Neurologic Manifestations of Incontinentia Pigmenti

Updated: Dec 11, 2018
  • Author: Celia H Chang, MD; Chief Editor: Amy Kao, MD  more...
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This article discusses what was formerly referred to as incontinentia pigmenti type 2, also known as Bloch-Sulzberger syndrome, a rare, X-linked, dominantly inherited disorder of skin pigmentation that is often associated with ocular, dental, and central nervous system abnormalities. Incontinentia pigmenti refers to the loss of melanin from basal cells in the epidermis; melanin collects in the dermis as free pigment or aggregates of melanophages. Garrod described the first patient in 1906; Sulzberger described the pathologic changes in 1928; and Haber first recognized the multisystem nature of the disease. Happel first recognized that the skin changes occur along the lines of Blaschko in 1985. [1]

Incontinentia pigmenti was previously described as sporadic with linkage to band Xp11.21 and X-linked dominant at locus Xq28; however, the disease with linkage to band Xp11.21 represents what has been referred to as incontinentia pigmenti type 1 or hypomelanosis of Ito.

See also the Medscape Reference Dermatology article Incontinentia Pigmenti.



In 2000, the International Incontinentia Pigmenti Consortium reported that incontinentia pigmenti is caused by a genomic rearrangement of the gene for NEMO, or nuclear factor kappa B essential modulator (IKBKG-IKK gamma). [2] The defect in the X chromosome is proximal to the gene for factor VIII at Xq28. Two thirds of new mutations originate with the father. NEMO consists of 10 exons, and most mutations cause deletions of exons 4-10, resulting in a truncated protein. Small duplications, substitutions, and small mutations have also been reported. [3]

Incontinentia pigmenti has also been found to be allelic with hypohidrotic ectodermal dysplasia with severe immunodeficiency (EDAID), an X-linked immunodeficiency syndrome with developmental and immunologic defects in males. Puel et al found that the 110_111insC NEMO mutation is the most upstream premature translation termination codon, but it results in a pure immunodeficiency syndrome because a Kozakian methionine codon reinitiates translation. [4]

In 2002, Bardaro et al reported a second copy of the NEMO gene, deltaNEMO, which is 31.6 kb from exon 10 and contains exons 3-10. [5] The deltaNEMO pseudogene deletion has complicated the diagnosis of incontinentia pigmenti.

Activation of the transcription factor nuclear factor KB (NF-KB) requires the NEMO protein. NEMO binds to Lys 63-linked polyubiquitin. NF-KB is important in immune, inflammatory, and apoptotic pathways. [6] NF-KB protects cells from apoptosis in response to tumor necrosis factor-alpha (TNF-alpha). An inhibitory molecule of the IKB family interacts with NF-KB to sequester it in the cytoplasm. The IKB is phosphorylated by a multiprotein complex with two kinases subunits. The NEMO protein is required for the activation of the kinase complex. Hypomorphic mutations may impair but not abolish NEMO protein function.

NEMO is an ubiquitous protein that becomes active during embryogenesis. The skin, eyes, and hair all are affected. In the mouse model, mature osteoclasts, which are essential for tooth eruption, are lacking. In the skin, NF-KB regulates cell growth in the stratified epithelium and apoptosis. NF-KB may also have a role in maintenance of blood vessel architecture. Cerebral microangiopathy and hemorrhagic infarcts cause some of the neurologic morbidity. The skin manifestations occur along the lines of Blaschko, which represent the routes of embryonic cell migration. The skin findings in incontinentia pigmenti represent changes in the epidermal cells. Nenci et al found that TNF signaling is necessary for development of the skin lesions in incontinentia pigmenti. [7]

NEMO mutations have been reported in males with immunodeficiency both with and without anhidrotic ectodermal dysplasia (EDA-ID). EDA-ID is an X-linked condition that is characterized by abnormal teeth, sparse hair, and scarce or absent sweat glands. A more severe NEMO mutation is reported to cause osteopetrosis, lymphedema, and hemangiomas (OL-EDA-ID). Hyper-IgM syndrome is also reported in EDA-ID.

Incontinentia pigmenti can also cause immunodeficiency in women and this may not manifest in the neonatal period. The cells with the NEMO mutation undergo selective apoptosis, which accounts for some of the X inactivation skewing seen in women.





The incidence of incontinentia pigmenti is 1 case per 40,000 population.


Incontinentia pigmenti is a genodermatosis and can be associated with malignancies (ie, chromosomal instability syndrome), such as acute myelogenous leukemia, Wilms tumor, malignant rhabdoid tumors, and retinoblastoma.


Incontinentia pigmenti is more common in whites than in other races.


See the list below:

  • Incontinentia pigmenti usually affects females, as it is an X-linked dominant disease; male fetuses usually do not survive.

  • The male-to-female ratio is 1:19-37.


The initial skin lesions are usually present at birth.