Clinical Study of 40 Cases of Incontinentia Pigmenti

STUDY Clinical Study of 40 Cases of Incontinentia Pigmenti

Smaı¨l Hadj-Rabia, MD; David Froidevaux, MD; Nathalie Bodak, MD; Dominique Hamel-Teillac, MD; Asma Smahi, PhD; Yasmina Touil, MD; Sylvie Fraitag, MD; Yves de Prost, MD; Christine Bodemer, MD, PhD

Objective: To analyze the distribution of manifesta- sions were rarely absent in the patients with IP. Ocular and tions in a pediatric cohort and define guidelines for fol- neurological abnormalities were frequent (20% and 30%, low-up of incontinentia pigmenti (IP). respectively) but rarely severe (8% and 7.5%, respectively).

Design: Retrospective study of 47 children referred to Conclusions: Clinical diagnosis is the first main step for the Department of Pediatric Dermatology with a diag- a correct phenotype/genotype correlation, which re- nosis of IP between 1986 and 1999. mains indispensable to better understand the pathological mechanisms of IP and develop new therapies. In doubt- Setting: The private or institutional practice of partici- ful cases, molecular analysis is helpful but characteristic pating dermatologists and pediatricians. histological features must be added as major criteria for IP diagnosis. Multidisciplinary follow-up is needed, par- Main Outcome Measures: Evaluation of IP clinical ticularly during the first year of life, to detect possible diagnosis using the Landy and Donnai criteria. ophthalmologic and neurological complications. Neu- roimaging ought to be performed in the case of abnor- Results: Because hyperpigmentation following the Bla- mal neurological examination results or when vascular schko lines may be observed in several pigmented dis- retinopathy is detected. orders, 7 patients were found misdiagnosed. During the neonatal period, erythema, vesicles, and hyperkeratotic le- Arch Dermatol. 2003;139:1163-1170

NCONTINENTIA PIGMENTI (IP), or and pustules (stage 1); verrucous lesions Bloch-Sulzberger syndrome, is a (stage 2); linear hyperpigmentation (stage rare X-linked dominant genoder- 3); and pallor and scarring (stage 4). Stages, matosis that affects mostly fe- however, may overlap or not occur at all in male patients and is usually le- a same patient.5 A linear hyperpigmenta- thalI for males in utero. It is a multisystem tion that follows the Blaschko lines leads disorder, primarily of ectodermal origin, to IP (a disease with a highly evocative accompanied by dental, ocular, and cen- name). However, Blaschko linear hyperpig- tral nervous system disorders such as sei- mentation can be observed in a heterog- zures, spastic paralysis, microcephaly, and eneous group of mosaic conditions, eg, hy- mental retardation.1,2 The typical pheno- pomelanosis of Ito (HI). Thus, IP clearly ap- type results from a functional mosaicism, pears to have been overdiagnosed in the itself a consequence of lyonization (the past.6,7 For this reason, the frequency of the random inactivation of one of the two X clinical features associated with the highly chromosomes in women).3 diagnosticcutaneousmanifestationsaredis- cussed in the literature. Landy and Donnai5 For editorial comment classified IP criteria into 2 groups, negative see page 1206 family history and first-degree family his- From the Departments of tory (Table 1). These criteria remain es- Dermatology (Drs Hadj-Rabia, The identification of nuclear factor– sential for distinguishing such disorders and Froidevaux, Bodak, kappa B (NF-␬B) essential modulator their clinical and genetic implications.5 Hamel-Teillac, Touil, de Prost, (NEMO) as the disease-causing gene, and The aim of our study was to evaluate and Bodemer), Medical the skewing of the X chromosome inacti- with the Landy and Donnai criteria a series Genetics (Drs Hadj-Rabia and vation, are powerful new tools that have of 47 patients previously diagnosed as hav- Smahi), and Pathology made the diagnosis of unusual forms of IP ing IP. We also analyzed the distribution of (Dr Fraitag), Hoˆpital 4 Necker–Enfants-Malades, easier. Nevertheless, the diagnosis of IP is clinical manifestations and compared our Paris, France. The authors have based on clinical examination. The skin le- findings with the data in the literature, no relevant financial interest in sions may occur in 4 classically successive thereby demonstrating the importance of at- this article. diagnostic stages: erythema, then vesicles tentive clinical examination.

