Graham-Little-Piccardi-Lasseur Syndrome 

Updated: May 14, 2018
Author: Patricia T Ting, MD, MSc, FRCPC, LMCC(Canada); Chief Editor: Dirk M Elston, MD 

Overview

Background

In 1914, Piccardi described the first case of progressive scalp cicatricial alopecia, noncicatricial alopecia in the axilla and groin, and follicular lichen planus on the trunk and extremities, to which he gave the name cheratosi spinulosa (keratotic spinulosa). In 1915, Graham-Little published a similar case of a 55-year-old woman, referred by Lassueur of Lausanne, Switzerland.[1] Later, Feldman also reported another similar case, which he termed lichen planus et acuminatus atrophicans in 1936. Subsequently, several other cases were reported.

Graham-Little-Piccardi-Lasseur syndrome (GLPLS) is a rare lichenoid dermatosis defined by the triad of multifocal cicatricial alopecia of the scalp; noncicatricial alopecia of the axilla and groin; and a follicular lichen planus eruption on the body, scalp, or both.

Pathophysiology

Based on clinical and histological studies, Graham-Little-Piccardi-Lasseur syndrome (GLPLS) is considered a variant of lichen planus consisting of follicular lichen planus (of the body and/or scalp) and lichen planopilaris (of the scalp).[2] Estimates show that at least 50% of patients with GLPLS experience at least one episode of typical oral and/or cutaneous lichen planus. Similar to lichen planus, GLPLS is likely the result of a T-cell–mediated immune response of unknown etiology, which involves destruction of keratinocytes expressing specific antigens.[3, 4]

Etiology

The etiology of Graham-Little-Piccardi-Lasseur syndrome (GLPLS) is unknown; however, several hypotheses have been proposed, including the following:

  • Immunologic: HLA-DR is one of several HLA subtypes associated with lichen planus and GLPLS. HLA antigens are hypothesized to enhance a T-cell–mediated immune response of unknown etiology. Rodríguez-Bayona et al found autoantibodies to centromere passenger protein INCENP, a protein responsible for chromosomal segregation and mitosis regulation, in one patient with GLPLS.[5]

  • Genetic: With the exception of one 2004 report by Viglizzo et al that documented a familial pattern of GLPLS correlated with the presence of HLA-DR1 in a mother and daughter,[6] reports of GLPLS are usually sporadic, without any indication of genetic predisposition.

  • Viral (hepatitis B virus): Both GLPLS and lichen planus have been reported to be rare events following hepatitis B virus vaccination. The hepatitis B virus vaccine is hypothesized to stimulate the immune system and trigger lichen planus eruptions in a nonspecific manner. Lichen planus–like eruptions have not been reported with other vaccinations.[7]

  • Hormonal: In 2004, Vega-Gutiérrez et al reported a case of GLPLS in a 19-year-old phenotypically female (genetically XY) patient with androgen insensitivity syndrome (testicular feminization).[8] While the significance of both these findings is unknown, the authors implied that a hormonal etiology may be associated with the noncicatricial alopecia of the axilla and groin observed in persons with GLPLS. In 2016, Donovan reported a second case of GLPLS in a 40-year-old woman with complete androgen insensitivity syndrome.[9]

  • Others: Neuropsychological stress, vitamin deficiency (specifically vitamin A), and altered hormone levels have been suggested because most GLPLS patients are perimenopausal or postmenopausal women.

Epidemiology

Frequency

Graham-Little-Piccardi-Lasseur syndrome (GLPLS) is relatively rare. A Medline search from 1951-2016 (all languages included) produced fewer than 50 cases of GLPLS in the literature.

Race

Most reported patients with Graham-Little-Piccardi-Lasseur syndrome (GLPLS) are middle-aged white women; however, no ethnic predisposition has been noted.

Sex

Reports show females are affected with Graham-Little-Piccardi-Lasseur syndrome (GLPLS) more frequently than males, although limited numbers preclude meaningful interpretation from the case reports.

Only a few case reports in the literature cite affected males,[10] which may be secondary to fewer males demonstrating concern over the disease.

Age

Reported patients with Graham-Little-Piccardi-Lasseur syndrome (GLPLS) are aged 30-60 years.

