Case report
Bloch-Sulzberger syndrome: a case report

Introduction

Incontinentia pigmenti (IP, Bloch-Sulzberger syndrome) is a very rare X-linked dominantly inherited genodermatosis predominant among females as it is usually lethal in males [1-6]. There are however single reports of male patients with IP and XXY karyotype [7, 8]. Incontinentia pigmenti was first described by Garrod in 1906 [9], and further defined by Bardach [10], Bloch in 1926 [11], Sulzberger in 1928 [12] and Siemens in 1929 [13], however only the names of Bloch and Sulzberger feature in the eponym. Incontinentia pigmenti is a multisystem, ectodermal disorder characterized by skin lesions (100%) accompanied by dental (90%), central nervous system (CNS) (40%), bone (40%) and ocular (35%) abnormalities. In 1993, Landy and Donnai [4], after they had evaluated a group of over 100 pa­­tients with IP, proposed the diagnostic criteria for this neurodermatosis, as shown in Table 1.

Dermatologic manifestations are among the most important signs of IP as skin lesions observed in almost all individuals with IP are relatively easy to diagnose [1-4]. Fortunately, skin lesions are the least damaging aspect of the disease and actually do not require any treatment as spontaneous resolution of lesions is one of the features of the disease. The hallmark feature of IP is cutaneous eruption along the lines of Blaschko that evolves in four distinct stages:

• 1st stage: inflammatory, erythematous, vesiculobullous lesions, usually configured in a linear pattern (birth to 1-2 weeks),

• 2nd stage: papules, verrucous lesions with hyperkeratosis (2-6 weeks),

• 3rd stage: hyperpigmentation of the skin (3-6 months),

• 4th stage: hypopigmentation and atrophy of the skin

(2-3 decade).

One of the late manifestations of IP are subungual tumors of IP (STIPs), which usually appear after puberty, between 15 and 40 years of life [14, 15]. Subungual tumors of IPs are usually observed on fingers rather than on toes, and clinically resemble plain warts, epidermoid cysts, fibromas, keratoacanthoma (KA) and squamous cell carcinoma (SCC) [16]. Subungual tumors of IPs tend to destroy the underlying bone of the distal phalanx, due to pressure necrosis. Subungual tumors of IPs may be associated with a very intense pain due to fast growth. Although the histological picture of STIPs may cause misdiagnosis as it resembles KA or SCC, radiographic appearance with bone destruction in the distal phalanx without accompanying sclerosis or periosteal reaction may help to make the right diagnosis [16].

Case report

We present a full-term infant with cutaneous manifestation of IP. The girl was born by uncomplicated delivery as the first child of unrelated parents in the 40th week of pregnancy (Hbd 40+6), Apgar 9 points and signs of intrauterine hypotrophy (body mass at birth 2360 g). On the third day of life, she developed linear rash on the skin of the medial and lateral side of the left lower limb. Examination revealed numerous papules and discrete vesicles on an erythematous background. Within few days, lesions spread on the skin of the right lower limb and the left arm. A significant asymmetry in the distribution of lesions was observed, since mainly the left side of the body was involved, with solitary lesions affecting the left forearm and numerous lesions on the left thigh and lower leg and the Achilles tendon (Figures 1, 2). On the skin of medial sites of both thighs, linear lesions were symmetric and arranged along the lines of Blaschko. The examination of hair and nails did not reveal any abnormalities.



Diagnostic approach



A standard diagnostic approach in IP includes a skin biopsy with assessment of the nervous system and the organ of vision [1-4, 7, 8, 17, 18]. Neurologic examination revealed slightly increased muscle tone with no other anomalies. A cranial ultrasound did not reveal any abnormalities of the brain structures. On ophthalmological examination, the anterior chamber of the eye was normal, while scarce extravasations were observed on the fundus. The X-ray of the skeletal system did not reveal any abnormalities. C-reactive protein (20.47 mg/l) and leukocytes in the peripheral blood were elevated (14.9-29.6 K/l) as signs of pneumonia were observed in the first days of life. Additionally, glucose blood levels showed hypoglycemia (25-60 mg/dl). Intrauterine blood smear did not reveal eosinophilia, which is a significant sign in IP.