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No Incidence of IP in at Least 1 First-Degree Female Relative Evidence of IP in at Least 1 First-Degree Female Relative Major Criteria Typical neonatal rash Suggestive history or evidence of typical rash Erythema, vesicles, eosinophilia Skin manifestation of IP Typical hyperpigmentation Hyperpigmentation Mainly on trunk Scarring Following Blaschko lines Hairless streaks Fading in adolescence Alopecia at vertex Linear, atrophic, hairless lesions Anomalous dentition Wooly hair Retinal disease Multiple miscarriages of male fetuses Minor Criteria (Supportive Evidence) Dental involvement Alopecia Wooly hair, abnormal nails

At least 1 major criterion is necessary to make a firm diagnosis of sporadic The diagnosis of IP is likely in a first-degree female relative of an IP. Minor criteria, if present, will support the diagnosis; because of their affected female patient if any of the mentioned minor criteria high incidence, complete absence should induce a degree of uncertainty. are present, alone or in combination.

*According to Landy and Donnai.5

Table 2. Clinical and Biological Characteristics of the 3 Patients With Uncertain Diagnosis

Patient No.

Characteristic 12 3 Age of suspected IP 2 y 1 d 1 d Typical neonatal rash NA Erythema NA Linear hyperpigmentation Occurred at 2 y Occurred at 10 d Occurred at 1 d Fading in adolescence NA NA NA Hypopigmentation NA NA NA Dental involvement NA NA NA Alopecia Transient and occipital Vertex NA Eosinophilia 768/µL NA NA Family history Psychomotor delay (brother) Reticular hyperpigmentation (mother) Associated disorders NA Bipolar aphtosis, myocardiopathy Uretherocele Chromosome X inactivation Random Not contributive Random NEMO rearrangement NA NA NA

Abbreviations: IP, incontinentia pigmenti; NA, not applicable (absent); NEMO, nuclear factor–kappa B essential modulator.

METHODS RESULTS

We reviewed the clinical records of pediatric patients diag- Forty-seven patients believed to have IP (43 girls and 4 nosed as having IP and referred to the Department of Pediatric boys) were referred to us during this period with rel- Dermatology at Hoˆpital Necker–Enfants-Malades, Paris, France, evant medical records. However, we considered that only between 1986 and 1999. The medical records of all affected pa- 40 of them (37 girls and 3 boys) had been rightly diag- tients, which included neonatal data as well as inpatient and nosed. Age at diagnosis was unknown for 7 of the chil- outpatient records, were reviewed by 2 experienced derma- dren who had IP; for the remainder, median age was 6 tologists (D.F. and C.B.). They used a standardized form to col- lect clinical information (mostly regarding cutaneous, ocular, months 9 days (range, birth to 12 years). Among the 7 dental, and neurological manifestations as well as family his- patients with a questionable IP diagnosis, 3 were finally tory) and investigation results. When necessary, obstetric and diagnosed with HI, 1 with orofacial-digital syndrome, and pediatric medical records were consulted, as well as special- diagnosis is still uncertain in the last 3 cases (Table 2). ists from other disciplines who followed up the patients. The clinical data were analyzed according to the criteria set by Landy SKIN MANIFESTATIONS and Donnai5 (Table 1). Skin biopsy samples obtained from 28 patients were ex- Information was available for all 40 patients. Dermato- amined by the same pediatric dermatopathologist (S.F.). Eo- logical manifestations were present as early as the first sinophilic count in peripheral blood analysis was performed day after birth in 27 (68%) of them, during the neonatal in 26 patients and skeletal radiographs in 20. period in 9 (22%), and after the age of 3 months in 4