Prognosis

Progressive cicatricial alopecia of the scalp leading to permanent hair loss may elicit psychosocial distress in patients with Graham-Little-Piccardi-Lasseur syndrome (GLPLS). Cicatricial scalp alopecia has a poor prognosis. This type of hair loss is permanent. Noncicatricial alopecia of the axilla and groin often spontaneously resolves.

Follicular lichen planus eruption on the body usually responds well to treatment; however, recurrence is not uncommon.

GLPLS has not been associated with underlying systemic diseases or increased mortality rates.

Patient Education

Educate Graham-Little-Piccardi-Lasseur syndrome (GLPLS) patients on the psychosocial aspects of progressive cicatricial alopecia. If indicated, discuss options and sources for cosmetic hairpieces to disguise end-stage scarring scalp alopecia.

 

Presentation

History

Graham-Little-Piccardi-Lasseur syndrome (GLPLS) patients are usually otherwise healthy middle-aged women.

GLPLS is typically sporadic and nonfamilial. In 2004, Viglizzo et al reported one case of GLPLS in a 47-year-old mother and her 19-year-old daughter.[6]

The course of disease is slowly progressive (months to years) and often chronic. In 2003, Ghislain et al reported a 50-year-old woman who initially presented with disseminated lichen planus, which then progressed to the classic triad of GLPLS over a 20-year period.[11]

While the chronological course of GLPLS is variable, most patients usually present with clinical findings in the following order, called the triad of GLPLS:

  • Cicatricial alopecia of the scalp

  • Noncicatricial alopecia of the axilla and groin

  • Follicular lichen planus eruption of the body, scalp, or both

In most patients, cicatricial scalp alopecia does not respond to medical interventions and results in progressive and permanent patchy hair loss. In contrast, follicular lichen planus eruptions usually demonstrate a good response to medical treatments.

Physical Examination

Symptoms from the triad of Graham-Little-Piccardi-Lasseur syndrome (GLPLS) need not be present simultaneously.

Cicatricial scalp alopecia is chronic and progressive through the following several stages:

  • Mild perifollicular erythema (with or without pruritus)

  • Follicular hyperkeratosis (keratotic and/or spiny papules)

  • Patches of cicatricial alopecia with occasional tufts of normal hair

  • Loss of residual normal tufts and hair follicles

  • Cicatricial alopecia with permanent hair loss, clinically identical to pseudopelade of Brocq, in end-stage GLPLS

Noncicatrizing alopecia of axilla, groin, and occasionally eyebrows and follicular lichen planus of the skin (trunk, proximal limbs), scalp, or both usually resolve without treatment.

Patients have a history of typical cutaneous and/or oral lichen planus.

In 1999, Bardazzi et al reported one case of GLPLS associated with hepatitis B vaccination and further suggested that GLPLS may also be associated with liver disease (ie, hepatitis).[12]

See the images below.

Follicular lichen planus eruption. Follicular lichen planus eruption.
Lichen planopilaris of the scalp resulting in cica Lichen planopilaris of the scalp resulting in cicatricial alopecia.
 

DDx

 

Workup

Laboratory Studies

Some epidemiological studies describe a loose association between mucocutaneous lichen planus and hepatitis C. However, this association has not yet been described in case reports of Graham-Little-Piccardi-Lasseur syndrome (GLPLS).

Initial investigations may include antinuclear antibodies (ANA), antiextractable nuclear antigens (AENA), hepatitis B and C serology, and liver function tests to exclude other associated systemic causes of cicatricial alopecia.

Imaging Studies

No imaging studies are required for Graham-Little-Piccardi-Lasseur syndrome (GLPLS).

Procedures

Punch biopsies of the scalp parallel to hair shaft growth (or directed at 45° angle in African Americans) may confirm the presence of cicatricial alopecia. Multiple biopsy samples may be required for transverse (horizontal) and vertical sections, and immunohistochemistry. Histologically, the end-stage lesions in Graham-Little-Piccardi-Lasseur syndrome (GLPLS) are indistinguishable from those of pseudopelade of Brocq, discoid lupus erythematosus, folliculitis decalvans, frontal fibrosing alopecia, and other forms of cicatricial alopecia.

