eMedicine Specialties > Dermatology > Diseases of Pigmentation

Elejalde Syndrome

Noah S Scheinfeld, MD, JD, FAAD, Assistant Clinical Professor, Department of Dermatology, Columbia University; Consulting Staff, Department of Dermatology, New York Medical College-Metropolitan Hospital; Private Practice
Ann M Johnson, MD, Pediatric Radiology Fellow, Department of Radiology, The Children's Hospital of Philadelphia

Updated: Feb 12, 2008

Introduction

Background

Elejalde syndrome (ES) was first described in 1977¹ in 3 consanguineous families in Columbia. The largest series of patients has been reported in Mexico.

Silvery hair and CNS dysfunction characterize this rare autosomal recessive syndrome. The main cutaneous features of ES 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. ES 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. ES must be distinguished from Chédiak-Higashi syndrome and Griscelli syndrome.

ES (Online Mendelian Inheritance in Man [OMIM] entry #256710² ) should not be confused with another Elejalde syndrome (OMIM entry #200995), also known as acrocephalopolydactylous dysplasia.

Pathophysiology

In 2000, Lambert et al³ stated that the neurologic abnormalities seen in ES 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 ES must be sought in the variety of genes involved in organellogenesis and intracellular trafficking.

In 2000, Sanal et al⁴ referred to neuroectodermal melanolysosomal disease as an allelic variant of Griscelli syndrome. In 2002, Anikster et al⁵ suggested that families previously thought to have Griscelli syndrome due to mutations in the MYO5A gene (OMIM entry #160777) may in fact have had ES.

The absence of immunologic defects allows ES to be distinguished from Griscelli syndrome (at least type 1). Sanal et al⁴ suggest that ashen is a mouse model of ES; however, in 2000, Wilson et al⁶ 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)² .

Frequency

United States

ES is extremely rare, with fewer than 20 patients reported.

International

In 1977, Elejalde et al¹  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 ES is from Mexico, but whether this finding indicates an increased incidence is unknown.

Afifi et al⁷ reported on an Egyptian male patient with ES who had silvery hair since birth, generalized hypopigmentation, severe primary CNS dysfunction, and normal hematological and immunologic profiles.

Mortality/Morbidity

• Death occurs from neurologic collapse in childhood. One report noted deaths of children aged 3 months to 4 years. Another report⁸ noted that a patient with ES was alive at age 12 years.
• The main morbidity comes from neurologic dysfunction and psychomotor regression and dysfunction.
• Another report noted that one patient with ES died of respiratory infection at age 5.5 years.

Race

A racial predilection is not known.

Sex

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

Age

This disease usually starts to manifest during infancy.

• In 1999, Duran-McKinster et al⁹ noted that the age at onset of neurologic signs ranged from 1 month to 11 years.
• In 2001, Ivanovich et al⁸ noted a 12-year-old boy with ES 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 al⁸ suggested that this patient is reportedly the oldest living child with ES. It is not clear if the patient had ES.

Clinical

History

Children with ES can manifest with 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 ES have severe mental retardation since the first months of life. They do not seem to recognize their parents, they have almost complete absence of movements, they are severely hypotonic, and they are 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 1999,⁹ the age at onset of neurologic signs ranged from 1 month to 11 years.
  • The manifestations of the brain pathology of ES consisted of severe muscular hypotonia, ocular alterations, and seizures.
  • Duran-McKinster et al⁹ 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

• Immune impairment is absent.
• Ophthalmologic findings include nystagmus, diplopia, and congenital amaurosis.
• Respiratory infections can occur, but their relationship to the disease is unclear.
• 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.
• Chen¹⁰ noted that omphalocele can be a finding in persons with ES.

Causes

The pathophysiology of ES is not fully understood (see Pathophysiology).

Differential Diagnoses

Chediak-Higashi Syndrome
Griscelli Syndrome

Workup

Laboratory Studies

• Immunologic test results are normal.

Imaging Studies

• Results of CT and MRI of the brain are usually abnormal, 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 changes⁷

Other Tests

• Findings on electroencephalograms are usually abnormal.

Histologic Findings

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

The skin melanocytes of patients with ES 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 ES 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 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 these patients is unclear.

Follow-up

Further Inpatient Care

• Patients must be cared for closely and fed when they reach the stage of neurologic collapse.

Further Outpatient Care

• Outpatient care is the same as that for inpatient care (see Further Inpatient Care above).

Prognosis

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

Miscellaneous

Medicolegal Pitfalls

• Not much is done to treat patients with ES. A medicolegal pitfall could be not providing genetic counseling but that is unclear.
• This disease must be distinguished from Chédiak-Higashi syndrome and Griscelli syndrome so that therapy, if any, can be provided to the patient.

References

1. 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.

2. McKusick VA, Rasmussen SA. 256710 Neuroectodermal Melanolysosomal Disease. Online Mendelian Inheritance in Man. Available at http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?256710. Accessed March 26, 2003.