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Table 3. Skin Manifestations of the 40 Patients With Incontinentia Pigmenti and Their Topography*

Age of Onset Topography Lesion Total Stage Ͻ1mo 1moto1y Ͼ1 y Unknown Limbs Trunk Face Folds Extremities (N = 40) 1 33 (89) 2 (5) 0 2 35 (95) 19 (51) 4 (11) 7 (19) 12 (32) 37 2 8 (25) 7 (22) 0 17 25 (78) 6 (19) 3 (9) 2 (6) 10 (31) 32 3 6 (17) 10 (28) 2 (6) 18 28 (78) 24 (67) 5 (14) 12 (33) 3 (8) 36 4 5 (42) 4 (33) 4 (33) 0 12 (100) 2 (17) 0 0 0 12

*Data are given as number (percentage) of patients for each lesion stage. Diagnosis was performed before 1 month of life for 36 patients and before 1 year for all 40 patients.

A C

B D

Figure 1. Skin features of incontinentia pigmenti. A, Erythema and vesicles following Blaschko lines (stage 1); B, hyperkeratotic and verrucous lesions (stage 2); C, linear hyperpigmentation (stage 3); and D, pale, atrophic, hairless linear lesions (arrow) (stage 4).

(10%); skin lesions were present before the second week Linear hyperpigmented stage 3 lesions were pres- of life in 36 (90%). Data are reported in Table 3 and ent in 36 (90%) patients, but absent in 4 (10%) who were manifestations shown in Figure 1. referred before the age of 2 months. Hyperpigmented le- Erythema and vesicles (stage 1) were the first mani- sions initiated skin manifestations in 2 patients and were festations in 37 (92%) of the 40 patients, but stage 1 was present at birth in 1. absent in 3 (8%), and 2 had late recurrences of stage 1 Finally, stage 4 manifestations were recorded in 12 lesions: 7 episodes of blisters occurred during the first (30%) patients but absent in 20 (50%), and information year in one of them, and several episodes until the age was not available for 8 (20%) patients. Linear, reticulate, of 3 years in the other. or macular atrophic lesions were described in 9 (75%) of Typical stage 2 hyperkeratotic lesions were noted the 12 patients; lesions were present before the second week in 32 (80%) patients but were absent in 6 (15%), and in- of life in 4, and after 1 year in 2. Linear hypopigmentation formation was not available for 2 (5%). For 1 patient, stage was noted in 4 (10%) of the 40 patients with IP. Informa- 1 skin manifestations were absent and skin disease be- tion on the evolution of pigmentation anomalies was not gan with hyperkeratotic lesions. Frequently diffuse, stage available because there was no long-term follow-up. 2 lesions were limited to the scalp (1 case) or the ex- Alopecia of the vertex was observed in 11 (28%) of tremities (2 cases). the 40 patients, was absent in 24 (60%), and informa-

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Table 4. Neurological Manifestations and Neuroimaging Findings in 15 of 40 Patients With Incontinentia Pigmenti*

Patient No.

1 2 3456789101112131415 Manifestations Seizures + + +++++++ + − − − − − Delayed psychomotor development − − −+−−−++ + + + + − − Mental retardation − − −−−−−++ − − + − − − Hemiplegia + − −+−−−−− − − − − − − Hemiparesia − − −−+−−−− − − − − − − Coma + (D) + (D) +−−−−−− − − − − − − Neuroimaging findings Transfontanellar ultrasound − A −−−−−−− − N − − N − Cerebral atrophy + + +++−−−− − − − − − − Porencephalia + + −−+−−−− − − − − − − Hemorrhagic necrosis + + +++−−−− − − − − − − Lateral ventricle enlargement − + −++−−−− − − − − − − Leukodystrophy − − −−−−−−− − − − − − + Corpus callosum hypoplasia + − −−−+−−− − − − − − −

