Incontinentia pigmenti (IP; Online Mendelian Inheritance in Man catalog #308300) is an X-linked dominant ectodermal disorder caused by mutations of the inhibitor of κ polypeptide gene enchancer in B cells, kinase γ (IKBKG)/ nuclear factor κB, essential modulator (NEMO) gene. Hemizygous IKBKG/NEMO loss-of-function (LoF) mutations are lethal in males, thus patients are female, and the disease is always transmitted from an IP-affected mother to her daughter. We present 2 families with father-to-daughter transmission of IP and provide for the first time molecular evidence that the combination of somatic and germ-line mosaicism for IKBKG/NEMO loss of function mutations in IP males resulted in the transmission of the disease to a female child. We searched for the IKBKG/NEMO mutant allele in blood, urine, skin, and sperm DNA and found that the 2 fathers were somatic and germ-line mosaics for the p.Gln132×mutation or the exon 4–10 deletion of IKBKG/NEMO, respectively. The highest level of IKBKG/NEMO mutant cells was detected in the sperm, which might explain the recurrence of the disease. We therefore recommend careful clinical evaluation in IP male cases and the genetic investigation in sperm DNA to ensure correct genetic counseling and prevent the risk of paternal transmission of IP.

Incontinentia pigmenti (IP; Online Mendelian Inheritance in Man [OMIM] catalog #308300) is a rare, multisystemic genomic disorder. It is primarily a sporadic condition for which >2000 cases have been documented worldwide.1,2 The disease has an X-linked dominant inheritance and affects the skin and other tissues of ectodermal origin. Skin lesions are the first clinical manifestation and appear in the neonatal period with a vesiculobullous eruption (stage I); they proceed in a 3-stage evolution varying in duration from months to years: the verrucous and hyperkeratotic stage (stage II), the hyperpigmented stage (stage III), and the hypopigmented stage (stage IV), usually continuing throughout life.3 These skin defects, following Blaschko lines, are considered the major criteria for an IP clinical diagnosis.4,6 Systemic involvement include ocular (mainly a retinal vascular involvement), neurologic (seizures, spastic paralysis, mental retardation), and dental (dental shape anomalies, hypodontia, and delayed eruption) abnormalities.6 

IP is caused by inhibitor of κ polypeptide gene enchancer in B cells, kinase γ (IKBKG)/ nuclear factor κB, essential modulator (NEMO) gene mutations (GenBankNM_003639.3, OMIM #300248).7IKBKG/NEMO encodes for NEMO/ inhibitor of the κB kinase γ (IKKγ), the regulatory subunit of the inhibitor of the κB kinase (IKK)-complex required for the canonical activation of nuclear factor κB (NF-κB) pathway involved in fundamental physiologic and pathologic functions.8,9 The majority of IP cases (80%) show a genomic deletion (NEMO deletion exon 4-10 [del4-10]), removing IKBKG/NEMO exons 4–10 and abolishing the protein function.2 However, large genomic rearrangements and point mutations in the coding were reported (20% of cases).10,11 The architecture of the IKBKG/NEMO locus favors aberrant recombination during either meiotic or mitotic divisions, causing de novo mutations and the high frequency of sporadic cases.10,12 

The IP pathogenesis is due to a “functional mosaicism” created by an X inactivation that in females represents an advantage, protecting carriers of heterozygous IKBKG/NEMO mutations from the severe consequences seen in males. Cells expressing the mutated X chromosome are selectively eliminated, so IP females exhibit extremely skewed X inactivation. In contrast, males hemizygous for the IKBKG/NEMO loss of function (LoF) mutation show an extensive apoptosis responsible for the early fetal lethality.13 Although the classic IP phenotype is almost entirely restricted to females, occasionally 46,XY males present an IP phenotype.14 These rare cases show the characteristic skin lesions and, in accordance with the pathogenic mosaic model of the disease, they are postzygotic genetic mosaics for the IKBKG/NEMO mutation.15,16 IP has also been diagnosed in males with a 47,XXY karyotype (Klinefelter syndrome).17 Generally IP males are isolated cases without evidence of transmission of IKBKG/NEMO mutation to the offspring, although unexpected types of inheritance, such as father-to-daughter transmission18,20 or multiple IP offspring from unaffected parents,21 have been reported. An unequivocal demonstration of gonadal mosaicism in the affected father as the cause of IP recurrence has not been reported.

