A mutation in the CHS1/LYST gene located on the long arm of chromosome 1 results in a rare autosomal recessive disorder called Chediak–Higashi syndrome. These mutations cause dysfunction of the lysosomal trafficking regulator protein and giant granule formation in granule-containing cells. Chediak–Higashi syndrome presents in two forms: nonsense mutations (classic Chediak–Higashi syndrome) that account for more than 85% of cases and missense mutations or small deletions (atypical Chediak–Higashi syndrome) that occur in approximately 10% to 15% of cases.
In the classic Chediak–Higashi syndrome presentation, onset is during childhood and is characterized by severe immunologic defects, oculocutaneous albinism, mild bleeding diathesis, and neurological symptoms. This form of Chediak–Higashi syndrome can lead to a fatal condition known as the accelerated phase or hemophagocytic lymphohistiocytosis. Atypical Chediak–Higashi syndrome usually presents in adulthood with neurodegenerative disorders, without hemophagocytic lymphohistiocytosis complication.1 Childhood-onset cases who do not die from infection eventually progress to the accelerated phase of the disease characterized by fever, anemia, and widespread lymphohistiocytic infiltration in all organ systems, resulting in hepatosplenomegaly, jaundice, and lymph-adenopathy.2 Neurological problems are usually a late manifestation of the disease, reported in both the classic and atypical forms of Chediak–Higashi syndrome with involvement of both the central and peripheral nervous systems. Neurological manifestations include peripheral neuropathy, cerebellar ataxia, progressive cognitive dysfunction, Parkinson disease, spinocerebellar degeneration, cranial nerve palsies, and optic neuropathy.3,4 To our knowledge, transient neurological deficit with Chediak–Higashi syndrome has not yet been reported. We describe a case of Chediak–Higashi syndrome in the accelerated phase with transient sixth nerve palsy.
A 6-year-old boy who was a known case of Chediak–Higashi syndrome and had been treated with corticosteroids, cyclosporine A, intravenous immunoglobulin, and various antibiotics presented to the pediatric department with complaints of high-grade fever, perioral swelling, abdominal distention, and diplopia since 14 days prior to the presentation. He was the third child of a consanguineous marriage, with normal psychomotor development, and no history of familial disease.
He had characteristic features of grayish hair, hypopigmented skin, and a moon face appearance (Figure 1A). The physical examination findings were significant for axillary temperature of 38.7°C, periodontal abscess formation in the oral cavity, abdominal distension with engorged vessels (Figure 1B), hepatomegaly, and huge splenomegaly. Petechiae and purpura were also seen on the lower extremities. The cardiovascular system examination was within normal limits.
(A) Grayish hair, hypopigmented skin, and a moon face appearance. (B) Abdominal distension with engorged vessels.
On ophthalmologic examination, best corrected distance visual acuities in the right and left eyes were 5/10 and 6/10, respectively, with Snellen chart. On extraocular muscle movement examination, the left eye had minus three abduction limitation and 35 and 25 prism diopters left eye distance and near esotropia, respectively, were detected on alternate prism cover test (Figure 2, upper row). Generalized chorioretinal atrophy, foveal hypoplasia of both eyes, and subhyaloid hemorrhage in the nasal quadrant of the left eye were seen on funduscopic examination (Figure 3A).
Primary position esotropia and abduction limitation in the left eye (upper row) and improved esotropia and abduction limitation (lower row).
(A) Subhyaloid hemorrhage in the nasal quadrant of the left eye. (B) Global brain atrophy and white matter signal alternation without abnormal enhancement.
On complete blood count, hemoglobin, white blood cell count, and platelet count were 8 g/dL, 7,000/mm3, and 70/mm3, respectively. Giant granules in neutrophils, eosinophils, and granulocytes were seen in the peripheral blood smear. Bone marrow aspiration also revealed giant inclusion bodies in leukocyte precursor cells and Chediak–Higashi abnormal giant granules in neutrophilic, eosinophilic, and lymphoid cells.
Brain magnetic resonance imaging showed global atrophy and white matter signal alternation without abnormal enhancement (Figure 3B).
A lumbar puncture was done and cerebrospinal fluid pressure was 140 mm of H2O (14 mm Hg) with normal cerebrospinal fluid analysis. Thus, according to these clinical and paraclinical findings, the diagnosis of the accelerated phase of Chediak–Higashi syndrome was made. Treatment was initiated with intravenous immunoglobulin, prednisolone, cotrimoxazol, vancomycin, ceftazidime, and increasing dose of cyclosporine A. After 2 weeks of therapy, sixth nerve palsy was resolved (Figure 2, lower row), but no improvement in general condition was observed. Bone marrow transplantation was planned, but the patient died before we could pursue bone marrow transplantation.
