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Slivers of skin may diagnose silver hair syndromes


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By Warren R. Heymann, MD
Jan. 7, 2019

As my hair gets progressively grayer trying to keep up with molecular advances in dermatology, it is refreshing to read how simple tests may help distinguish the rare silver hair syndromes (SHS): Chediak-Higashi (CHS) and Griscelli (GS).

Silver Hair Syndromes

CHS is an autosomal recessive disorder characterized by oculocutaneous albinism, easy bruising, abnormal functions of the natural killer cells, and recurrent pyogenic infections. It is caused by a mutation in the lysosomal trafficking regulator (LYST) gene (aka CHS1 gene), that controls synthesis, fusion, and transport of cytoplasmic granules. Patients may also develop neurological symptoms such as ataxia and neuropathies, especially in atypical forms of the disease. Abnormally large intracytoplasmic granules, especially in white blood cells and bone marrow, are diagnostic; melanocytes are also affected. Morbidity is a result of recurrent infections or the development of an accelerated phase due to hemophagocytic lymphohistiocytosis. Eighty-five percent of deaths occur in the first decade of life; those who survive into adulthood develop progressive neurological symptoms. Treatment is with an allogeneic hematopoietic stem cell transplantation. This, however, only cures the hematological and immune dysfunction; it does not halt progressive neurological impairment. (1) Elejalde syndrome (neuroectodermal melanolysosomal disease) presents with silvery hair and severe central nervous system dysfunction. 

GS is a rare autosomal recessive disease manifested by pigmentary dilution of skin, silver gray hair, variable immunodeficiency, neurological impairment, and abnormal accumulation of melanosomes in melanocytes. There are 3 variants of GS – all 3 types present with silvery gray hair, pale skin with a capacity for tanning when sun-exposed, and ocular alterations secondary to pigment diminution.

Understanding GS is based on knowledge of melanosome transport via the tripartite complex composed of Myosin Va, a motor protein that attaches to melanosomes via interaction with Mlph, and Rab27a. This complex is involved in vesicle transport and membrane trafficking. Mutations of each component are responsible for the phenotypic expression of each type.

GS type 1 presents with primary neurological impairment manifesting as severe developmental delay, muscular hypotonia, and mental retardation. It results from mutations of the myosin 5A gene (MYO5A), which encodes an organelle motor protein, Myosin 5A (MyoVa), which has a determining role in neuron function. GS2 is caused by mutations in the gene encoding the small GTPase Rab27a. Rab27a-deficiency causes defects in the exocytosis of cytotoxic granules from T cells and natural killer (NK) cell and melanosome exocytosis. The clinical hallmarks are severe infections and an accelerated phase with hemophagocytic lymphohistiocytosis (HLH), which can be fatal if not treated promptly. Although chemotherapy can achieve remission, only allogeneic hematopoietic stem cell transplantation is potentially curative. GS type 3 presents with hypopigmentation of skin and hair without any systemic involvement. No treatment is required. This variant is due to a melanophillin gene defect. (3)

Clinicians can discern the differences between the SHS by light microscopy of the hair. In CHS, aberrant melanosomes are distributed throughout the hair shaft. (4) In GS, melanin appears unevenly in the medulla, and has been described as a “road dividing line”-like appearance. (5)

Ridaura-Sanz et al evaluated 16 patients with SHS (5 CHS, 11 GS) for the distribution of melanin granules in skin and hair shafts and correlated their observations with clinical diagnoses. CHS was characterized by small granules of melanin uniformly distributed throughout the epidermis.  By using H&E and Fontana Masson stains, GS was characterized by an irregular pigment distribution in the epidermal basal layer with large and dense granules alternating with areas lacking melanin pigment. In two cases, study of the hair was not conclusive, but the skin showed the characteristic pattern of Griscelli syndrome. The authors concluded that skin biopsies are useful in differentiating CHS from GS, serving  as a complementary study in cases in which hair shaft pigment distribution does not support the diagnosis, especially in patients with fair hair. (A limitation of this study was that the diagnoses of CHS and GS were not molecularly confirmed.) (6)

Although the gold standard of diagnosis for SHS is molecular identification of mutation, it is satisfying that with a simple examination of the hair, combined with a routine skin biopsy, a precise diagnosis can be rendered.

Point to Remember: The diagnosis of SHS may be clinically confirmed by simple examination of the hair shaft combined with a routine skin biopsy.

1. Ajitkumar A, Ramphul K. Chediak Higashi syndrome. StatPearls [Internet]. Treasure Island (FL): StarPearls Publishing 2018-2018 Jun 10 (accessed November 15, 2018).
2. Mohammadzadeh Shanehsaz S. Elejalde syndrome. Dermatol Online J 2015; 22; 21: 3.
Shah BJ, et al. Griscelli syndrome type-3. Indian Dermatol Online J 2016; 7: 506-8.
3. De Almeida Jr HL, et al. Ultrastructural aspects of hairs of Chediak-Higashi syndrome. J Eur Acad Dermatol Venereol 2018; 32: e227-9.
4. Katoulis AC, et al. “Road-dividing line”-like pigmentation of hair as a diagnostic clue for Griscelli syndrome. Skin Appendage Disord 2016; 2: 143-6.
5. Ridaura-Sanz C, et al. Usefulness of the skin biopsy as a tool in the diagnosis of silvery hair syndrome. Pediatr Dermatol 2018; 35: 780-3.


 

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