Abbreviations: A, abnormal; D, death; N, normal; +, present; −, absent. *Neurological manifestations occurred before 3 weeks of life in patients 2, 3, 4, 8, and 9. Age of onset is unknown for the others. Patients 14 and 15 had normal neurological examination results. Patients 3 and 13 are males. Patients 7 and 15 had retinal detachment and patient 11 had occlusion of the central retinal artery.

tion was not available for 5 (12%). Alopecia was present prominent features in the 5 patients who had a com- in 7 patients younger than 6 months and in 4 older than puted tomographic scan. Porencephalia was reported in 6 years. 3 (25%) of the 12 patients, enlargement of lateral ven- Nail dystrophy was present in only 3 (10%) of the tricles also in 3 (25%), and hypoplasia of the corpus cal- 30 patients for whom this information was noted. Nails losum in 2 (17%). Leukodystrophy was detected in pa- were striated and thick in a 4-month-old girl, while ony- tient 15, who presented with severe retinal detachment. cholysis and hyperkeratosis of the 10 fingernails were present in another severely affected 10-year-old girl. Tra- DENTAL ABNORMALITIES chyonychia was noted at birth in 1 girl and supernumerary nipples were noted in 2. At evaluation, 23 (58%) of the 40 patients with a veri- fied IP diagnosis were younger than 1 year and teeth ex- NEUROLOGICAL INVOLVEMENT amination was impractical, but information was avail- AND NEUROIMAGING able for 17 (42%) patients. Among these 17 patients, 10 (59%) presented with tooth abnormalities: 7 (70%) with Clinical neurological manifestations were observed in 13 partial anodontia of deciduous or permanent teeth, and (32%) of the 40 patients (Table 4, patients 1-13). Neu- 5 (50%) with conical teeth; this was an isolated condi- rological manifestations occurred within the first weeks, tion in only 2 (20%). Microdontia and delayed eruption even within the first day of life, in the 5 (38%) children of permanent teeth were reported in only 1 patient. Two in this group cared for since birth in our department. sisters and their mother had isolated cleft palate. Seizures were the prominent feature in 10 (77%) of the 13 patients with neurological involvement. Grand mal EYE ABNORMALITIES seizures occurred in 2 patients (patients 8 and 9) and led to death due to vascular cerebral damage: thalamic hem- Information concerning a detailed ophthalmologic orrhage in one and ischemia and necrosis of both hemi- examination was available for 34 (85%) of the 40 spheres in the other. These 2 individuals presented with patients studied and anomalies were noted in 7 (20%) of early and extensive skin manifestations. Delayed psy- them. The association of ocular and neurological mani- chomotor development was noted in 7 (54%) of the 13 festations is reported in Table 4. Strabismus was noted patients, while mental retardation was reported in 3 in 4 patients (12%); the condition was isolated in 3 (9%) (23%), and a spastic hemiplegia sequela was reported in and was associated with ophthalmoplegia of the sixth 2 (15%). cranial nerve as a complication of cerebral hemorrhage Neuroimaging performed in 12 of the 13 patients in the fourth. Unilateral microphtalmia was reported in revealed neurological manifestations in 10, and 2 had nor- 2 patients (6%); it was associated with retinal detach- mal results (Table 4, patients 14 and 15). Transfonta- ment in one and with retinal detachment, aneurysm, nellar ultrasonography was performed in 3 (25%) of these hemorrhage, cataract, early seizures, and monocular 12 patients; a computed tomographic scan in 5 (42%), blindness as a sequela in the other. Each of the following all of whom had neurological symptoms; and magnetic features was reported in only 1 patient: unilateral retinal resonance imaging (MRI) in 6 (50%). Cerebral atrophy pigmentation, coloboma, and occlusion of the central and focal or extensive hemorrhagic necrosis were the retinal artery.

