Cutaneous telangiectases in neonatal lupus erythematosus

CLINICAL AND LABORATORY STUDIES I

Cutaneous telangiectases in neonatal lupus erythematosus Caroline M. Thornton, MD, a Lawrence F. Eichenfield, MD, a, b Elizabeth A. Shinall, MD, c Elaine Siegfried, MD, d Linda G. Rabinowitz, MD, c Nancy B. Esterly, MD, ° Anne W. Lucky, MD, e and Sheila Fallon Friedlander, M D a, b San Diego, California,"

Milwaukee, Wisconsin," St. Louis, Missour# and Cincinnati, Ohio Background:Persistent telangiectases are a feature of neonatal lupus erythematosus (NLE) but have generally been noted in areas of prior inflammatory disease. The occurrence of vascular macules and papules at sites without preceding dermatitis has not been reported in NLE. Objective:Our purpose was to emphasize a previously unidentified aspect of cutaneous NLE: the presence of angiomatous or matlike telangiectases in sites without antecedent or concurrent dermatitis. Methods: We describe seven patients in which telangiectatic macules or angiomatous papules were primary or early features of NLE. Results: Five infants lacked a history of preceding or concurrent inflammatorylesions at sites of telangiectasia development. In four infants findings included vulvar or inguinal angiomatous papules. Conclusion: Telangiectases may be a presenting feature of NLE, can be found in sun-protected sites, and may occur independent of "lupus dermatitis." ( J AM ACAD DERMATOL 1995;33:19-25.) Neonatal lupus erythematosus (NLE) is an uncommon immune-mediated disease associated with the transplacental transfer of maternal IgG autoantibodies. Approximately half the affected neonates have congenital heart block. Cutaneous lesions occur in approximately 50% of patients and typically consist of transient, erythematous, annular, scaling plaques in sun-exposed areas, resembling subacute cutaneous lupus erythematosus (SCLE) clinically and histologically. Skin lesions and heart block are seen simultaneously in less than 10% of patients with From the Divisionof Dermatology, University of California, San Diego, San Diego Medical Centera; the Department of Pediatric Dermatology, Children's Hospital and Health Center, San Diegob; the Departments of Dermatology and Pediatrics, Medical College of Wisconsin, Milwaukee¢; the Division of Dermatology and Department of Pediatrics, St. Louis University Health Sciences Center, St. Louisd; and the Dermatology Associates of Cincinnati, Ohio? Presented in part at the Fifty-third Annual Meeting of the American Academy of Dermatology, New Orleans, La., Feb. 4-9, 1995, and at the summer meeting of the Society for Pediatric Dermatology, Hilton Head, S.C., June 22-25, 1994. Accepted for pubfication Jan. 5, 1995. Reprint requests: Sheila Fallon Friedlander, MD, Pediatric Dermatology, Children's Hospital and Health Center, 3030 Children's Way, Suite 408, San Diego, CA 92123. Copyright ® 1995 by the American Academy of Dermatology, Inc. 0190-9622/95 $3.00+0 16/1/63138

NLE.1 Transient hepatitis, anemia and thrombocytopenia can also occur. 25 Persistent telangiectasia is a feature of N L E but has generally been noted in areas of prior inflammatory disease. Thus telangiectases have been thought to represent residual findings. As in SCLE, telangiectases typically become more evident as inflammatory lesions resolve. We describe seven infants with prominent vascular papules or telangiectatic macules early in the course of N L E (Tables I and II). In four of these children primary vulvar or inguinal angiomatous papules developed without prior inflammation or scale. To our knowledge this clinical manifestation of N L E has not been described previously. CASE REPORTS Case 1 A 7-month-old white girl was born at term after an uncomplicated pregnancy. Telangiectatic skin lesions were first noted at 2 weeks of age. Examination revealed 1 to 3 mm cherry red macules and papules with an irregular border on her scalp, lips, and left labium majus (Figs. 1 and 2). The family had not noticed any antecedent skin disease. A biopsy specimen revealed superficial telangiectases 19

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Thornton et al.

Table I. Clinical findings Inflammatorylesions

Vascular lesions Patient

Age at

No.

