Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Incontinentia pigmenti

Moise L Levy, MD
Section Editor
Jennifer L Hand, MD
Deputy Editor
Rosamaria Corona, MD, DSc


Incontinentia pigmenti (IP, Bloch-Sulzberger syndrome, MIM #308300) is an X-linked dominant genodermatosis that is usually lethal in males before birth [1-3]. IP is caused by loss-of-function mutations in the IKBKG/NEMO (inhibitor of kappa polypeptide gene enhancer in B-cells, kinase gamma/nuclear factor-kappa B essential modulator) gene, encoding the nuclear factor-kappa-B essential modulator, a regulatory protein that activates genes involved in cell survival, inflammation, and immunity [4].

The disorder is seen almost uniformly in females, although it may occasionally occur in males with somatic mosaicism or XXY karyotype [1]. In females, IP typically presents with a staged, linear cutaneous eruption and anomalies of teeth, hair, and nails. Approximately one-third of patients have ocular and neurologic abnormalities. Because of the involvement of skin, hair, nails, and teeth, IP can be considered a form of ectodermal dysplasia [2].


IP occurs in approximately 1:40,000 to 1:50,000 births [1,3]. Virtually all cases are seen in females because affected males usually do not survive until birth. Males born with the condition have either somatic mosaicism or a XXY karyotype (Klinefelter syndrome) [5].


In the majority of cases, IP is due to mutations in the IKBKG/NEMO (inhibitor of kappa polypeptide gene enhancer in B-cells, kinase gamma/nuclear factor-kappa B essential modulator) gene, located at Xq28 [6]. These mutations occur "de novo" in approximately 65 percent of the IP cases. IKBKG/NEMO encodes the NEMO/I-kappa-B kinase (IKK)-gamma protein, a regulatory subunit of the inhibitor of the IKK complex, which activates NF-kappa B, leading to the activation of genes involved in cell survival, inflammation, and immunity. (See "Combined immunodeficiencies", section on 'Defects of NF-kappa-B regulation'.)

Approximately 90 percent of the IKBKG/NEMO mutations in IP are recurrent or nonrecurrent deletions of exons 4 to 10 resulting in complete loss of NEMO/IKK-gamma function [7-9]. Microdeletions, missense, frameshift, nonsense, and splice-site mutations leading to complete or partial loss of NEMO/IKK-gamma activity account for the remaining cases [9]. Milder (hypomorphic) IKBKG/NEMO mutations that impair but do not abolish NF-kappa B signaling result in males with a rare form of X-linked hypohidrotic ectodermal dysplasia associated with immunodeficiency [10].

