Incontinentia Pigmenti Do You Know the Signs? Ben-Jiang Ma, Phd, MHS, PA-C

Incontinentia Pigmenti Do You Know the Signs? Ben-Jiang Ma, PhD, MHS, PA-C

Ben-Jiang Ma A 21-year-old woman with type 1 diabetes is pattern that consists of four stages: is a Hospitalist at admitted for recurrent diabetic ketoacidosis. • The vesicular stage (stage I) is charac- IPC Healthcare/ Physical exam reveals hypopigmented, linear, terized by linear erythematous papules TeamHealth Southeast Florida, streaky patches on the medial aspects of the and blisters that manifest in newborns. Lake Mary, Florida. bilateral lower legs (Figure 1A). The patient • The verrucous stage (stage II) begins denies tenderness, pruritus, or paresthesia. as the blisters start to heal—usually af- There is obvious symmetrical hair loss on ter several weeks—and is distinguished the lateral aspects of the eyebrows, as well by hyperkeratotic warty papules in lin- as slightly wooly male-pattern hair distribu- ear or swirling distribution. This stage tion with patchy alopecia on the vertex of the resolves on its own within months. head (Figure 1B). She has very poor dentition • The hyperpigmentation stage (stage with hypodontia and malformed teeth (Figure III) is when swirling macules or patches 1C). Her fingernails and toenails appear nor- develop. This hallmark stage of IP tends mal, with no visible atrophy (Figure 1D). What to remain static until adolescence. explains her condition? • The hypopigmentation stage (stage IV) manifests with faded streaky patch- ncontinentia pigmenti (IP), also known es, which may be subtly atrophic. This as Bloch-Sulzberger syndrome, is a rare, final stage usually develops in the sec- I X-linked dominant genodermatosis in- ond or third decade of life.2,3 volving the cutaneous, ophthalmic, neuro- All these cutaneous lesions follow Blaschko logic, and dental systems.1-3 It results from lines—invisible lines believed to result from X-inactivation due to mutations in the NF- embryonic cell migration that become vis- kappaB essential modulator (NEMO) gene ible with the manifestation of cutaneous or with deletion of exons 4-10 in most cases. mucous lesions.6 The NEMO gene encodes a regulatory Other associated cutaneous findings in- component of the IkappaB kinase complex clude patchy alopecia, nail dystrophy, and required to activate the NF-kappa B path- oral/dental anomalies such as hypodontia, way, which is important for many immune, oligodontia, and tooth deformities. In ad- inflammatory, and apoptotic processes.4-6 dition, ophthalmologic involvement can This deletional mutation is typically lethal result in strabismus, cataracts, and retinal IN THIS in normal 46,XY male karyotypes. Male fe- vascular changes that can lead to blindness. ARTICLE tuses with this mutation usually die in utero, Central nervous system manifestations in- • Presenting making the reported cases predominantly clude seizures, cognitive impairment, and stages, female.4,7 spastic paralysis.3 page 40 The estimated incidence of IP is between 4 • Diagnostic 1/10,000 and 1/100,000. Due to the rarity DIFFERENTIAL DIAGNOSIS criteria, of the condition, IP may be underrecog- Because IP is uncommon, it may be eas- page 42 nized and underdiagnosed. ily overlooked or misdiagnosed as another, similar cutaneous manifestation. Cutane- • Management of IP, CLINICAL PRESENTATION ous sarcoidosis, for example, is a skin lesion page 42 Characteristic skin lesions of IP begin to of noncaseating granuloma. It can present develop at birth or in utero, in an evolving as patches, papules, ulcers, scars, ichthyo-

40 Clinician Reviews • AUGUST 2017 clinicianreviews.com FIGURE 1 Cutaneous Manifestations of Stage IV IP A B

C D

Stage IV incontinentia pigmenti manifested in this patient with streaky, hypopigmented patches on the medial aspect of the left lower extremity (A); not shown: symmetrical lesions on the right medial leg; bilateral hair loss of the eyebrows with male-pattern hair distribution (B); poor dentition with hypodontia and oligodontia (C); and close to normal development of the fingernails (D); toenails, not shown, are normal.

