This research aimed to investigate the dentofacial characteristics of patients with Incontinentia Pigmenti (IP) (or Bloch-Sulzberger) syndrome in childhood, juvenile, and adulthood developmental stages.
Fifteen female patients with a clinical diagnosis of IP, genetically confirmed by molecular testing, were included in this study. The records of 25 nonsyndromic females with Class I occlusion and lateral cephalograms obtained at similar developmental stages were selected from the American Association of Orthodontists Foundation Legacy Collection as a control group. Dentofacial features of subjects with IP and those in the control group were compared statistically using t test and Mann-Whitney rank-sum test (significance was defined as P <0.05).
In general, patients with IP had shorter maxillary and mandibular length, straight skeletal profile, hypodivergent growth pattern with a tendency to mandibular protrusion, shorter anterior facial height, Class III compensatory positioning of incisors, more retruded lips, and smaller maxillary incisor exposure. The degree of hypodontia severity had a significant impact on skeletal, dental, and soft-tissue features in patients with IP.
The results of this study showed that, since childhood, the dentofacial characteristics of patients with IP were progressively distancing from those of nonsyndromic patients with Class I occlusion, presenting their own orthodontic needs.
Patients with IP syndrome showed medium to large deviations in dentofacial features.
From childhood, IP dentofacial features were gradually moving away from normality.
IP syndorme had a straight skeletal profile, chin protrusion and short facial height.
Skeletal features were associated with dental compensation and more retruded lips.
Hypodontia influenced skeletal, dental, and soft-tissue features of patients with IP.
Incontinentia pigmenti (IP) (or Bloch-Sulzberger) syndrome is a rare X-linked dominant genodermatosis, which appears almost exclusively in women. It is usually lethal in men, whereas heterozygous females survive owing to functional mosaicism. IP is primarily of ectodermal origin and causes variable abnormalities of the skin, eyes, hair, nails, teeth, and the central nervous system. , Although its prevalence is low (1-9 per 1 million), more than 80% of patients with IP present dental anomalies (number, form, size, and structure), 18% have delayed eruption, and 40% present some skeletal deficiency, suggesting a high demand for orthodontic treatment. , , Indeed, straight lateral profile, hypodontia, peg-shaped teeth, and maxillary deficiency are common dentoskeletal findings in IP reports, besides other general traits as alopecia on the vertex and skin lesions, which may vary according to the stage of IP ( Fig 1, A – F ). , , , ,
Although skin lesions are not the most worrying sequelae associated with IP disorder, their identification is very useful for screening and diagnosing IP. Indeed, cutaneous manifestations occur in almost 100% of patients with IP and may be considered nearly pathognomonic if they follow a specific pattern, stage progression, and timeline. , , Most persons with IP begin to express the phenotypic skin lesions at or near birth in the form of erythema with linear vesicles and pustules distributed on the torso and/or extremities ( Fig, 1 D ). As vesicles become dry and hyperkeratotic, linearly arranged verrucous papules and plaques begin to appear with the peak of onset between 2 and 6 weeks of age. Although these newborn skin lesions are not observable in a small percentage of patients, most patients with IP (98%) will present the hallmark of IP syndrome, which are whorls and streaks of brown pigmentation following lines of Blaschko and appear between infancy and adolescence ( Fig 1 , E ). By adulthood, the majority of these hyperpigmented lesions have disappeared. However, before the disappearance of hyperpigmented lesions, other typical lesions of adults and adolescents with IP may appear, which are pale and hairless patches or streaks more evident on the lower leg ( Fig 1 , F ). These late changes appear to be permanent and are often the only sign of skin involvement in adult patients. , ,
IP is a single-gene disorder caused by mutations in IKBKG , formerly known as NEMO , which is located on the X chromosome at position q28. The common IP deletion is observed at exons 4 through 10, occurring in about 80% of known patients. , , , , , Although IP diagnosis is commonly based on skin lesions, molecular genetic testing seems to be especially relevant in orthodontics because it has been demonstrated that patients with IP with negative genetic testing for IKBKG pathogenic variant were significantly less likely to have dental manifestations. In addition, molecular diagnosis may confirm the clinical suspicion and is essential for providing definite genetic counseling and prenatal diagnosis. , ,
In one of his editorials, Turpin stated that orthodontists are not always prepared to diagnose and treat less usual orthodontic problems, such as those associated with dysfunctional or syndromic patients, and the databases (eg, National Library of Medicine) represent an important source of learning. However, the dentofacial characteristics of patients with IP have not been systematically studied, and most of the knowledge comes from case reports. , , In addition, most reported patients were not genetically tested for IP disorder, and misdiagnosis may occur, making these findings less reliable. , Some of these studies found that patients with IP present maxillary and mandibular anteroposterior hypoplasia, transverse maxillary deficiency, counterclockwise mandibular rotation, prominent chin, besides a shortened facial height. , , , In addition, dental anomalies involving oligodontia in the maxillary and mandibular arches and peg-shaped teeth have been reported. , , , To shed some light on these clinical findings, this study evaluated the dentofacial characteristics of a group of patients with IP in childhood, juvenile, and adulthood stages, comparing them with Class I nonsyndromic subjects at similar developmental stages.
