Elejalde Syndrome a Melanolysosomal

OBSERVATION Elejalde Syndrome—A Melanolysosomal Neurocutaneous Syndrome Clinical and Morphological Findings in 7 Patients

Carola Duran-McKinster, MD; Rodolfo Rodriguez-Jurado, MD; Cecilia Ridaura, MD; M. A. de la Luz Orozco-Covarrubias, MD; Lourdes Tamayo, MD; Ramon Ruiz-Maldonando, MD

Background: Silvery hair and severe dysfunction of the and seizures. Mental retardation since the first months central nervous system (neuroectodermal melanolyso- of life was noted in 4 cases. Psychomotor development somal disease or Elejalde syndrome) characterize this rare was normal in 3 cases, but suddenly the patients pre- autosomal recessive disease. Main clinical features in- sented with a regressive neurologic process. Four pa- clude silver-leaden hair, bronze skin after sun expo- tients died between 6 months and 3 years after the onset sure, and neurologic involvement (seizures, severe hy- of neurologic dysfunction. One patient showed charac- potonia, and mental retardation). Large granules of teristic ultrastructural findings of Elejalde syndrome. melanin unevenly distributed in the hair shaft are observed. Abnormal melanocytes and melanosomes and ab- Conclusions: Elejalde syndrome is different from Che´- normal inclusion bodies in fibroblasts may be present. diak-Higashi and Griscelli syndrome and is character- Differential diagnosis with Che´diak-Higashi syndrome ized by silvery hair and frequent occurrence of fatal neu- and Griscelli syndrome must be done. rologic alterations. Psychomotor impairment may have 2 forms of presentation: congenital or infantile. Al- Observations: We studied pediatric patients with sil- though Elejalde syndrome and Griscelli syndrome are very hair and profound neurologic dysfunction. Im- similar, the possibility that they are 2 different diseases, mune impairment was absent. Age of onset of neuro- although probably allelic related, is suggested. logic signs ranged from 1 month to 11 years; the signs included severe muscular hypotonia, ocular alterations, Arch Dermatol. 1999;135:182-186

ILVERY hair was first recog- distribution of melanin in small and large nized as a pathologic feature clumps irregularly arranged along the hair in Che´diak-Higashi syn- shaft was observed. No accelerated phase drome (CHS).1-3 Oculocuta- has been reported in these patients but re- neous hypopigmentation and current infections and early death are the silvery-gray hair, a marked defective che- usual outcomes. S 5 motaxis of neutrophils, and an apparent In 1979, Elejalde et al first de- association with lymphoid malignancy scribed 3 consanguineous families as hav- characterize this rare autosomal reces- ing neuroectodermal melanolysosomal dis- sive disorder. The diagnosis is usually ease (NEMLD). The main features were an based on the presence of pathogno- autosomal recessive heredity character- monic, anomalous giant cytoplasmic gran- ized by silvery hair, profound dysfunc- ules in neutrophils and in a wide variety tion of the central nervous system, abnor- of other granule-containing cells. Mela- mal melanocytes and melanosomes, and nin in the hair shaft is abnormally distrib- abnormal inclusion bodies in fibroblasts uted in multiple small clumps with a regu- and other cells. Apparently ignoring Ele- lar pattern. Death occurs at an early age, jalde’s description, in recent years sev- following an “accelerated phase” after eral articles have been published describ- From the Departments which infections and/or lymphomalike or- ing patients with the combination of silvery of Dermatology gan infiltration occurs.3 hair and neurologic involvement with- (Drs Duran-McKinster, In 1978, Griscelli et al4 described a out giant cytoplasmic granules or immu- de la Luz Orozco-Covarrubias, different condition characterized also by nologic dysfunction and classifying them Tamayo, and Ruiz-Maldonando) 6 and Pathology silvery-gray hair associated with a pro- as having the following diseases: CHS, (Drs Rodriguez-Jurado and foundly disturbed B-cell and T-cell im- Griscelli disease with cerebral involve- Ridaura), National Institute of munity. No abnormal cytoplasmic gran- ment,7 and Griscelli disease with neuro- Pediatrics, Mexico City, Mexico. ules were present in leukocytes. A different logical involvement.8 Unlike CHS and