sis, and alopecia. The development of cu- Erythema multiforme (EM) is another taneous sarcoidosis can be idiopathic or dermatologic condition frequently encoun- iatrogenic, particularly in patients using an- tered in children and young adults. Its char- ti-TNF therapy. The diagnosis is made clini- acteristic round target lesion usually has cally and can be confirmed pathologically.8 two rings surrounding the dusky-appearing Stage I IP can also be confused with central zone. Atypical lesions can be bul- neonatal herpes simplex virus-1 (HSV-1) lous or crusty, mimicking the appearance of infection, given the similarities in vesicular stage I or II IP. EM is usually a self-limiting morphology and linear distribution. The di- condition, but specific treatment may be re- agnosis of HSV-1 can be made based on his- quired if the infectious agent is identified.10 tory, physical exam, and pathology. Given Vitiligo, the development of white patch- the serious sequelae of neonatal HSV-1 in- es due to the loss of melanocytes, is an- fection, antiviral therapy should not be de- other item in the differential. Although it layed until confirmation of the diagnosis in most commonly involves the skin, the hair infants with vesicular eruptions.9 may also be affected. The diagnosis is made

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TABLE In stages I and II of IP, pathologic features Clinical Diagnostic Criteria include spongiotic dermatitis with charac- for Incontinentia Pigmenti teristic eosinophils and large dyskeratotic cells.3,13 In stage IV, skin biopsies may reveal Major Criteria slight atrophy and scattered apoptotic cells in the epidermis and epidermal hypopig- No evidence of IP in a first- Evidence of IP in a first-degree mentation due to reduced melanocytes. degree female relative: female relative: The dermis typically appears thickened and Linear, atrophic, hairless lesions Anomalous dentition is absent hair follicles and sweat glands.14 Pathohistologic findings Hyperpigmentation In a 2014 update, these pathologic features Typical neonatal rash (erythema, Alopecia at vertex were proposed to be included in the major vesicles) Hairless streaks diagnostic criteria.12 Typical hyperpigmentation Scarring (mainly on trunk, following Multiple male miscarriages TREATMENT/MANAGEMENT Blaschko lines, fading in Retinal disease Treatment of IP is centered on the involved adolescence) Suggestive history or evidence of organ systems. For cutaneous lesions, treat- typical rash ment is not usually necessary unless in- Skin manifestations of IP flammation persists. In such cases, topical Wooly hair steroids or tacrolimus have been used with some success.15,16 In the vesicular stage, the Minor Criteria patient should be monitored for bacterial infection, with appropriate prevention or Abnormal nails Dental involvement treatment as necessary. Alopecia Retinal disease With other involved systems—such as Breast or nipple anomalies Wooly hair dental, ophthalmologic, or neurologic (eg, seizures or other encephalopathy) anoma- Abbreviation: IP, incontinentia pigmenti. Sources: Landy. J Med Genet. 19932; Hadj-Rabia. Arch Dermatol. 20033; lies—consultation and follow-up with the Minic´. Clin Genet. 2014.12 relevant specialist is warranted.

In this case, the patient denied family history clinically and can be confirmed with skin of IP. She did have a history of infantile cata- biopsy if needed.11 ract and seizure. Her presenting signs were typical of stage IV IP: hypopigmented streaky DIAGNOSIS patches on the skin of the lower legs, dental Diagnostic criteria for IP have been pro- abnormalities, somewhat wooly hair, alopecia posed, with family history playing a role on the head, and loss of hair on the lateral (see Table).2,3,12 Results of a case-study se- aspects of the eyebrows. The uniqueness of ries indicate that 28% of patients with IP this case is that the patient also had type 1 have a family history involving at least one diabetes, a condition with a strong genetic first-degree female relative. IP was consid- predisposition. However, there is no evidence ered “sporadic” in 62% of cases studied.3 supporting an association between IP and ei- Without a family history of IP, at least one ther type of diabetes. major criterion must be present to support the diagnosis. These include CONCLUSION • Neonatal rash (erythema, vesicles) Although rare, when IP does occur, its • Linear, atrophic, hairless lesions manifestations are vast and severe enough • Hyperpigmentation (mainly on trunk, to significantly reduce quality of life for following Blaschko lines) patients; when it occurs in males, it is usu- In a patient with a family history of IP, ally lethal. This genetic disorder can affect the presence of any major criterion strongly multiple body systems, making knowledge supports the diagnosis. These, as well as mi- of its symptoms essential for proper diagno- nor criteria, are outlined in the Table.2,3,12 sis. Because its characteristic stages may be

