Bloch and Sulzberger, in 1926 and 1928 respectively, were credited for the first description of the clinical syndrome of incontinentia pigmenti (IP), known as Bloch-Sulzberger syn- drome. It is a rare genodermatoses occurring in approximately 1 in 50,000 newborns.
GENETICS/BASIC DEFECTS
1. Inheritance
a. X-linked dominant transmission, usually prenatally lethal in males, suggested by pedigree analyses b. A high affected female/affected male ratio c. Instances of female-to-female transmission
d. 1:1:1 affected female:normal female:normal male ratio in the offspring of an affected mother
e. Increased incidence of miscarriages in patients with incontinentia pigmenti, presumably representing affected male conceptuses that typically fail to sur- vive past the second trimester
2. Female patients with IP mutations a. Dizygosity for the X chromosome b. Skewed X-inactivation
i. Cells expressing the mutant X chromosome are eliminated selectively around the time of birth, so that females with IP exhibit extremely skewed X-inactivation, based on the Lyon hypothesis (random inactivation of one X chromosome in each cell of the female at an early developmental stage, resulting in an X-chromosomal mosaic for each female with one X functioning in some of the cells and the other X functioning in the rest of the cells)
ii. Female heterozygous for an X-linked inconti- nentia pigmenti gene: the pigmented areas on the skin represent cell populations in which the abnormal gene is active and the areas of normal skin tissue in which the normal gene is active iii. Highly variable phenotype explainable by the
chance variability in the number and position of the cells carrying the active incontinentia pig- menti gene
3. The gene for IP: linked genetically to the factor VIII gene in Xq28
4. Expression of the disease IP: caused by mutations in the NEMO (NF-κB essential modulator)/IKKγ (IκB kinase-γ) gene located at Xq28
a. NEMO/IKKγ: an essential component of the newly dis- covered nuclear factor κB (NF-κB) signaling pathway.
When activated, NF-κB controls the expression of multiple genes, including cytokines and chemokines, and protects cells against apoptosis
b. NEMO/IKKγ deficiency causes the phenotypical expression of the disease via the NF-κB pathway c. A knockout mice heterozygous for NEMO/IKKγ gene
deficiency develops a clinical phenotype very similar to that of incontinentia pigmenti
5. Mechanisms for occasional survival of affected males a. Presence of an extra X chromosome (47,XXY
Klinefelter syndrome) b. Skewed X inactivation c. Hypomorphic alleles
d. Mosaics for common mutations (somatic mosaicism) e. A parent with gonadal mosaicism
6. Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID):
a. A disorder allelic to incontinentia pigmenti but with different phenotype due to various natures of genetic mutations underlying the 2 disorders
b. A rare X-linked recessive disorder affecting only males
c. Caused by mutations in the NEMO gene
d. Possible family history of IP in boys with EDA-ID e. Presentation with severe recurrent infections caused
by common encapsulated bacterial pathogens, sug- gesting functional defects in the immune response f. Rare opportunistic diseases
i. Mycobacterial infections ii. Cytomegaloviral infections iii. Pneumocystis carinii pneumonitis g. Immunologic studies
i. Normal or increased levels of B cells ii. Normal T-cell counts
iii. Normal to low levels of IgG iv. Elevated levels of either IgM or IgA
7. Eosinophil recruitment through eotaxin release by activat- ed keratinocytes
8. Incontinentia nomenclature: the localization of the gene for IP to Xq28, coupled with reports of children with
“incontinentia pigmenti” and X-autosome translocations with breakpoints at Xp11, resulting in a nomenclature dif- ferentiation of IP1 and IP2. However, IP1 and IP2 desig- nation should be abandoned
a. IP1
i. Disorder applied to cases associated with Xp11 breakpoints
