Clinical diagnosis of incontinentia pigmenti in a cohort of male patients

Fusco, Francesca; Fimiani, Giorgia; Tadini, Gianluca; Michele, D. De; Ursini, Matilde Valeria

doi:10.1016/j.jaad.2006.09.019

Cited by 69 publications

(43 citation statements)

References 8 publications

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“…Exclusion of EDA-ID diagnosis was based on the absence of immunodeficiency, while 6 out of 22 IP males showed a somatic mosaicism for the common IKBKG exon 4_10 deletion and one showed a 47,XXY karyotype that is compatible with male survival [Kenwrick et al, 2001;Fusco et al, 2007]. Postzygotic mosaicism with the concurrent presence of both WT or deleted alleles of IKBKG is the only possibility to explain the survival of male subjects with the loss of function mutation of IKBKG.…”

Section: Ip Males Are Mosaics For Ikbkg Mutationmentioning

confidence: 99%

“…Incontinentia pigmenti (IP; MIM] 308300) is a severe X-linked dominant genodermatosis that is lethal in males [Landy and Donnai, 1993;Fusco et al, 2007]; in females, it has a highly variable and often severe clinical presentation always associated with skin defects characterized by four distinct dermatological stages. In addition, IP female patients can also suffer from severe ophthalmological, odontological or neurological defects [HadjRabia et al, 2003].…”

Section: Introductionmentioning

confidence: 99%

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Alterations of the IKBKG locus and diseases: an update and a report of 13 novel mutations

et al. 2008

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Communicated by Andrew O.M. WilkieMutations in the inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma (IKBKG), also called nuclear factor-kappaB (NF-kB) essential modulator (NEMO), gene are the most common single cause of incontinentia pigmenti (IP) in females and anhydrotic ectodermal dysplasia with immunodeficiency (EDA-ID) in males. The IKBKG gene, located in the Xq28 chromosomal region, encodes for the regulatory subunit of the inhibitor of kappaB (IkB) kinase (IKK) complex required for the activation of the NF-kB pathway. Therefore, the remarkably heterogeneous and often severe clinical presentation reported in IP is due to the pleiotropic role of this signaling transcription pathway. A recurrent exon 4_10 genomic rearrangement in the IKBKG gene accounts for 60 to 80% of IP-causing mutations. Besides the IKBKG rearrangement found in IP females (which is lethal in males), a total of 69 different small mutations (missense, frameshift, nonsense, and splice-site mutations) have been reported, including 13 novel ones in this work. The updated distribution of all the IP-and EDA-ID-causing mutations along the IKBKG gene highlights a secondary hotspot mutation in exon 10, which contains only 11% of the protein. Furthermore, familial inheritance analysis revealed an unexpectedly high incidence of sporadic cases (465%). The sum of the observations can aid both in determining the molecular basis of IP and EDA-ID allelic diseases, and in genetic counseling in affected families. Hum Mutat 29(5), [595][596][597][598][599][600][601][602][603][604] 2008.

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Section: Ip Males Are Mosaics For Ikbkg Mutationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Alterations of the IKBKG locus and diseases: an update and a report of 13 novel mutations

et al. 2008

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“…IP is generally lethal in males, although we reported on IP male patients presenting the characteristic clinical defects observed in IP females [Fusco et al, 2007;Kenwrick et al, 2001]. DNA analysis performed on those male patients showed the concomitant presence of the wild-type IKBKG allele and exon4_10 deletion of IKBKG allele, clearly suggesting that the IP males are mitotic mosaics for the IP mutation with a rate of about 80% IKBKG versus 20% IKBKGdel [Fusco et al, 2007].…”

Section: Identification Of the Mer67bdup In An Ip Malementioning

confidence: 68%

“…DNA analysis performed on those male patients showed the concomitant presence of the wild-type IKBKG allele and exon4_10 deletion of IKBKG allele, clearly suggesting that the IP males are mitotic mosaics for the IP mutation with a rate of about 80% IKBKG versus 20% IKBKGdel [Fusco et al, 2007].…”

Section: Identification Of the Mer67bdup In An Ip Malementioning

confidence: 97%

“…Indeed, a significant number of de novo genomic recombination, which account for the high incidence of sporadic cases (65%), occur in the IKBKG locus [Fusco et al, 2008]. In addition, somatic IKBKGdel mosaicisms have been discovered, masking the expression of the mutation that would otherwise be lethal, in surviving IP males [Fusco et al, 2007;Kenwrick et al, 2001]. …”

Section: Introductionmentioning

confidence: 99%

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Microdeletion/duplication at the Xq28 IPlocuscauses a de novoIKBKG/NEMO/IKKgammaexon4_10 deletion in families with incontinentia pigmenti

et al. 2009

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The Incontinentia Pigmenti (IP) locus contains the IKBKG/NEMO/IKKgamma gene and its truncated pseudogene copy, IKBKGP/deltaNEMO. The major genetic defect in IP is a heterozygous exon4_10 IKBKG deletion (IKBKGdel) caused by a recombination between two consecutive MER67B repeats. We analyzed 91 IP females carrying the IKBKGdel, 59 of whom carrying de novo mutations (65%). In eight parents, we found two recurrent nonpathological variants of IP locus, which were also present as rare polymorphism in control population: the IKBKGPdel, corresponding to the exon4_10 deletion in the pseudogene, and the MER67Bdup, that replicates the exon4_10 region downstream of the normal IKBKG gene. Using quantitative DNA analysis and microsatellite mapping, we established that both variants might promote the generation of the pathological IKBKGdel. Indeed, in family IP-516, the exon4_10 deletion was repositioned in the same allele from the pseudogene to the gene, whereas in family IP-688, the MER67Bdup generated the pathological IKBKGdel by recombination between two direct nonadjacent MER67Bs. Moreover, we found an instance of somatic recombination in a MER67Bdup variant, creating the IKBKGdel in an IP male. Our data suggest that the IP locus undergoes recombination producing recurrent variants that might be "at risk" of generating de novo IKBKGdel by NAHR during either meiotic or mitotic division.

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Arch Pediatr Adolesc Med

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Clinical diagnosis of incontinentia pigmenti in a cohort of male patients

Cited by 69 publications

References 8 publications

Alterations of the IKBKG locus and diseases: an update and a report of 13 novel mutations

Alterations of the IKBKG locus and diseases: an update and a report of 13 novel mutations

Microdeletion/duplication at the Xq28 IPlocuscauses a de novoIKBKG/NEMO/IKKgammaexon4_10 deletion in families with incontinentia pigmenti

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