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Table 5. Histological Features From 21 Biopsies of Patients A With Incontinentia Pigmenti*

Lesion Stage

123 Biopsies, No. 11 8 2 Histological features Eosinophilic spongiosis 11 3 0 Dyskeratosis 10 8 1 Free melanin in dermis 3 5 2 Dermal infiltration by lymphocytes 561 and eosinophils

*Stage of skin eruption was known for 21 biopsies. Histological features reflect progressive keratinocyte apoptosis and may be added as major B criteria for incontinentia pigmenti diagnosis.

IP IN BOYS

Our series included 3 boys (8%) with a sporadic form of IP. One presented with stage 4 skin manifestations only. His karyotype was normal (46,XY). The second presented with skin manifestations, and with such neurological abnormalities as hemiparesia of the left arm and porencephalia of the left globus pallidus on computed tomographic scan. The third presented with skin manifestations, strabismus, and seizures, and MRI showed is- chemic lesions of the frontal lobes (Table 4). His karyo- C type was normal (46,XY).

ASSOCIATED DISORDERS

One patient had associated Down syndrome. It was diagnosed by chromosomal analysis (47,XX+21) and prob- ably related to maternal age. Each of the following was reported in this patient only: exudative enteropathy, megalo-urether, port-wine stains on the superior lip and scalp, laryngomalacia, tumor of the vertebral lumbar ca- nal, and recurrent pulmonary infections.

FAMILY HISTORY Figure 2. Histological features of incontinentia pigmenti. A, Spongiosis by eosinophils (stage 1) (hematoxylin-eosin, original magnificationϫ40); On examination, 11 (28%) of the 40 patients studied had B, dyskeratosis (stage 2) (hematoxylin-eosin, original magnificationϫ250); a family history of IP involving at least the mother. Clini- and C, free melanin in dermis (stage 3) (hematoxylin-eosin, original cally, IP was considered sporadic in 25 patients (62%). All magnificationϫ100). Histological features reflect keratinocyte apoptosis; they are helpful for incontinentia pigmenti diagnosis and could be included affected boys were diagnosed as having a sporadic form. as major incontinentia pigmenti criteria. Information was not available for 4 (10%) of the patients.

HISTOLOGICAL FEATURES 15400/µL. Skeletal radiographs showed normal bones in the 20 patients tested. A skin biopsy sample was obtained for 26 of the 40 patients, and skin lesion stage was known for 21 of the MOLECULAR INVESTIGATIONS samples. There were 11 with histological analysis of stage 1 lesions, 8 of stage 2 lesions, and 2 of stage 3 lesions. Karyotype screening performed in 7 (18%) of the 40 pa- The results are reported in Table 5 and shown in tients (3 with familial forms, 3 with sporadic forms, and Figure 2. 1 with an undetermined form of IP) showed an abnormal result only in the girl with Down syndrome. EOSINOPHILIA AND SKELETAL Samples of DNA were available for only 12 patients RADIOGRAPHIC FINDINGS (1 with familial and 11 with sporadic forms of IP). In- activation of an X chromosome and NEMO deletion were Eosinophilia was present in 23 of the 26 patients tested. tested in all of them. The skewing of chromosome X in- Absolute eosinophil counts ranged between 550/µL and activation was constant; it concerned the maternal X chro-

