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Year : 2017  |  Volume : 60  |  Issue : 3  |  Page : 424-426
Incontinentia pigmenti, an x-linked dominant disorder, in a 2-year-old boy with Klinefelter syndrome

1 Department of Dermatology, Christian Medical College, Ludhiana, Punjab, India
2 Department of Dermatology, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry, Tamil Nadu, India
3 Department of Cytogenetics, Christian Medical College, Vellore, Tamil Nadu, India
4 Department of Pathology, Christian Medical College, Vellore, Tamil Nadu, India
5 Department of Ophthalmology, Christian Medical College, Vellore, Tamil Nadu, India
6 Department of Dermatology, Venereology and Leprosy, Christian Medical College, Vellore, Tamil Nadu, India

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Date of Web Publication22-Sep-2017


Incontinentia pigmenti (IP) is a rare X-linked dominant disorder, in which skin lesions distributed along Blaschko's lines appear shortly after birth. Early lesions which are erythematous/bullous evolve over time into warty lesions, hyperpigmented swirls/macules, and atrophic hypopigmented streaks. Clinical features are heterogeneous. Abnormalities of the teeth, nails, hair, eyes, central nervous system, and breast may also be present. While intelligence is generally normal, varied degrees of intellectual disability/developmental delay have been reported. Lifespan is normal. IP is associated with mutations of the inhibitor of kappa light polypeptide gene enhancer in B cell, kinase gamma (IKBKG) gene on chromosome Xq28. This gene is involved in the activation of nuclear factor kappa B which protects cells against apoptosis; therefore, cells with IKBKG mutations are extremely susceptible to apoptosis. X-linked dominant disorders are lethal to male fetuses. Males who survive with IP either have mosaicism or an additional X chromosome (Klinefelter syndrome). We present a 22-month-old boy with IP and Klinefelter syndrome.

Keywords: Incontinentia pigmenti, inhibitor of kappa light polypeptide gene enhancer in B cell, kinase gamma gene, Klinefelter syndrome, mosaicism, X-linked dominant disorder

How to cite this article:
Williams A, Chandrashekar L, Srivastava VM, Thomas M, Horo S, George R. Incontinentia pigmenti, an x-linked dominant disorder, in a 2-year-old boy with Klinefelter syndrome. Indian J Pathol Microbiol 2017;60:424-6

How to cite this URL:
Williams A, Chandrashekar L, Srivastava VM, Thomas M, Horo S, George R. Incontinentia pigmenti, an x-linked dominant disorder, in a 2-year-old boy with Klinefelter syndrome. Indian J Pathol Microbiol [serial online] 2017 [cited 2021 Jul 23];60:424-6. Available from: https://www.ijpmonline.org/text.asp?2017/60/3/424/215402

   Introduction Top

Incontinentia pigmenti (IP) or Bloch-Sulzberger syndrome is a rare X-linked dominant genodermatosis caused by mutations of the inhibitor of kappa light polypeptide gene enhancer in B cell, kinase gamma (IKBKG) (Nuclear Factor κB, Essential Modulator, OMIM#300248 [NEMO]) gene on chromosome X, band q28.[1] IP is characterized by skin lesions which appear shortly after birth.[1] The lesions initially appear erythematous, then as bullae or vesicles and evolve over time into warty lesions, hyperpigmented lesions, and finally into hypopigmented atrophic patches that remain throughout life.[1],[2] The phenotype of IP is heterogeneous.[1] Apart from the skin lesions, abnormalities of the teeth, nails, hair, and breast/nipple may also be present. Abnormalities of the eyes and central nervous system may be seen in up to one-third of patients and are associated with more severe forms of the disease.[4] Intelligence is generally normal, but developmental delay and varying degrees of intellectual disability may be seen.[3],[4] Life expectancy is normal. Being an X-linked dominant disorder, IP is usually lethal in males.[1] We present a 22-month-old boy with the characteristic skin lesions of IP as well as myopia, retinal pigmentary changes, seizures, and cortical dysrhythmia whose survival is explained by a 47, XXY karyotype (Klinefelter syndrome).