We report an exceptional type of father-to-daughter transmission for an X-linked dominant disease in 2 families with IP-affected fathers.

The IP patient (Fig 1A; IP-II:1) in Family 1 is a 2-year-old girl presenting with retinopathy and periventricular leukomalacia due to premature birth (27 weeks’ gestation). In her first few months of life, she showed typical IP skin with vesicles on the trunk and limbs (stage I) that progressed to hyperkeratotic warty lesions (stage II) and pigmented spots in a linear and whorled pattern on the trunk and limbs (20 months, stage III). She had woolly hair on the vertex and an incomplete deciduous dentition; there were no alterations in her fingernails. A skin biopsy performed at during stage I confirmed a marked dyskeratosis and eosinophilic infiltration consistent with IP (Table 1). Her father was diagnosed with IP (Fig 1A; IP-I:1). He is a 40-year-old man, born from unrelated parents. He presented with seizures at day 6, a rash at day 7, and the typical alterations, including linear streaks of vesicles following Blaschko lines on the trunk, back, and extremities. The IP clinical diagnosis was confirmed by skin biopsy. In addition, he had a delayed eruption of the teeth, with only 1 incisor evident at age 1 year, at which time he also had retinal detachment in the left eye and glaucoma in the right eye. He had a normal 46,XY karyotype (Table 1).

FIGURE 1

DNA sequencing and analysis of the mosaicism in Family 1. (A) The sequence analysis of the c.394C>T in exon 3 of the IKBKG/NEMO gene on DNA from peripheral blood of each member of IP trios and (B) from different tissues of the IP-male father (I:1) is shown. The new heterozygous mutation NEMOc.394C>T is present in the IP proband (II:1) (A) and in affected skin, urine, and sperm DNA samples from the IP father (I:1) (B), whereas only the normal wild-type sequence is present in the peripheral blood of the mother (I:2) and father (I:1) (A) and in fibroblast cell lines derived from affected skin biopsy of the father (I:1) (B). The percentage of cellular mosaicism for the NEMOc.394T allele (C) in DNA from peripheral blood, fibroblast cell lines, affected skin biopsy, urine, and sperm samples of the IP-male father (I:1) is expressed as the mean of at least 3 experiments performed in triplicate (see Supplemental Tables 2 and 3).

FIGURE 1

DNA sequencing and analysis of the mosaicism in Family 1. (A) The sequence analysis of the c.394C>T in exon 3 of the IKBKG/NEMO gene on DNA from peripheral blood of each member of IP trios and (B) from different tissues of the IP-male father (I:1) is shown. The new heterozygous mutation NEMOc.394C>T is present in the IP proband (II:1) (A) and in affected skin, urine, and sperm DNA samples from the IP father (I:1) (B), whereas only the normal wild-type sequence is present in the peripheral blood of the mother (I:2) and father (I:1) (A) and in fibroblast cell lines derived from affected skin biopsy of the father (I:1) (B). The percentage of cellular mosaicism for the NEMOc.394T allele (C) in DNA from peripheral blood, fibroblast cell lines, affected skin biopsy, urine, and sperm samples of the IP-male father (I:1) is expressed as the mean of at least 3 experiments performed in triplicate (see Supplemental Tables 2 and 3).

