Elejalde Syndrome 

Updated: Jan 27, 2020
Author: Chris G Adigun, MD, FAAD; Chief Editor: Dirk M Elston, MD 

Overview

Background

Elejalde syndrome (ES) was first described in 1977[1] in 3 consanguineous families in Columbia. Elejalde syndrome is also referred to as neuroectodermal melanolysosomal disease.[2] The largest series of patients has been reported in Mexico. It has been suggested that Elejalde syndrome is the same disease entity as Griscelli syndrome type 1 caused by MYO5A gene mutations.[3] Still, the exact basis for Elejalde syndrome remains to be defined.[4]  Elejalde syndrome continues to be discussed by clinicians who assess children with silver hair.[5, 6]

Silvery hair and CNS dysfunction characterize this rare autosomal recessive syndrome. The main cutaneous features of Elejalde syndrome include silver-leaden (silvery) hair and intense tanning after sun exposure (bronze skin color on sun-exposed areas).

Severe neurologic impairment (eg, seizures, severe hypotonia, mental retardation) either is congenital or develops during childhood. The immune system is not impaired. Elejalde syndrome has a wide spectrum of ophthalmologic abnormalities.

Large granules of melanin are unevenly distributed in the hair shaft. Abnormal melanocytes, melanosomes, and abnormal inclusion bodies may be present in fibroblasts. Elejalde syndrome must be distinguished from Chédiak-Higashi syndrome[7, 8]  (CHS) and Griscelli syndrome (GS).

Elejalde syndrome (Online Mendelian Inheritance in Man [OMIM] entry #256710[3] ) should not be confused with another Elejalde syndrome (OMIM entry 200995), also known as acrocephalopolydactylous dysplasia. A number sign (#) denotes the entry for Elejalde syndrome because neuroectodermal melanolysosomal disease, or Elejalde disease, and Griscelli syndrome type 1 (GS1; 214450) are really the same entity. GS1 is caused by mutation in the MYO5A gene (160777).[9]

Modern genetic studies have more firmly fixed the relative place of Elejalde in children and adults.[10, 11]

While the syndrome is rare, Elejalde syndrome remains in the differential diagnosis of CHS and GS and is actively discussed in several papers when assessing the combination of silver hair and immunodeficiency.[12, 13]

Saini et al equated GS1 with Elejalde syndrome.[14] They noted the case of a 3-year-old boy with a viral infection who experienced fever, regression of neurological function, focal seizures, and altered sensorium. Physical findings included spastic quadriparesis. extensor plantars, silvery-gray hair, bilateral papilledema, hepatosplenomegaly, and brisk muscle-stretch reflexes. The child was noted to have normal retinae, irises, and skin pigmentation. GS1 (also known as Elejalde syndrome) was confirmed using hair microscopy.

Pathophysiology

The pathophysiology of Elejalde syndrome is not fully understood. Some have stated that it is the result of a distorted gene product responsible for early melanin formation. The abnormal melanosomes form leaden-to-silvery–colored hair and cause defective CNS function. Molecular defects that underlie a variety of pigmentary disorders have been defined and provide a framework for the understanding of syndromes such as Elejalde syndrome.[15]

In 2000, Lambert et al[16] stated that the neurologic abnormalities seen in Elejalde syndrome are probably not caused by abnormal neuromelanin deposition. Instead, Lambert et al posited that the neurologic abnormalities may be linked to impaired function of a molecule playing a common role in melanocytic and neuronal organelle function. Lambert et al believe that the likely candidate genes for Elejalde syndrome must be sought in the variety of genes involved in organellogenesis and intracellular trafficking.

In 2000, Sanal et al[17] referred to neuroectodermal melanolysosomal disease as an allelic variant of Griscelli syndrome. In 2002, Anikster et al[18] suggested that families previously thought to have Griscelli syndrome due to mutations in the MYO5A gene (OMIM entry #160777) may in fact have had Elejalde syndrome.