ii. Skin changes different from patients to patients iii. Serves no useful purpose either causally or clin-
ically
iv. More appropriately using descriptive phrase “X- autosome translocation associated with pigmen- tary abnormalities”
b. IP2: applied to cases of familial IP mapped to Xq28
539
CLINICAL FEATURES
1. Highly variable clinical presentations among affected female family members
a. Attributed to lyonization in females, resulting in func- tional mosaicism
b. Clonal expansion of the progenitor cell along lines of embryonic development in that each cell determines which X chromosome to express during the first weeks of gestation
i. Manifesting along the curvilinear lines of Blaschko in skin
ii. Percentage of progenitor cells that express the mutated X chromosome reflecting the extent of expression
iii. Mutation in a high percentage of ectodermal cells in severe cases
2. Clinical expression among small number of liveborn male patients
a. Generally not severer than that in affected females b. Many male patients with disease expression limited to
cutaneous involvement of one or two limbs
3. Cutaneous manifestations: most often the first observed sign of IP and are present in nearly all patients. They are classically subdivided into the following 4 classic cuta- neous stages:
a. Vesicular, vesiculobullous, or inflammatory stage i. Frequency: about 90% of cases
ii. Age of onset: within first 2 weeks of life (92%), by 6 weeks of age (4%), starting after the 1st year of life (several cases)
iii. Age at resolution: blisters generally clearing by 4 months, recurrence usually short-lived and less severe than the original eruption
iv. Clinical features: erythema, superficial vesicles in linear distribution on torso and extremities (64%) and extremities alone (33%)
b. Verrucous (wart-like) stage
i. Frequency: about 70% of cases
ii. Age of onset: peak of onset between 2–6 weeks of age
iii. Age at resolution: clearance by 6 months (80%) iv. Clinical features: verrucous hyperkeratotic papules and plaques almost exclusively involving extremities
c. Hyperpigmented stage
i. Frequency: nearly all patients with IP (98%) ii. Age of onset: 12–26 weeks of age
iii. Age at resolution: puberty
iv. Clinical features: whorls and streaks of brown pig- mentation following lines of Blaschko (multiple lines on the human body corresponding to the dis- tribution of linear nevi and dermatoses) on torso and extremities (65%) and torso alone (27%) d. Atrophic (dermal scarring) stage
i. Frequency: 42%
ii. Age of onset: early teens to adulthood iii. Age at resolution: permanent lesion
iv. Clinical features: pale, hairless, atrophic patches and/or hypopigmentation
4. Hair abnormalities (50%) a. Vertex alopecia
i. The most common hair manifestation ii. Most commonly mild and unnoticed iii. Follows inflammation and vesiculation
iv. May be associated with scarring
b. Agenesis of eyebrows and eyelashes: infrequent 5. Nail abnormalities (7–40%)
a. Ridging, pitting, or nail disruption
i. Starting early childhood and involving all or most of the fingernails and toenails
ii. Tend to regress and disappear with age b. Subungual and periungual keratotic tumors
i. Appear at a later stage ii. Affect fingers more than toes
iii. Continued growth results in pain, nail dystrophy, and destruction of the underlying bone of the terminal phalanx
iv. Bone lytic lesions caused by pressure from the overlying tumor
6. Dental anomalies (>80%)
a. Partial adontia or adontia (43%) b. Pegged and conical teeth (30%) c. Late eruption of teeth (18%) d. Enamel hypoplasia
7. Ophthalmologic anomalies (35%) a. Blindness (7.5%)
b. Nonretinal manifestations i. Strabismus (18–33%) ii. Optic atrophy (4%) iii. Cataracts (4%)
iv. Pseudoglioma (3.5%) v. Microphthalmia (3%)
vi. Rare conjunctival pigmentation, iris hypoplasia, nystagmus, and uveitis
c. Retinal manifestations i. Foveal hypoplasia
ii. Mottled or hypopigmented retinal pigment epithelium
iii. Avascular retina iv. Neovascularization
