Incontinentia pigmenti in male patients

doi:10.1016/j.jaad.2005.12.015

Journal of the American Academy of Dermatology

Volume 55, Issue 2, August 2006, Pages 251-255

https://doi.org/10.1016/j.jaad.2005.12.015 Get rights and content

Background

Incontinentia pigmenti (IP) is a rare X-linked dominant genodermatosis that is typified by distinctive cutaneous findings and often by abnormalities of teeth, hair, nails, eyes, musculoskeletal system, and central nervous system. The gene that is mutated in patients with IP has been mapped to Xq28 and encodes the NF-κB essential modulator, NEMO. Female patients with IP show functional mosaicism and cutaneous manifestations follow Blaschko's lines of ectodermal embryologic development. The condition is generally considered to be lethal in utero in male fetuses, suggesting that having some normal gene expression is critical for survival.

Observations

We observed 9 boys with IP. All had normal karotypes and no apparent family history of IP. In 8 of these 9 patients, lesions were localized to one extremity at presentation. The diagnosis was confirmed by histopathologic examination that showed eosinophils within intraepidermal, multiloculated vesicles. One of the boys later developed dental and neurologic abnormalities.

Limitations

The case series was small and the workup for these patients from different sites was not uniform.

Conclusions

Male individuals may show cutaneous and noncutaneous features of IP in a limited distribution that allows survival. Postzygotic mutation/somatic mosaicism is the likely mechanism. Given the potential sequelae associated with this condition, continuing follow-up of these patients is recommended.

Section snippets

Patient 1

A 2-week-old boy developed an eruption at 3 days of age that initially appeared on the left ankle and extended to the back aspect of the left leg in a linear pattern. The patient was adopted, with no known family history of IP.

Pustules, vesicles, and crusts extended in a linear pattern from the left lateral malleolus to the left popliteal fossa (Fig 1). No other cutaneous lesions were noted, including lack of nail dystrophy or scalp lesions. Complete neurologic, ophthalmologic, and

Discussion

IP is considered an X-linked dominant disorder, which is usually lethal in males. We describe 9 male patients with IP. In 8 of these 9 patients, lesions were localized to one extremity at presentation; in the ninth (patient 6), lesions involved more than one extremity, but were localized to one side of the body.

The diagnosis in each patient was confirmed histologically. In 8 of the 9 patients, the histologic examination of a vesicle revealed eosinophils within intraepidermal, multiloculated

References (24)

C. Makris et al.
Female mice heterozygous for IKK gamma/NEMO deficiencies develop a dermatopathy similar to the human X-linked disorder incontinentia pigmenti
Mol Cell
(2000)
M. Schmidt-Supprian et al.
NEMO/IKK gamma-deficient mice model incontinentia pigmenti
Mol Cell
(2000)
J.S. Prendiville et al.
Incontinentia pigmenti in a male infant with Klinefelter syndrome
J Am Acad Dermatol
(1989)
S. Aradhya et al.
Atypical forms of incontinentia pigmenti in male individuals result from mutations of a cytosine tract in exon 10 of NEMO (IKK-gamma)
Am J Hum Genet
(2001)
J. Zonana 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
(2000)
R.P. Erickson
Somatic gene mutation and human disease other than cancer
Mutat Res
(2003)
E.J. Mayer et al.
Novel corneal features in two males with incontinentia pigmenti
Br J Ophthalmol
(2003)
A.L. Berlin et al.
Incontinentia pigmenti: a review and update on the molecular basis of pathophysiology
J Am Acad Dermatol
(2002)
A. Smahi et al.
Genomic rearrangement in NEMO impairs NF-kappa B activation and is a cause of incontinentia pigmenti: the international incontinentia pigmenti (IP) consortium
Nature
(2000)
S. Greaves
The consequences of incontinentia pigmenti
Nat Cell Biol
(2000)

S. Aradhya 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)

A.E. Scheuerle

Male cases of incontinentia pigmenti: case report and review

Am J Med Genet

(1998)

Cited by (60)

