Open Access

Incontinentia pigmenti: report on data from 2000 to 2013

  • Francesca Fusco1Email author,
  • Mariateresa Paciolla1, 2,
  • Matilde Immacolata Conte1,
  • Alessandra Pescatore1,
  • Elio Esposito1,
  • Peppino Mirabelli3,
  • Maria Brigida Lioi2 and
  • Matilde Valeria Ursini1, 3
Orphanet Journal of Rare Diseases20149:93

https://doi.org/10.1186/1750-1172-9-93

Received: 6 March 2014

Accepted: 12 June 2014

Published: 24 June 2014

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.

Keywords

Incontinentia pigmentiGenomic disorderNeuroectodermal disorderMolecular diagnosisRegistryDatabase

Introduction

Incontinentia pigmenti (IP; OMIM#308300) is a rare multisystemic genomic disorder with an estimated prevalence at birth of 0.7/100,000 [1]. IP is X-linked and usually lethal in males, and affecting the skin, but also other neuroectodermal tissues, in females. The skin lesions are the first clinical manifestations that appear, starting in the neonatal period with a vesiculobullous eruption (Stage I) and following a three stage evolution varying in duration from months to years, namely a verrucous stage (Stage II), a hyperpigmented stage (Stage III), and finally a hypopigmented stage (Stage IV) usually continuing throughout life [2, 3]. Such skin defects, that follows Blaschko lines, are always present in IP and are therefore considered the main diagnostic criteria for IP according to Landy and Donnai (1993) [2]. The severity of the disease is related to the presence of neurological and/or ocular impairment [4]. 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 [7]. 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, OMIM#300248). Most cases have a recurrent deletion (IKBKGdel or NEMOdel4-10), removing exons 4–10 of the IKBKG/NEMO gene. Non recurrent genomic rearrangements in the IP locus and point mutations in the IKBKG/NEMO coding region have also been reported [911]. IKBKG/NEMO encodes for NEMO/IKKγ a regulatory subunit of the Inhibitor of the kappaB (IκB) Kinase (IKK) complex required for the canonical NF-κB pathway activation involved in many fundamental physiological and pathological functions [12, 13]. Most IP female patients present with a skewed X-inactivation. The X-chromosome linked IKBKG/NEMO mutation causes an unbalanced X-inactivation in female IP patients [14], as in other X-linked diseases [15, 16], because the absence of the NEMO/IKKγ protein makes the IP cells more sensitive to apoptosis [9]. In males, the extensive apoptosis is responsible for their early fetal lethality [17]. Occasionally, male patients with IP have been reported. They have shown the characteristic skin lesions observed in females and presented a postzygotic mosaicism for the IKBKG/NEMO exons4-10 gene deletion [18]. IP has also been diagnosed in males with a 47,XXY karyotype (Klinefelter syndrome) [19]. The large heterogeneity of defects, the severe clinical presentations, and the wide spectrum of IKBKG/NEMO alterations [7, 11, 14, 20] makes the selection of homogeneous groups of patients difficult, precluding any therapeutic approaches. Indeed, despite the considerable progress that has been made in detailing the basic pathology of the IP disorder, the gap between research and clinical care has remained wide. Moreover, the paucity of patients collected at each single diagnostic centre makes an overall epidemiological report difficult. The integration of scattered resources may be crucial for the success of future scientific accomplishments.

Methods

Here, we report the setting up of a central data repository relating to a cohort of IP patients, the data having been collected in a 13-year-long experience (2000–2013) at our Italian centre of expertise for the molecular diagnosis of IP [21]. The IP patients included in our study have been selected on the basis of the Landy and Donnai (1993) [2] diagnostic criteria, and they also meet the most recently updated IP criteria [22]. We have constructed the first platform for the integration of molecular and clinical data on IP patients. Our sample comprises 386 patients (261 from Italian, 105 from European and 20 from non-European clinical centers), with an annual average of 27.6 new cases of IP diagnosed per year (Figure 1).
Figure 1

Annual distribution of the IP samples that have been received by the IGB centre for molecular diagnosis.

