ELEJALDE SYNDROME: NEUROCUTANEOUS INSIGHTS INTO PATHOPHYSIOLOGY, DIAGNOSIS, AND MANAGEMENT

International Journal of Pharmaceutical Science and Health Care Volume 15, Number 5, 2025 Available online on http://www.rspublication.com/ijphc/index.html ISSN 2249 – 5738 DOI: 10.5281/zenodo.17456095 Original Article @2025 RS Publication, [email protected] 185 ELEJALDE SYNDROME: NEUROCUTANEOUS INSIGHTS INTO PATHOPHYSIOLOGY, DIAGNOSIS, AND MANAGEMENT Nellutla Kavyanjali*, Syeda Nishat Fathima Department of Pharmacology, Jayamukhi College of Pharmacy, Narsampet, Warangal-506332, Telangana, India Corresponding Author: Nellutla Kavyanjali Email ID: [email protected] ARTICLE INFO ABSTRACT ©2025 RS Publicaon Paper ID: IJPHC68F0AB03C75E6 Received: 2025-09-27 Published: 2025-10-27 DOI: https://dx.doi.org/ 10.5281/zenodo.1745 6095 Page No: 185-192 This review highlights Elejalde syndrome, a rare autosomal recessive neurocutaneous disorder characterized by silvery-gray hair, hypopigmented skin, and severe central nervous system dysfunction. It typically manifests in infancy or early childhood, presenting with progressive neurologic deterioration, psychomotor regression, and seizures, while sparing the immune system. Diagnosis is based on clinical features, hair and skin microscopy, neuroimaging, and genetic testing, with MYO5A mutations implicated in the underlying pathogenesis. Management remains supportive, focusing on seizure control, physiotherapy, nutritional support, and genetic counselling. The prognosis is generally poor, with most patients experiencing early neurologic collapse. KEYWORDS: Elejalde syndrome, silvery hair syndromes, MYO5A, neurocutaneous disorder, hypopigmentation, neurologic degeneration International Journal of Pharmaceutical Science and Health Care Available online on http://www.rspublication.com/ijphc/index.html ISSN 2249 – 5738 Cite This Paper: Nellutla KavyaAnjali and Syeda Nishat Fathima (2025). "ELEJALDE SYNDROME: NEUROCUTANEOUS INSIGHTS INTO PATHOPHYSIOLOGY, DIAGNOSIS, AND MANAGEMENT". INTERNATIONAL JOURNAL PHARMACEUTICAL SCIENCE AND HEALTH CARE (IJPHC), vol. 15, no. 5, 2025, pp. 185-192. DOI: https://dx.doi.org/10.5281/zenodo.17456095 International Journal of Pharmaceutical Science and Health Care Volume 15, Number 5, 2025 Available online on http://www.rspublication.com/ijphc/index.html ISSN 2249 – 5738 DOI: 10.5281/zenodo.17456095 Original Article @2025 RS Publication, [email protected] 186 INTRODUCTION: Elejalde syndrome, also known as neuroectodermal melanolysosomal disease, is an ultra-rare autosomal recessive neuroectodermal disorder first described in 1979. It is a rare genetic neurological disease characterized by silvery-gray hair, profound central nervous system dysfunction, abnormal melanocytes and melanosomes, and abnormal inclusion bodies in fibroblasts and other cells. Clinically, Elejalde syndrome overlaps with Chediak–Higashi syndrome and Griscelli syndrome type 1, but is distinguished by the absence of immunodeficiency and hematological abnormalities. The syndrome reflects dual pathology: impaired melanin synthesis and lysosomal trafficking dysfunction within neuroectodermalderived tissues. [1] EPIDEMIOLOGY: Elejalde syndrome is an extremely rare autosomal recessive neurocutaneous disorder, with the prevalence of <1/1000000 worldwide. It was first described in Colombia, with additional cases from Mexico, Egypt, and sporadic reports elsewhere, though true prevalence is unknown. No racial or sex predilection exists. Clinical manifestations typically appear in infancy or early childhood, with neurological signs ranging from one month to eleven years. Patients present with silvery-gray hair, hypopigmented skin, and severe central nervous system dysfunction, but immune function remains normal. Survival into late childhood is rare, and most cases are associated with consanguineous families. [2] CLINICAL MANIFESTATIONS: Elejalde syndrome is characterized by distinct pigmentary and neurological abnormalities. The condition primarily affects the skin, hair, and central nervous system (CNS), with clinical manifestations appearing as early as one month of age or during early childhood. Two major neurological patterns have been described: a congenital form and an infantile (regressive) form. In the congenital form, symptoms are evident in the first months of life, with severe intellectual disability, profound hypotonia, absence of voluntary movements, and lack of response to external stimuli. Affected infants often fail to recognize their parents and show marked psychomotor delay. In the infantile form, children initially develop normally but later, between three and eleven years of age, experience rapid psychomotor regression, losing the ability to speak, walk, and feed themselves, eventually becoming bedridden.[3] International Journal of Pharmaceutical Science and Health Care Volume 15, Number 5, 2025 Available online on http://www.rspublication.com/ijphc/index.html ISSN 2249 – 5738 DOI: 10.5281/zenodo.17456095 Original Article @2025 RS Publication, [email protected] 187 Neurological manifestations dominate the clinical picture and include seizures, severe generalized hypotonia, spastic or flaccid hemiplegia or quadriplegia, ataxia, hyporeflexia or hyperreflexia, and profound developmental delay. Convulsive episodes are frequent once neurological deterioration begins, and death often occurs within a few years of onset due to progressive neurodegeneration. Cutaneous and hair abnormalities are equally distinctive. The scalp, eyebrows, and eyelashes exhibit a characteristic silvery-gray or metallic sheen. The skin appears hypopigmented but develops a deep bronze or long-lasting tan after sun exposure due to abnormal melanin distribution within melanocytes. Microscopic examination of hair shafts shows large, irregular clumps of melanin, which help distinguish ES from other silvery hair syndromes. Ophthalmologic findings are also common, including nystagmus, diplopia, pupillary areflexia, and congenital amaurosis, reflecting the involvement of ocular neurons. Although immune function remains normal, some patients may experience recurrent respiratory infections unrelated to immunodeficiency. Rarely, omphalocele has been reported as an associated feature. DIAGNOSIS: The diagnosis of Elejalde syndrome (ES) is established based on a combination of clinical features, laboratory studies, imaging findings, histopathologic characteristics, and genetic confirmation. Early recognition is essential to distinguish ES from other silvery hair syndromes such as Chediak–Higashi and Griscelli syndromes.[4] Laboratory Studies: Immunologic testing in patients with Elejalde syndrome typically reveals normal immune function, helping to differentiate it from immunodeficiency-associated conditions like Griscelli and Chediak–Higashi syndromes. New degranulation assays may assist in the early and accurate diagnosis of Elejalde syndrome and related disorders. Light microscopy of hair shafts and skin biopsies serves as a first-line diagnostic tool, revealing irregular clumps of melanin within the hair shafts. Polarized microscopy can be particularly useful when light microscopy results are inconclusive, especially in fair-haired individuals or in settings where genetic testing is not readily available. Imaging Studies: Neuroimaging findings in Elejalde syndrome are typically abnormal. Computed tomography and magnetic resonance imaging scans frequently demonstrate periventricular white matter changes, cerebellar and cortical atrophy, and gray matter International Journal of Pharmaceutical Science and Health Care Volume 15, Number 5, 2025 Available online on http://www.rspublication.com/ijphc/index.html ISSN 2249 – 5738 DOI: 10.5281/zenodo.17456095 Original Article @2025 RS Publication, [email protected] 188 abnormalities. Some patients exhibit leukoencephalomalacia. MRI of the brain often reveals prominent cerebellar atrophy accompanied by mild frontoparietal cortical thinning, consistent with progressive neurodegeneration. Other Diagnostic Tests: Electroencephalograms generally show abnormal electrical activity, correlating with the seizure episodes and neurodegenerative progression seen in Elejalde syndrome. Chromosomal or molecular genetic analysis can confirm the diagnosis by identifying a mutation in the MYO5A gene located on chromosome 15q21.1, which encodes the myosin VA protein essential for melanosome transport. Histologic Findings: Histopathological examination of hair, skin, and tissue samples provides distinctive diagnostic evidence. Hair shafts show irregular melanin clumping, while skin biopsies reveal melanocytes with abnormally shaped melanosomes and defective melanin transfer to keratinocytes. Abnormal melanolysosomes may also appear in heterozygous carriers. In bone marrow, aberrant inclusion bodies are often found within fibroblasts, histiocytes, and lymphocytes, occasionally excreted into the extracellular matrix. In some cases, leptomeningeal and cerebellar biopsies demonstrate a thickened meningeal wall with dense lymphocytic infiltration, gemistocytic astrocytes, and multifocal necrosis