The most common neurological presentations of Chediak–Higashi syndrome are gradual or late onset, such as cognitive impairment, Parkinsonism, spasticity, ataxia, seizures, movement disorders, peripheral neuropathies, and cranial nerve palsies.3,5–7 However, the current case manifested with acute sixth nerve palsy that resolved after 2 weeks of immunomodulatory and steroid therapy. The mechanism of neurologic involvement of Chediak–Higashi syndrome is not clear yet. Different neuropathologic findings have been reported in Chediak–Higashi syndrome. Some studies reported lymphohistiocytic cell infiltration in peripheral nerves and degeneration of axon and myelin sheaths.6,8,9 Others have found intracytoplasmic inclusion granules in Schwann cells resembling lysosome and lipofuscin granules by electron microscopy.6,10,11 Mathis et al.12 considered lipofuscin granules in various endoneural cells as a neuropathological hallmark of Chediak–Higashi syndrome, which causes neuronal degenerative changes similar to those in age-related neurodegenerative disease. Misra et al.9 found axonal neuropathy without Schwann cell giant granule and inflammatory changes.
Neither endoneural infiltration of lymphohistiocytes nor lysosome and lipofuscin granule accumulation in the neural cells can justify acute and transient manifestation of our case. We propose small vessel infiltration and consequently ischemic insult to sixth cranial nerve as the etiology, which was improved by immunomodulatory therapy. Two other possible etiologies of transient sixth nerve palsy in this patient are posterior reversible encephalopathy syndrome and cyclosporine neurotoxicity. Magnetic resonance imaging findings of this patient suggest the diagnosis of posterior reversible encephalopathy syndrome, but classic clinical symptoms such as headache, altered consciousness, visual disturbances, and seizures13 were not present. Cyclosporine A induces neurological side effects in up to 40% of patients, and associated sixth nerve palsy has been reported in the past.14 In many of these cases, resolution of neurological symptoms usually occurred with reduction or withdrawal of cyclosporine A.15 In our patient, the dose of cyclosporine was increased to overcome hemophagocytic lymphohistiocytosis symptoms and this resulted in resolution of sixth nerve palsy, so the diagnosis of cyclosporine A neurotoxicity is less likely.
Neurologic manifestations of Chediak–Higashi syndrome usually take 10 to 20 years to appear. It is still unclear whether the neurologic findings in Chediak–Higashi syndrome result directly from dysfunction of lysosomal trafficking regulatory protein in neural cells, lymphohistositic infiltration, or both. However, the current case manifested with acute sixth nerve palsy in his childhood during the accelerated phase of Chediak–Higashi syndrome and the nerve palsy resolved with immunomodulatory therapy. We hypothesize that ischemic insult to the sixth cranial nerve due to lymphohistositic infiltration of small vessels is the underlying etiology.
- Zarzour W, Kleta R, Frangoul H, et al. Two novel CHS1 (LYST) mutations: clinical correlations in an infant with Chediak-Higashi syndrome. Mol Genet Metab. 2005;85:125–132. doi:10.1016/j.ymgme.2005.02.011 [CrossRef]
- Nargund AR, Madhumathi DS, Premalatha CS, Rao CR, Appaji L, Lakshmidevi V. Accelerated phase of Chediak-Higashi syndrome mimicking lymphoma—a case report. J Pediatr Hematol Oncol. 2010;32:e223–e226. doi:10.1097/MPH.0b013e3181e62663 [CrossRef]
- Desai N, Weisfeld-Adams JD, Brodie SE, et al. Optic neuropathy in late-onset neurodegenerative Chédiak-Higashi syndrome. Br J Ophthalmol. 2016;100:704–707. doi:10.1136/bjophthalmol-2015-307012 [CrossRef]
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- Lehky TJ, Groden C, Lear B, Toro C, Introne WJ. Peripheral nervous system manifestations of Chediak-Higashi disease. Muscle Nerve. 2017;55:359–365. doi:10.1002/mus.25259 [CrossRef]
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- Tardieu M, Lacroix C, Neven B, et al. Progressive neurologic dysfunctions 20 years after allogeneic bone marrow transplantation for Chediak-Higashi syndrome. Blood. 2005;106:40–42. doi:10.1182/blood-2005-01-0319 [CrossRef]
- Meyers J, Sung J, Cowen D, Wolf A. Pathological findings in the central and peripheral nervous systems in Chediak-Higashi disease. J Neuropathol Exp Neurol. 1963;22:357.
- Misra VP, King RH, Harding AE, Muddle JR, Thomas PK. Peripheral neuropathy in the Chediak-Higashi syndrome. Acta Neuropathol. 1991;81:354–358. doi:10.1007/BF00305881 [CrossRef]
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- Pezeshkpour G, Kurent JS, Krarup C, Buchthal F, Fauci A. Peripheral neuropathy in Chediak-Higashi syndrome. J Neuropathol Exp Neurol. 1986;45:353. doi:10.1097/00005072-198605000-00118 [CrossRef]
- Mathis S, Cintas P, de Saint-Basile G, Magy L, Funalot B, Vallat J-M. Motor neuronopathy in Chediak-Higashi syndrome. J Neurol Sci. 2014;344:203–207. doi:10.1016/j.jns.2014.06.026 [CrossRef]
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- Gupta AK, Bahri N. Isolated diplopia associated with calcineurin inhibitor therapy in a patient with idiopathic membranous nephropathy: a case report. BMC Nephrol. 2016;17:116. doi:10.1186/s12882-016-0309-4 [CrossRef]
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