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Oct 2017. | This topic last updated: Feb 16, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Swinney CC, Han DP, Karth PA. Incontinentia Pigmenti: A Comprehensive Review and Update. Ophthalmic Surg Lasers Imaging Retina 2015; 46:650.
  2. Landy SJ, Donnai D. Incontinentia pigmenti (Bloch-Sulzberger syndrome). J Med Genet 1993; 30:53.
  3. Narayanan MJ, Rangasamy S, Narayanan V. Incontinentia pigmenti (Bloch-Sulzberger syndrome). Handb Clin Neurol 2015; 132:271.
  4. Smahi A, Courtois G, Rabia SH, et al. The NF-kappaB signalling pathway in human diseases: from incontinentia pigmenti to ectodermal dysplasias and immune-deficiency syndromes. Hum Mol Genet 2002; 11:2371.
  5. Kenwrick S, Woffendin H, Jakins T, et al. Survival of male patients with incontinentia pigmenti carrying a lethal mutation can be explained by somatic mosaicism or Klinefelter syndrome. Am J Hum Genet 2001; 69:1210.
  6. Aradhya S, Woffendin H, Jakins T, et al. A recurrent deletion in the ubiquitously expressed NEMO (IKK-gamma) gene accounts for the vast majority of incontinentia pigmenti mutations. Hum Mol Genet 2001; 10:2171.
  7. Smahi A, Courtois G, Vabres P, et al. Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium. Nature 2000; 405:466.
  8. Minić S, Trpinac D, Obradović M. Incontinentia pigmenti diagnostic criteria update. Clin Genet 2014; 85:536.
  9. Conte MI, Pescatore A, Paciolla M, et al. Insight into IKBKG/NEMO locus: report of new mutations and complex genomic rearrangements leading to incontinentia pigmenti disease. Hum Mutat 2014; 35:165.
  10. Döffinger R, Smahi A, Bessia C, et al. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling. Nat Genet 2001; 27:277.
  11. Fusco F, Paciolla M, Conte MI, et al. Incontinentia pigmenti: report on data from 2000 to 2013. Orphanet J Rare Dis 2014; 9:93.
  12. Pescatore A, Esposito E, Draber P, et al. NEMO regulates a cell death switch in TNF signaling by inhibiting recruitment of RIPK3 to the cell death-inducing complex II. Cell Death Dis 2016; 7:e2346.
  13. Lee AG, Goldberg MF, Gillard JH, et al. Intracranial assessment of incontinentia pigmenti using magnetic resonance imaging, angiography, and spectroscopic imaging. Arch Pediatr Adolesc Med 1995; 149:573.
  14. Müller K, Courtois G, Ursini MV, Schwaninger M. New Insight Into the Pathogenesis of Cerebral Small-Vessel Diseases. Stroke 2017; 48:520.
  15. Ridder DA, Wenzel J, Müller K, et al. Brain endothelial TAK1 and NEMO safeguard the neurovascular unit. J Exp Med 2015; 212:1529.
  16. Buinauskaite E, Buinauskiene J, Kucinskiene V, et al. Incontinentia pigmenti in a male infant with Klinefelter syndrome: a case report and review of the literature. Pediatr Dermatol 2010; 27:492.
  17. Fusco F, Fimiani G, Tadini G, et al. Clinical diagnosis of incontinentia pigmenti in a cohort of male patients. J Am Acad Dermatol 2007; 56:264.
  18. Bodemer C. Incontinentia pigmenti and hypomelanosis of Ito. Handb Clin Neurol 2013; 111:341.
  19. Pearlman J, Griego RD, Levy ML, Friedman J. An unusual presentation of incontinentia pigmenti in a 4-month-old girl. Pediatr Dermatol 1996; 13:47.
  20. van Leeuwen RL, Wintzen M, van Praag MC. Incontinentia pigmenti: an extensive second episode of a "first-stage" vesicobullous eruption. Pediatr Dermatol 2000; 17:70.
  21. Hand JL. What's new with common genetic skin disorders? Curr Opin Pediatr 2015; 27:460.
  22. Minić S, Trpinac D, Gabriel H, et al. Dental and oral anomalies in incontinentia pigmenti: a systematic review. Clin Oral Investig 2013; 17:1.
  23. Chun SR, Rashid RM. Delayed onychodystrophy of incontinentia pigmenti: an evidence-based review of epidemiology, diagnosis and management. J Drugs Dermatol 2010; 9:350.
  24. Mahmoud BH, Zembowicz A, Fisher E. Controversies over subungual tumors in incontinentia pigmenti. Dermatol Surg 2014; 40:1157.
  25. Pena ZG, Brewer JD. Multiple subungual squamous cell carcinomas in a patient with incontinentia pigmenti. Dermatol Surg 2014; 40:1159.
  26. Ballester Nortes I, Allegue Gallego F, López-Ávila A, et al. Painful subungual tumours. Clin Exp Dermatol 2013; 38:802.
  27. Soltirovska Salamon A, Lichtenbelt K, Cowan FM, et al. Clinical presentation and spectrum of neuroimaging findings in newborn infants with incontinentia pigmenti. Dev Med Child Neurol 2016; 58:1076.
  28. Meuwissen ME, Mancini GM. Neurological findings in incontinentia pigmenti; a review. Eur J Med Genet 2012; 55:323.
  29. Minić S, Trpinac D, Obradović M. Systematic review of central nervous system anomalies in incontinentia pigmenti. Orphanet J Rare Dis 2013; 8:25.
  30. Basilius J, Young MP, Michaelis TC, et al. Structural Abnormalities of the Inner Macula in Incontinentia Pigmenti. JAMA Ophthalmol 2015; 133:1067.
  31. Pauly E, Linderkamp O, Pöschl J. Incontinentia pigmenti in combination with decreased IgG subclass concentrations in a female newborn. Biol Neonate 2005; 88:172.
  32. Fusco F, Pescatore A, Conte MI, et al. EDA-ID and IP, two faces of the same coin: how the same IKBKG/NEMO mutation affecting the NF-κB pathway can cause immunodeficiency and/or inflammation. Int Rev Immunol 2015; 34:445.
  33. Fusco F, Pescatore A, Steffann J, et al. Clinical Utility Gene Card for: incontinentia pigmenti. Eur J Hum Genet 2013; 21.
  34. Scheuerle AE, Ursini MV. Incontinentia pigmenti. In: GeneReviews [Internet], Pagon RA, Adam MP, Ardinger HH, et al (Eds), 2015.
  35. Gregersen PA, Sommerlund M, Ramsing M, et al. Diagnostic and molecular genetic challenges in male incontinentia pigmenti: a case report. Acta Derm Venereol 2013; 93:741.
  36. Hull S, Arno G, Thomson P, et al. Somatic mosaicism of a novel IKBKG mutation in a male patient with incontinentia pigmenti. Am J Med Genet A 2015; 167:1601.
  37. Pezzani L, Brena M, Callea M, et al. X-linked reticulate pigmentary disorder with systemic manifestations: a new family and review of the literature. Am J Med Genet A 2013; 161A:1414.
  38. Lugassy J, Itin P, Ishida-Yamamoto A, et al. Naegeli-Franceschetti-Jadassohn syndrome and dermatopathia pigmentosa reticularis: two allelic ectodermal dysplasias caused by dominant mutations in KRT14. Am J Hum Genet 2006; 79:724.
  39. Kaya TI, Tursen U, Ikizoglu G. Therapeutic use of topical corticosteroids in the vesiculobullous lesions of incontinentia pigmenti. Clin Exp Dermatol 2009; 34:e611.
  40. Ranchod TM, Trese MT. Regression of retinal neovascularization after laser photocoagulation in incontinentia pigmenti. Retina 2010; 30:708.
  42. Shah PK, Bachu S, Narendran V, et al. Intravitreal bevacizumab for incontinentia pigmenti. J Pediatr Ophthalmol Strabismus 2013; 50 Online:e52.
  43. Tomotaki S, Shibasaki J, Yunoki Y, et al. Effectiveness of Corticosteroid Therapy for Acute Neurological Symptoms in Incontinentia Pigmenti. Pediatr Neurol 2016; 56:55.
  44. Wolf DS, Golden WC, Hoover-Fong J, et al. High-dose glucocorticoid therapy in the management of seizures in neonatal incontinentia pigmenti: a case report. J Child Neurol 2015; 30:100.