Histological examination of the skin biopsy



The skin biopsy was performed by a dermatologist on the 20th day of life. Histological examination revealed characteristic features of the first, vesicular stage of IP which are as follows: epidermis with spongiosis, orthokeratosis, hypergranulosis and inflammatory infiltration with leukocytes, histiocytes and eosinophils (Figure 3).

The skin biopsy in the vesiculobullous stage usually demonstrates inflammatory dermatitis, with subcorneal vesicles filled with numerous eosinophils, while the warty stage merely reveals hyperkeratosis and chronic inflammation of the dermis. Finally, the pigmentary stage demonstrates melanin, which is found in the dermis or engulfed by dermal macrophages. The study of Fraitag et al. [19] revealed that most of the 26 biopsies in the late stage (IV) of IP showed a slight atrophy and some scattered apoptotic cells in the epidermis, epidermal hypopigmentation and a reduced melanocyte number, while the dermis appeared thickened and homogeneous and revealed a complete absence of hair follicles (23/26) and sweat glands (22/26). Furthermore, in the investigated biopsies there was no melanin incontinence or inflammatory cells, and the elastic network was normal. Recently, eotaxin – an eosinophil-selective chemokine – has been identified in the epidermis of skin lesions of patients with IP [20].



Differential diagnosis



In the blistering stage, other blistering skin conditions should be excluded, such as common infections caused by Herpes simples virus (HSV) or Staphylococcus aureus (Bullous impetigo – BI). Skin lesions caused by HSV are characterized by closely grouped vesicles, which rupture easily leaving erosions, often covered with honey-like crusts due to the secondary bacterial infection. Herpes simples virus infection is usually not accompanied by systemic symptoms or any organ abnormalities. Bullous impetigo, and its generalized form – staphylococcal scalded skin syndrome (SSSS) – is a serious skin infection, due to action of exfoliative toxins produced by S. aureus which leads to the formation of pus-filled blisters. Lesions in BI are usually diffuse and accompanied by systemic symptoms. Nikolsky’s sign may be observed and a very intense systemic treatment is necessary (systemic antibiotics i.v.). In the warty stage, IP may be confused with epidermal birthmarks (nevi) or warts. Epidermal birthmarks are not preceded by the onset of vesicles. In the pigmentary stage, sites of hyperpigmentation are uniquely arranged in whorls, which is why IP is unlikely to be confused with other causes of hyperpigmentation/discoloration of the skin [1-4].

Discussion

Incontinentia pigmenti is a familial, X-linked dominantly inherited, neurocutaneous syndrome. The perinatal incidence of IP is estimated at a level of 1 to 50 000 births, but it is probably higher. The disease is difficult to diagnose by non-dermatologists as it is sometimes confused with usually infectious conditions, such as HSV, BI or erythema toxicum [1, 17, 21]. The underlying defect in IP is a mutation in the essential modulator gene (NEMO), which results in the loss of activity of the regulatory component of the IB kinase (IKK) complex encoded by the NEMO/IKKγ gene. Deletion of exons 4 - 10 is observed in 80% of patients with IP [8, 17, 21]. Thus, nonfunctional IKK abolishes activity of nuclear factor- B (NFB), preventing the transcription of various target genes. NEMO seems to be involved in epidermal development and differentiation. This is why dysregulation of NFB is suspected to play an important role in the pathogenesis of skin diseases, such as psoriasis, sunburn, Lyme disease, allergic contact dermatitis, autoimmune diseases and skin cancers [21].

