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Clinical Utility Gene Card for: incontinentia pigmenti

2012; Springer Nature; Volume: 21; Issue: 7 Linguagem: Inglês

10.1038/ejhg.2012.227

1476-5438

Francesca Fusco, Alessandra Pescatore, Julie Steffann, Ghislaine Royer, Jean‐Paul Bonnefont, Matilde Valeria Ursini,

Dermatological and Skeletal Disorders

CHARACTERISTICS 1.1 Name of the disease (synonyms) Incontinentia pigmenti (IP); familial male-lethal type, Bloch-Sulzberger syndrome; IP TYPE II; IP2.1.2 OMIM# of the disease 308300.1.3 Name of the analysed genes or DNA/chromosome segments NEMO/IKBKG, X Chomosome, Xq28.1.4 OMIM# of the gene(s) 300248. Mutational spectrumIP is a rare X-linked genodermatosis, characterized by typical skin alterations, the hallmarks of the disease, and, in addition, by other neuroectodermal defects affecting the eyes, the nails, the hair, the teeth, and the central nervous system (CNS).The clinical diagnosis of IP is based on the presence of dermatological lesions that develop in four successive, sometimes overlapping, characteristic stages that start shortly after birth with an inflammatory vesicular rash (stage1), followed by verrucous lesions (stage2).The third stage is marked by the appearance of a skin area displaying hyperpigmentation that at the fourth stage becomes patches of atrophic hypopigmented skin.In addition, IP females have heterogeneous and often severe clinical signs including ophthalmological (strabismus, cataracts, optic atrophy, retinal vascular pigmentary abnormalities, microphthalmia), odontological, (partial anodontia, delayed dentition, cone/peg-shaped teeth, impactions) and neurological defects (seizures, spastic paralysis, motor, and mental retardation, microcephaly). 1 IP is a genomic disorder inherited as an X-linked dominant trait.IP is generally lethal in males while heterozygous females survive owing to functional mosaicism. 1All cases of IP are due to mutations in NEMO (nuclear-factor-kappa-B essential modulator)/IKBKG gene located in Xq28 region, and the mutation detection rate in IP is around 80%. IKBKG, encodes the regulatory subunit of the IkB kinase complex required for nuclear factor-kB (NF-kB) activation. 2,3utations in different domains of protein may produce different effects on NF-kB activation by reducing or abolishing the response after stimulations.Noteworthy, some IKBKG hypomorphic mutations, affecting the zinc finger (ZF) domain of the NEMO protein and reducing but do not eliminating NF-kB activation, were found in surviving male patients.These males are affected by a different disease, named hypohidrotic ectodermal dysplasia-associated with severe immunodeficiency (EDA-ID HED-ID OMIM#300291) or occasionally associated with osteopetrosis and lymphoedema (OL-EDA-ID). 4,5he most frequent mutation in IP (70%) is a recurrent exon 4_10 deletion (NEMOexon4_10del) due to non allelic homologous recombination that occurs between two repeats (MER67B) located in intron 3 and downstream exon 10, causing the removal of the entire genomic region from exon4 to 10. 6,7 Missense, nonsense, deletions, and insertions have been reported in addition to gross rearrangements. 8With the exception of a tract of cytosines in exon 10 that appears to be prone to mutations in IP/HED-ID, no mutational hotspots or common point mutations are seen.][8] No evident genotype-phenotype correlation is apparent from comparison of patients with different loss-of-function mutations.The majority of mutations are 'private' to specific families.The rate of de novo mutations is about 65%. Analytical methodsDifferent strategies for IKBKG mutation screening procedures are currently applied on genomic DNA extracted from peripheral blood: