Elejalde Syndrome

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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 no new cases have been reported in 2012, Elejalde syndrome remains in the differential diagnosis of CHS and GS and was 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.

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 allows Elejalde syndrome to be distinguished from Griscelli syndrome (at least type 1). 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]

United States

Elejalde syndrome is extremely rare, with fewer than 20 patients reported.

International

In 1977, Elejalde et al ^[1] described a new pigment mutation in 2 males and 1 female, each from a consanguineous marriage in an inbred Colombian kindred. Whether the disease is more common in Columbia is unknown. The large series of patients with Elejalde syndrome is from Mexico, but whether this finding indicates an increased incidence is unknown.

Afifi et al ^[23] 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. ^[24]

A racial predilection is not known.

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

Elejalde syndrome usually starts to manifest during infancy. In 1999, Duran-McKinster et al ^[25] 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 not hypopigmented; rather, it 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.

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.

Elejalde BR, Valencia A, Gilbert EF. Neuro-ectodermal melanolysosomal disease: an autosomal recessive pigment mutation in man [abstr]. Am J Hum Genet. 1977. 29:39A.

Elejalde BR, Holguin J, Valencia A, et al. Mutations affecting pigmentation in man: I. Neuroectodermal melanolysosomal disease. Am J Med Genet. 1979. 3(1):65-80. [Medline].

McKusick VA, Rasmussen SA. 256710 Neuroectodermal Melanolysosomal Disease. Online Mendelian Inheritance in Man. Available at http://www.ncbi.nlm.nih.gov/omim/256710. Accessed: March 26, 2003.

Elejalde syndrome. Available at http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=33445. Accessed: June 21, 2009.

Lee JY, Eldeeb MS, Hsu CK, Saito R, Abouzeid SA, McGrath JA. Further evidence for genotype-phenotype disparity in Griscelli syndrome. Br J Dermatol. 2016 Jul 15. [Medline].

Galve J, Martín-Santiago A, Clavero C, Saus C, Alfaro-Arenas R, Pérez-Granero A, et al. Spontaneous repigmentation of silvery hair in an infant with congenital hydrops fetalis and hypoproteinemia. Cutis. 2016 Jun. 97 (6):E1-5. [Medline].

Introne WJ, Westbroek W, Cullinane AR, Groden CA, Bhambhani V, Golas GA, et al. Neurologic involvement in patients with atypical Chediak-Higashi disease. Neurology. 2016 Apr 5. 86 (14):1320-8. [Medline].

Gil-Krzewska A, Saeed MB, Oszmiana A, Fischer ER, Lagrue K, Gahl WA, et al. An actin cytoskeletal barrier inhibits lytic granule release from natural killer cells in patients with Chediak-Higashi syndrome. J Allergy Clin Immunol. 2017 Dec 11. [Medline].

Cassandra L. Kniffin and Victor A. McKusick. Elejalde disease. Online Mendelian Inheritance in Man®. Available at http://www.omim.org/entry/256710. Accessed: January 17, 2014.

Tey HL. A practical classification of childhood hypopigmentation disorders. Acta Derm Venereol. 2010. 90:6-11. [Medline].

Tey HL. Approach to hypopigmentation disorders in adults. Clin Exp Dermatol. 2010 Apr 26. [Medline].

Sahana M, Sacchidanand S, Hiremagalore R, Asha G. Silvery grey hair: clue to diagnose immunodeficiency. Int J Trichology. 2012 Apr. 4(2):83-5. [Medline]. [Full Text].

Cagdas D, Ozgür TT, Asal GT, et al. Griscelli syndrome types 1 and 3: analysis of four new cases and long-term evaluation of previously diagnosed patients. Eur J Pediatr. 2012 Oct. 171(10):1527-31. [Medline].

Saini AG, Nagaraju S, Sahu JK, Rawat A, Vyas S, Singhi P. Teaching neuroImages: Griscelli syndrome and CNS lymphohistiocytosis. Neurology. 2014 Apr 8. 82(14):e122-3. [Medline].

Dessinioti C, Stratigos AJ, Rigopoulos D, Katsambas AD. A review of genetic disorders of hypopigmentation: lessons learned from the biology of melanocytes. Exp Dermatol. 2009 Sep. 18(9):741-9. [Medline].

Lambert J, Vancoillie G, Naeyaert JM. Elejalde syndrome revisited. Arch Dermatol. 2000 Jan. 136(1):120-1. [Medline].

Sanal O, Yel L, Kucukali T, et al. An allelic variant of Griscelli disease: presentation with severe hypotonia, mental-motor retardation, and hypopigmentation consistent with Elejalde syndrome (neuroectodermal melanolysosomal disorder). J Neurol. 2000 Jul. 247(7):570-2. [Medline].

Anikster Y, Huizing M, Anderson PD, et al. Evidence that Griscelli syndrome with neurological involvement is caused by mutations in RAB27A, not MYO5A. Am J Hum Genet. 2002 Aug. 71(2):407-14. [Medline]. [Full Text].