Close modal
TABLE 1

Clinical Characteristics and Age of Presentation in IP patients

Family 1Family 2
IP Male, I:1IP Child, II:1IP Male, I:1IP-Child, II:1IP-Child, II:2
Age, y 40 34 
Skin defects      
Stage I Day 7; trunk, back, limbs First months; trunk, limbs Infantile age; trunk, limbs, back At birth; trunk, limbs, scalp At birth; limbs, trunk, scalp 
Stage II First months Yes Unknown Limbs Limbs 
Stage III Yes 20 mo; trunk, limbs Unknown 7 mo; trunk, limbs 4 mo; trunk, limbs 
Stage IV From 12 y; limbs Unknown From 12 y limbs Unknown Yes 
Ocular defects Retinal detachment (left eye), glaucoma (right eye) Retinopathy Myopia Diffuse fundus hypopigmentation Diffuse fundus hypopigmentation 
Neurologic defects Seizure at day 6 Periventricular leukomalacia Normal Normal Normal 
Orodental defects Delayed eruption of the teeth Incomplete deciduous dentition One cone-shaped tooth Accessory cusp in molars Absence of a permanent lateral incisor and accessory cusp in primary molars 
Hair defects Hypotrichotic scarring patch on the vertex Woolly hair on vertex Unknown Atrophic, scarring baldness Atrophic, scarring baldness 
Fingernail defects Normal Normal Unknown Ridged toe Normal 
Sweat pores Normal Normal Normal Normal Normal 
Histologic results IP compatible IP compatible Not performed Not performed Not performed 
Developmental evolution Normal Deficient Normal Normal Normal 
Karyotyping 46, XY Not performed 46, XY Not performed Not performed 
Family 1Family 2
IP Male, I:1IP Child, II:1IP Male, I:1IP-Child, II:1IP-Child, II:2
Age, y 40 34 
Skin defects      
Stage I Day 7; trunk, back, limbs First months; trunk, limbs Infantile age; trunk, limbs, back At birth; trunk, limbs, scalp At birth; limbs, trunk, scalp 
Stage II First months Yes Unknown Limbs Limbs 
Stage III Yes 20 mo; trunk, limbs Unknown 7 mo; trunk, limbs 4 mo; trunk, limbs 
Stage IV From 12 y; limbs Unknown From 12 y limbs Unknown Yes 
Ocular defects Retinal detachment (left eye), glaucoma (right eye) Retinopathy Myopia Diffuse fundus hypopigmentation Diffuse fundus hypopigmentation 
Neurologic defects Seizure at day 6 Periventricular leukomalacia Normal Normal Normal 
Orodental defects Delayed eruption of the teeth Incomplete deciduous dentition One cone-shaped tooth Accessory cusp in molars Absence of a permanent lateral incisor and accessory cusp in primary molars 
Hair defects Hypotrichotic scarring patch on the vertex Woolly hair on vertex Unknown Atrophic, scarring baldness Atrophic, scarring baldness 
Fingernail defects Normal Normal Unknown Ridged toe Normal 
Sweat pores Normal Normal Normal Normal Normal 
Histologic results IP compatible IP compatible Not performed Not performed Not performed 
Developmental evolution Normal Deficient Normal Normal Normal 
Karyotyping 46, XY Not performed 46, XY Not performed Not performed 

Skin defects: stage I, Vesicles and pustules on erythematous base; stage II, papules, verrucous lesions, and hyperkeratosis; stage III, localized hyperpigmentation; stage IV, hypopigmented, hairless streaks with atrophy and scarring. Ocular defects: retinal detachment, hypopigmented retinal pigment epithelium. Neurologic defects: seizures, spastic paralysis, mental retardation. Orodental defects: anodontia, conical teeth, delayed eruption, accessory cusps. Hair defects: vertex alopecia. Fingernail defects: ridging, pitting.

IP patient II:1 (Fig 2A) in Family 2 is a 7-year-old girl. She had the typical IP neonatal skin presentation (stage I), which progressed to hyperkeratotic warty lesions (stage II) and a linear and whorled pattern of pigmented spots on the trunk and the limbs (7 months, stage III). Alopecia, fingernail dystrophy, dental defects, and retinal hypopigmentation were present. We observed no central nervous system abnormalities (Table 1). Her sister (IP-II:2, Fig 2A) is a 4-year-old female. She had IP neonatal skin (stage I) and subsequent IP lesions similar to her sister (Fig 2A; IP-II:1) with stage III occurring at 4 months. She presented with alopecia, dental defects, and fundus hypopigmentation. No nail dystrophy or central nervous system alterations were noted (Table 1). Their father is 34 years old (Fig 2A; IP-I:1), born from unrelated parents. He presented at birth an IP-like cutaneous rash (stage I) and linear streaks of vesicles following Blaschko lines on the trunk, back, and extremities. A skin biopsy was not performed. An accessory cusp in 1 canine was noted. He had a normal 46,XY karyotype (Table 1).

