Neurologic Manifestations of Incontinentia Pigmenti 

Updated: Dec 11, 2018
Author: Celia H Chang, MD; Chief Editor: Amy Kao, MD 

Overview

Background

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.

Pathophysiology

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.

Epidemiology

Frequency

International

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

Mortality/Morbidity

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.

Race

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

Sex

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.

Age

The initial skin lesions are usually present at birth.

 

Presentation

History

Usually, the diagnosis is made clinically on the basis of a history of sequential cutaneous lesions and associated features. Landy and Donnai have recommended the following diagnostic criteria.[8, 9]

A least 1 major criteria is necessary for a diagnosis of sporadic incontinentia pigmenti. Major criteria include the following:

  • Typical neonatal rash

  • Typical hyperpigmentation

  • Linear, atrophic, hairless lesions.

Individuals with a least 1 first-degree female relative who was previously diagnosed with incontinentia pigmenti may also be diagnosed with minor criteria which include the following:

  • Dental involvement

  • Wooly hair, abnormal nails

  • Retinal disease

Physical

Four stages of skin change occur in most patients, mostly on the body along the sides of the torso. Few males develop stage 4 lesions.

Stage 1

Stage 1 is the vesicular stage, with linear vesicles, pustules, and bullae with erythema along the lines of Blaschko. This stage is present at birth but may recur during childhood with febrile illnesses. See the images below.

Incontinentia pigmenti. Linear streak of pigmentat Incontinentia pigmenti. Linear streak of pigmentation and erythematous vesicles along the pattern of Blaschko lines on the left arm
Forearm vesicles with overlying granulation tissue Forearm vesicles with overlying granulation tissue characteristic of incontinentia pigmenti

Stage 2

Stage 2 is the verrucous stage, with warty, keratotic papules and plaques. Stage 2 occurs between ages 2 and 8 weeks.

Stage 3

Stage 3 is the hyperpigmented stage, with macular hyperpigmentation in a swirled pattern along the lines of Blaschko. These changes often involve the nipples, axilla, and groin. Stage 3 occurs between ages 12 and 40 weeks. See the images below.

Incontinentia pigmenti. The back and buttock regio Incontinentia pigmenti. The back and buttock region are covered with swirls and streaks of hyperpigmentation and purple discoloration with patches of vesicles, all along the lines of Blaschko.
Incontinentia pigmenti. Streaks of hyperpigmentati Incontinentia pigmenti. Streaks of hyperpigmentation on the chest and proximal right arm

Stage 4

Stage 4 is the hypopigmented stage, with hypopigmented streaks and/or patches and cutaneous atrophy. Stage 4 is present from infancy through adulthood.

Recurrent papular skin eruptions have also been reported.

Onychodystrophy or nail dysplasia occurs in 40-60% of patients with incontinentia pigmenti. Other nail changes can include subungual keratotic tumors.

Ocular changes are seen in about one third of female patients and in two thirds of male patients with incontinentia pigmenti.[10, 11] The changes can include the following:

  • Retinal pigmentary changes with mottled diffuse hypopigmentation, which is nearly pathognomonic

  • Abnormal peripheral retinal vessels with areas of nonperfusion, which is also nearly pathognomonic

  • Microphthalmia

  • Retrolental mass formation (pseudoglioma or retinoblastoma with intraocular calcifications)

  • Cataracts, leukocoria, or band keratopathy

  • Strabismus

  • Optic atrophy or foveal hypoplasia

  • Congenital glaucoma

  • Blue sclera

  • Exudative retinal detachment can be very rapidly progressive (< 6 mo) or fluctuate over many years.

  • Retinal pigmentary changes

Teeth and jaw changes occur in approximately 65-90% of patients. These changes can include delayed eruption of teeth; caries; partial anodontia; hypodontia; microdontia; abnormally shaped teeth—round, conical, or peg; micrognathia; prognathia; and gothic palate. Areas of focal hypermineralization and decreased enamel mineralization can also occur.

The hair is thin and sparse; alopecia is seen in 35-70% of people with incontinentia pigmenti. The hair changes can include a wooly hair nevus, which is a coarse, lusterless, and wiry patch of hair.