v. Vitreous hemorrhages vi. Fibrovascular proliferation vii. Retinal detachment (3%) 8. Neurologic deficits (30%)
a. Infantile spasms and seizure disorder (13%) b. Mental retardation (12%)
c. Spastic paralysis (11%) d. Motor retardation (7.5%) e. Microcephalus (5%)
f. Infrequent manifestations i. Cerebellar ataxia ii. Congenital hearing loss iii. Muscle paresis
iv. Aseptic encephalomyelitis 9. Other associated anomalies
a. Nipple anomalies
i. Supernumerary nipple ii. Nipple hypoplasia iii. Breast hypoplasia/aplasia
b. Oral anomalies
i. High arched palate ii. Cleft lip/palate c. Skeletal anomalies
i. Dwarfism
ii. Chondrodysplasias iii. Short stature
iv. Spina bifida v. Skull defects vi. Club foot
d. Increased risk of serious and unusual infection in some patients
e. Occasional hypohidrosis with increased rates of bac- terial skin infections: may be evidence of the contin- uum between IP and the allelic anhidrotic ectodermal dysplasia-immune deficiency
f. Cardiac abnormalities i. Tricuspid insufficiency
ii. Pulmonary vein-to-superior vena cava shunt 10. Diagnostic criteria for incontinentia pigment (Landy and
Donnai, 1993)
a. Negative family history (no evidence of IP in a first- degree female relative): at least one major criterion is necessary to make a firm diagnosis of sporadic incon- tinentia pigmenti. The minor criteria, if present, will support the diagnosis. Because of their high inci- dence, complete absence of minor criteria should induce a degree of uncertainty
i. Major criteria
a) Typical neonatal rash (erythema, vesicles, eosinophilia)
b) Typical hyperpigmentation (mainly trunk, Blaschko’s lines, fading in adolescence) c) Linear, strophic, hairless lesions ii. Minor criteria
a) Dental involvement b) Alopecia
c) Woolly hair/abnormal nails d) Retinal disease
b. Positive family history (evidence of IP in a first- degree female relative of an affected female) plus demonstration of any of the following features, alone or in combination
i. Suggestive history or evidence of typical rash ii. Skin manifestation of IP
a) Hyperpigmentation b) Scarring
c) Hairless streaks d) Alopecia at vertex iii. Anomalous dentition
iv. Woolly hair v. Retinal disease
vi. Multiple male miscarriages
DIAGNOSTIC INVESTIGATIONS
1. Major histopathologic features from skin biopsy samples a. Vesicular, vesiculobullous, or inflammatory stage
i. Spongiotic dermatitis
ii. Dermal and epidermal eosinophilia iii. Eosinophil-filled vesicles
b. Verrucous stage i. Papillomas
ii. Epidermal hyperplasia iii. Hyperkeratosis
iv. Dyskeratotic cells c. Hyperpigmented stage
i. Dermal melanophages
ii. Vascuolar changes in basal layer of epidermis d. Atrophic stage
i. Loss of rete ridges ii. Loss of dermal sweat coils
2. CBC: marked peripheral blood leukocytosis an eosino- philia
3. Abnormal immune system: not a consistent finding 4. CT/MRI imagings of the brain
a. Optic atrophy b. Retinal vasculopathy
c. Hypoplasia of the corpus callosum d. Ventriculomegaly
e. Periventricular white matter lesions f. Ischemic strokes
g. Hemorrhagic necrosis h. Porencephalic cyst
5. Magnetic resonance angiography/spectroscopy for cere- bral ischemia and a vaso-occlusive phenomenon
6. Fluorescein angiography for retinal vascular abnormalities 7. EEG for seizures
8. Chromosome analysis in male patients with IP
9. Molecular genetic testing: mutation detection for the major- ity of families, facilitated by the high frequency of specific deletion, using Southern blotting, PCR amplification, or DNA sequencing
a. X-inactivation assay and Xq28 marker studies:
X-inactivation analysis is indicated wherever a recombination event between Xq28 markers and the disease locus is suspected. Absence of recombination between the disease locus and Xq28 loci suggests that mosaicism is responsible for the discrepancy where Xq28 marker studies are at odds with the clinical assessment
b. Identification of the NEMO gene mutation as a bio- logical marker for a molecular diagnosis of IP