Various phenotypes of patients with IP offer a great opportunity for expanding the current knowledge of the function of this transcription factor. It has been shown experimentally that the NFB pathway is important in limb morphogenesis as well as odontogenesis and retinogenesis. This is why, apart from characteristic skin lesions, arranged in a linear pattern along the lines of Blaschko and evolving through 4 distinct stages, other systems are usually involved [1-4, 17, 18, 22-24]. Systems that may be involved in IP include as follows:

• the teeth – delayed eruption, microdontia, hypodontia, dysplasia,

• CNS – seizures, spasticity, mental deficiency, microcephaly,

• the eyes – uveitis, keratitis, cataract, retinal dysplasia, strabismus, retinal detachment, retrolental dysplasia, blue sclerae, pigment retinopathy,

• the musculoskeletal system – hemiatrophy, extra rib, hemivertebrae, kyphoscoliosis, syndactyly, short arms and legs,

• the hair – alopecia.

The high rate of neurological disturbances and blindness in the population of neonates with IP remains the most important challenge for clinicians. For that reason, newborns with the suspicion of IP should be carefully diagnosed by the ophthalmologist and neurologist as these disorders decrease the quality of life significantly. The variety of neurological symptoms is very wide, including recurrent strokes and acute disseminated encephalo­myelitis [22-25]. Current results of neuroradiologic and histopathologic observations indicate that vascular anomalies in CNS might be responsible for neurologic complications in IP [23, 26, 27].

Chromosomal instability seen in IP patients may increase the risk of malignancy in young children [28]. Due to mutation in the NEMO gene, which protects against TNF--induced apoptosis, IP is considered as a pre-apoptotic state leading to male lethality and cell destruction in females. This may account for the dyskeratosis observed in the histological examination of verrucous lesions in the course of IP. Moreover, the late manifestation of IP, STIP, may clinically resemble keratoacanthoma, which is a pre-malignant condition, or even SCC [14-16]. In adolescents and young adults with IP, recurrent cases of SCC have also been described [29, 30].



Treatment options



There is no specific treatment. Most of the therapeutic methods are claimed to be ineffective as they do not hasten the resolution of any of phases in the course of IP. However, vesicubullous lesions which appear due to inflammatory infiltration of the epidermis (mainly with eosinophils) are expected to respond to topical treatment with corticosteroids. It was proved that topical steroids reduced the expression of eotaxin in the epidermis of patients with IP [20, 31]. Topical use of steroids and antiseptic agents (diflucortolone valerate, chlorquinaldol 1%) was observed to contribute to resolution of vesicular lesions [20, 31]. Furthermore, tacrolimus (0.1% ointment), a topical calcineurin inhibitor, has been reported recently to be an effective agent in the treatment of IP [32, 33]. According to Jessup et al., tacrolimus halted the progression of the disease through its subsequent disfiguring stages [32]. Even though systemic and topical antibiotics may show anti-inflammatory effects on the level of the skin, they are not effective in the course of IP, except for lesions with secondary bacterial infection [1, 8]. In patients with solitary STIP, the first-line treatment is surgical excision, though multiple new lesions appear in other locations. Moreover, the treatment with 5-fluorouracil injections with a good clinical outcome has also been reported [20]. Finally, therapy with retinoids is also worth considering as reports of resolution of lesions and growth of nails after the systemic treatment with acitretin (25 mg for 2 months) as well as topical application of retinoic acid were reported [16, 34, 35]. All-trans-retinoic acid (ATRA) regulates synthesis of NFB components and activates apoptosis of various cell lines. Acitretin, which is a synthetic analog of retinoic-acid-receptor, prevents the formation of STIPs probably by inducing NEMO-independent mechanisms [36, 37].

Although skin lesions are the least damaging aspect of Bloch-Sulzberger syndrome, the proper diagnosis is very important, thus a careful head-to-toe clinical examination is critical in the evaluation of a child with suspected IP. Dermatological examination and diagnosis is the first step in the multidisciplinary approach including pediatricians, ophthalmologists, neurologists, dermatologists and dental consultants, which is recommended in patients with the suspicion of IP.