The central nervous system is involved in 10-40% of patients.[11, 12] The manifestations can include the following:

  • Microcephaly

  • Mental retardation

  • Spasticity

  • Seizures (can present in the neonatal period)

  • Ataxia

  • Encephalopathy (can present in the neonatal period)

  • Hyperactivity

  • Strokes (can present in the neonatal period) (See the image below.)

    Diffuse cerebral infarcts and edema associated wit Diffuse cerebral infarcts and edema associated with incontinentia pigmenti
  • Encephalocele[13]

Skeletal and structural anomalies can occur in approximately 14% of patients but are usually associated with severe neurological deficits. The anomalies can include the following:

  • Somatic asymmetry

  • Hemivertebrae

  • Scoliosis

  • Spina bifida

  • Syndactyly

  • Acheiria (congential absence of the hands)

  • Ear anomalies

  • Extra ribs

  • Skull deformities

  • Breast anomalies can occur in 1% of patients; anomalies can include hypoplasia and supernumerary.

Primary pulmonary hypertension

Cardiopulmonary failure

Causes

Most cases are caused by a deletion in the NEMO gene. Approximately one half of all cases are spontaneous mutations. Most of the new mutations occur in the germline cells in the father's gonads.

  • Female carriers may have only subtle findings with stage 4 skin and teeth abnormalities.

  • Males with XXY (ie, Klinefelter syndrome) have been reported. Other males who survived are believed to have postzygotic mutation, half chromatid mutation, an unstable permutation, somatic mosaicism, or hypomorphic mutations. Not all males have evidence of NEMO mutations and may have findings unilaterally or even just in one limb.

  • Almost all women with incontinentia pigmenti have skewed inactivation of the defective X chromosome, which may become more pronounced over time, as it is not always detected in newborns.

 

DDx

Diagnostic Considerations

Differential for multiorgan involvement

  • MIDAS syndrome - X-linked dominant dermato-ocular syndrome with similar skin changes but different eye changes

  • Hypomelanosis of Ito (incontinentia pigmenti achromians) - Swirls or streaks of hypopigmentation and depigmentation; not inherited; no stage 1 or 2; 33-50% with multisystem involvement—eye, skeletal, neurological abnormalities; Xp11

  • Focal dermal hypoplasia of Goltz - X-linked dominant disorder with similar findings, Xp22

  • Naegeli syndrome - Autosomal dominant dermato-ocular syndrome with symptoms starting at age 2, mostly on the hands and feet, and similar ocular changes

  • X-linked chondrodysplasia punctata - Has more skeletal dysplasia, congenital cataracts, and alopecia, as well as follicular pitting, which is not seen in incontinentia pigmenti

  • Dyskeratosis congenita - Skin findings similar to stages 3 and 4 but no inflammatory changes. It is also associated with progressive pancytopenia with bone marrow failure being a frequent cause of death. This has been mapped to the DKC1 gene, which is proximal to the factor VIII gene on the X chromosome.

Differential for stage 1 lesions

  • Arthropod reaction

  • Bullous congenital ichthyosiform erythroderma (epidermolytic hyperkeratosis)

  • Bullous dermatosis

  • Bullous impetigo

  • Bullous mastocytosis

  • Bullous pemphigoid

  • Drug reaction

  • Epidermolysis bullosa, especially Dowling Meara type

  • Eosinophilic cellulitis (Wells syndrome)

  • Eosinophilic pustular folliculitis (Ofuji disease)

  • Erythema toxicum neonatorum

  • Hypereosinophilic syndrome

  • Herpes simplex and varicella zoster

  • Milker nodule

  • Pemphigus

  • Polycythemia rubra vera

  • Porokeratosis of Mibelli (benzyl hydrochlorothiazide induced)

  • Scabies

  • Subcorneal pustular dermatosis (Sneddon Wilkinson disease)

Differential for stage 2 lesions

  • Linear epidermal nevus

  • Lichen striatus

Differential for stage 3 lesions

  • Linear and whorled nevoid hypermelanosis

  • Dermatopathia pigmentosa reticularis

 

Workup

Laboratory Studies

See the list below:

  • Complete blood count (CBC) frequently shows eosinophilia in about one third of males.