Sex

Age at onset

1

F

2 wk

2

F

4 wk

Scalp, lips, vulva Vulva

2 mo

Scalp

M

Birth

4

M

5 mo

5

F

Birth 3 yr

6

F

4 mo

7

M

3 mo

Location

Telangiectatic mats Angiomatous papules

None

None

None

None

2 mo

Forehead

Annular scaly plaques

Mild HSM

Face, chest

Erythema Scale

HSM, ~ platelets, liver enzymes

Abdomen, back, jawline, frontal scalp None

Red-brown annular plaques

None

None

None

Face, trunk extremities

Erythematous papules

None

Face, scalp, trunk

Erythema, scale

None

Macular and None papular punetate telangiectases

Violaceous 1 wk atrophic scars, telangiectatic mats Telangiectatic 3 wk mats

Morphology

Associated findings

onset

Telangiectatic mats Dark purple Birth Temporal punctate aspect of telangiectatic scalp, macules forehead postauricular and minimally region, raised neck, lips papules Postauricular Punctate 4 wk area, groin telangiectases

Postauricular region Forehead, neck, axillae, groin, hard palate Upper facial region, mandible, earlobes, lips Forehead, ears, trunk

Location

Morpholoby

HSM, Hepatosplenomegaly.

(Fig. 3). Laboratory screening included a chemistry panel, complete blood cell count, and urinalysis, all of which were normal. Six months later the patient's mother reported that she had photosensitivity, chronically dry eyes, and dry mouth. The mother's antinuclear antibody (ANA) titer was greater than 1:640and anti-Ro(SS-A) and anti-La(SS-B) antibodies were present, confirming a clinical diagnosis of Sj6gren's syndrome. The patient's serum was not evaluated until 21 months of age, at which time the ANA, anti-Ro(SS-A) and anti-La(SS-B) antibody titers were negative. The patient's telangiectases persisted until she was 21 months of age (Fig. 4), when they were successfully treated with the 585 nm pulsed dye laser.

Case 2

A 6-month-old white girl had telangiectatic scalp lesions. She was born at term after an uncomplicated pregnancy. At 1 month of age, she had multiple nonscaling 1 to 2 mm telangiectatic macules and angiomatous papules on the labia majora. When the patient was 21/2 months of age, erythematous, scaly periorbital plaques developed after sun exposure. At 6 months of age, examination revealed erythematous, scaly, annular plaques of the periorbital area, forehead, and anterior aspect of the scalp with prominent telangiectatic mats, hypopigmentation, and localized alopecia. Multiple 1 to 2 mm telangiectatic macules and papules persisted on the labia majora. She also had mild hepatosplenomegaly. Potassium

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Fig. 1. Case 1 (7 months of age). Telangiectases in hatband distribution.

Fig. 3. Case 1 (7 months of age). Superficial telangiectases. (Hematoxylin-eosin stain; X l0.)

Fig. 2. Case 1 (7 months of age). Telangiectases on left labium majus.

Fig. 4. Case 1 (17 months of age). Persistent telangiectases on lips.

hydroxide preparation and fungal culture of the scaling plaques were negative. Examination at 7 months of age revealed a fading erythematous eruption and scattered macular and papular telangiectases of the periorbital area, forehead, and scalp (Fig. 5). The discrete telangiectatic papules of the vulva persisted (Fig. 6). Maternal serologic examination revealed an ANA tiIer of more than 1:1280, with negative anti-Ro(SS-A) and positive anti-La(SS-B) antibody titers. At 7 months of age the infant had an ANA titer of less than 1:40; both anti-Ro(SS-A) and anti-La(SS-B) antibodies were absent. Results of a chemistry panel and complete blood

cell count were normal, as were electrocardiogram findings. Telangiectases of the scalp and vulva persisted when the patient was 18 months of age (Fig. 7). Although the patient's mother had no symptoms at childbirth, severe photosensitivity and diffuse arthralgias subsequently developed. Case 3 A 22-month-old white boy had "purple spots" since 4 months of age, He was born at term after a pregnancy complicated by anemia. At birth he had an erythematous scaly eruption on his face and chest, and purple macules

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II. Patient and maternal serologic values

Table

Patient serology

Maternal serology Technique (Ro and La)

Patient No.