Incontinentia pigmenti in boys: Causes and consequences
2020, Annales de Dermatologie et de Venereologie
Incontinentia pigmenti (IP) is an X-linked genodermatosis caused by mutation of the NEMO/IKBKG gene. While lethal in male foetuses, heterozygous females survive because of X-inactivation mosaicism. Herein we discuss 9 male patients with IP.
This is an observational, descriptive, retrospective, multicentre, French study carried out with the help of the SFDP research group. Statistical analysis was performed both on our own patients and on those reported in the literature.
Nine boys with no family history of IP but with typical neonatal skin reactions were included. Genetic analysis of blood (n = 8) and skin biopsy (n = 3) confirmed the diagnosis of IP by identification of common deletion of the IKBKG/NEMO gene (exons 4 to 10) in the state of somatic mosaic in 6 and 2 cases respectively. Where analysed, the karyotype was normal (n = 6). Over a median follow-up period of 48 months (3 months to 10 years), 3 patients had neurological abnormalities, 2 had severe ophthalmologic abnormalities, and 1 had dental abnormalities. Extensive skin involvement is a systemic risk factor, unlike cutaneous scarring.
IP in boys is often due to a mosaic mutation that should be sought in blood and skin. Long-term neurological and ophthalmological monitoring is essential, especially in cases of extensive skin involvement.
L’incontinentia pigmenti (IP) est une génodermatose de transmission dominante liée à l’X, due à une mutation du gène NEMO/IKBKG. Létale chez le fœtus masculin, les filles hétérozygotes pour la mutation survivent grâce à un mosaïcisme fonctionnel. Nous rapportons neuf cas d’IP chez des enfants de sexe masculin.
Il s’agit d’une étude observationnelle descriptive, rétrospective, multicentrique française, menée avec l’aide du groupe de recherche de la société française de dermatologie pédiatrique (SFDP). Une analyse statistique a ensuite été réalisée sur nos cas et ceux rapportés dans la littérature.
Neuf garçons, sans antécédents familiaux d’IP, ont été inclus. Tous avaient une éruption cutanée néonatale typique. Les analyses génétiques sur le sang (n = 8) et sur biopsie cutanée (n = 3) confirmaient le diagnostic d’IP en trouvant le réarrangement prévalent du gène IKBKG/NEMO (délétion des exons 4 à 10) à l’état de mosaïque somatique dans six et deux cas respectivement. Le caryotype, réalisé dans six cas, était normal. Avec une médiane de suivi de 48 mois (3 mois – 10 ans), trois patients présentaient des anomalies neurologiques, deux des anomalies ophtalmiques sévères et un des anomalies dentaires. La présence d’une atteinte cutanée étendue est un facteur de risque d’atteinte systémique, à la différence de la présence de lésions cicatricielles.
L’IP chez le garçon est souvent due à une mutation en mosaïque qu’il convient de chercher dans le sang et la peau. Une surveillance neurologique et ophtalmologique à long terme est essentielle, surtout en cas d’atteinte cutanée étendue.
Incontinentia pigmenti
2020, Rosenberg’s Molecular and Genetic Basis of Neurological and Psychiatric Disease: Volume 2
Incontinentia pigmenti (IP; Bloch–Sulzberger syndrome) is an X-linked dominantly inherited genodermatosis that affects the skin in combination with anomalies of other organs, including the central nervous system. IP results from mutations in the inhibitor of kappa beta kinase gamma (IKBKG), formerly known as NEMO, located on locus Xq28. Absence of IKBKG results in complete inhibition of nuclear factor kappa beta signaling leading to the varied manifestations seen in IP. The wide spectrum of clinical manifestations in IP results from lyonization of the X chromosome with skewed X inactivation. Therefore IP, although rare, may serve as a prototypical example of the clinical presentation of X-linked dominant disorders.
Nature's Canvas: An Infant With Stripes and Whorls
2019, Pediatric Neurology
Common spongiotic dermatoses
2017, Seminars in Diagnostic Pathology
Citation Excerpt :
Incontinentia pigmenti (IP) is an X-linked dominant genodermatoses. A mutation of the NEMO gene is noted, which encodes inhibitors of the transcription factor NFkB, causing a transactivation of the pathway.15–17 Clinically the disease follows a rash that changes according to the age of the kid.
This review article focuses on the spongiotic tissue reaction pattern and some of the common entities that practicing pathologists can frequently encounter in their practice. The spongiotic tissue reaction pattern is the single most common one encountered in the routine analysis of inflammatory dermatoses, and the most non-specific one as well. Spongiotic dermatoses include a very large list of disorders which are best grouped under neutrophilic, eosinophilic, miliarial, follicular and pityriasiform forms of spogiosis. The dermatoses that will be discussed under this category include contact dermatitis, eczema, pityriasis rosea, stasis dermatitis, seborrheic dermatitis and others.