42 Clinician Reviews • AUGUST 2017 clinicianreviews.com INCONTINENTIA PIGMENTI

present at birth or in infancy, early identi- 8. Katta R. Cutaneous sarcoidosis: a dermatologic masquer- ader. Am Fam Physician. 2002;65(8):1581-1584. fication and diagnosis of IP can help guide 9. Faloyin M, Levitt J, Bercowitz E, et al. All that is vesicular is treatment intervention. CR not herpes: incontinentia pigmenti masquerading as herpes simplex virus in a newborn. Pediatrics. 2004;114(2):e270-272. 10. Siedner-Weintraub Y, Gross I, David A, et al. Paediatric erythema multiforme: epidemiological, clinical and laboratory REFERENCES characteristics. Acta Derm Venereol. 2016 Nov 10. doi: 1. Roberts AP. Incontinentia pigmenti (Bloch-Sulzberger). Br 10.2340/00015555-2569. Med. J. 1958;1(5079):1106-1107. 11. Gawkrodger DJ, Ormerod AD, Shaw L, et al. Guideline for 2. Landy SJ, Donnai D. Incontinentia pigmenti (Bloch-Sulzberg- the diagnosis and management of vitiligo. Br J Dermatol. er syndrome). J Med Genet. 1993;30(1):53-59. 2008;159(5):1051-1076. 3. Hadj-Rabia S, Froidevaux N, Bodak D, et al. Clinical study of 12. Minic´ S, Trpinac D, Obradovic´ M. Incontinentia pigmenti 40 cases of incontinentia pigmenti. Arch Dermatol. 2003; diagnostic criteria update. Clin Genet. 2014;85(6):536-542. 139(9):1163-1170. 13. Jean-Baptiste S, O’Toole EA, Chen M, et al. Expression of 4. Smahi A, Courtois G, Vabres P, et al. Genomic rearrangement eotaxin, an eosinophil-selective chemokine, parallels eosino- in NEMO impairs NF-kappaB activation and is a cause of phil accumulation in the vesiculobullous stage of incontinen- incontinentia pigmenti. Nature. 2000;405(6785):466-472. tia pigmenti. Clin Exp Immunol. 2002;127(3):470-478. 5. Aradhya S, Courtois G, Rajkovic A, et al. Atypical forms of 14. Hadj-Rabia S, Rimella A, Smahi A, et al. Clinical and histo- incontinentia pigmenti in male individuals result from muta- logic features of incontinentia pigmenti in adults with nuclear tions of a cytosine tract in exon 10 of NEMO (IKK-gamma). factor-κ B essential modulator gene mutations. J Am Acad Am J Hum Genet. 2001;68(3):765-771. Dermatol. 2011;64(3):508-515. 6. Poziomczyk CS, Recuero JK, Bringhenti L, et al. Incontinen- 15. Kaya TI, Tursen U, Ikizoglu G. Therapeutic use of topical tia pigmenti. An Bras Dermatol. 2014;89(1):26-36. corticosteroids in the vesiculobullous lesions of incontinentia 7. Kenwrick S, Woffendin H, Jakins T, et al. Survival of male pigmenti. Clin Exp Dermatol. 2009;34(8):e611-613. patients with incontinentia pigmenti carrying a lethal mutation 16. Jessup CJ, Morgan SC, Cohen LM, Viders DE. Incontinentia can be explained by somatic mosaicism or Klinefelter Syn- pigmenti: treatment of IP with topical tacrolimus. J Drugs drome. Am J Hum Genet. 2001;69(6):1210-1217. Dermatol. 2009;8(10):944-946.