Age

1

7 mo

ANA <1:40

2

7 mo <1:40

3

Birth

Anti-Ro -

-

Anti-La* -

-

Hemagglutination assay Ouchterlony gel ELISA

+ (204.3 EU/ml) + (272.1 EU/ml) -'~

ELISA

5

1:80, homogeneous + (182.3 EU/ml) 5 wk 1:1280, speckled + (150.9 EU/ml) 3 yr Not done -t

6 7

4 mo 5 mo

-

Ouchterlony Ouchterlony

4

1:50 1:80, speckled

+ +

ELISA

ANA >1:640,

speckled > 1:1280, mixed 1:160, speckled 1:2560, homogeneous 1:2560, homogeneous NA 1:1280, mixed

Anti-Ro

Anti-La

+

+

-

+

+

+

+

+

+

+

NA +

NA +

+, Positive; - , negative; ELISA, enzyme-linked immunosorbent assay; NA, not available. *Normal value, up to 20 EU/ml. t a t age 3 years (not done perinatally).

bilaterally on the temporal aspect of the scalp, forehead, retroauricular areas, lateral aspect of the neck, and lips. He also had hepatosplenomegaly, normal cardiac findings, elevated liver enzyme levels, and thrombocytopenia. The patient's ANA titer was 1:80 with a homogeneous pattern. Anti-Ro(SS-A) antibody titer was 182.3 enzyme-linked immunosorbent assay units (EU)/ml (normal, up to 20 EU/ml), and anti-La(SS-B) antibody titer was 204.3 EU/ml (normal, up to 20 EU/ml), confirming the clinical diagnosis of NLE. Sj/Sgren's syndrome was subsequently diagnosed in his mother. Her ANA titer was 1:160 with a speckled pattern, anti:Ro(SS-A) antibody titer was 1:128, anti-La(SS-B) antibody titer was 1:32, and rheumatoid factor titer was 1:640: She reported only dry mouth. The lupus eruption and the clinical and laboratory abnormalities resolved, but the telangiectases persisted. Examination at 22 months of age revealed bilaterally symmetric dark purple, punctate telangieetatic macules, and minimally raised papules on the temporal aspect of the scalp, forehead, retroauricular areas, lateral aspect of the neck, and lips. Case

4

A 5-week-old white boy had a truncal eruption of 1 week's duration. He was born at term after an uncomplicated pregnancy to a 25-year-old mother with a history of lupus erythematosus "confined to the skin" that had been clinically inactive since adolescence. Examination revealed approximately 15 discrete 0.5 to 1.0 cm, redbrown, minimally elevated annular lesions on the abdomen, back, mandible, and frontal aspect of the scalp.

Findings of a complete blood cell count, urinalysis, and liver function tests were within normal limits. The ANA titer was 1:1280 with a speckled pattern, anti-Ro antibody titer was 150.9 EU/ml, and anti-La antibody titer was 272.1 EU/ml. A skin biopsy specimen at 5 weeks of age confirmed the diagnosis of NLE. Direct immunofluorescence studies revealed faint linear deposits of IgM and granular deposits of C3 along the basement membrane zone.

At 5 months of age the punctate telangiectases developed at sites other than those of the antecedent lupus eruption. Examination revealed dark purple punctate tdangiectatic macules and minimally raised papules in the retroauricular areas, groin, forehead, lateral aspect of the neck, axillae, and hard palate. A biopsy specimen taken from an inguinal lesion at 5 months of age showed superficial dilated vessels containing erythrocytes and lined by a thin endothelium of uniform cells, mild epidermal hyperplasia, and hyperkeratosis. These findings were suggestive of angiokeratoma. All the telangiectatic lesions persisted. The patient's older sister has similar vascular lesions (patient 5, see Tables I and II). A younger sister was seen at 10 weeks of age with cutaneous and serologic findings diagnostic of NLE. No telangiectases had developed by 4 months of age. DISCUSSION The typical lesions of N L E may be present at birth but more commonly develop within the first 2 months of life. The eruption often occurs after sun exposure, frequently in photoexposed sites such as