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 Table 1. Clinical Features* PATIENTS AND METHODS Patient Age at Onset Parents’ Ophthalmological No./Sex of First Signs Consanguinity Examination Results From February 1971 to January 1997, all clinical records 1/M 1 mo Negative Nystagmus, esotropia of patients with silvery hair seen at the Department of 2/F 3 y Negative Nystagmus, Dermatology of the National Institute of Pediatrics were hypopigmented retina reviewed. Clinical and pathological findings of our pa- 3/F 11 y† Positive Diplopia, papilledema tients were compatible with CHS in 6 cases, GS in 2 cases, 4/M 2 mo† Positive Congenital amaurosis, and Elejalde syndrome in 7 cases. Patients with silvery hypopigmented papilla hair and neurologic involvement were selected for this 5/M 1 mo Negative Pupillar areflexia study. The following data were collected: sex, age, pa- 6/F 6 y Positive Diplopia rental consanguinity and family history, age of onset of 7/F 1 mo† Negative Congenital amaurosis neurologic alterations, ophthalmologic examination, clinicalandneurologicfeatures,andfollow-up.Datafrom *Allpatients had bronzed skin color and silver-gray hair color. the following laboratory tests were recorded: complete †With other family members affected. peripheral blood cell count from the 6 patients and bone marrow aspirate from 3. Immunologic studies in all patients included serum IgG, IgA, and IgM. Antinuclear antibodies, complement, and phagocytic function were tested with nitroblue tetrazolium. Cell-mediated immunity was evaluated by delayed hypersensitivity skin tests with phytohemagglutinin, concanavalin A, Candida, and purified protein-derivative (tuberculin) antigens as well as with T-lymphocyte subsets. Isohemagglutinin anti- body titers against blood groups were obtained in patients 1 and 2. A complete neurologic examination was performed by an experienced pediatric neurologist in all of the patients. Specific studies included the following: electroencephalogram, cerebrospinal fluid analysis, and visual- and auditory-evoked potentials. Ce- rebral tomographic scan and magnetic resonance imaging were performed for 5 patients. Skin biopsy specimens from the arm or leg were obtained from each patient, and sections were made for light microscopy in all patients and for transmission elec- tron microscopy in 2 (patients 3 and 6). Samples of hair were obtained from all of the patients and parents for light microscopic examination. Figure 1. Characteristic bronzed skin color and silvery hair in scalp, eyelashes, and eyebrows in Elejalde syndrome (patient No. 4).

Griscelli syndrome (GS), NEMLD does not exhibit de- scalp and body hair, eyebrows, and eyelashes had a sil- fects in cellular or humoral immunity but a severe im- very color (Figure 1). Skin and hair color of the pa- pairment of the central nervous system. tients contrasted with the dark skin and black hair of fam- Herein, we describe 7 patients with NEMLD (Ele- ily members. Samples of the hair observed by light jalde syndrome) seen in the National Institute of Pedi- microscopy showed the same characteristics in the 7 pa- atrics of Mexico. tients, consisting of an abnormal distribution of melanin in small and large clumps, irregularly distributed along RESULTS the hair shaft with no other abnormalities. A complete ophthalmologic examination showed a wide spectrum of The results of the general features are summarized in abnormalities (Table 1). Table 1. The patients’ age at onset of neurologic signs Che´diak-Higashi syndrome and GS were excluded ranged from l month to 11 years (mean age, 3 years). All in the analysis of our patients for the following reasons: patients were born at term after an uneventful preg- there was no clinical or laboratory evidence of immuno- nancy and normal delivery. Consanguinity of the par- logic impairment and abnormal giant intracytoplasmic ents (first or second cousins) was reported in 3 patients. granules in neutrophils could not be found in periph- Three patients had other family members (2 cousins in eral blood smears or in bone marrow aspirates in pa- patient 3, a brother in patient 4, and 2 sisters in patient tients 5, 6, and 7. Patient 6 had the only blood cell count 7) with silvery hair. They had died in the first decade of with persistent leukopenia. Humoral and cellular immu- life following a regressive neurologic process. nologic test results were within normal limits in all cases. In all patients, the physical examination revealed a Neurologic alterations were the most striking features lighter skin color in covered areas that contrasted with (Table 2). The 4 youngest patients (patients 1, 4, 5, and the patient’s bronzed skin on sunlight-exposed areas. The 7) were severely mentally retarded since the first months

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Neuromuscular Alterations Patient Mental No. Initial Progression Seizures Development Electroencephalogram 1 Hypotonia Spastic quadriparesis Yes Severely retarded Normal 2 Hypotonia Flaccid quadriplegia Yes Regressive Severe encephalopathy 3 Hemiplegia Flaccid hemiplegia Yes Regressive Diffuse anterior encephalopathy 4 Hypotonia Flaccid quadriplegia Yes Severely retarded Generalized epileptogenous process 5 Hypotonia Spastic quadriplegia Yes Severely retarded Generalized encephalopathy 6 Hypotonia Ataxia Yes Regressive Encephalopathy, epileptogenous process 7 Hypotonia Flaccid quadriplegia No Severely retarded Normal