  • Genetic testing for NEMO mutations - Southern blot or direct sequencing of exons (see GeneTests)

Imaging Studies

CT scan or MRI of the brain should be performed if the neurologic examination or the child's development are abnormal or if vascular retinal findings are present. CNS lesions also correlate with scalp lesions. CNS findings are usually present at birth or within the first few months of life. CT and MRI findings may include the following:

  • Atrophy

  • Hypoplasia and partial agenesis of corpus callosum

  • Gray matter dysplasia

  • Periventricular white matter disease (A transient white matter lesion on MRI has been reported.)

  • Strokes or focal encephalomalacia; lesions extend radially and can involve structures from the ependyma to the cortex. The lesions do not correspond to usual vascular territories.

  • Diffuse cortical necrosis

Fluorescein angiography is helpful in defining the retinal vascular abnormalities.

Other Tests

DNA testing

Procedures

Skin biopsy is used to confirm the diagnosis.

Histologic Findings

The 4 cutaneous stages are associated with the following histologic findings:

  • Stage 1 has eosinophilic spongiosis that is characterized by spongiotic dermatitis with eosinophils in an inflammatory reaction, vacuolated basal cells, and dyskeratotic cells.

  • Stage 2 has papillated epidermal hyperplasia that is characterized by dyskeratotic cells, eosinophils in the dermis and epidermis, hyperkeratosis, acanthosis, and vacuolated basal cells.

  • Stage 3 is the postinflammatory stage that is characterized by a thickened papillary dermis, many melanophages, deposits of melanin in the dermis, and vacuolar alteration of epidermal basal cell layer.

  • Stage 4 is the atrophic, hypopigmented stage that is characterized by increased melanin in the upper dermal layers, hyperkeratosis, acanthosis, atrophy, scarring, and an absence of skin appendages.

 

Treatment

Medical Care

No specific treatment is available for incontinentia pigment.[14]

  • The stage 1 lesions should be left intact and kept clean.

  • Kaya et al reported almost complete resolution of stage 1 lesions in 5 days after applying diflucortolone valerate .1% and chlorquinaldol 1% twice a day. They thought the rapid resolution of the lesions was due to response of the eosinophilic inflammation to the topical steroids.[15]

  • Meticulous dental care is very important.

  • Lin et al performed intravitreal injection of an anti-VEGF agent (bevacizumab 1.25 mg/.05 mL) in a patient who had failed laser photocoagulation therapy. Five days after the injection, the neovascular frond became avascular and was successfully removed surgically. Unfortunately, the eye subsequently developed a persistent pupillary membrane, another episode of retinal detachment, and rubeosis iridis with neovascular glaucoma.[16]

Consultations

See the list below:

  • Ophthalmologist

  • Dentist

  • Geneticist

  • Neurologist, only if neurologic abnormalities are present

 

Follow-up

Further Outpatient Care

See the list below:

  • Routine ophthalmologic follow-up is essential to prevent blindness. Wong et al recommended frequent examinations, following the schedule below:

    • As soon as possible after birth

    • Monthly until the infant is 3-4 months of age

    • Every 3 months until the child is 1 year old

    • Twice a year until the child is 3 years old

    • Yearly thereafter

  • Ophthalmologic treatments may include the following:

    • Photocoagulation for fibrovascular proliferation

    • Vitreoretinal surgery for retinal detachments

  • Dental (See Physical.)

  • Neurologist, only if neurologic abnormalities are present

Prognosis

Prognosis can be quite variable. Bryant et al reported that a child with neonatal seizures and persistent subcortical and periventricular white matter abnormalities on brain MRI had resolution of the seizures and was successfully tapered off anticonvulsants at 7 months of age. At age 11, the child had a normal neurologic examination and she was adequate to advanced in her academic skills for her age.[17]

Patient Education

Because incontinentia pigmenti is an X-linked dominant disease, genetic counseling regarding the risk of having affected offspring is very important.