FIGURE 2

NEMOdel4-10 amplification and analysis of the mosaicism in Family 2. Long-range PCR tests specific for NEMOdel4-10, performed as described previously,22 in each member of Family 2 (A) reveal the presence of NEMOdel4-10 in the 2 probands, IP-II:1 and IP-II:2 (lane 3 and lane 5). DNA control (lane 1) is a positive PCR control carrying the NEMOdel4-10 allele. (B) Long-range PCR tests specific for NEMOdel4-10 on DNA from different tissues of the IP-male father (I:1): unaffected skin (lane 2), affected skin (lane 3), urine (lane 4), and sperm (lane 5) show the presence of the NEMOdel4-10 allele only in sperm DNA (lane 5). The NEMOdel4-10 allele mosaicism (C) in DNA from peripheral blood, unaffected and affected skin biopsy, urine, and sperm samples of the IP-male father (I:1) was detected using probes P6 and P7 by quantitative PCR. The percentage of mosaicism was calculated as the mean of the results of both probes (P6 and P7) using a standard curve as described in Supplemental Tables 4 and 5. (D) A schematic representation of the IP locus is shown. Low copy repeat 1 (LCR1) contains IKBKG/NEMO gene (exons 3–10), and LCR2 contains IKBKG pseudogene/NEMOP (exons 3–10). MER67B repeated sequences are shown in both LCRs; they are able to generate by nonallelic homologous recombination (NAHR) the deletion NEMOdel4–10, the deletion in the pseudogene NEMOPdel, and the gene duplication, MER67Bdup.10,12 The IKBKG/NEMO gene architecture: coding exons (from exon2 to exon10), 5′-UTR (exons 1D, 1A, 1B, and 1C). The quantitative PCR amplicons used to reveal the NEMOdel4–10 deletion (P6, P7) are indicated by rectangles. P3 and P8 are located outside the NEMOdel4-10 and are indicated with a circle and diamond, respectively.

FIGURE 2

NEMOdel4-10 amplification and analysis of the mosaicism in Family 2. Long-range PCR tests specific for NEMOdel4-10, performed as described previously,22 in each member of Family 2 (A) reveal the presence of NEMOdel4-10 in the 2 probands, IP-II:1 and IP-II:2 (lane 3 and lane 5). DNA control (lane 1) is a positive PCR control carrying the NEMOdel4-10 allele. (B) Long-range PCR tests specific for NEMOdel4-10 on DNA from different tissues of the IP-male father (I:1): unaffected skin (lane 2), affected skin (lane 3), urine (lane 4), and sperm (lane 5) show the presence of the NEMOdel4-10 allele only in sperm DNA (lane 5). The NEMOdel4-10 allele mosaicism (C) in DNA from peripheral blood, unaffected and affected skin biopsy, urine, and sperm samples of the IP-male father (I:1) was detected using probes P6 and P7 by quantitative PCR. The percentage of mosaicism was calculated as the mean of the results of both probes (P6 and P7) using a standard curve as described in Supplemental Tables 4 and 5. (D) A schematic representation of the IP locus is shown. Low copy repeat 1 (LCR1) contains IKBKG/NEMO gene (exons 3–10), and LCR2 contains IKBKG pseudogene/NEMOP (exons 3–10). MER67B repeated sequences are shown in both LCRs; they are able to generate by nonallelic homologous recombination (NAHR) the deletion NEMOdel4–10, the deletion in the pseudogene NEMOPdel, and the gene duplication, MER67Bdup.10,12 The IKBKG/NEMO gene architecture: coding exons (from exon2 to exon10), 5′-UTR (exons 1D, 1A, 1B, and 1C). The quantitative PCR amplicons used to reveal the NEMOdel4–10 deletion (P6, P7) are indicated by rectangles. P3 and P8 are located outside the NEMOdel4-10 and are indicated with a circle and diamond, respectively.