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 mosome in 4 patients (in 3 with sporadic forms and in with published data (80% vs 70%, Figure 1B), as well as the patient with the familial form of IP) and the paternal the lesions’ time of appearance (within the first 2 months X chromosome in the 8 remaining patients. The NEMO of life) and duration (they cleared within 6 months).5,14 rearrangement (deletion of exons 4 through 10) was pres- Verrucous lesions may be localized (Table 3), and are ent in 9 of the 12 patients (4 with sporadic and 5 with highly evocative on the scalp. Late onset of focal verru- familial forms). cous lesions has been reported.20 In our series, stage 3 linear hyperpigmentation began at 2 weeks of life, ear- 5 COMMENT lier than previously reported (Table 3 and Figure 1C). On the trunk, the spontaneous occurrence and nonscar- Between 1986 and 1999, 47 children diagnosed as hav- ring resolution of Blaschko linear hyperpigmentation are ing IP in the Department of Pediatric Dermatology were major characteristics of IP.5 Such isolated hyperpig- reevaluated using the Landy and Donnai criteria, and 7 mented lesions during adulthood may be confused with were found misdiagnosed. Hypomelanosis of Ito had been other pigmented disorders. Interestingly, 1 of 2 biopsy mistaken for IP in 3 patients, 2 girls and 1 boy. Since birth, results of stage 3 lesions showed free dermal melanin as- these 3 chidren had had linear hyperpigmentation fol- sociated with focal dyskeratosis. Pale, stage 4 macular and lowing the Blaschko lines, with indistinct edges to the reticular atrophic lesions were observed in only 9 (22%) hyperpigmented or hypopigmented areas, and no re- of the 40 patients in our series. These lesions occurred corded episodes of vesicular or verrucous lesions. They before 1 year of age in 78% of cases (Table 3 and Figure had no family history of HI and no psychomotor devel- 1D). Classically, stage 4 begins later than the other stages; opmental delay, which is more frequent in the excep- and because it persists in adulthood, it is helpful in the tional cases of familial HI.8-10 Genetic counseling is dif- tardive diagnosis of IP in women.5,14 ferent in the case of HI as, unlike IP, it is frequently related Hair, nail, dental, and nipple involvements are mi- to chromosomal anomalies.11 Orofacial-digital syn- nor but useful criteria for IP diagnosis in adults.5 The fre- drome was diagnosed in a girl who presented with lin- quency of alopecia of the vertex was less (28%) in our ear hyperpigmentation and hypopigmentation, micro- retrospective study than previously reported in the lit- cephaly, cleft palate, ear abnormalities, coloboma of the erature (38%).5,14 Wooly hair has been reported but hair optic nerve, and interventricular communication.12 Di- shaft is usually found normal on microscopic examina- agnosis is still uncertain for the 3 remaining girls who tion.21 Nail involvement ranges from mild pitting to ony- had nonfading linear hyperpigmentation at birth (Table chogryphosis.22 The low frequency of nail anomalies in 2). No episodes of vesicular or verrucous lesions were our study (8% vs 40% elsewhere5) may be related to our recorded for these children. Follow-up lasts up to 5 years. recording only severe forms. In 1 case, subungual hy- The absence of histological IP features, the random na- perkeratosis