Material and methods
In this repeated cross-sectional study, 15 consecutive patients with IP were clinically diagnosed at the Pediatric Dermatology Service of Santo Antonio Children’s Hospital, Porto Alegre, Brazil, and recruited for this study between years 2003 and 2012. This study was approved by the Institutional Review Board of the Federal University of Rio Grande do Sul, under no. 2.934.476. Patients with IP were white subjects with Southern and Central European Caucasian ancestry. All patients with IP presented cutaneous manifestations of IP, which were consistent with the clinical criteria suggested by Landy and Donnai. In addition, patients with IP were submitted to molecular genetic testing on the IKBKG gene. The IKBKG pathogenic variant characterized by the classic exon 4_10 deletion was detected by multiplex polymerase chain reaction and confirmed by conventional polymerase chain reaction in all patients with IP. Because IP is generally lethal in utero for males, this sample was composed only of female patients with IP. No patient had IP associated with cleft lip and palate or any other craniofacial anomaly. In addition, patients with IP had no history of orthodontic treatment.
Patients with IP were divided into 3 groups according to the developmental stage. Five patients with IP with a mean age of 5.32 (standard deviation [SD], 0.97) years were allocated into the childhood group, and 3 of these patients were followed through the juvenile stage and included in the juvenile group. The juvenile group was composed of 7 patients with IP with a mean age of 9.33 (SD, 1.16) years, and only 1 of these patients was followed through the adolescence stage and included in the adulthood group. Seven patients with IP with a mean age of 23.89 (SD, 8.54), low or no growth potential, and presenting cervical vertebral maturation stage more advanced than cervical stage 4 were allocated in the adulthood group. Lateral cephalograms were obtained at each developmental stage for patients with IP. The degree of hypodontia severity was classified as absent (score 0, no missing teeth), mild (score 1, 1 or 2 missing teeth), moderate (score 2, 3-5 missing teeth), severe (score 3, 6-10 missing teeth), and extremely severe (score 4, >10 missing teeth). , To select the control group, a set of demographic information (age, sex, and occlusion relationship) was searched on the Web site of the American Association of Orthodontists Foundation (AAOF) Craniofacial Growth Legacy Collection ( www.aaoflegacycollection.org/ ) using the SEARCH tab on the Home Page of this Web site to access the AAOF Legacy Collection database. , The search recovered 17 patients from Burlington Growth, 7 from Oregon Growth, and 1 from Bolton-Brush Growth studies. The control group was composed of 25 nonsyndromic female patients with Angle Class I occlusion presenting lateral cephalograms taken at developmental stages similar to those of the IP groups.
Lateral cephalograms were obtained in centric occlusion. Cephalograms were analyzed with Radiocef Studio 2 software (version 2.0, release 12.82; Radio Memory©, Belo Horizonte, Brazil). Cephalometric measurements were obtained by a single investigator (F.D.S.M), previously calibrated, and checked for landmarks and outlines of anatomic structures by a second examiner (S.E.B). Any disagreements between examiners were resolved by a weighted reevaluation to the satisfaction of both examiners. A customized cephalometric analysis was used, including dental, skeletal, and soft-tissue measurements from known analyses: Steiner, Tweed, Ricketts, and McNamara, totaling 27 variables (12 angular, 14 linear, and 1 ratio) evaluated in each of the 94 digital cephalometric tracings. Lateral cephalograms from the AAOF Legacy Collection and patients with IP had different magnification factors, which were corrected on the cephalometric software to match a 0% magnification factor.
To evaluate the study error, 18 lateral cephalograms were randomly selected and redigitized by the same examiner (F.D.S.M). The agreement between repeated measurements of each variable (intraexaminer reliability) was evaluated by the intraclass correlation coefficient.