Close modal

Genomic DNA was extracted from peripheral blood leukocytes in all members of 2 trios (child/children, mother, and father) and from the skin, urine,23 and sperm24 of the affected fathers. The IKBKG/NEMO gene deletion (NEMOdel4-10), the risk alleles for IP (NEMO pseudogene [NEMOP] del4-10) and (duplication of MEdium Reiterated 67B [MER67B] repeat sequences [MER67Bdup]), and the mutational analysis of the IKBKG/NEMO exons were performed by polymerase chain reaction (PCR) as previously described.22 

In Family 1 we identified a novel, nonsense mutation in exon3 (NM_003639:c.394C>T; NP_003630.1:p.Gln132×) of the IKBKG/NEMO gene in IP female II:1 (Fig 1A), predicted to produce a premature stop codon in position 132 in the coiled-coil 1 (CC1) domain and an inactive NEMO protein. The mutation was absent in the IKBKG/NEMO gene and pseudogene in the DNA from the peripheral blood of her IP father (Fig 1A; I:1) and of her clinically unaffected mother (Fig 1A; I:2). We excluded an event of gene conversion from the pseudogene to the IKBKG/NEMO gene that can occur, albeit rarely, in the parent germ line.10,12 Because the father (IP-I:1; 46,XY) presented the clinical features of IP (Table 1), we investigated whether he was a somatic and germ-line mosaic for NEMOc.394C>T, identified in his IP-female child. We screened for NEMOc.394C>T the DNA from an adult biopsy of the affected skin (hypopigmented, stage IV) and from the urine and sperm. Sequence analysis revealed the heterozygous NEMOc.394C>T mutation in the skin, urine, and sperm. However, we were unable to reveal the mutation in DNA from the fibroblast culture derived from the same skin biopsy (Fig 1B). One possible explanation is that the fibroblasts carrying the LoF NEMOc.394C>T mutation are susceptible to cell death during continuous culture in vitro.

We quantified the degree of mosaicism in IP patient I:1 DNA from different tissues, using a TaqMan SNP Genotyping assay (Supplemental Tables 2 and 3). The NEMOc.394C>T mutation was detectable in DNA from the affected skin in 20% of cells, in the urine in 8.3% of cells, and in the germ line in 16.7% of cells (Fig 1C). We did not find any evidence of mosaicism for NEMOc.394C>T in the peripheral blood and fibroblasts culture from the affected skin (Fig 1C), confirming the results obtained by direct sequencing (Fig 1B).

In Family 2, we detected the NEMOdel4-10 mutation in the 2 IP sisters (Fig 2A; IP-II:1; IP-II:2), which was absent in DNA from the blood of the parents (Fig 2A; I:1; I:2). The presence of the NEMO deletion in both children highlighted an abnormal recurrence of a de novo mutation in this family. The risk alleles for IP (MER67dup, NEMO pseudogene deletion [NEMOPdel])12 were ruled out by PCR analysis in DNA from both parents. Therefore, we investigated the IP father (46,XY) for the presence of the NEMOdel4-10 allele in different tissues: blood (Fig 2A, I:1), unaffected and affected adult skin (stage IV), urine, and sperm (Fig 2B). The NEMOdel4–10 mutation was detectable only in sperm DNA (Fig 2B).

We then established the degree of mosaicism in the IP patient I:1 DNA from different tissue sources by quantifying the copy number variations in the IP locus (Fig 2D) (Supplemental Tables 4 and 5) by quantitative PCR using probes previously described.10 The percentage of cells carrying the NEMOdel4-10 allele in DNA from the urine was 25%, whereas in the germ line it was 35% (Fig 2C). We did not detect the NEMOdel4–10 mutant cells in the peripheral blood and skin lesions of the IP father (Fig 2C), although some IKBKG/NEMO mutant cells in the affected skin would have been expected, as observed in the IP father of Family 1 (Fig 1C and Supplemental Tables 4 and 5).