of all fingernails was painful and neither topi- ture of X chromosome inactivation, and the absence of cal treatment with salicylic acid nor retinoic acid given NEMO gene rearrangement permitted to exclude IP for orally was efficient.23 Unfortunately, follow-up was not all the misdiagnosed children. The association of inflam- possible. Supernumerary nipples were noted in 2 girls. matory colitis, bipolar aphtosis, and linear hyperpigmen- As it is 10 times more frequent in patients with IP than tation previously reported as Behc¸et disease with IP did in the general population,5 breast involvement may be not satisfy the Landy criteria.13 Nevertheless, such an as- added as a minor criterion for IP diagnosis. The early age sociation may provide a key for understanding the mo- of our patients may explain the low frequency (25%) of lecular basis of IP and should to be further explored. dental involvement, which is usually common in IP.5,7,14 According to the Landy and Donnai criteria, 40 pa- The deciduous and/or permanent dentitions may be af- tients had been rightly diagnosed as having IP (Table 1). fected. Partial anodontia (lateral incisors and premo- All 4 classic stages of IP skin lesions were found (Table lars) and conical teeth (incisors and canines) are com- 3 and Figure 1). Several stages may overlap, making di- mon in IP5 and were noted in in 70% of our patients; agnosis difficult. However, the first 2 stages are rarely ab- however, these tooth abnormalities are frequent in the sent during the neonatal period, and the features of the pediatric population (6% and 0.33% for partial anodon- last 2 stages are helpful for diagnosing IP in adulthood. tia and conical teeth, respectively24). Microdontia, enamel Stage 1 lesions frequently occur, and were noted in dysplasia, delayed eruption, or caries have also been re- 92% of our cases. They are characteristic of IP and no ported in IP.24 During the neonatal period, panoramic ra- differential diagnosis may be evoked regarding vesicles diography is not necessary. Cleft palate has been de- following the Blaschko lines and preceded by erythema scribed in 1.1% of patients with IP, vs 0.28% in the general scattered over the face (Figure 1A). As previously re- population.25 ported,14 stage 1 lesions appear before the second week The severity of IP is related to ocular and neuro- of life in 90% of cases and clear within the first 4 months. logical impairment.5,7 In our series, ocular involvement In our series, recurrence of stage 1 lesions was noted in was less frequent (20%) than that reported (approxi- 2 patients and reported elsewhere.15 The frequency of such mately 40%)14,26 because we chose not to record myopia late recurrences, sometimes several years after the neo- and astigmatism, which are common in the general popu- natal period, remains unknown.16-19 Thus, a diagnosis of lation.27,28 Ophthalmologic manifestations are divided into IP could be considered in the case of a child presenting retinal (retinal detachment, visual loss) and nonretinal with recurrent inflammatory lesions of unknown origin (strabismus, cataract, pigmentation of the conjunctiva).29 along the Blaschko lines. The frequency of stage 2 ver- The incidence of strabismus is significantly higher in IP rucous and keratotic lesions in our series was consistent than the 3.7% found in the general population.30 Mi-

