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

Abstract

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-kappaB 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.

What’s Sex Got to Do With COVID-19? Gender-Based Differences in the Host Immune Response to Coronaviruses

“…Skewed X-inactivation favoring the wildtype allele has been observed in heterozygous women, which supports the notion that X inactivation may confer a protective advantage against immunodeficiency disorders ( 77 ). Moreover, men with KS have been observed to escape lethality from incontinentia pigmenti ( 78 ). As a result, the presence of an additional X chromosome in women and KS men may decrease the likelihood of NEMO dysfunction and serve as an advantage in the SARS-CoV-2 response.…”

Incontinentia pigmenti diagnostic criteria update

“…Although IP has been identified as a disease lethal for males, approximately 120 males who meet the diagnostic criteria for IP have been reported (7). Survival in a male is most often mediated through somatic mosaicism (41,42). In some cases it is mediated through the 47,XXY karyotype (Klinefelter syndrome) (41,42).…”

“…Survival in a male is most often mediated through somatic mosaicism (41,42). In some cases it is mediated through the 47,XXY karyotype (Klinefelter syndrome) (41,42).…”

A healthy delivery of twins by assisted reproduction followed by preimplantation genetic screening in a woman with X-linked dominant incontinentia pigmenti

“…IP is a rare X-linked dominant genodermatosis with its incidence of 0.7-2/100,000 newborns [ 12 , 13 , 14 ], which is lethal in males in utero in 97% of cases [ 15 ]. As a result, many women with IP have recurrent early miscarriages [ 16 ]. Although IP is usually lethal in males, approximately 72 cases of surviving male fetuses with IP have so far been reported [ 17 ].…”

“…Although IP is usually lethal in males, approximately 72 cases of surviving male fetuses with IP have so far been reported [ 17 ]. The IP Consortium has proposed three mechanisms resulting in the survival of males carrying a mutation in the IKBKG gene: hypomorphic alleles, the 47,XXY karyotype (Klinefelter syndrome), and somatic mosaicism [ 16 ]. IP presents multisystemically but especially dermatologically, involving four typical stages of vesiculo-bullous, verrucous, hyperpigmented, and hypopigmented skin.…”