All the clinical information has been obtained for each patient through their completion of a clinical IP questionnaire developed by the Incontinentia Pigmenti International Foundation (IPIF, [http://www.ipif.org/ip_consortium.html], further extended by the France Incontinentia Pigmenti association (FIP, [http://incontinentia-pigmenti.fr/]) and by the Italian ASSociation of Incontinentia Pigmenti (IPASSI, [http://www.incontinentiapigmenti.it/]). A clinical IP questionnaire is available upon request from these organizations. We have integrated the clinical data with molecular diagnosis results for the IKBKG/NEMO alteration, by way of a well-standardized protocol [10, 14, 23]. The technical development of the register has involved significant preparatory work consisting in the building up of an in-house electronic database which is comprehensive and permissive, and which has a flexible structure able to register in an anonymous form the pool data from the patients. We have assigned one record to each IP sample, registered with a pseudonymous code. Each record has three domains: the pedigree, the clinical and the genetic domain. The Web domain will be available at link [http://www.igb.cnr.it/ipgb]. The data are not accessible to everyone but only to authorized users through the use of a protected password. A data-mining interface has been developed to ensure maximum flexibility so that users can perform any search they want using the “search” button placed in the homepage after the “log in”. It is possible to perform multiple searches at once. To make the database permissive and flexible the first page contains only the three domains set.

Results

The pedigree and clinical information are available for 308 IP cases, while the genetic data are available for 193 samples, respectively (Table 1). The pedigree domain contains more detailed entries accommodating the family data, for example the presence of an IP mother, sister, or grandmother, indicating the inheritance of the disease. We have registered 233 sporadic cases (75.6%) and 72 familial cases (23.4%) in our IP cohort.
Table 1

IP data registry

 

Number of cases

Percentage of cases

Database information

386 records

 

IP female samples

349

90.4

IP male samples

37

9.6

Pedigree domain

308 available

 

Sporadic cases

233

75.6

Familial cases

72

23.4

Clinical domain*

308 available

 

Skin defects

308

100

CNS defects

97

31.5

Ophthalmologic defects

94

30.5

Teeth defects

134

43.5

Hair defects

82

26.6

Fingernail defects

45

14.6

Developmental evolution

30

9.7

Genetic domain

193 available

 

NEMOdel4-10

145

75.1

IKBKG/NEMO point mutation

32

22.1

IP locus rearrangement

7

3.6

No known alteration found

9

4.7

*IP patients can have more than one defect affecting different organ systems.

The clinical domain consists of seven clinical items, one for each aspect of the phenotype presentation: “Skin defects”, “CNS defects”, “Ophthalmologic defects”, “Teeth defects”, “Hair defects”, “Fingernail defects” and “Developmental evolution”. A drop-down menu has been assigned to each item that, in most cases, contains details about all the specific alterations affecting the tissue, and, in addition, an open space for the annotation of novel clinical features. For example, the item “Skin defects contains a drop-down menu indicating the stage of the IP skin abnormality, the age of onset, the type of alteration, and the region of the body in which the alteration is present. We report that the most frequent first symptoms leading to diagnosis, typically skin alterations (Stage I), appear before the first year in 99% of cases. The second stage and the third stage are reported within the first year in 96.6% and in 82.8% of cases, respectively. After this date the fourth stage is generally present (Table 2). The specific frequency of each IP specific neuroectodermal defect observed in our cohort is shown in Table 1. CNS abnormalities were present in 31.5% (Table 1). In 17 cases, these were diagnosed by magnetic resonance imaging (Table 3).
Table 2

IP skin clinical data

 

Skin alteration age of onset

Skin defects

IP cases

<1° month

1° month-1° year

>1° year

Stage I

183

160(87.4%)

21(11.5%)

2(1.1%)

Stage II

90

38(42.2%)

49(54.4%)

3(3.3%)

Stage III

87

18(27.6%)

58(55.2%)

11(17.1%)

Stage IV

81

0

0

81(100%)

Table 3

IP clinical data

Type of defect

Number of cases**

Percentage of cases

CNS defects

97

 