Wilson SM, Yip R, Swing DA, et al. A mutation in Rab27a causes the vesicle transport defects observed in ashen mice. Proc Natl Acad Sci U S A. 2000 Jul 5. 97(14):7933-8. [Medline].

Li YR, Zhong A, Dong H, Ni LH, Tan FQ, Yang WX. Myosin Va plays essential roles in maintaining normal mitosis, enhancing tumor cell motility and viability. Oncotarget. 2017 Aug 15. 8 (33):54654-54671. [Medline].

Wagner W, Brenowitz SD, Hammer JA 3rd. Myosin-Va transports the endoplasmic reticulum into the dendritic spines of Purkinje neurons. Nat Cell Biol. 2011 Jan. 13(1):40-8. [Medline].

Miyata M, Kishimoto Y, Tanaka M, et al. A role for myosin Va in cerebellar plasticity and motor learning: a possible mechanism underlying neurological disorder in myosin Va disease. J Neurosci. 2011 Apr 20. 31(16):6067-78. [Medline].

Afifi HH, Zaki MS, El-Kamah GY, El-Darouti M. Elejalde syndrome: clinical and histopathological findings in an Egyptian male. Genet Couns. 2007. 18(2):179-88. [Medline].

Sori T, Nath AK, Thappa DM, Jaisankar TJ. Hypopigmentary disorders in children in South India. Indian J Dermatol. 2011 Sep-Oct. 56(5):546-9. [Medline]. [Full Text].

Duran-McKinster C, Rodriguez-Jurado R, Ridaura C, et al. Elejalde syndrome–a melanolysosomal neurocutaneous syndrome: clinical and morphological findings in 7 patients. Arch Dermatol. 1999 Feb. 135(2):182-6. [Medline].

Ivanovich J, Mallory S, Storer T, Ciske D, Hing A. 12-year-old male with Elejalde syndrome (neuroectodermal melanolysosomal disease). Am J Med Genet. 2001 Feb 1. 98(4):313-6. [Medline].

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Raghuveer C, Murthy SC, Mithuna MN, Suresh T. Silvery Hair with Speckled Dyspigmentation: Chediak-Higashi Syndrome in Three Indian Siblings. Int J Trichology. 2015 Jul-Sep. 7 (3):133-5. [Medline].

Bryceson YT, Pende D, Maul-Pavicic A, et al. A prospective evaluation of degranulation assays in the rapid diagnosis of familial hemophagocytic syndromes. Blood. 2012 Mar 22. 119(12):2754-63. [Medline].

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Noah S Scheinfeld, JD, MD, FAAD Assistant Clinical Professor, Department of Dermatology, Weil Cornell Medical College; Consulting Staff, Department of Dermatology, St Luke’s Roosevelt Hospital Center, Beth Israel Medical Center, New York Eye and Ear Infirmary; Assistant Attending Dermatologist, New York Presbyterian Hospital; Assistant Attending Dermatologist, Lenox Hill Hospital, North Shore-LIJ Health System; Private Practice

Noah S Scheinfeld, JD, MD, FAAD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Ann M Johnson, MD Assistant Professor of Clinical Radiology, University of Pennsylvania School of Medicine; Director, Body MRI, Department of Radiology, Children’s Hospital of Philadelphia

Ann M Johnson, MD is a member of the following medical societies: American Roentgen Ray Society, Radiological Society of North America, Society for Pediatric Radiology, International Society for Magnetic Resonance in Medicine, Society of Computed Body Tomography and Magnetic Resonance

Disclosure: Nothing to disclose.

David F Butler, MD Former Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Society for MOHS Surgery, Association of Military Dermatologists, Phi Beta Kappa

Disclosure: Nothing to disclose.

Jeffrey P Callen, MD Professor of Medicine (Dermatology), Chief, Division of Dermatology, University of Louisville School of Medicine

Jeffrey P Callen, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, American College of Rheumatology

Disclosure: Received income in an amount equal to or greater than $250 from: Lilly; Amgen <br/>Received honoraria from UpToDate for author/editor; Received honoraria from JAMA Dermatology for associate editor; Received royalty from Elsevier for book author/editor; Received dividends from trust accounts, but I do not control these accounts, and have directed our managers to divest pharmaceutical stocks as is fiscally prudent from Stock holdings in various trust accounts include some pharmaceutical companies and device makers for i inherited these trust accounts; for: Allergen; Celgene; Pfizer; 3M; Johnson and Johnson; Merck; Abbott Laboratories; AbbVie; Procter and Gamble; Amgen.

Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Julie C Harper, MD Assistant Program Director, Assistant Professor, Department of Dermatology, University of Alabama at Birmingham

Julie C Harper, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Received honoraria from Stiefel for speaking and teaching; Received honoraria from Allergan for speaking and teaching; Received honoraria from Intendis for speaking and teaching; Received honoraria from Coria for speaking and teaching; Received honoraria from Sanofi-Aventis for speaking and teaching.

Elejalde Syndrome

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