   Case Report Top

A 22-month-old boy presented with linear hyperpigmented streaks over the chest, axillae, medial aspects of the upper and lower limbs, groin, and right pinna distributed symmetrically along the  Lines of Blaschko More Details [Figure 1]. The axillary, groin, and popliteal lesions were palpable and warty. The limbs also showed hypopigmented and atrophic streaks. Hair, nails, and teeth appeared normal. Vision was 6/19 in both eyes (Cardiff test at 1 m). Pigmentary changes were seen in the mid-periphery of the fundus. His height was 82.3 cm, head circumference - 47 cm. and weight - 12.3 kg. A clinical diagnosis of IP was made.
Figure 1: Hyperpigmented streaks along lines of Blaschko (arrow)

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He was born at term and weighed 1.9 kg at birth. A “rash” resembling “prickly-heat” was evident on the first postnatal day. There were no vesicles or bullae. By the fourth postnatal day, there were linear hyperpigmented streaks on the trunk and limbs; the warty lesions developed subsequently. At about 8 months of age, he developed seizures with tonic posturing without loss of consciousness. Developmental milestones were normal. There was no dysmorphism.

Laboratory investigations showed normal serum biochemistry and hemogram with 8% eosinophils in the differential white blood cell count. The electroencephalogram showed cortical dysrhythmia. Further imaging could not be done. Skin biopsy of the popliteal lesion was consistent with IP with orthokeratosis, acanthosis, spongiosis, basal cell vacuolation with occasional dyskeratotic cells, and small intraepidermal vesicles containing lymphocytes, histiocytes, and occasional eosinophils. Moderate pigment incontinence and dermal edema with moderate perivascular chronic inflammation were also noted [Figure 2]a and [Figure 2]b. Cytogenetic analysis of long-term cultures of skin fibroblasts and phytohemagglutinin-stimulated cultures of peripheral blood using standard techniques showed a 47, XXY karyotype (Klinefelter syndrome) in all fifty metaphases obtained from both tissues [Figure 3]. Mutation analysis was not done for this patient.
Figure 2 (a and b): Epidermis with hyperkeratosis, acanthosis, and occasional necrotic keratinocytes (arrow), dermal edema and pigment incontinence (arrowhead) in the superficial dermis

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Figure 3: 47,XXY (Klinefelter syndrome), skin fibroblasts

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   Discussion Top

The skin lesions in our patient fulfilled the clinical criteria for the diagnosis of IP as described by Landy and Donnai.[2] His skin biopsy showed changes consistent with IP and his karyotype showed Klinefelter syndrome. The mutation in the majority (80%) of patients with IP is a partial deletion of the IKBKG gene.[1] The remaining patients have point mutations, duplications, or other sequence changes which are associated with milder forms of the disease (hypomorphic mutations).[4],[5] The IKBKG/NEMO gene encodes a protein complex which activates nuclear factor kappa B (NF-κB), a transcription factor which has an antiapoptotic effect. When the IKBKG mutation is present, as in IP, NF-κB is not activated, predisposing cells to apoptosis.[1],[4]

Early in the life of a female embryo, one of the two X chromosome homologs (maternal or paternal) is inactivated randomly so that only one X chromosome homolog is active. Less commonly, X inactivation may be unbalanced (skewed) with the majority of cells showing preferential inactivation of one parental X chromosome homolog. Preferential inactivation of a mutated X chromosome facilitates the survival of female carriers of these mutations.[6] Females with IP who survive show skewed X inactivation so that the X chromosome homolog carrying the IKBKG mutation is inactive in the majority of cells.[7]