Journal of the American Academy of Dermatology Volume 33, Number I

Fig. 5. Case 2 (7 months of age). Annular plaques with scattered telangieetases on face and scalp.

the face and scalp. Most cutaneous abnormalities in N L E are transient and resolve within 6 to 8 months, correlating with clearance of maternal antibodies. The cutaneous findings of N L E are generally typical SCLE lesions without the telangiectasia associated with discoid lupus erythematosus lesions. 6 When they occur in NLE, residual telangiectases characteristically become evident as the scaly annular polycyclic lesions resolve. Telangiectases have been noted to persist for several years. It appears that in all previously reported cases, the persistent telangiectases have been noted in sites of antecedent or concurrent inflammatory lesions. Five of our seven patients are unique in that the angiomas and telangiectatic mats appeared in sites neither previously nor simultaneously affected by an inflammatory eruption. This series of patients is also notable for the occurrence of vascular lesions in the diaper area, an infrequently reported finding. In two of our patients vulvar angiomatous lesions were the initial findings. In both these patients the diagnosis of Fabry's disease was considered because of the unusual appearance and location of these lesions, leading to a delay in diagnosis of NLE. According to the literature, angiomatous papules in the vulvar area of N L E patients is exceptionally rare. This perceived rarity may be inaccurate because of relative underreporting or incorrect diagnoses, or both. The only previously reported case of groin lesions appeared in 1967. Reed et al. v described a neonate with scaling erythematous macules on the forehead, neck, trunk, and diaper areas. A few scattered angiomatous papules developed as the discoid lesions re-

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Fig. 6. Case 2 (7 months of age). Discrete telangiectatic papules on vulva.

Fig. 7. Case 2 (18 months of age). Persistent telangiectases on forehead and scalp. gressed. Histologically these were angiokeratomas and were thought to be caused by previous inflammation. At follow-up 10 years later the child had several persistent angiokeratomas of the trunk, labia majora, and left eyelid, v, 8 This case report illustrates that telangiectatic papules or mats in an infant at any site should suggest a possible diagnosis of NLE. The term telangiectasia refers to an eruption composed of small focal red macules and papules created by abnormally prominent capillaries, venules, and arterioles. 9 In N L E these dilatations probably represent acquired exaggerations of preexisting cutaneous vessels rather than developmental anomalies or true neoplasms. Telangiectases are a characteristic marker of connective tissue diseases such as scleroderma, C R E S T syndrome (calcinosis, Raynaud's phenomenon, esophageal involvement,

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Thornton et al.

sclerodactyly; and telangiectasia), dermatomyositis, and systemic lupus erythematosus. Braverman l° has characterized the ultrastructure of cutaneous telangiectases. The macular telangiectases in scleroderma and the papular lesions in hereditary hemorrhagic telangiectasia consist of dilated postcapillary venules with a lymphocytic infiltrate. Angiokeratomas are composed of dilated superficial collecting venules that lack significant inflammation. Both macular and papular telangiectases have been observed in NLE. Biopsy specimens of telangiectatic lesions were obtained from four of our seven patients. The histopathologic findings in each reveal superficial vascular dilatations with no significant inflammatory or histiocytic infiltrate, consistent with a diagnosis of angiokeratoma. The presence or absence of inflammation could be affected by the timing of the biopsy relative to the development of the telangiectasis. The nature of the acquired trauma leading to vascular dilatation in NLE remains speculative. Possible pathogenic mechanisms include the following: • Residue f r o m prior inflammation. A clinically apparent, a mild unrecognized, or in utero lupus eruption may precede telangiectasia developmentin NLE. It is possible that irritation in the diaper areas contributed to the development of inguinal telangiectases in our patients who did not have preceding erythematous, scaly lesions. However, other factors must play a role, because telangiectases are not a typical finding in resolved diaper dermatitis. Braverman et al. 11 have suggested that epidermal or inflammatory cells may secrete angiogenic factors that induce the formation of telangiectases in hereditary hemorrhagic telangiectasia and scleroderma. Such a mechanism may also contribute to telangiectasia formation in NLE. ° I m m u n e complex deposition. NLE is associated with the transplacental transfer of maternal autoantibodies directed against the extractable nuclear ribonucleoprotein antigens: Ro(SS-A) and La(SS-B). Anti-Ro(SS-A) antibodies are present in more than 90% of NLE sera, and anti-La(SS-B) antibodies have been noted in approximately 50% of NLE sera. ~2 UVB light and viral infections caused by cytomegalovirus and Epstein-Barr virus have been shown to upregulate the production and translocation of the Ro(SS-A) and La(SS-B) antigens from the cytoplasm to the membrane