Descriptive statistics for the cephalometric measurements were calculated for each developmental stage for the IP and control groups. Because several cephalometric variables did not show the normal distribution for both groups and observation stages, the comparisons were performed using parametric or nonparametric statistical tests according to the results of Shapiro-Wilk normality tests. , The chronological age and cephalometric variables of IP and control groups were compared in each developmental stage using the t test and Mann-Whitney rank-sum test. The distribution of the degree of hypodontia severity was described and correlated with the cephalometric variables using the Spearman correlation test.
The effect size for 2 independent groups was evaluated using the standardized difference between 2 means (Cohen d). Effect size was classified as small (d = 0.2), medium (d = 0.5), and large (d ≥ 0.8) according to Cohen’s suggestion.
Statistical analyses were performed on the Statistica for Windows software (version 7.0; Stat Soft, Tulsa, Okla). The results were considered statistically significant at P <0.05.
The ranges of intraclass correlation coefficient showed good (NSGn, 0.851; 95% confidence interval, 0.646-0.941) to excellent (AFH, 0.998; 95% confidence interval, 0.994-0.999) reliability of cephalometric measurements.
In the childhood stage, the IP group had a significantly smaller maxillary length than the control group. The mandibular length was similar between groups. Notwithstanding, mandibular protrusion was significantly greater in the IP group ( Table I ). The ANB angle and facial convexity were smaller in the IP group, showing a marginal trend toward significance ( Table I ). The lower anterior facial height was significantly smaller in the IP group, and the Frankfort-mandibular plane angle was slightly more closed in this group but not statistically significant ( Table I ). The maxillary incisors were significantly more proclined and protruded in the IP group. Contrarily, the mandibular incisors showed a tendency for greater lingual tipping in this group ( Table I ).
|Variables||IP group (n = 5)||Control group (n = 25)||P value||Effect size (Cohen d)|
|Age (y)||5.32||0.97||5.19||0.33||0.759 †||0.179|
|Maxillary skeletal components|
|SNA (°)||80.56||4.37||82.50||2.85||0.213 ‡||0.525|
|Co-A (mm)||69.68||4.36||76.32||5.03||0.010 ∗ , ‡||1.410|
|A-Nperp (mm)||0.09||4.92||−0.30||2.53||0.786 ‡||0.099|
|Mandibular skeletal components|
|SNB (°)||77.24||3.10||77.01||3.08||0.884 ‡||0.074|
|Co-Gn (mm)||86.16||6.07||90.53||6.90||0.199 ‡||0.672|
|P-Nperp (mm)||−3.00||5.08||−9.27||4.51||0.009 ∗ , ‡||1.305|
|ANB (°)||3.32||3.85||5.48||2.06||0.062 †||0.699|
|NAP (°)||4.88||9.27||11.84||4.58||0.054 †||0.951|
|SN.GoGn (°)||32.78||2.54||33.21||4.22||0.828 ‡||0.123|
|FH.MP (°)||25.73||3.80||28.86||3.44||0.072 ‡||0.863|
|NSGn (°)||66.08||2.19||66.35||2.77||0.839 ‡||0.108|
|BaN.PtGn (°)||0.46||1.97||−0.44||2.66||0.478 ‡||0.384|
|UAFH (N-ANS, mm)||38.76||3.39||38.29||4.06||0.810 ‡||0.125|
|LAFH (ANS-Me, mm)||48.97||3.27||55.88||4.34||0.005 ∗ , †||1.798|
|AFH (N-Me, mm)||87.73||4.66||94.17||7.18||0.066 ‡||1.064|
|PFH (S-Go, mm)||54.77||3.87||57.97||5.13||0.199 ‡||0.704|
|PFH/AFH (%)||62.39||1.88||61.61||3.77||0.661 ‡||0.261|
|Maxillary dentoalveolar components|
|Mx1.PP (°)||102.35||13.51||95.97||7.23||0.133 ‡||0.588|
|Mx1.NA (°)||16.68||6.52||8.92||6.30||0.018 ∗ , ‡||1.210|
|Mx1-NA (mm)||2.69||1.37||1.21||1.48||0.049 ∗ , †||1.037|
|Mandibular dentoalveolar components|
|Md1.MP (°)||81.63||9.52||87.14||5.62||0.086 ‡||0.704|
|Md1.NB (°)||14.15||11.32||20.13||5.44||0.075 ‡||0.673|
|Mx1-NB (mm)||1.69||2.54||2.59||1.39||0.261 ‡||0.439|
|Overjet (mm)||3.41||2.24||3.59||2.08||0.559 †||0.083|
|Overbite (mm)||−0.30||3.41||0.97||1.80||0.228 ‡||0.465|
|MxLip protrusion (mm)||4.39||2.30||4.50||2.09||0.914 ‡||0.050|
|MdLip protrusion (mm)||2.36||2.92||2.46||1.85||0.926 ‡||0.041|
|Mx1 exposure (mm)||2.94||1.51||4.47||2.29||0.166 ‡||0.788|
In general, the significant dentofacial differences observed between groups in the childhood stage were maintained in the juvenile stage, whereas other differences emerged. The maxillary and mandibular lengths were significantly shorter, and the mandible was significantly more protruded in the IP group ( Table II ). The IP group presented a significantly straighter skeletal profile than the control group ( Table II ). Mandibular growth direction was significantly different between groups because of the greater mandibular counterclockwise rotation in the IP group ( Table II ). The anterior facial height was significantly lower in the IP group, determining a short faced pattern ( Table II ). Maxillary incisors were significantly more proclined, whereas the mandibular incisors were significantly more retroclined and retruded in the IP group ( Table II ). Maxillary incisor exposure was significantly smaller in the IP group, and the lower lip was more retruded, nearly being statistically significant ( Fig 2 and Table II ).