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

4. Sanal O, Yel L, Kucukali T, Gilbert-Barnes E, Tardieu M, Texcan I, 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. Jul 2000;247(7):570-2. [Medline].

5. Anikster Y, Huizing M, Anderson PD, Fitzpatrick DL, Klar A, Gross-Kieselstein E, et al. Evidence that Griscelli syndrome with neurological involvement is caused by mutations in RAB27A, not MYO5A. Am J Hum Genet. Aug 2002;71(2):407-14. [Medline].

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

7. 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].

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

9. Duran-McKinster C, Rodriguez-Jurado R, Ridaura C, de la Luz Orozco-Covarrubias M, Tamayo L, Ruiz-Maldonando R. Elejalde syndrome--a melanolysosomal neurocutaneous syndrome: clinical and morphological findings in 7 patients. Arch Dermatol. Feb 1999;135(2):182-6. [Medline].

10. Chen CP. Syndromes and disorders associated with omphalocele (III): single gene disorders, neural tube defects, diaphragmatic defects and others. Taiwan J Obstet Gynecol. Jun 2007;46(2):111-20. [Medline].

11. Bahadoran P, Ortonne JP, Ballotti R, de Saint-Basile G. Comment on Elejalde syndrome and relationship with Griscelli syndrome. Am J Med Genet A. Feb 1 2003;116(4):408-9. [Medline].

12. Cahali JB, Fernandez SA, Oliveira ZN, Machado MC, Valente NS, Sotto MN. Elejalde syndrome: report of a case and review of the literature. Pediatr Dermatol. Jul-Aug 2004;21(4):479-82. [Medline].

13. Duran-McKinster C, Rodrigez-Jurado R, Orozco-Covarrubias L, Tamayo-Sanchez L. Clinical and morpholigical findings in Chediak-Higashi syndrome, Griscelli syndrome and Elejalde syndrome. 20th World Congress of Dermatology. 2002;P1583.

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

15. Hornyak TJ. The developmental biology of melanocytes and its application to understanding human congenital disorders of pigmentation. Adv Dermatol. 2006;22:201-18. [Medline].

16. Lambert J, Naeyaert JM, De Paepe A, Van Coster R, Ferster A, Song M, et al. arg-cys substitution at codon 1246 of the human myosin Va gene is not associated with Griscelli syndrome. J Invest Dermatol. Apr 2000;114(4):731-3. [Medline].

17. Libby RT, Lillo C, Kitamoto J, Williams DS, Steel KP. Myosin Va is required for normal photoreceptor synaptic activity. J Cell Sci. Sep 1 2004;117(Pt 19):4509-15. [Medline].

18. Scheinfeld NS. Syndromic albinism: a review of genetics and phenotypes. Dermatol Online J. Dec 2003;9(5):5. [Medline].

19. Silhánová E, Plevová P, Curík R, Kaspercík I, Krepelová A. Elejalde syndrome--a case report. Am J Med Genet A. Oct 15 2006;140(20):2223-6. [Medline].

Keywords

ES, neuroectodermal melanolysosomal disease, NEMLD, Griscelli syndrome, Chédiak-Higashi syndrome

Contributor Information and Disclosures

Author

Noah S Scheinfeld, MD, JD, FAAD, Assistant Clinical Professor, Department of Dermatology, Columbia University; Consulting Staff, Department of Dermatology, New York Medical College-Metropolitan Hospital; Private Practice
Noah S Scheinfeld, MD, JD, FAAD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

Coauthor(s)

Ann M Johnson, MD, Pediatric Radiology Fellow, Department of Radiology, The Children's Hospital of Philadelphia
Disclosure: Nothing to disclose.

Medical Editor

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: Nothing to disclose.

Pharmacy Editor

David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Director, Division of Dermatology, Scott and White Clinic; Director Dermatology Residency Training Program, Scott and White Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa
Disclosure: 3M Pharmaceutical Grant/research funds Other; Graceway Pharmaceuticals Grant/research funds Other

Managing Editor

Jeffrey P Callen, MD, Professor of Medicine, 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, and American College of Rheumatology
Disclosure: Amgen Honoraria Consulting; Abbott Honoraria Consulting; Electrical Optical Sciences Honoraria Consulting; Centocor Honoraria Consulting

CME Editor

Joel M Gelfand, MD, MSCE, Medical Director, Clinical Studies Unit, Assistant Professor, Department of Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania
Joel M Gelfand, MD, MSCE is a member of the following medical societies: Society for Investigative Dermatology
Disclosure: AMGEN Consulting fee Consulting; AMGEN Grant/research funds None; Genentech Consulting fee Consulting; Centocor Consulting fee Consulting; Centocor Grant/research funds None; Covance Consulting fee Consulting; Shire  Consulting

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

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