Journal of the AmericanAcademyof Dermatology July 1995 surface, optimizing exposure to circulating antibodies or stimulating antibody production. 12Particulate anti-Ro(SS-A) and/or anti-La(SS-B) IgG and complementdepositionin the epidermis or in the nascent vessels may provoke superficial vascular dilatation that persists even after maternal antibody is cleared from the infant's circulation at 6 to 8 months of age. • Hormonal factors. Estrogens evoke vascular changes in cutaneous arterial vessels, creating "spider telangiectasia" during pregnancy and in patients with cirrhosis. Lee 1has suggested that maternal sex steroids may be important in the pathogenesis of cutaneous NLE. • Photodamage. Telangiectases commonly occur in sun-damaged skin and in infants with photosensitivity disorders such as Bloom's, Cockayne's, and Rothmund-Thomson syndromes. Keratinocytes in tissue culture express Ro(SS-A), La(SS-B), and uridine-rich ribonucleoprotein (U1RNP) on the plasma membrane after sublethal exposure to UV light.12,13 In NLE telangiectases are often photodistributed, although groin lesions may occur. In addition to persistent telangiectases, transient petechiae may result from the thrombocytopenia sometimes seen in NLE. Lee et al. I4 have reported that the assays most useful for verifying the diagnosis of NLE are immunodiffusion and native 60 Kd Ro(SS-A) enzyme-linked immunosorbent assay, 14 a highly sensitive, quantifiable solid-phase assay that requires highly purified antigen. Ouchterlony gel double diffusion is widely used in clinical laboratories, because of ease of performance and availability of antigen sources, and remains a cost-effective and reliable assay for determining the presence of maternal anti-Ro(SS-A) antibodies. 6,15 Despite high antibody titers, approximately half the mothers of afflicted infants have no symptoms at childbirth and therefore should be carefully questioned regarding ocular, oral, or joint abnormalities. In the majority evidenceof connectivetissue disease, most commonly Sjrgren's syndrome, eventually develops. They should be informed that they are at increased risk of having subsequent infants with NLEJ Sun avoidance is essential in infants with NLE and may prevent the development of telangiectases. Pulsed dye laser therapy has been successfully used to treat the vascular dilatations in two of our patients.

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10. Braverman IM. Ultrastructure and organization of the cutaneous microvasculature in normal and pathologic states. J Invest Dermatol 1989;93(suppl):2S-9S. 11. Braverman IM, Keh A, Jacobson BS. Ultrastructure and three-dimensional organization of the telangiectases of hereditary hemorrhagic telangiectasia. J Invest Dermatol 1990;95:422-7. 12. Zappi E, Sontheimer R. Clinical relevance of antibodies to Ro/SS-A and La/SS-B in subacute cutaneous lupus erythematosus and related conditions. Immunol Invest 1993;22:189-203. 13. LeFeber WP, Norris DA, Ryan SP, et al. Ultraviolet light induces binding of antibodies to selected nuclear antigens on cultured human keratinocytes. J Clin Invest 1984;74:154551. 14. Lee LA, Frank MB, McCubbin VR, et al. Autoantibodies of neonatal lupus erythematosus. J Invest Dermatol 1994; 102:963-6. 15. Lee LA, Roberts CM, Frank MB, et al. The autoantibody response to Ro/SSA in cutaneous lupus erythematosus. Arch Dermatol 1994;130:1262-8.