Pigmentary disorders of the eyes and skin
2015, Clinics in Dermatology
Citation Excerpt :
Early, frequent ophthalmologic screenings of infants with IP are recommend to maximize chances of preserving vision.88,89 Several recent studies show the considerable variation of ocular findings (Table 2).82,84,85,90–95 In oculodermal melanocytosis, or nevus of Ota, a hamartoma of spindle-shaped melanocytes can be found in the skin, eyes, and central nervous system.
Oculocutaneous albinism, Menkes syndrome, tuberous sclerosis, neurofibromatosis type 1, dyskeratosis congenita, lentiginosis profusa syndrome, incontinentia pigmenti, and Waardenburg syndrome all are genodermatoses that have well established gene mutations affecting multiple biological pathways, including melanin synthesis, copper transport, cellular proliferation, telomerase function, apoptosis, and melanocyte biology. Onchocerciasis results from a systemic inflammatory response to a nematode infection. Hypomelanosis of Ito is caused by chromosomal mosaicism, which underlies its phenotypic heterogeneity. Incomplete migration of melanocytes to the epidermis and other organs is the underlying feature of nevus of Ota. Vogt-Koyangi-Harada and vitiligo have an autoimmune etiology; the former is associated with considerable multiorgan involvement, while the latter is predominantly skin-limited.
Incontinentia pigmenti (Bloch-Sulzberger syndrome)
2015, Handbook of Clinical Neurology
Citation Excerpt :
Rare examples of mother-to-son transmission escaping male lethality and two instances of father-to-daughter transmission have been reported (Hecht et al., 1982; Emery et al., 1993). Various mechanisms have been proposed to account for males with IP and a normal karyotype, including postzygotic somatic mutation and mosaicism (Pacheco et al., 2006; Fusco et al., 2007). Based on a series of reports of females with IP with X-autosome translocation, it was proposed that the IP gene was located at Chr Xp11.
Incontinentia pigmenti (IP; Bloch–Sulzberger syndrome; OMIM #308300) is an X-linked dominant neurocutaneous disorder with presumed male lethality. It is usually diagnosed in female newborns based on skin features (erythematous, vesicular, or bullous eruption in linear streaks). The skin lesions evolve into a verrucous stage, followed by atrophy and scarring, leaving linear areas of hypopigmentation and hyperpigmented macules in bizarre patterns following Blaschko's lines. Systemic and neurologic complications include focal seizures and hemorrhagic cerebral infarction in infants, and retinal vasculopathy leading to blindness. Hypodontia, conical or pegged teeth, and linear areas of alopecia persist into adulthood.
IP is caused by mutation of the IKBKG/NEMO gene on Xq28. Deletion of exons 4 to 10 (NEMOΔ4-10) accounts for about 80% of cases (familial and sporadic). NEMO mutation leads to loss of function of NF-κB, a critical protein that modulates cellular proliferation, apoptosis, and response to proinflammatory factors, leading to the characteristic features of IP. In female carriers, selective loss of cells expressing the mutant X-chromosome results in completely skewed X-inactivation in the majority of cases. Study of mouse models in which various components of the NF-κB pathway (including NEMO) have been knocked out has contributed significantly to our understanding of disease pathogenesis.

View all citing articles on Scopus

Funding sources: None.

Conflicts of interest: None identified.

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ReportIncontinentia pigmenti in male patients

Background

Observations

Limitations

Conclusions

Section snippets

Patient 1

Discussion

Mol Cell

Mol Cell

J Am Acad Dermatol

Am J Hum Genet

Am J Hum Genet

Mutat Res

Novel corneal features in two males with incontinentia pigmenti

Br J Ophthalmol

Incontinentia pigmenti: a review and update on the molecular basis of pathophysiology

J Am Acad Dermatol

Genomic rearrangement in NEMO impairs NF-kappa B activation and is a cause of incontinentia pigmenti: the international incontinentia pigmenti (IP) consortium

Nature

The consequences of incontinentia pigmenti

Nat Cell Biol

A recurrent deletion in the ubiquitously expressed NEMO (IKK-gamma) gene accounts for the vast majority of incontinentia pigmenti mutations

Hum Mol Genet

Male cases of incontinentia pigmenti: case report and review

Am J Med Genet

Report
Incontinentia pigmenti in male patients