i. Carrier testing for the mother who has an affected daughter with a known mutation
ii. Determine whether the miscarried or stillborn male fetus has IP
iii. Prenatal testing of a fetus at risk
GENETIC COUNSELING
1. Recurrence risk a. Patient’s sib
i. Recurrence risk: <1%, provided the mother is not a carrier of the gene: a small increased risk due to either a new mutation in a second child or germline mosaicism in a parent
ii. Recurrence risk of 50% for sisters to be affected when the mother is a carrier of the gene
iii. Recurrence risk of 50% for brothers to be affected (prenatally aborted fetuses or stillborns) when the mother is a carrier of the gene
b. Offspring of an affected female
i. Daughters: 50% affected; 50% normal
ii. Sons: 50% affected (prenatally aborted fetuses or stillborns); 50% normal (all the live-born sons will be normal)
c. Offspring of an affected male i. All daughters affected ii. All sons normal
2. Prenatal diagnosis possible if the disease-causing muta- tion has been detected in the families at risk
a. Determination of the fetal sex by amniocentesis or CVS
b. An increased risk of miscarriage or stillborn for an affected male fetus
c. Molecular genetic testing of a female fetus 3. Management
a. Reduce the risk of secondary infection of blisters b. Keep lesions dry
c. Avoid trauma to blisters d. Dental care
e. Early photocoagulation or cryotherapy in cases of retinal involvement
f. Intervention programs for learning disabilities and developmental delay
g. Anti-seizure medications for seizures
REFERENCES
Aradhya S, Courtois G, Rajkovic A, et al.: Atypical forms of incontinentia pig- menti in male individuals result from mutations of a cytosine tract in exon 10 of NEMO (IKKgamma). Am J Hum Genet 68:765–767, 2001.
Aradhya S, Woffendin H, Jakins T, et al.: A recurrent deletion in the ubiqui- tously expressed NEMO (IKK-gamma) gene accounts for the vast majority of incontinentia pigmenti mutations. Hum Mol Genet 10:
2171–2179, 2001.
Avrahami E, Harel S, Jurgenson U, et al.: Computed tomographic demonstra- tion of brain changes in incontinentia pigmenti. Am J Dis Child 139:
372–374, 1985.
Adeniran A, Townsend PL, Peachey RD: Incontinentia pigmenti (Bloch- Sulzberger syndrome) manifesting as painful periungual and subungual tumours. J Hand Surg [Br] 18:667–669, 1993.
Berlin AL, Paller AS, Chan LS: Incontinentia pigmenti: a review and update on the molecular basis of pathophysiology. J Am Acad Dermatol 47:169–187;
quiz 188–190, 2002.
Bessems PJ, Jagtman BA, van de Staak WJ, et al.: Progressive, persistent, hyperkeratotic lesions in incontinentia pigmenti. Arch Dermatol 124:29–30, 1988.
Bitoun P, Philippe C, Cherif M, et al.: Incontinentia pigmenti (type 1) and X;5 translocation. Ann Genet 35:51–54, 1992.
Bloch B: Eigentumliche bischer nicht beschriebene pigmentaffektion (inconti- nentia pigmenti). Schweiz Med Wochenschr 7:404–405, 1926.
Cannizzaro LA, Hecht F: Gene for incontinentia pigmenti maps to band Xp11 with an (X;10) (p11;q22) translocation. Clin Genet 32:66–69, 1987.
Chatkupt S, Gozo AO, Wolansky LJ, et al.: Characteristic MR findings in a neonate with incontinentia pigmenti. AJR Am J Roentgenol 160:372–374, 1993.
Cohen PR: Incontinentia pigmenti: clinicopathologic characteristics and differ- ential diagnosis. Cutis 54:161–166, 1994.
Curth HO, Warburton D: The genetics of incontinentia pigmenti. Arch Dermatol 92:229–235, 1965.
de Grouchy J, Turleau C, Doussau de Bazignan M, et al.: Incontinentia pigmenti (IP) and r(X). Tentative mapping of the IP locus to the X juxtacen- tromeric region. Ann Genet 28:86–89, 1985.
Devriendt K, Matthijs G, Fryns JP, et al.: Second trimester miscarriage of a male fetus with incontinentia pigmenti. Am J Med Genet 80:298–299, 1998.
Di Landro A, Marchesi L, Reseghetti A, et al.: Warty linear streaks of the palm and sole: possible late manifestations of incontinentia pigmenti. Br J Dermatol 143:1102–1103, 2000.