A skin biopsy of associated follicular papules may reveal the presence of histologic findings that correlate with the triad of GLPLS.

The presence of noncicatricial alopecia in the axilla and groin can usually be diagnosed clinically, and further skin biopsies are not necessary.

Histologic Findings

In the early stage, an inflammatory perifollicular lichenoid infiltrate can be observed and is often associated with the infundibuloisthmic (bulge) region of the follicle.[13] This infundibuloisthmic region contains stem cells responsible for regenerating the lower two thirds of the hair follicle, which is nonpermanent. The bulb region is spared. In end-stage Graham-Little-Piccardi-Lasseur syndrome (GLPLS), atrophic dermis and fibrosed and empty hair shafts can be seen. One additional histological finding is keratinous follicular plugs with loss of sebaceous glands.

A lichenoid lymphocytic infiltrate composed of mostly CD8 and CD4 T cells may irreversibly damage stem cells and hair follicles. Profibrogenic cytokines such as interleukin (IL)–4 and IL-6, transforming growth factor (TGF)–beta, and interferon (IFN)–gamma have been reported in association with lichen planopilaris of the scalp.[14]

Direct immunofluorescence studies have reported nonspecific immunoglobulin M, and occasionally immunoglobulin G and immunoglobulin A, at the hair follicle infundibulum and isthmus, as well as linear fibrinogen deposition along the dermoepidermal junction.[15]

Histopathology of follicular papules

Findings include (1) lichenoid lymphocytic infiltrate in the upper dermis, (2) hyperkeratosis and focal hypergranulosis, (3) acanthosis with occasional saw-toothed rete ridges, and (4) dyskeratotic keratinocytes (Civatte or colloid bodies).

 

Treatment

Medical Care

Topical, intralesional, and systemic corticosteroids; retinoids; psoralen plus ultraviolet light A (PUVA); antimalarials; and tetracycline antibiotics have been used with limited success in patients with Graham-Little-Piccardi-Lasseur syndrome (GLPLS). In recent years, various case reports have documented successful treatment of GLPLS with cyclosporine A,[16, 17] thalidomide,[18, 19, 20] and metronidazole (authors' observation). No definite treatments have been developed for GLPLS. Patients tend to be treated empirically for this condition.

Corticosteroids (topical, intralesional, systemic) have not been shown to be effective in the treatment of cicatricial alopecia associated with GLPLS, although they are moderately effective for follicular lichen planus. High- and super high-potency topical corticosteroids are still the treatment of choice for mild cicatricial alopecia or in patients in whom systemic medications are contraindicated. Intralesional triamcinolone acetonide is often ineffective for the treatment of cicatricial scalp alopecia. The same results have been documented for treatment with systemic corticosteroids, for which many adverse effects are known (eg, immunosuppression, osteoporosis, avascular necrosis, Cushing syndrome, diabetes, cataracts).

Cyclosporin A was effective for the treatment of 5 eligible patients with GLPLS. The dose ranges from 3-5 mg/kg/d for 3-5 months. This dose has been reported to be more effective in the first stage of cicatricial alopecia prior to dermal alteration. A significant decrease in follicular papules, attenuation of hair loss, and patchy hair regrowth have been documented. Patients remained free of symptoms for up to 20 months following treatment, with no adverse effects reported. This medication may also be used for alopecia areata, lupus erythematosus, lichen planus, and lichen planopilaris. In 3 patients with lichen planopilaris resistant to treatment with oral hydroxychloroquine or topical and intralesional corticosteroids, cyclosporin A aborted further progression of cicatricial alopecia.

Thalidomide at 50-150 mg/d for up to 2 months has been associated with significant hair regrowth of cicatricial scalp alopecia in 2 case reports. More recently, however, thalidomide titrated up to 200 mg/d (from an initial 1-mo dose of 100 mg/d) was reported to be ineffective in a case series of 6 patients (4 with lichen planopilaris and 2 with pseudopelade of Brocq) during a 6-month open-label trial. Previously, thalidomide has been successful in attenuating and reversing immune-mediated alopecia associated with discoid lupus erythematosus and erosive mucosal lichen planus.