We demonstrate for the first time the combination of somatic and germ-line mosaicism for IKBKG/NEMO LoF mutations in IP males, resulting in the transmission of the disease to a female child. Both mutations were present as low-level mosaicism in the germ cells: 16.7% in gonadal cells carrying the NEMOc.394C>T allele in Family 1 and 35% for NEMOdel4–10 in Family 2. The percentage of the mutated cells was lower in the urine sediment (8.3% and 25%) and in the affected skin (20% and 0%) in Family 1 and Family 2, respectively. In the peripheral blood cells, the mutated cells were undetectable.

Overall these findings suggest the following:

  1. Peripheral blood is not the appropriate tissue to reveal the somatic mosaicism in the IP male, although it represents the main source of DNA in IP routine diagnosis.

  2. We recommend genetic investigation in sperm DNA because the gonadal cells carrying the IKBKG/NEMO LoF mutation are able to survive differently from other cells (fibroblasts and blood cells), which instead disappear because of a selective disadvantage due to the lack of NEMO protein.

The combined somatic and germ-line mosaicism in IP males, suggests a nonclonality of the germ line in which the mosaicism arose at a totipotent cell stage of development within the first few cell divisions of the embryo, probably by postzygotic mutation. Thus, the timing of the mutation should affect the abundance of the mutant cells, the presence of the mutation in the germ cells, and, by extension, the potential recurrence risk for the same mutation to be transmitted to multiple offspring.25 

The 2 cases reported here highlight that mosaicism should be considered as a possible inheritance pattern in genetic counseling with a recurrence risk estimation in families with male IP cases. In males with suspected IP, the causative IKBKG/NEMO mutation should be identified in sample DNA from a biopsy of the affected skin in childhood and in germ-line cells in adulthood.

     
  • del4-10

    deletion exon 4-10

  •  
  • IP

    incontinentia pigmenti

  •  
  • IKBKG

    inhibitor of κ polypeptide gene enhancer in B cells, kinase γ

  •  
  • LoF

    loss of function

  •  
  • MER67Bdup

    duplication of MER67B repeat sequences

  •  
  • NEMO

    nuclear factor κB, essential modulator

  •  
  • NEMOP

    NEMO pseudogene

  •  
  • NF-κB

    nuclear factor κB

  •  
  • OMIM

    Online Mendelian Inheritance in Man

  •  
  • PCR

    polymerase chain reaction

Dr Fusco made substantial contributions to the conception and design of the study, analyzed clinical and molecular data, and performed the interpretation of data; she wrote and critically revised the manuscript for important intellectual content; Drs Conte and Branda contributed to the study conduct and analysis of molecular data; Drs Diociaiuti, Bigoni, Ferlini, and El Hachem contributed to conduct and analysis of clinical data; Dr Ursini made substantial contributions to the conception and design of the study and wrote and critically revised the manuscript for important intellectual content; and all authors approved the final manuscript as submitted.

FUNDING: All phases of this study were supported by the Incontinentia Pigmenti International Foundation (http://www.ipif.org), the Italian Incontinentia Pigmenti Association (http://www.incontinentiapigmenti.it), the French Incontinentia Pigmenti Association (http://incontinentia-pigmenti.fr), by Regione Campania (Legge5, LR5 2007) to Dr Ursini, and by CNR-DSB Progetto Bandiera “InterOmics” to Drs Fusco and Ursini.

We thank the patients, their families, and physicians. We also thank the Italian Incontinentia Pigmenti Association (www.incontinentiapigmenti.it), the French Incontinentia Pigmenti Association (http://incontinentia-pigmenti.fr), and the Incontinentia Pigmenti International Foundation (www.ipif.org). We acknowledge the Incontinentia Pigmenti Genetic Biobank (www.igb.cnr.it/ipgb) of the Biobanking and BioMolecular Resources Research Infrastructure–European Reasearch Infrastructure Consortium (BBRMI–ERIC) for making the samples available. This study protocol was adherent to the principles of the Declaration of Helsinki and received approval from the local ethics committee. Parental informed written consent was provided on behalf of the patients involved in this study.

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

Supplementary data