of the cerebellar folia. No viral inclusions or necrotizing vasculitis are observed. Immunohistochemistry shows that approximately 80% of the inflammatory lymphocytes are T cells, though this finding is nonspecific and may overlap with various neuroinflammatory conditions. DIFFERENTIAL DIAGNOSIS: Silvery-gray hair and pigmentary abnormalities are characteristic of a group of rare autosomal recessive disorders collectively referred to as silvery hair syndromes (SHS). These include Elejalde syndrome (ES), Chediak–Higashi syndrome (CHS), and Griscelli syndrome (GS). Although these conditions share similar clinical pigmentation features, they differ markedly in their immunological, neurological, and genetic profiles. [5] Elejalde syndrome is distinguished by silvery-gray hair and severe neurological impairment, including seizures, hypotonia, and developmental delay. Importantly, immunologic function remains normal, setting ES apart from CHS and GS. Histologically, ES shows large melanin granules unevenly distributed in hair shafts, abnormal melanosomes in melanocytes, and distinctive inclusion bodies in fibroblasts. Genetically, ES is considered an International Journal of Pharmaceutical Science and Health Care Volume 15, Number 5, 2025 Available online on http://www.rspublication.com/ijphc/index.html ISSN 2249 – 5738 DOI: 10.5281/zenodo.17456095 Original Article @2025 RS Publication, [email protected] 189 allelic variant of Griscelli syndrome, associated with mutations in the MYO5A gene on chromosome 15q21. In contrast, Chediak–Higashi syndrome is characterized by oculocutaneous hypopigmentation, silver-gray hair, recurrent infections, and bleeding tendencies due to defective neutrophil chemotaxis and platelet dysfunction. It is caused by mutations in the LYST gene located at 1q42–1q43. Griscelli syndrome, on the other hand, presents with silver-gray to golden hair and variable cellular immunodeficiency due to mutations in RAB27A or MYO5A, leading to impaired melanosome transport. Pathologically, Elejalde syndrome lacks the immune deficiency seen in CHS and GS but exhibits more profound neurological dysfunction. It is postulated that abnormal melanin distribution and neuromelanin dysfunction in the central nervous system contribute to progressive neurodegeneration. The involvement of neuromelanin links ES to mechanisms similar to those implicated in Parkinson’s and other neurodegenerative disorders. PATHOPHYSIOLOGY: The pathogenesis of Elejalde syndrome is complex and involves abnormalities in melanin synthesis, organelle trafficking, and neuroectodermal development. Melanocytes, which originate from the neural crest (neurectoderm), migrate extensively during embryogenesis to various tissues including the central nervous system (CNS) (such as the substantia nigra, locus coeruleus, cranial sensory ganglia, and pia-arachnoid), as well as to peripheral and visceral organs such as the retina, adrenal medulla, gallbladder, and colon. Given their wide distribution, any mutation affecting melanocyte structure or function can have widespread consequences, particularly within the CNS and skin. In Elejalde syndrome, abnormalities in melanin metabolism and melanosome structure are central features. Normally, skin melanin is synthesized from tyrosine and DOPA through the action of tyrosinase and is transferred to keratinocytes. In contrast, neuronal melanin (neuromelanin) remains stored within neuronal cytoplasm and is not transferred. Tyrosinase activity is absent in the CNS, suggesting that alternative biochemical pathways regulate neuromelanin synthesis. It is postulated that disrupted metabolism of DOPA, catecholamines, and tyrosine—all precursors of melanin—may underlie the severe CNS dysfunction observed in ES.[6-8] International Journal of Pharmaceutical Science and Health Care Volume 15, Number 5, 2025 Available online on http://www.rspublication.com/ijphc/index.html ISSN 2249 – 5738 DOI: 10.5281/zenodo.17456095 Original Article @2025 RS Publication, [email protected] 190 Microscopically, fibroblasts, lymphocytes, and bone marrow cells in ES contain abnormal, membrane-bound granules filled with osmiophilic material and dense homogeneous matrices. These structures represent accumulated melanin precursors or related compounds, leading to the formation of irregular, hypomelanized melanosomes in skin and hair bulbs. Electron microscopy reveals large vacuoles and membrane-bound inclusions that differ from those seen in lipofuscin or ceroid pigments. The absence of tyrosinase and peroxidase activity in these cells