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 crophthalmia, which occurred in 6% of our patients, has eosinophilic spongiosis characterize IP. With stage 3 le- also been reported in IP.29 The frequency of only severe sions or, later, with residual linear hyperpigmentation in ocular impairment, ie, retinal detachment or visual loss, adults, the association of both apoptosis and free mela- was similar to that reported in previous studies and close nin is highly suggestive of IP. Although their absence can- to 8%.14 Retinal detachment is a consequence of neovas- not exclude a positive diagnosis, the detection of such cularization following retinal ischemia caused by abnor- histologic features should be considered a major crite- mal peripheral retinal vessels.29 The entire process may rion for IP diagnosis. Intensity of skin manifestations and occur slowly over several years or quickly within the first eosinophil count are not related to more severe visceral month of life. Thus, careful and regular ophthalmologic involvement and have no prognostic value.5 follow-up is required during the first year7,26 so that spe- Careful and systematic examination of first-degree cific therapy for retinal detachment, such as laser treat- relatives allowed the detection of minor manifestations ment, may be implemented.31 Since vascular abnormali- in the relatives of 11 of our 40 patients. In 2000, IP was ties may explain severe ocular and neurological shown to be caused by mutations of the NEMO 10 ex- involvement, neuroradiological explorations must be per- ons gene. In 9 (80%) of our 12 patients for whom DNA formed if any vascular retinopathy is identified.31-33 Leu- samples were available, the disease-causing mutation was kodystrophy was detected by MRI in a 9-year-old girl who a large-scale deletion of exons 4 to 10, which produces presented with severe retinal detachment and normal neu- an unstable protein.4 The NF-␬B pathway is involved in rological examination, and MRI or computed tomogra- local inflammatory response and in the control of kerat- phy scan may detect microphthalmia and retinal detach- inocyte apoptosis, which explains the clinical and his- ment.31,34 In IP, vascular retinopathy constitutes a tological features of apoptosis in IP.15 The severity of the predictive risk factor for cerebral involvement. clinical manifestations of the disease are not related to In 1976, Carney14 stressed the frequency of neuro- the type of mutation. Skewed X inactivation is detected logical manifestations, which he reported occurring in in over 98% of female patients with IP and in our series, 30.5% of his 653 patients. Landy and Donnai, however, it was detected in all 12 tested girls. Testing X inactiva- consider that Carney overestimated this frequency be- tion is helpful for diagnosing mild forms of IP or iden- cause of misdiagnosed cases and found neurological mani- tifying the parental origin of the mutated X chromo- festations in 18% of their own 111 patients.5 In our se- some in sporadic cases.47 Germline mutations in the ries, even when considering the Landy and Donnai criteria, father’s gonads explains over 80% of sporadic IP cases.48 neurological impairment was found to be frequent (32%) As indicated earlier, the mutated X chromosome was of and severe—causing death in 2 cases (Table 4). Mental paternal origin in 8 of the 11 sporadic cases in our se- retardation, found in about 8% of patients with IP, could ries, revealing the occurrence of paternal-germline mo- be a consequence of early and frequent convulsive epi- saicism. Usually, affected male fetuses die in utero at the sodes, mostly within the first year of life.5,14,35-38 Thus, the end of the first trimester.49,50 As the diagnosis is not sys- child should be watched carefully during this period. Lim- tematically established, the frequency of IP in boys is prob- ited data concerning central nervous system imaging have ably underestimated; in this study, 3 boys with normal been published.37-40 In our series, MRI and computed to- karyotype fulfill the criteria. In boys, the disease may oc- mographic scan results confirmed the findings of clini- cur with a broad spectrum of phenotypic manifesta- cal examination. Cerebral atrophy, porencephalia, hem- tions, from isolated skin involvement to severe neuro- orrhage, and hypoplasia of the corpus callosum (2 cases logical impairment.51 Genetically, such cases may be in this study) have been also reported elsewhere.34,41,42 explained by the presence of the Klinefelter syndrome The IP-induced pathogenesis of the central nervous sys- (47,XXY) or early somatic mutation of the NEMO tem is still unknown, but developmental inflammatory gene.51-54 Interestingly, NEMO mutations have also been mechanisms, occlusive phenomena in small vessels, or reported in anhidrotic ectodermal dysplasia with im- both, have been suggested.34,36,37,43 Developmental mal- mune deficiency.55 This emphasizes the strong relations formations such as spina bifida seem to be fortuitous in between these 2 diseases affecting ectoderm-derived struc- IP. We observed 1 case, with isolated megalo-urether; this tures.56 led to excluding the diagnoses of mammo-renal or acro- The diagnosis of IP is initially based on clinical cri- mammo-renal syndromes, in which urinary malforma- teria. Dermatologists and pediatricians are those first con- tions are associated with abnormal nipples.44 cerned. As, at birth, both eosinophilic spongiosis and Few paraclinical explorations are required for IP di- apoptosis are characteristic of IP, histological features may agnosis. According to Landy and Donnai, eosinophilia be added as major criteria for diagnosis. The follow-up is a major criterion during the neonatal period. Eosino- of patients with IP is based on multidisciplinary collabo- philia then decreases slowly to normal values and is usu- ration, and its primary goal is the detection of rare oph- ally not complicated by visceral disorders.45 Histologi- thalmologic and neurological involvement as early as pos- cal analysis may be helpful for diagnosis.46 Stage 1 lesions sible in the first year of life. Neuroimaging is performed are characterized by eosinophilic spongiosis of the epi- when abnormal findings on neurological examination, dermis (in 100% of patients in our series), which disap- vascular retinopathy, or both, are detected. Genetic coun- pears at the beginning of stage 2 lesions. Focal dyskera- seling must involve both patient and relatives. In doubt- tosis occurs very early, persists until the onset of stage 4 ful cases, DNA studies are helpful to ascertain or rule out lesions (Table 5 and Figure 2), and was clearly deter- the diagnosis. Clinical diagnosis is the first main step to- mined to be related to keratinocyte apoptosis.4 During ward a correct phenotype/genotype correlation, which the neonatal period, association of both apoptosis and remains indispensable for a better understanding of the

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