Photographs were used courtesy of Dr. Aleksandra Dańczak-Pazdrowska and Dr. Leszek Bartoszak.

References

 1. Chang JT, Chiu PC, Chen YY, et al. Multiple clinical manifestations and diagnostic challenges of incontinentia pigmenti: 12 years' experience in 1 medical center. J Chin Med Assoc 2008; 71: 455-60.

 2. Jentarra G, Snyder SL, Narayanan V. Genetic aspects of neurocutaneous disorders. Semin Pediatr Neurol 2006; 13: 43-7.

 3. Ehrenreich M, Tarlow MM, Godlewska-Janusz E, et al. Incontinentia pigmenti (Bloch-Sulzberger syndrome): a systemic disorder. Cutis 2007; 79: 355-62.

 4. Landy SJ, Donnai D. Incontinentia pigmenti (Bloch-Sulzberger syndrome). J Med Genet 1993; 30: 53-9.

 5. Hallas TE, Gislason T, Gislason D. Mite allergy and mite exposure in Iceland. Ann Agric Environ Med 2011; 18: 13-7.

 6. Stankiewicz-Choroszucha BL, Wawrzyniak ZM, Lipiec A, et al. Consequences of smoke inhalation in the ‘Epidemiology of Allergic Diseases in Poland’ project (ECAP). Ann Agric Environ Med 2011; 18: 420-8.

 7. Aradhya S, Courtois G, Rajkovic A, et al. Atypical forms of incontinentia pigmenti in male individuals result from mutations of a cytosine tract in exon 10 of NEMO (IKK-gamma). Am J Hum Genet 2001; 68: 765-71.

 8. Berlin AL, Paller AS, Chan LS. Incontinentia pigmenti: a review and update on the molecular basis of pathophysiology. J Am Acad Dermatol 2002; 47: 169-87.

 9. Garrod A. Peculiar pigmentation of a skin of an infant. Trans Clin Soc Lond 1906; 39: 216.

10. Bardach M. Systematislette Naevubildungen bei einem eineiigen Zwillingspoor. Z Kinderheilkd 1925; 39: 542.

11. Bloch B. Eigentumliche bisher nicht beschriebene pigmentaffektion (incontinentia pigmenti). Schweiz Med Wehnschi 1926; 7: 404-5.

12. Sulzberger F. Uber eine bisher nicht beschriebene congenitale Pigmentanomalie. Arch Dermatol Syph 1928; 154: 19-32.

13. Siemens H. Die Melanosis cori degenerativa eine neue Pigmentdermatose. Arch Dermatol Syph 1929; 157: 382-91.

14. Adeniran A, Townsend PL, Peachey RD. Incontinentia pigmenti (Bloch-Sulzberger syndrome) manifesting as painful periungual and subungual tumours. J Hand Surg Br 1993; 18: 667-9.

15. Simmons DA, Kegel MF, Scher RK, et al. Subungual tumors in incontinentia pigmenti. Arch Dermatol 1986; 122: 1431-4.

16. Young A, Manolson P, Cohen B, et al. Painful subungal dyskeratotic tumors in incontinentia pigmenti. J Am Acad Dermatol 2005; 52: 726-9.

17. Nelson DL. NEMO, NFkappaB signaling and incontinentia pigmenti. Curr Opin Genet Dev 2006; 16: 282-8.

18. Kitakawa D, Fontes PC, Magalhaes FA, et al. Incontinentia pigmenti presenting as hypodontia in a 3-year-old girl: a case report. J Med Case Reports 2009; 3: 116.

19. Fraitag S, Rimella A, de Prost Y, et al. Skin biopsy is helpful for the diagnosis of incontinentia pigmenti at late stage (IV): a series of 26 cutaneous biopsies. J Cutan Pathol 2009; 36: 966-71.

