To analyze the distribution of manifestations in a pediatric cohort and define guidelines for follow-up of incontinentia pigmenti (IP).
Retrospective study of 47 children referred to the Department of Pediatric Dermatology with a diagnosis of IP between 1986 and 1999.
The private or institutional practice of participating dermatologists and pediatricians.
Evaluation of IP clinical diagnosis using the Landy and Donnai criteria.
Because hyperpigmentation following the Blaschko lines may be observed in several pigmented disorders, 7 patients were found misdiagnosed. During the neonatal period, erythema, vesicles, and hyperkeratotic le sions were rarely absent in the patients with IP. Ocular and neurological abnormalities were frequent (20% and 30%, respectively) but rarely severe (8% and 7.5%, respectively).
Clinical diagnosis is the first main step for a correct phenotype/genotype correlation, which remains indispensable to better understand the pathological mechanisms of IP and develop new therapies. In doubtful cases, molecular analysis is helpful but characteristic histological features must be added as major criteria for IP diagnosis. Multidisciplinary follow-up is needed, particularly during the first year of life, to detect possible ophthalmologic and neurological complications. Neuroimaging ought to be performed in the case of abnormal neurological examination results or when vascular retinopathy is detected.
"Overall, the prevalence of functional Central Nervous System (CNS) manifestations is approximately 30% [5,6] ranging from a single-seizure episode to severe motor and intellectual disability . Ophthalmologic abnormalities are present in approximately 20%–37% of IP patients [5,6,8]. IP is due to a mutation of the X-linked IKBKG/NEMO gene (Inhibitor of Kappa polypeptide gene enhancer in B-cells, Kinase Gamma/Nuclear Factor κB, Essential Modulator, GenBank NM_003639.3, "
[Show abstract][Hide abstract] ABSTRACT: We report here on the building-up of a database of information related to 386 cases of Incontinentia Pigmenti collected in a thirteen-year activity (2000-2013) at our centre of expertise. The database has been constructed on the basis of a continuous collection of patients (27.6/year), the majority diagnosed as sporadic cases (75.6%). This activity has generated a rich source of information for future research studies by integrating molecular/clinical data with scientific knowledge. We describe the content, architecture and future utility of this collection of data on IP to offer comprehensive anonymous information to the international scientific community.
"Overall, the prevalence of functional CNS manifestations is approximately 30% [Fusco et al., 2004; Meuwissen and Mancini, 2012; Mini´c et al., 2013a] ranging from a single-seizure episode to severe motor and intellectual disability. Ophthalmologic abnormalities comprising strabismus, retinopathy, congenital cataract, and microphthalmia are present in approximately 20%–37% of IP patients [Hadj-Rabia et al., 2003; Fusco et al., 2004; Mini´c et al., 2013a]. "
[Show abstract][Hide abstract] ABSTRACT: Incontinentia pigmenti (IP) is an X-linked-dominant Mendelian disorder caused by mutation in the IKBKG/NEMO gene, encoding for NEMO/IKKgamma, a regulatory protein of nuclear factor kappaB (NF-kB) signaling. In more than 80% of cases, IP is due to recurrent or nonrecurrent deletions causing loss-of-function (LoF) of NEMO/IKKgamma. We review how the local architecture of the IKBKG/NEMO locus with segmental duplication and a high frequency of repetitive elements favor de novo aberrant recombination through different mechanisms producing genomic microdeletion. We report here a new microindel (c.436_471delinsT, p.Val146X) arising through a DNA-replication-repair fork-stalling-and-template-switching and microhomology-mediated-end-joining mechanism in a sporadic IP case. The LoF mutations of IKBKG/NEMO leading to IP include small insertions/deletions (indel) causing frameshift and premature stop codons, which account for 10% of cases. We here present 21 point mutations previously unreported, which further extend the spectrum of pathologic variants: 14/21 predict LoF because of premature stop codon (6/14) or frameshift (8/14), whereas 7/21 predict a partial loss of NEMO/IKKgamma activity (two splicing and five missense). We review how the analysis of IP-associated IKBKG/NEMO hypomorphic mutants has contributed to the understanding of the pathophysiological mechanism of IP disease and has provided important information on affected NF-kB signaling. We built a locus-specific database listing all IKBKG/NEMO variants, accessible at http://IKBKG.lovd.nl.
Human Mutation 02/2014; 35(2). DOI:10.1002/humu.22483 · 5.14 Impact Factor
"However, Fusco et al.
 in a series of 59 genetically confirmed IP females found eight patients with CNS anomalies, only four of whom had associated ocular anomalies. In the Hadj-Rabia et al.
 study only three of 13 IP patients with CNS anomalies had associated ocular anomalies. In the present analyses of literature data 101 (54.30%) of the IP patients had associated ocular anomalies. "
[Show abstract][Hide abstract] ABSTRACT: The objective of this study was to present a systematic review of the central nervous system (CNS) types of anomalies and to consider the possibility to include CNS anomalies in Incontinentia pigmenti (IP) criteria. The analyzed literature data from 1,393 IP cases were from the period 1993-2012. CNS anomalies were diagnosed for 30.44% of the investigated IP patients. The total number of CNS types of anomalies per patient was 1.62. In the present study there was no significantly higher number of anomalies per patient in females than males. The most frequent CNS types of anomalies were seizures, motor impairment, mental retardation, and microcephaly. The most frequently registered CNS lesions found using brain imaging methods were brain infarcts or necrosis, brain atrophies, and corpus callosum lesions. IKBKG exon 4-10 deletion was present in 86.00% of genetically confirmed IP patients. The frequency of CNS anomalies, similar to the frequency of retinal anomalies in IP patients, concurrent with their severity, supports their recognition in the list of IP minor criteria.
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