Doffinger R, Smahi A, Bessia C, et al.: X-linked anhidrotic ectodermal dyspla- sia with immunodeficiency is caused by impaired NF-kappaB signaling.
Nat Genet 27:277–85, 2001.
Francois J: Incontinentia pigmenti (Bloch-Sulzberger syndrome) and retinal changes. Br J Ophthalmol 68:19–25, 1984.
Francis JS, Sybert VP: Incontinentia pigmenti. Semin Cutan Med Surg 16:54–60, 1997.
Garcia-Dorado J, de Unamuno P, Fernandez-Lopez E, et al.: Incontinentia pig- menti: XXY male with a family history. Clin Genet 38:128–138, 1990.
Gilgenkrantz S, Tridon P, Pinel-Briquel N, et al.: Translocation (X;9)(p11;q34) in a girl with incontinentia pigmenti (IP): implications for the regional assignment of the IP locus to Xp11? Ann Genet 28:90–92, 1985.
Goldberg MF, Custis PH: Retinal and other manifestations of incontinentia pigmenti (Bloch-Sulzberger syndrome). Ophthalmology 100:1645–1654, 1993.
Gordon H, Gordon W: Incontinentia pigmenti: clinical and genetical studies of two familial cases. Dermatologica 140:150–168, 1970.
Gurevitch AW, Farrell W, Horlick S, et al.: Incontinentia pigmenti: a systemic genodermatosis with striking cutaneous findings. Clin Pediatr (Phila) 12:396–401, 1973.
Happle R: Lyonization and the lines of Blaschko. Hum Genet 70:200–206, 1985.
Happle R: Incontinentia pigmenti versus hypomelanosis of Ito: the whys and wherefores of a confusing issue. Am J Med Genet 79:64–65, 1998.
Harre J, Millikan LE: Linear and whorled pigmentation. Int J Dermatol 8:529–537, 1994.
Hodgson SV, Neville B, Jones RW, et al.: Two cases of X/autosome translocation in females with incontinentia pigmenti. Hum Genet 71:231–234, 1985.
Jackson R: The lines of Blaschko: a review and reconsideration. Br J Dermatol 95:349–360, 1976.
Jain A, Ma CA, Liu S, et al.: Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia. Nat Immunol 2:223–228, 2001.
Jessen RT, Van Epps DE, Goodwin JS, et al.: Incontinentia pigmenti. Evidence for both neutrophil and lymphocyte dysfunction. Arch Dermatol 114:1182–1186, 1978.
Kajii T, Tsukahara M, Fukushima Y, et al.: Translocation (X;13)(p11.21;q12.3) in a girl with incontinentia pigmenti and bilateral retinoblastoma. Ann Genet 28:219–223, 1985.
Kasai T, Kato Z, Matsui E, et al.: Cerebral infarction in incontinentia pigmenti:
the first report of a case evaluated by single photon emission computed tomography. Acta Paediatr 86:665–667, 1997.
Kenwrick S, The International IP Consortium: Survival of male patients with incontinentia pigmenti carrying a lethal mutation can be explained by somatic mosaicism or Klinefelter syndrome. Am J Hum Genet 69:
1210–1217, 2001.
Kirchman TT, Levy ML, Lewis RA, et al.: Gonadal mosaicism for incontinen- tia pigmenti in a healthy male. J Med Genet 32:887–890, 1995.
Landy SJ, Donnai D: Incontinentia pigmenti (Bloch-Sulzberger syndrome).
J Med Genet 30:53–59, 1993.
Lee AG, Goldberg MF, Gillard JH, et al.: Intracranial assessment of incontinen- tia pigmenti using magnetic resonance imaging, angiography, and spec- troscopic imaging. Arch Pediatr Adolesc Med 149:573–580, 1995.
Makris C, Godfrey VL, Krahn-Senftleben G, et al.: Female mice heterozygous for IKK gamma/NEMO deficiencies develop a dermatopathy similar to the human X-linked disorder incontinentia pigmenti. Mol Cell 5:969–79, 2000.
Mascaro JM, Palou J, Vives P: Painful subungual keratotic tumors in inconti- nentia pigmenti. J Am Acad Dermatol 13:913–918, 1985.