suggests that the accumulated material represents incompletely synthesized melanin or defective pigment precursors. Histochemical and ultrastructural studies indicate that these granules may contain lipid components similar to those found in melanin, ceroid, and lipofuscin, but without typical autofluorescence or pigmentation. Thus, they may represent an atypical form of melanin or a melanin-related compound. These findings support the hypothesis that Elejalde syndrome arises from a defective gene product responsible for early melanin formation and intracellular pigment processing, resulting in leaden-to-silvery hair and severe neurological impairment. Molecular studies have clarified that ES is allelic to Griscelli syndrome, with mutations involving the MYO5A gene located on chromosome 15q21.1. The myosin-Va protein, encoded by this gene, plays a critical role in intracellular organelle transport, particularly the movement of melanosomes within melanocytes and the trafficking of endoplasmic reticulum components in Purkinje neuron dendritic spines. This protein is essential for cerebellar learning and neural plasticity, and its dysfunction explains the neurological degeneration and ataxia seen in affected individuals. Elejalde syndrome may also be linked to an inactivating mutation in the FGFR gene. The presence of craniosynostosis as a hypermorphic condition supports this possibility, correlating with the documented hyperproliferation of fibroblasts across various tissues such as the skin, liver, kidney, and pancreas, and the enhanced fibroblast proliferation observed in culture. TREATMENT: Currently, there is no definitive or curative therapy for Elejalde syndrome. Pharmacologic interventions, including steroids, anticonvulsants, and antipyretics, have been employed in affected patients; however, these measures have consistently failed to modify disease progression. Management is therefore primarily supportive and symptomatic, focusing International Journal of Pharmaceutical Science and Health Care Volume 15, Number 5, 2025 Available online on http://www.rspublication.com/ijphc/index.html ISSN 2249 – 5738 DOI: 10.5281/zenodo.17456095 Original Article @2025 RS Publication, [email protected] 191 on seizure control, prevention of complications, and overall patient comfort. Given the progressive nature of neurologic deterioration, close longitudinal monitoring is essential to identify and address emerging complications promptly. Given the autosomal recessive inheritance of Elejalde syndrome, genetic counseling is essential, particularly in consanguineous families. Carrier testing and prenatal diagnosis may be offered to at-risk families to inform reproductive decisions. PROGNOSIS: The prognosis of Elejalde syndrome is generally poor, with most reported cases resulting in fatal outcomes during childhood. Patients experience progressive neurologic deterioration, eventually losing the ability to move or care for themselves. Death typically occurs as a consequence of neurologic collapse, with reported ages at death ranging from 3 months to 5.5 years. Rarely, some patients survive into late childhood, with one case reported at 12 years of age. Morbidity is primarily driven by severe psychomotor regression and central nervous system dysfunction, which significantly impair quality of life and contribute to early mortality. CONCLUSION: Elejalde syndrome is an extremely rare neuroectodermal disorder characterized by silvery hair, hypopigmentation, and progressive neurological deterioration. Management remains supportive, prognosis is poor, and further research is essential to develop effective therapies. REFERENCES: 1. Inamadar, A., & Palit, A. (2007). Silvery hair with bronze-tan in a child: A case of Elejalde disease. Indian Journal of Dermatology Venereology and Leprology, 73(6), 417. https://doi.org/10.4103/0378-6323.37063 2. Duran-McKinster, C., Rodriguez-Jurado, R., Ridaura, C., de la Luz OrozcoCovarrubias, M., Tamayo, L., & Ruiz-Maldonando, R. (1999). Elejalde syndrome--a melanolysosomal neurocutaneous syndrome: clinical and morphological findings in 7 patients. Archives of dermatology, 135(2), 182–186. https://doi.org/10.1001/archderm.135.2.182 International Journal of Pharmaceutical Science and Health Care Volume 15, Number 5, 2025 Available online on http://www.rspublication.com/ijphc/index.html ISSN 2249 – 5738 DOI: 10.5281/zenodo.17456095 Original Article @2025 RS Publication, [email protected] 192 3. Cahali, J. B., Fernandez, S. A., Oliveira, Z. 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