*For all patients, the visual and auditory evoked potentials were abnormal, except where indicated otherwise.

of life. They did not seem to recognize their parents, had of different sizes and different electrodensity character- almost complete absence of movements, were severely istic of NEMLD were found in some fibroblasts hypotonic, and were unresponsive to external stimuli. (Figure 4). The biopsy of leptomeningeal tissue and the However, patients 2, 3, and 6 had no history of neuro- cerebellar cortex performed in patient 6 revealed a thick- logic impairment and developed normally. By the ages ened wall of meningeal membranes with a dense inflam- of 3, 11, and 6 years, respectively, they developed sev- matory infiltrate composed mainly by lymphocytes, scanty eral rapidly regressive psychomotor processes. They were plasma cells, and macrophages. The biopsy of the cer- unable to speak, walk, feed themselves, and had to be bed- ebellar cortex specimen showed this dense infiltrate pre- ridden. Patient 3 was first admitted suffering severe mi- dominantly around small veins. No necrotizing vascu- graine status followed by hemiparesis. A few months later litis was observed but cerebellar folia revealed multifocal she complained of weakness in her legs that progressed necrosis in the entire width. No viral inclusions were to severe hypotony involving the entire body. Patient found and no microorganism was identified with peri- 6 first developed atactic cerebellar movements. The odic acid–Schiff stain. Multifocal necrosis of the cerebel- patient was unable to maintain muscular tone of the lar folia was accompanied by numerous foamy macro- neck, became profoundly hypotonic, and never walked, phages combined with gemistocytic astrocytes (astrocytes spoke, or fed herself again. Once the neurologic alter- with eosinophilic, abundant cytoplasm, and eccentric ations were initiated, all patients, except patient 7, suf- nucleus) and mononuclear inflammatory cells. Immu- fered convulsive episodes. Neuromuscular disorders in- nohistochemistry studies demonstrated that 80% of cluded constant severe generalized hypotonia as well as lymphocytes in the inflammatory infiltrate were T cells. hyperactive deep tendon reflexes. Therapeutic measures included steroids, anticonvul- In all patients, cerebrospinal fluid tested for bacte- sants, and antipyretics and were unsuccessful in all rial cultures yielded no growth. The electroencephalo- patients. In patients 3, 4, and 5, parents refused to allow grams were abnormal in 6 patients. The magnetic reso- their children to remain in the hospital, all 3 died at nance imaging and computed tomographic features of the home between 1 and 3 years after the onset of disease. brain revealed abnormalities in different areas in 4 patients. In patient 6, a rapid neurologic deterioration was observed. The patient required intensive care assistance Patient Magnetic Resonance Imaging and Computed Tomographic Findings and died 6 months after admission. Necropsy was not 1 Within normal limits permitted. We were unable to obtain information about 2 Not performed the remaining patients. 3 Abnormal findings in periventricular white matter and cerebellum 4 Abnormal findings in gray matter and cerebellum; COMMENT atrophy of the brain 5 Leukoencephalomalacia; abnormal findings in Pigmentary abnormalities characterized by hypopig- cerebellum; and atrophy of the brain mented skin and silvery hair at birth are shared by CHS, 6 Abnormal findings in white and gray matter GS, and Elejalde syndrome, and they have been respon- and cerebellum sible for the erroneous classification of these conditions 7 Within normal limits as partial albinism. Tanning of the skin is evident after Patient 7 was described as normal for her age. sun exposure and is long lasting. A defective transfer of Skin biopsy specimens observed by light micro- melanin from melanocytes to the surrounding keratino- scopical examination showed irregular distribution and cytes provoking a heavily pigmented basal layer ex- irregular size of melanin granules in the basal layer, as plains the persistent bronze skin. The phenotype of these confirmed by Fontana-Masson stain (Figure 2). patients is not reminiscent of albinism, a condition in Ultrastructural study in patients 3 and 6 revealed which cutaneous melanocytes are almost absent and ery- melanocytes with different stages of melanosome forma- thema and sunburn without tanning is frequent after sun tion. Melanocytes with different electrodensity in mela- exposure. nosome matrix were observed in patient 6 (Figure 3). Analysis of hair samples by light microscopical ex- Round intracytoplasmic and extracytoplasmic granules amination is of great diagnostic value. An abnormal dis-

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 Figure 2. Section of skin showing increased pigment in the melanocytes and Figure 4. Ultrastructural appearance of dermal fibroblast revealing round cells of the stratum basale (Fontana-Masson technique, original intracytoplasmic and extracytoplasmic granules of different sizes. They magnification ϫ40). exhibit diverse electrodensity composition (original magnification ϫ12 000).

