostly subtle hypopigmentation; a lower frequency of infections during childhood, adolescence, and adulthood; and mild bleeding manifestations. They survive until adulthood without experiencing an accelerated phase. Nonetheless, during adolescence or adulthood, they develop progressive neurologic symptoms, including intellectual deficit, dementia, peripheral neuropathy, parkinsonism, balance abnormalities, and tremor. [9]

Oculocutaneous albinism is prominent, and, together with photophobia and silvery hair, it is helpful in early diagnosis. The skin is fair, the retinae are pale, and the irides are translucent. The hair is light blonde or silvery gray and may be sparse. Iris hypopigmentation may be associated with decreased retinal pigmentation, and ocular manifestations include photophobia, decreased visual acuity, nystagmus, and strabismus. [9] The degree of hypopigmentation varies and typically affects skin, hair, and eyes. A speckled hyperpigmentation or dark skin may uncommonly be seen in more pigmented races, leading to the suspicion of other diseases with a consequent delay in diagnosis.

In CHS, patients are affected by frequent and severe pyogenic infections secondary to abnormal functioning of polymorphonuclear leukocytes, which is associated with albinism and a bleeding tendency. Recurrent skin infections occur frequently and range from superficial pyoderma to deep subcutaneous abscesses and ulcers that heal slowly and result in atrophic scars. Staphylococcus aureus is the most common causative agent. Deep ulcerations resembling pyoderma gangrenosum have also been described.

The complete syndrome includes oculocutaneous albinism with photophobia, neurologic features, recurrent infections, and enterocolitis.

Severe gingivitis and oral mucosal ulceration are common. Oral ulcerations and periodontal disease also occur. [11, 12]

CHS may present with neurologic dysfunction and should be considered in the differential diagnosis of children and young adults first seen with symptoms of spinocerebellar degeneration or movement disorders. Common physical findings include abnormal gait, clumsiness, seizures, paresthesia, mental retardation, and peripheral neuropathy. In many persons with CHS, neurologic changes appear in the lymphoproliferative lymphomalike phase. Progressive neurologic deterioration is common in patients who survive early childhood. Generally, such patients eventually enter an accelerated phase of the disease with widespread infiltration by lymphocytes and histiocytes, causing rapid enlargement of the liver, the spleen, and the lymph nodes, and with concurrent severe leukopenia and thrombocytopenia, resulting in death from infection or bleeding.

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Causes

Chédiak-Higashi syndrome (CHS) is inherited in an autosomal recessive pattern. Parental consanguinity is often reported. The genetic hallmark of CHS is mutations in the CHS1/LYST gene located on band 1q42-43. Mutations of this gene result in a defect in granule morphogenesis in multiple tissues. The gene encodes a protein called the lysosomal trafficking regulator, which regulates the synthesis, transport, and fusion of cytoplasmic vesicles. The abnormalities observed in these vesicles result in grossly enlarged and nonfunctional lysosomes, which are identified during cytology as giant, coalesced, azurophilic granules present mostly in granulocytes and monocytes, but also in fibroblasts, melanocytes, astrocytes, Schwann cells, and hematopoietic cells. These granules are specific to CHS, and their presence in granulocytes from peripheral blood and bone marrow is the basis of diagnosis. Clinical CHS phenotypes correlate with molecular genotypes. CHS patients with deletions in the LYST gene usually present with a fulminant accelerated phase early in life, whereas, those with missense mutations have a better prognosis, characterized by the absence of an accelerated phase and no neurological involvement. [3, 6, 13]

Patients with CHS exhibit alterations in neutrophils. These alterations include neutropenia, which may be profound; decreased deformability, resulting in impaired chemotaxis; and delayed phagolysosomal fusion, resulting in impaired bactericidal activity.

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Complications

The thrombocytopenia and depletion of coagulation factors lead to petechiae, bruising, and gingival bleeding. Renal function may be impaired because of the involvement of the renal tubular epithelium. The progressive visual loss and the constriction of visual field can occur.

Chédiak-Higashi syndrome (CHS) patients are affected by frequent and severe pyogenic infections secondary to the abnormal functions of polymorphonuclear leukocytes. Most children with CHS receive early attention because of troublesome recurrent bacterial infections. The most common sites of infection are the skin, respiratory tract, and mucous membranes. Staphylococcus and Streptococcus are the species most frequently isolated from these sites. Periodontal disease and bone loss of dental alveoli associated with various microorganisms are common.

CHS may present with neurologic dysfunction and should be considered in the differential diagnosis of children and young adults first seen with symptoms of spinocerebellar degeneration or movement disorders. Common physical findings include motor and sensory neuropathies, ataxia, tremors, cranial nerve palsies, low cognitive abilities, learning disabilities, and seizures. Patients who survive to the second or third decade may exhibit neurologic deterioration, including parkinsonism and dementia, and are often confined to a wheelchair. [9]

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