Seizures

39

40.2

Mental retardation

29

29.9

Spastic paresis

16

16.5

Cerebral atrophy

13

13.4

Microcephaly

11

11.3

Hydrocephaly

5

5.1

Ischemic strokes*

5

5.1

White matter alterations*

4

4.1

Arachnoid cysts*

3

3.1

Cortico-subcortical atrophy*

3

3.1

Brain morphological alterations*

2

2.1

Teeth defects

134

 

Delayed primary dentition

46

34.3

Cone/peg shaped teeth

30

22.3

Delayed permanent dentition

30

22.3

Teeth dystrophy

23

17.2

Impactions

23

17.2

Ophthalmologic defects

94

 

Vision defects

16

17

Retinopathy

15

15.9

Retinal detachment

8

8.5

Microphthalmia

6

6.4

Retinal neuropathy

6

6.4

Retinal vascular visorders

5

5.3

Hair defects

82

 

Alopecia

8

9.7

Hypertrichosis

3

3.6

Fingernail defects

45

 

Nail dystrophy

29

64

Developmental evolution

30

 

Recurrent infections

36

11.7

Syndactyly of fingers or toes

4

1.3

*Data obtained by Magnetic Resonance Imaging analysis in 17 IP cases.

**IP patients can have more than one defect affecting different organ systems.

The genetic domain of the database contains four items: “NEMOdel4-10”, “IKBKG/NEMO point mutation”, “IP locus rearrangement”, and “No known alteration found” (Table 1). The mutation names comply with the accepted guidelines proposed by the Human Genome Variation Society [http://www.hgvs.org/mutnomen] [24]. The genetic domain reveals that 75.1% of patients have the NEMOdel4-10 deletion, 22.1% have an IKBKG/NEMO point mutation, 3.6% have an extended deletion in the IKBKG/NEMO locus, and 4.7% have no known alteration in the IP locus (Table 1).

Finally, in each domain (pedigree, clinical, and genetic) an additional item, named “Supplementary Information”, records in the database any supplementary data from the patient and his/her family when these are available (examples: presence of miscarriages; presence of nonpathogenic alterations in IP locus[25] such as deletions or point mutations in the NEMO pseudogene).

Discussion

The building up of this database represents the first detailed integrated clinical/molecular diagnostic platform on IP patients, the largest collection of an IP cohort in Italy and to the best of our knowledge the first presented to the scientific community worldwide. Thus, this phenotype and genotype database related to IP acts as a unique attempt to improve patient care and healthcare planning since it collects together information that would otherwise be scattered. Finally, we strongly believe that the use of the database is a powerful tool to facilitate the selection of biological samples and/or the enrolment of patients for the organization of appropriate clinical trials. Physicians wishing to include patients in the IP database may contact the Authors: Francesca Fusco and/or Matilde Valeria Ursini by email (incontinentia.pigmenti@igb.cnr.it).

Abbreviations

IP: 

Incontinentia Pigmenti

OMIM: 

Online Mendelian Inheritance in Man

CNS: 

Central Nervous System

IKBKG: 

Inhibitor of Kappa polypeptide gene enhancer in B-cells, Kinase gamma

NEMO: 

Nuclear factor κB Essential MOdulator

IKKγ: 

Inhibitor of Kappa Kinase gamma

IκB: 

Inhibitor of NF-κB

IKK: 

IκB Kinase

NF-κB: 

Nuclear Factor-κB

IPIF: 

Incontinentia Pigmenti International Foundation

FIP: 

France Incontinentia Pigmenti association

IPASSI: 

Italian Incontinentia Pigmenti ASSociation.

Declarations

Acknowledgments

We are grateful to the patients, their families and physicians, the association France Incontinentia Pigmenti (FIP, [http://incontinentia-pigmenti.fr/]) the Italian Incontinentia Pigmenti ASSociation (IPASSI, [http://www.incontinentiapigmenti.it/]), DHITECH, Progetto Formazione PON n°01-02342 for the fellowship to M.I.C and the Basilicata Innovazione [http://www.basilicatainnovazione.it] for supporting M.P.

Authors’ Affiliations

(1)
Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’, IGB-CNR
(2)
University of Basilicata
(3)
Fondazione SDN IRCCS

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