Case report: Variability in clinical manifestations within a family with incontinentia pigmenti

Abstract

Diagnosing skin diseases in children can be a complex interdisciplinary problem. Incontinentia pigmenti (IP), also known as Bloch-Sulzberger syndrome, is a rare hereditary genodermatosis related to a mutation in the IKBKG gene. We present a family case of IP described from the perspective of various specialists, including dermatologists, oncologists, geneticists, dentists, and trichologists. The peculiarity of this case is the development of squamous cell carcinoma (SCC) on the shin of a 10-year-old female patient with IP. The patient had a positive family history: her mother and two sisters also displayed clinical manifestations of IP with involvement of skin, teeth and hair. The presence of exons 4-10 deletion in the IKBKG gene in all affected females was confirmed by detailed genetic evaluation using long-range PCR, and also high degree of X-chromosome inactivation skewing was demonstrated. The family underwent a comprehensive examination and was followed up for 2 years with successful symptomatic treatment of dermatologic manifestations. Recommendations were also made regarding dental and hair problems. By the end of the follow-up period, patients had stabilized, with the exception of a 36-year-old mother who developed generalized morphea. The study demonstrates the varying expressiveness of clinical symptoms among family members and emphasizes the importance of timely diagnosis for effective management of patients with IP.

Keywords: IKBKG/NEMO deletion; X-chromosome inactivation; dental abnormalities; family case report; hair; incontinentia pigmenti; squamous cell carcinoma.

Figure 1

Phenotypic characteristics of the proband P. (A) Hyperkeratotic nodule on the skin of right shin. (B) Skin area with growth of an exophytic mass, epidermis with marked hyperkeratosis, verrucous papillomatosis and acanthosis, linear lichenoid lymphocytic infiltration (hematoxylin and eosin), x80. (C) Invasive complexes of neoplastic epithelium in the dermis, with dense lymphocytic infiltration, x200. (D) Concentric aggregations of the neoplastic epithelium with central keratinization, impaired maturation, moderate cytologic atypia, x350. (E) Сurrent state of the area of operation. (F) Dermatoscopy reveals Wickham streae (left) and pseudo follicular openings surrounded by violaceous halo (right), typical for hypertrophic lichen ruber planus. (G,H) First days of life. (G) Erythematous rush. (H) Vesicles and erosions on the patient skin. (I–K) Present state. (I) Overview. (J,K) Areas of hyperpigmentation involving inner leg and armpit. (L) Homogenous brown pigmentation is visible under dermoscopy (Dermlite 4, polarized mode). (M) Confocal microscopy reveals uneven melanin accumalation in hyperpigmented spots. (N) Parietal hair thinning, brownish discoloration of the scalp in previously affected areas. (O) Areas of scarring alopecia, single hairs predominate (Dermlite x 10, polarized mode). (P) Dental malformations.

Figure 2

Phenotypic characteristics of the proband’s mother M (A–F) and sister S1 (G–J). (A–C) Areas of irregular pigmentation in M. (D) Parietal zone with hair thinning. (E) Dental malocclusion (adentia of both upper lateral insicors and also two molars on the lower jaw are missing). (F) Orthopantomogram shows anomalies in the positioning of individual teeth, adentia of both maxillary lateral insicors and two molars on the lower jaw. (G,H) Areas of hyperpigmentation on the trunk and legs in S1. (I) Parietal zone with sparse hair growth. (J) Mild dental malformations.

Figure 3

Phenotypic characteristics of proband’s sister S2 (A–G) and trichoscopic hair evaluation of family members (H–K). (A) Overall view. (B) Light brown linear, curved and “star-like” macules are preserved on the trunk. (C) Severe alopecia in parietal zone. (D) Compensatory tilt of the head to the left, corners of the mouth downwards, lips are not closed in the resting position. (E) Laying of the tongue between the teeth on the right side in the area of missing teeth. (F) The smile is asymmetrical, the tongue is inserted between the teeth on the right side. (G) Orthopantomogram reveals multiple tooth adentia. (H) Trichoscopy of the scalp of S1 and S2 demonstrates growth of mostly single hair, white peripilar dots (blue arrows), honeycomb-shaped pigmentation (green oval), and scalp discoloration (red arrows). (I) Keratinous perifollicular desquamation (purple arrow). (J) Boomerang-type hair bending in the proximal zone of growing single hair (shown by arrows). (K) A large number of single growing hair (brown arrows) and the presence of vellus hair (black arrows) on the scalp of M.

Figure 4

Molecular-genetic analysis. (A) Long-range PCR with IKBKG primer pair In2/JF3R revealed IP-specific 2.6-kb band in patient samples (M – mother, P – proband, S1 – sister 1, S2 -sister 2) and the absence of PCR-product in healthy people (F – father of the family and (−) – negative control). (B) In contrast, bands amplified with primers specific for IKBKGP (JF3R/Rev2) showed no appreciable specificity between patients and controls. (C) Fragment analysis of PCR products amplified from undigested HPAII (−) and digested HPA (+) DNA of F, M and S2. In the F DNA, one major peak decreases significantly after HpaII digestion. In the undigested M DNA, the two major peaks represent two alleles with different numbers of short tandem repeats at the AR locus, after digestion the short allele is practically disappeared (red arrow). The S2 DNA displays the preferential loss of the active father’s (F) allele (red arrow), while the inactivated M allele is preserved.