Survival of Male Patients with Incontinentia Pigmenti Carrying a Lethal Mutation Can Be Explained by Somatic Mosaicism or Klinefelter Syndrome

• Published in: American journal of human genetics Vol. 69; no. 6; pp. 1210 - 1217
• Main Authors: Kenwrick, S, Woffendin, H, Jakins, T, Shuttleworth, S G, Mayer, E, Greenhalgh, L, Whittaker, J, Rugolotto, S, Bardaro, T, Esposito, T, D'Urso, M, Soli, F, Turco, A, Smahi, A, Hamel-Teillac, D, Lyonnet, S, Bonnefont, J P, Munnich, A, Aradhya, S, Kashork, C D, Shaffer, L G, Nelson, D L, Levy, M, Lewis, R A
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.12.2001; University of Chicago Press; The American Society of Human Genetics
• Subjects: Alleles; Biological and medical sciences; Child; Child, Preschool; Dermatology; Dosage Compensation, Genetic; Female; Genes, Lethal - genetics; Humans; I-kappa B Kinase; Incontinentia Pigmenti - genetics; Incontinentia Pigmenti - pathology; Infant; Infant, Newborn; Karyotyping; Klinefelter Syndrome - genetics; Male; Medical sciences; Meiosis - genetics; Mosaicism - genetics; Pedigree; Pigmentary diseases of the skin; Polymerase Chain Reaction; Protein Serine-Threonine Kinases - genetics; Sequence Deletion - genetics; Survival Rate; Chromosomal aberration; Endocrinopathy; Klinefelter syndrome; Sex linked character; Skin disease; Relapse; Prognosis; Aneuploidy; Male; Supernumerary X chromosome; Inactivation; Essential; Characterization; Hair (head); Exon; Gene; Deletion; Dominant character; X-Chromosome; Male genital diseases; Human; Hair; Immunopathology; Nervous system diseases; Pigmentation disorder; Incontinentia pigmenti; Stomatology; Dental disease; Teeth; Sexual differentiation disorder; Recurrent; Congenital disease; In utero; Survival; Genetic disease; Ectodermal dysplasia; Eye disease; Malformation; Cytogenetics; Abnormal chromosome; Mosaicism; Mutation; Sweat gland disease
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/324591

Incontinentia pigmenti (IP), or “Bloch-Sulzberger syndrome,” is an X-linked dominant disorder characterized by abnormalities of skin, teeth, hair, and eyes; skewed X-inactivation; and recurrent miscarriages of male fetuses. IP results from mutations in the gene for NF-κB essential modulator ( NEMO), with deletion of exons 4–10 of NEMO accounting for >80% of new mutations. Male fetuses inheriting this mutation and other “null” mutations of NEMO usually die in utero. Less deleterious mutations can result in survival of males subjects, but with ectodermal dysplasia and immunodeficiency. Male patients with skin, dental, and ocular abnormalities typical of those seen in female patients with IP (without immunodeficiency) are rare. We investigated four male patients with clinical hallmarks of IP. All four were found to carry the deletion normally associated with male lethality in utero. Survival in one patient is explained by a 47,XXY karyotype and skewed X inactivation. Three other patients possess a normal 46,XY karyotype. We demonstrate that these patients have both wild-type and deleted copies of the NEMO gene and are therefore mosaic for the common mutation. Therefore, the repeat-mediated rearrangement leading to the common deletion does not require meiotic division. Hypomorphic alleles, a 47,XXY karyotype, and somatic mosaicism therefore represent three mechanisms for survival of males carrying a NEMO mutation.