The absence of immunologic defects distinguishes Elejalde syndrome from Griscelli syndrome. Sanal et al[17] suggest that ashen is a mouse model of Elejalde syndrome; however, in 2000, Wilson et al[19] showed that a mutated Rab27a gene, not the MYO5A gene, causes the pathology of the ashen mouse. This discussion is summarized from the OMIM page on this disease (see OMIM Elejalde syndrome).[3]

Myosin-Va is a very important gene in the brain.[20]  Its gene product is involved in the transport mechanism of the endoplasmic reticulum with the Purkinje neuron dendritic spines.[21] It is involved with cerebellar learning function and neural plasticity.[22]

Epidemiology

Frequency

United States

Elejalde syndrome is extremely rare, with 20 patients reported as of 2019.[13]

International

In 1977, Elejalde et al[1] described a new pigment mutation in two males and one female, each from a consanguineous marriage in an inbred Colombian kindred. Whether the disease is more common in Columbia is unknown. A large series of patients with Elejalde syndrome is from Mexico, but whether this finding indicates an increased incidence is unknown.[23]

Afifi et al[24] reported on an Egyptian male patient with Elejalde syndrome who had silvery hair since birth, generalized hypopigmentation, severe primary CNS dysfunction, and normal hematological and immunologic profiles.

A 2011 survey of hypopigmentary diseases in India noted no cases of Elejalde syndrome.[25]

Race

A racial predilection is not known.

Sex

Elejalde syndrome is an autosomal recessive disease; therefore, no difference in sexual frequency exists.

Age

Elejalde syndrome usually starts to manifest during infancy. In 1999, Duran-McKinster et al[23] noted that the age at onset of neurologic signs ranged from 1 month to 11 years.

In 2001, Ivanovich et al[26] noted a 12-year-old boy with Elejalde syndrome and compared this condition with Chédiak-Higashi syndrome and Griscelli syndrome. This boy demonstrated severe developmental delay, seizure activity, exotropia, nystagmus, ataxia, and silvery-gray hair and eyebrows. The skin of this patient was bronzed with diffuse freckling in sun-exposed areas. The boy had no history of recurrent infections, and results from immunologic studies were normal. Ivanovich et al[26] suggested that this patient is reportedly the oldest living child with Elejalde syndrome. It is not clear if the patient had Elejalde syndrome.

Prognosis

All cases of Elejalde syndrome but one have been reported as being fatal; therefore, the prognosis is suboptimal. Patients with Elejalde syndrome undergo neurologic collapse and eventually are not able to move or care for themselves.

Death occurs from neurologic collapse in childhood. One report noted deaths of children aged 3 months to 4 years. Another report[26] noted that a patient with Elejalde syndrome was alive at age 12 years. Another report noted that one patient with Elejalde syndrome died of respiratory infection at age 5.5 years.

The main morbidity comes from neurologic dysfunction and psychomotor regression and dysfunction.

 

Presentation

History

Children with Elejalde syndrome can manifest with the disease as early as 1 month of life or in early childhood. The skin and neurologic systems are the most commonly affected. Psychomotor impairment may have 2 forms of presentation: congenital or infantile.

Some patients with Elejalde syndrome had severe mental retardation since the first months of life. They did not seem to recognize their parents, had almost complete absence of movements, were severely hypotonic, and were unresponsive to external stimuli.

Another group of patients had no history of early neurologic impairment and developed normally. By the time the patients were aged 3-11 years, they developed several rapidly regressive psychomotor processes. They were unable to speak, walk, and feed themselves, and they were bedridden.

Other symptoms include severe migraine headaches followed by hemiparesis, leg weakness progressing to severe hypotony involving the entire body, atactic cerebellar movements progressing into an inability to maintain muscular tone of the neck, profound hypotonia, and a resultant inability to walk or to speak.

Once the neurologic alterations occur, most patients have convulsive episodes. Neuromuscular disorders include constant severe generalized hypotonia as well as hyperactive deep tendon reflexes.

In a study by Duran-McKinster et al in 1999,[23] the age at onset of neurologic signs ranged from 1 month to 11 years. The manifestations of the brain pathology of Elejalde syndrome consisted of severe muscular hypotonia, ocular alterations, and seizures. Duran-McKinster et al[23] note mental retardation that first occurred before age 6 months in 4 patients. Psychomotor development was appropriate in 3 patients; however, the patients suddenly demonstrated a regressive neurologic process. Four patients died between age 6 months and 3 years after neurologic dysfunction began.

Others have noted spastic hemiplegia or quadriplegia and seizures that decrease over time.

Physical Examination

Immune impairment is absent. Ophthalmologic findings include nystagmus, diplopia, and congenital amaurosis. Respiratory infections can occur, but their relationship to the disease is unclear.[13] The scalp and body hair, the eyebrows, and the eyelashes have a silvery color. The skin can have a bronze or deep-tan color after sun exposure.[13] Chen[27] noted that omphalocele can be a finding in persons with Elejalde syndrome. Silvery hair syndrome occurs in both Elejalde syndrome and Griscelli syndrome, so the two other signs and symptoms need to be assessed to distinguish the two.[28]

 

DDx

 

Workup

Laboratory Studies

Immunologic test results are normal for persons with Elejalde syndrome. New degranulation assays might aid in prompt diagnosis of diseases like Elejalde syndrome.[29]

Light microscopy of hair and skin biopsies are first-line tools to differentiate Elejalde syndrome from other silvery hair syndromes.[30] Polarized microscopy can also be a useful differentiating tool when light microscopy is inconclusive, as may occur in fair-haired patients, and when financial constraints preclude chromosomal analysis.[31]

Imaging Studies

Results of CT and MRI of the brain are usually abnormal in Elejalde syndrome patients, and findings include the following:

  • Abnormal findings in the periventricular white matter and the cerebellum

  • Abnormal findings in the gray matter and atrophy of the brain

  • Leukoencephalomalacia

  • Brain MRI - Prominent cerebellar atrophy with mild frontoparietal cortical atrophic changes[24]

Other Tests

Findings on electroencephalograms are usually abnormal in Elejalde syndrome patients.

Chromosomal analysis can be used to confirm a suspicion of Elejalde syndrome by revealing a mutation in the MYOVA protein found on band 5q21.1.[30]

Histologic Findings

Upon microscopic examination, hair samples from patients with Elejalde syndrome demonstrate irregular clumps of melanin.

The skin melanocytes of patients with Elejalde syndrome possess irregularly shaped melanosomes marked by an incomplete transfer-block toward surrounding keratinocytes. A few abnormal melanolysosomes occur in obligatory heterozygotes.

In the bone marrow, the abnormal structures have been noted to be excreted into the extracellular space. Ultrastructurally, abnormal inclusion bodies can be noted in fibroblasts, bone marrow histiocytes, and lymphocytes.

In one patient, a biopsy of leptomeningeal tissue and the cerebellar cortex revealed a thickened wall of meningeal membranes with a dense inflammatory infiltrate composed of mainly lymphocytes, scanty plasma cells, and macrophages.

The tissue of the cerebellar cortex in his patient showed a dense inflammatory infiltrate predominantly surrounding small veins and venules. Examination did not reveal necrotizing vasculitis. Cerebellar folia revealed multifocal necrosis in the entire width. Examination did not demonstrate viral inclusions or periodic acid-Schiff–positive microorganisms.

Multifocal necrosis of the cerebellar folia was accompanied by numerous foamy macrophages combined with gemistocytic astrocytes (astrocytes with eosinophilic, abundant cytoplasm and an eccentric nucleus) and mononuclear inflammatory cells.

Immunohistochemistry studies in patients with Elejalde syndrome have demonstrated that 80% of lymphocytes in the inflammatory infiltrate are T cells. The significance of this is unclear because such findings can be found in diverse viral diseases or immunoallergic conditions.

 

Treatment

Medical Care

Therapeutic measures for Elejalde syndrome patients have included the use of steroids, anticonvulsants, and antipyretics, and they have been unsuccessful in all patients. Thus, whether any medical therapy can be recommended for Elejalde syndrome patients is unclear.

Long-Term Monitoring

Substantial psychosocial implications are associated with pigmentary disorders, and these must be considered in patient care.[32]