|IP group (n = 5)||Control group (n = 25)|
|Variables||Mean||SD||Mean||SD||P value||Effect size (Cohen d)|
|Age (y)||9.33||1.16||9.08||0.19||0.615 †||0.301|
|Maxillary skeletal components|
|SNA (°)||79.79||2.81||81.02||2.91||0.330 ‡||0.430|
|Co-A (mm)||74.70||3.49||82.10||5.41||0.001 ∗ , ‡||1.625|
|A-Nperp (mm)||−1.86||3.29||−0.43||2.61||0.235 ‡||0.481|
|Mandibular skeletal components|
|SNB (°)||78.75||3.32||76.72||3.03||0.136 ‡||0.638|
|Co-Gn (mm)||95.77||4.71||101.59||7.27||0.024 ∗ , †||0.950|
|P-Nperp (mm)||−2.06||5.49||−7.19||4.40||0.014 ∗ , ‡||1.031|
|ANB (°)||1.07||2.39||4.32||1.97||0.008 ∗ , †||1.483|
|NAP (°)||−1.98||3.48||7.95||4.61||<0.001 ∗ , †||2.431|
|SN.GoGn (°)||28.86||5.97||33.77||4.01||0.015 ∗ , ‡||0.965|
|FH.MP (°)||22.91||6.11||27.69||3.73||0.014 ∗ , ‡||0.944|
|NSGn (°)||64.51||3.44||67.50||2.45||0.014 ∗ , ‡||1.001|
|BaN.PtGn (°)||0.74||5.04||−1.78||2.99||0.101 ‡||0.608|
|UAFH (N-ANS, mm)||43.97||4.43||44.57||4.04||0.733 ‡||0.141|
|LAFH (ANS-Me, mm)||51.37||3.69||60.31||4.91||<0.001 ∗ , †||2.058|
|AFH (N-Me, mm)||95.34||7.86||104.89||7.75||0.003 ∗ , †||1.223|
|PFH (S-Go, mm)||62.44||4.81||64.73||4.85||0.278 ‡||0.474|
|PFH/AFH (%)||65.72||5.29||61.81||3.81||0.087 †||0.848|
|Maxillary dentoalveolar components|
|Mx1.PP (°)||113.02||9.12||108.30||5.10||0.081 ‡||0.638|
|Mx1.NA (°)||26.45||8.20||20.11||6.25||0.034 ∗ , ‡||0.869|
|Mx1-NA (mm)||4.90||1.89||3.95||1.63||0.200 ‡||0.538|
|Mandibular dentoalveolar components|
|Md1.MP (°)||88.17||8.92||92.03||6.17||0.195 ‡||0.503|
|Md1.NB (°)||17.86||7.29||24.91||5.31||0.007 ∗ , ‡||1.105|
|Mx1-NB (mm)||2.25||1.42||4.32||1.36||0.001 ∗ , ‡||1.488|
|Overjet (mm)||3.54||2.51||4.12||1.72||0.480 †||0.269|
|Overbite (mm)||1.87||1.29||1.66||1.76||0.776 ‡||0.136|
|MxLip protrusion (mm)||2.86||2.21||3.54||1.76||0.401 ‡||0.340|
|MdLip protrusion (mm)||0.35||2.50||2.01||1.78||0.056 ‡||0.764|
|Mx1 exposure (mm)||2.36||1.99||5.33||2.03||0.003 ∗ , †||1.477|