McCrary JA III, Smith JL: Conjunctival and retinal incontinentia pigmenti.
Arch Ophthalmol 79:417–22, 1968.
Menni S, Piccinno R, Biolchini A, et al.: Immunologic investigations in eight patients with incontinentia pigmenti. Pediatr Dermatol 7:275–277, 1990.
Miteva L, Nikolova A: Incontinentia pigmenti: a case associated with cardio- vascular anomalies. Pediatr Dermatol 18:54–56, 2001.
Moss C, Ince P: Anhidrotic and achromians lesions in incontinentia pigmenti.
Br J Dermatol 116:839–849, 1987.
O’Brien JE, Feingold M: Incontinentia pigmenti. A longitudinal study. Am J Dis Child 139:711–712, 1985.
Ormerod AD, White MI, McKay E, et al.: Incontinentia pigmenti in a boy with Klinefelter’s syndrome. J Med Genet 24:439–441, 1987.
Pascual-Castroviejo I, Roche MC, Martinez Fernandez V, et al.: Incontinentia pigmenti: MR demonstration of brain changes. AJNR Am J Neuroradiol 15:1521–1527, 1994.
Pfau A, Landthaler M: Recurrent inflammation in incontinentia pigmenti of a seven-year-old child. Dermatology 191:161–163, 1995.
Roberts WM, Jenkins JJ, Moorhead EL II, et al.: Incontinentia pigmenti, a chromosomal instability syndrome, is associated with childhood malig- nancy. Cancer 62:2370–2372, 1988.
Rosenfeld SI, Smith ME: Ocular findings in incontinentia pigmenti.
Ophthalmology 92:543–546, 1985.
Russell DL, Finn SB: Incontinentia pigmenti (Bloch-Sulzberger syndrome):
a case report with emphasis on dental manifestations. J Dent Child 34:494–500, 1967.
Scheuerle AE: Male cases of incontinentia pigmenti: case report and review.
Am J Med Genet 77:201–218, 1998.
Schamburg-Lever G, Lever WF: Electron microscopy of incontinentia pigmenti.
J Invest Dermatol 61:151–158, 1973.
Sefiani A, Abel L, Heuertz S, et al.: The gene for incontinentia pigmenti is assigned to Xq28. Genomics 4:427–429, 1989.
Smahi A, Hyden-Granskog C, Peterlin B, et al.: The gene for the familial form of incontinentia pigmenti (IP2) maps to the distal part of Xq28. Hum Mol Genet 3:273–278, 1994.
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 405:466–472, 2000.
Sulzberger MB: Uber eine bischer nicht beschriebene congenitale pigmen- tanomalie (incontinentia pigmenti). Arch Dermatol Syph (Berl) 154:19–32, 1928.
Sybert VP: Incontinentia pigmenti nomenclature. Am J Hum Genet 55:
209–211, 1994.
Sybert VP: A case revisited: recent presentation of incontinentia pigmenti in association with a previously reported X; autosome translocation. Am J Med Genet 75:334, 1998.
Wettke-Schäfer R, Kanter G: X-linked dominant inherited diseases with lethal- ity in hemizygous males. Hum Genet 64:1–23, 1983.
Wiklund DA, Weston WL: Incontinentia pigmenti. A four-generation study.
Arch Dermatol 116:701–703, 1980.
Worret WI, Nordquist RE, Burgdorf WH: Abnormal cutaneous nerves in incon- tinentia pigmenti. Ultrastruct Pathol 12:449–454, 1988.
Zillikens D, Mehringer A, Lechner W, et al.: Hypo- and hyperpigmented areas in incontinentia pigmenti. Light and electron microscopic studies. Am J Dermatopathol 13:57–62, 1991.
Zonana J, Elder ME, Schneider LC, et al.: A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO).
Am J Hum Genet 67:1555–1562, 2000.
Fig. 1. Two girls with incontinentia pigmenti showing classical hyper- pigmentation on the trunk following Blaschko lines.
Fig. 2. A girl with incontinentia pigmenti showing streaks and whorls of brown pigmentation on the leg and trunk.