Oral metronidazole at 500 mg twice daily for 8 weeks was used successfully at the authors' center for a female patient with GLPLS, with notable resolution of follicular papules and attenuation of cicatricial alopecia. To the authors' knowledge, this is the first report of GLPLS treated with metronidazole. In a 2000 study by Büyük and Kavala of patients with generalized lichen planus, 13 (68%) of 19 patients showed complete response to 500 mg of oral metronidazole administered twice daily.[21]

Long-Term Monitoring

Regular follow-up is recommended to assess the course of Graham-Little-Piccardi-Lasseur syndrome (GLPLS) and the effectiveness of prescribed treatments. Ask patients about any adverse effects to medications and manage accordingly.

Conduct appropriate laboratory studies as indicated with the use of systemic medications (ie, cyclosporine, thalidomide). Take necessary steps to prevent permanent cicatricial alopecia.

 

Medication

Medication Summary

Topical, intralesional, and systemic corticosteroids; retinoids; and PUVA have been used with limited success. In recent years, various case reports have documented successful treatment of Graham-Little-Piccardi-Lasseur syndrome (GLPLS) with cyclosporine A, thalidomide, and metronidazole (authors' observation). No definite treatments have been developed for GLPLS. Patients tend to be treated empirically for this condition.

Immunosuppressant agents

Class Summary

Immunosuppressant agents interfere with the immune processes that promote inflammation.

Cyclosporine A (Sandimmune, Neoral)

Cyclosporine A is an 11-amino acid cyclic peptide and natural product of fungi. It acts on T-cell replication and activity. It is a specific modulator of T-cell function and an agent that depresses cell-mediated immune responses by inhibiting helper T-cell function. Preferential and reversible inhibition of T lymphocytes in the G0 or G1 phase of the cell cycle is suggested.

Cyclosporine A binds to cyclophilin, an intracellular protein, which, in turn, prevents the formation of IL-2 and subsequent recruitment of activated T cells.

Cyclosporine A has approximately 30% bioavailability, but marked interindividual variability is reported. It specifically inhibits T-lymphocyte function with minimal activity against B cells. Maximum suppression of T-lymphocyte proliferation requires that the drug be present during the first 24 hours of antigenic exposure.

Cyclosporine A suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions (eg, delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, graft vs host disease) for a variety of organs.

Thalidomide (Thalomid)

Thalidomide is an immunomodulatory agent that may suppress excessive production of TNF-alpha and may down-regulate selected cell-surface adhesion molecules involved in leukocyte migration.

Tacrolimus topical (Protopic)

Tacrolimus topical reduces itching and inflammation by suppressing the release of cytokines from T cells. It also inhibits the transcription of genes that encode IL-3, IL-4, IL-5, GM-CSF, and TNF-alpha, all of which are involved in the early stages of T-cell activation. Additionally, it may inhibit the release of preformed mediators from skin mast cells and basophils and may down-regulate the expression of FcERI on Langerhans cells. Tacrolimus topical can be used in patients as young as 2 years. Drugs of this class are more expensive than topical corticosteroids.

Antibiotics

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Metronidazole (Protostat, Flagyl)

Metronidazole is an imidazole ring-based antibiotic active against various anaerobic bacteria and protozoa. It is used in combination with other antimicrobial agents (except to treat Clostridium difficile enterocolitis).

Corticosteroids

Class Summary

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Betamethasone dipropionate (Diprolene)

Betamethasone dipropionate is a class I superpotent topical steroid; it suppresses mitosis and increases the synthesis of proteins that decrease inflammation and cause vasoconstriction.

Clobetasol (foam, spray, cream, ointment)

Clobetasol is a class I superpotent topical steroid; it suppresses mitosis and increases the synthesis of proteins that decrease inflammation and cause vasoconstriction.

Prednisone (Orasone, Meticorten, Sterapred, Deltasone)

Prednisone may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Antimalarial

Hydroxychloroquine sulfate (Plaquenil)

Hydroxychloroquine inhibits chemotaxis of eosinophils and locomotion of neutrophils and impairs complement-dependent antigen-antibody reactions. Hydroxychloroquine sulfate 200 mg is equivalent to 155 mg hydroxychloroquine base and 250 mg chloroquine phosphate. Weight-based dose adjustment and monitoring help to mitigate the risk of retinal toxicity.