X-linked dominant diseases are usually lethal in males who have only one X chromosome homolog; however, there are reports of over sixty males surviving with IP.[1] The international IP consortium has suggested that survival of males with IP might be due to somatic mosaicism which may be of a low level or gain of an additional X chromosome (47, XXY, KS).[8] In males with IP and KS, the presence of two X chromosomes leads to heterozygosity for the mutation as in IP females, with skewed X inactivation enabling survival.[1] KS is estimated to be present in 7% of males with IP.[1] The clinical features of these males are similar to females except that ~ 15% present with unilateral lesions in the early stages of the disease.[9] Intellectual disability or developmental delay was present in up to 35% of IP males. As with IP, KS may also be associated with some degrees of learning disability.[1],[9]

While individuals with features of IP should undergo screening for IKBKG gene mutations, this is currently not widely available in our country. IP males should be karyotyped to detect KS. Some IP males with normal karyotypes might actually have low-level mosaicism for KS which may not be detectable by karyotyping. Therefore, it is recommended that fluorescence in situ hybridization analysis is routinely done to detect low-level mosaicism for a 47, XXY cell line in IP males with normal karyotypes.[10]

This report describes the features of a male with IP and highlights the importance of karyotyping in this rare condition. Awareness of the association between IP and KS in males will enable an early diagnosis to be made, as the physical features of KS become fully evident only at puberty. This will help to plan supportive treatment for both conditions and provide counseling about their long-term impact.

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Conflicts of interest

There are no conflicts of interest.

   References Top

Scheuerle AE, Ursini MV. Incontinentia Pigmenti. In: Pagon RA, Adam MP, Ardinger HH, et al. editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. 08 June, 1999. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1472/. [Last updated on 2015 Feb 12].  Back to cited text no. 1
Landy SJ, Donnai D. Incontinentia pigmenti (Bloch-Sulzberger syndrome). J Med Genet 1993;30:53-9.  Back to cited text no. 2
Minic S, Trpinac D, Obradovic M. Systematic review of central nervous system anomalies in incontinentia pigmenti. Orphanet J Rare Dis 2013;8:25.  Back to cited text no. 3
Smahi A, Courtois G, Vabres P, Yamaoka S, Heuertz S, Munnich A, et al. Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium. Nature 2000;405:466-72.  Back to cited text no. 4
Conte MI, Pescatore A, Paciolla M, Esposito E, Miano MG, Lioi MB, et al. Insight into IKBKG/NEMO locus: Report of new mutations and complex genomic rearrangements leading to incontinentia pigmenti disease. Hum Mutat 2014;35:165-77.  Back to cited text no. 5
Migeon BR. Non-random X chromosome inactivation in mammalian cells. Cytogenet Cell Genet 1998;80:142-8.  Back to cited text no. 6
Parrish JE, Scheuerle AE, Lewis RA, Levy ML, Nelson DL. Selection against mutant alleles in blood leukocytes is a consistent feature in incontinentia pigmenti type 2. Hum Mol Genet 1996;5:1777-83.  Back to cited text no. 7
Kenwrick S, Woffendin H, Jakins T, Shuttleworth SG, Mayer E, Greenhalgh L, et al. Survival of male patients with incontinentia pigmenti carrying a lethal mutation can be explained by somatic mosaicism or Klinefelter syndrome. Am J Hum Genet 2001;69:1210-7.  Back to cited text no. 8
Ardelean D, Pope E. Incontinentia pigmenti in boys: A series and review of the literature. Pediatr Dermatol 2006;23:523-7.  Back to cited text no. 9
Franco LM, Goldstein J, Prose NS, Selim MA, Tirado CA, Coale MM, et al. Incontinentia pigmenti in a boy with XXY mosaicism detected by fluorescence in situ hybridization. J Am Acad Dermatol 2006;55:136-8.  Back to cited text no. 10

Correspondence Address:
Renu George
Department of Dermatology, Venereology and Leprosy, Christian Medical College, Vellore - 632 004, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_91_16

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