20. Jean-Baptiste S, O'Toole EA, Chen M, et al. Expression of eotaxin, an eosinophil-selective chemokine, parallels eosinophil accumulation in the vesiculobullous stage of incontinentia pigmenti. Clin Exp Immunol 2002; 127: 470-8.

21. Bell S, Degitz K, Quirling M, et al. Involvement of NF-kappaB signalling in skin physiology and disease. Cell Signal 2003; 15: 1-7.

22. Cartwright MS, White DL, Miller LM 3rd, et al. Recurrent stroke in a child with incontinentia pigmenti. J Child Neurol 2009; 24: 603-5.

23. Avrahami E, Harel S, Jurgenson U, et al. Computed tomographic demonstration of brain changes in incontinentia pigmenti. Am J Dis Child 1985; 139: 372-4.

24. Shah SN, Gibbs S, Upton CJ, et al. Incontinentia pigmenti associated with cerebral palsy and cerebral leukomalacia: a case report and literature review. Pediatr Dermatol 2003; 20: 491-4.

25. Matsumoto N, Takahashi S, Toriumi N, et al. Acute disseminated encephalomyelitis in an infant with incontinentia pigmenti. Brain Dev 2009; 31: 625-8.

26. Mangano S, Barbagallo A. Incontinentia pigmenti: clinical and neuroradiologic features. Brain Dev 1993; 15: 362-6.

27. Pascual-Castroviejo I, Roche MC, Martinez Fernandez V, et al. Incontinentia pigmenti: MR demonstration of brain changes. AJNR Am J Neuroradiol 1994; 15: 1521-7.

28. Roberts WM, Jenkins JJ, Moorhead EL 2nd, et al. Incontinentia pigmenti, a chromosomal instability syndrome is associated with childhood malignancy. Cancer 1988; 62: 2370-2.

29. Korstanje MJ, Bessems PJ. Incontinentia pigmenti with hyperkeratotic lesions in adulthood and possible squamous cell carcinoma. Dermatologica 1991; 183: 234-6.

30. Jamnadas B, Agarwal R, Caddy CM. A rare case of SCC in a young patient with incontinentia pigmenti. J Plast Reconstr Aesthet Surg 2008; 61: 973-4.

31. Kaya TI, Tursen U, Ikizoglu G. Therapeutic use of topical corticosteroids in the vesiculobullous lesions of incontinentia pigmenti. Clin Exp Dermatol 2009; 34: e611-3.

32. Jessup C, Morgan S, Cohen L, et al. Incontinentia pigmenti: treatment of IP with topical tacrolimus. J Drugs Dermatol 2009; 10: 944-6.

33. Silny W, Sadowska A, Dańczak-Pazdrowska A, Polańska A. Application of tacrolimus in the treatment of skin diseases other than atopic dermatitis. Postep Derm Alergol 2011; 28: 41-5.

34. Malvehy J, Palou J, Mascaro JM. Painful subungual tumour in incontinentia pigmenti. Response to treatment with etretinate. Br J Dermatol 1998; 138: 554-5.

35. Donati P, Muscardin L, Amantea A, et al. Detection of HPV-15 in painful subungual tumors of incontinentia pigmenti: successful topical therapy with retinoic acid. Eur J Dermatol 2009; 19: 243-7.

36. Manna SK, Aggarwal BB. All-trans-retinoic acid upregulates TNF receptors and potentiates TNF-induced activation of nuclear factors-kappaB, activated protein-1 and apoptosis in human lung cancer cells. Oncogene 2000; 19: 2110-9.

37. Farina AR, Masciulli MP, Tacconelli A, et al. All-trans-retinoic acid induces nuclear factor kappaB activation and matrix metalloproteinase-9 expression and enhances basement membrane invasivity of differentiation-resistant human SK-N-BE 9N neuroblastoma Cells. Cell Growth Differ 2002; 13: 343-54.