Figure 5. Light microscopy of hairs showing clumped pigment in small granules regularly distributed in Che´diak-Higashi syndrome (middle) and small and large clumps irregularly distributed characteristic of Griscelli syndrome and Elejalde syndrome (above), contrasting with normal hair (below).

or infantile form of the onset of Elejalde syndrome was not previously reported. The sudden presentation of central nervous system dysfunction in Elejalde syndrome can Figure 3. Ultrastructural appearance of melanocyte exhibiting different be compared with the “accelerated phase” described in electrodensity in melanosomes matrix (original magnification ϫ12 000). CHS in which recurrent episodes of infections and death are observed. A triggering factor for the sudden dysfunc- tribution of melanin in clumps in the hair shaft leaves tion has not been identified. spaces free of melanin and impairs the refraction and ab- Our patient 6 presented with persistent leukopenia sorption of light. As a result, the hair shaft is light col- and died of a neurologic regressive process. This ored with a silver-leaden shine. Small melanin granules patient’s condition raises the question of the possible regularly distributed in both cortical and medullar zones existence of cases of Elejalde syndrome with immune are characteristic of CHS, while GS and Elejalde syn- compromise. drome share the same pattern, consisting of small and The histopathological findings of the cerebellar bi- large melanin clumps irregularly distributed along the opsy specimen (patient 6) were nonspecific, but these ab- hair shaft (Figure 5). normalities can be contained within chronic necrotizing/ Four of our patients were severely retarded almost inflammatory lesions, which are observed in diverse viral from birth. The remaining 3 patients seemed to develop diseases or immunoallergic conditions.9 Some viral in- normally until neuromuscular alterations started in the fections can be excluded because none were found in the form of a regressive neurologic process. Clinical mani- studied specimen. The presence of numerous T lympho- festations of neurologic impairment in Elejalde syn- cytes in the lesions suggests that these cells are respon- drome may have 2 different forms of presentation: (1) sible for the tissue damage. Unfortunately, we could not congenital, as observed in our youngest patients (pa- perform T-cell subset detection studies to determine if tients 1, 4, 5, and 7) and in the first known cases of Ele- the lymphocytes were cytotoxic T cells. Furthermore, it jalde syndrome,5 or (2) infantile, first developing dur- is important to consider angiocentric immunoprolifera- ing childhood (patients 2, 3, and 6). The noncongenital tive lesions as they have been observed in immunocom-

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 promised patients as benign lymphocytic infiltrations, eg, tosomal recessive mode of inheritance. Differential di- lymphomalike in CHS or real lymphomas.10 agnosis with another condition associated with light and Melanin in the skin and hair and neuromelanin in sometimes silvery hair include the infantile form of si- the brain probably play an important role in the patho- alic acid–storage disease, a lysosomal storage disorder logic alterations found in Elejalde syndrome. The skin characterized by coarse facial features, hepatospleno- pigmentation and the characteristic silvery hair are due megaly, and development delay. Histological evidence of to a distribution of melanin in clumps. It is not known if lysosomal storage and vastly increased tissue and urine the abnormal distribution of melanin is due to a struc- levels of free sialic acid are present.13,14 No microscopic tural melanocytic anomaly or to a biochemical defect in description of the hair shaft has been made. melanin composition. The relation between melanin and neuromelanin and the role of neuromelanin in neuro- Accepted for publication June 26, 1998. logic alterations are not known. Perhaps the distribu- This manuscript was presented in the 19th World Con- tion of melanin in clumps that in the skin causes only a gress of Dermatology during the hair symposia, Sydney, Aus- color change is responsible for serious neurologic alter- tralia, June 20, 1997. ations in the brain. We do not know the characteristics Reprints: Carola Duran-McKinster, MD, Apartado of neuromelanin in the central nervous system of our Postal 101-16, Mexico City, 04530 Mexico. patients, but the clinical picture of a severe neuromuscular dysfunction could be related to its abnormal quan- REFERENCES tity or quality. Elejalde syndrome should be identified as an inde- pendent entity, different from CHS and GS. The CHS gene 1. Beguez-Cesar A. Neutropenia cronica maligna familiar con granualciones atipi- cas de los leucocitos. Bol Soc Cubana Pediatr. 1943;15:900-922. product has been identified and mapped on chromo- 2. Chediak MM. Nouvelle anomalie leucocytaire de caractere constitutionnel et some 1q42-1q43. This gene was designated “LYST” (ly- familial. Rev Hematol. 1952;7:362-367. sosomal trafficking regulator) and is believed to be in- 3. Higashi O. 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