The cutaneous presentation of this disease is stepwise unlike other syndromes. The sequence of these lesions may be irregular but there are four stages of the skin eruptions.

A family history is reported in the mother in about 28% patients. In about 62% patients, the syndrome manifests sporadically.

First stage

It is present at birth and if not seen at birth then most of the patients develop it within the first two weeks of birth. There is presence of vesicular eruptions on a base of erythema and the lesions follow Blaschko lines.

The lesions are more often seen over the trunk and the extremities but may be seen on other parts of the body as well. They are generally present till the fourth month of life and then resolve. Rarely recurrence of vesicular lesions have been reported in association with a febrile illness or routine immunization [4] [5].

Second stage

Verrucous lesions are seen over the skin. They are typically wart like and thickened plaques appear as if on a healed lesion. They develop on the lines of Blaschko and are generally seen after the first stage of skin eruption. They occur in 80% of the patients and resolve over few weeks to months.

Third stage

This stage involves the development of hyperpigmented skin where discoloration may be in the form of whorls and streaks. This is also seen along the lines of Blaschko. They cannot be correlated with the previous lesions; neither do they compulsorily appear on the same areas as the verrucous and the vesicular skin eruptions. They develop slowly and resolve during adolescence only.

The lesions are spread over the trunk, extremities, skin folds and the neck and occur in more than 90% patients.

Fourth stage

This stage comprises of hypopigmented and atrophic patches which may be seen after the stage 3 and persist throughout adulthood. It is usually seen as hairless streaks or light colored linear patches. This is a very characteristic feature of this syndrome.

The dental and the oral changes are very prominent and seen in 50-80% patients [6]. There is delay in eruption of the teeth. Partial anodontia or hypodontia may be noticed. There is abnormal growth of teeth, typically pegged or conical in shape. Occasionally a part of the teeth may be missing or the enamel may be under developed. The most common association is high arched palate and cleft palate.

Retinal changes involve the retinal vasoocclusive changes along with ischemia, optic atrophy and developmental defects which lead to blindness and loss of visual acuity [7]. It leads to retinal detachment and a series of changes which ultimately lead to blindness. Other changes which may be seen are keratitis, cataracts and conjunctival pigmentation.

Neurological symptoms are seen due to microvascular vasoocclusive ischemia resulting in extensive infarction caused by cerebral arteries. Along with ischemic vascular insult we have developmental delay, neonatal seizures, recurrent acute stroke, mental retardation, ataxia, microcephaly and porencephaly as other central nervous manifestations occurring in this syndrome [8] [9].

Hair manifestations include scarring alopecia and nail involvement includes nail dystrophy like pitting/ridging, onycholysis or hyperkeratosis [10].

• Short Stature

  stature and lowset ears and subnormal fertility phantom limb syndrome - syndrome consisting of discomfort or pain in a limb that has been amputated PMS, premenstrual syndrome - a syndrome that occurs in many women from 2 to 14 days before the onset of [thefreedictionary.com]

  Minor Criteria: Occur, but Not Necessary for Diagnosis Growth Short stature in adolescence and adulthood Head Microcephaly in cases of severe intracranial damage during pregnancy and infancy Eyes Microphthalmos, a small eye if there is severe retinal [nfed.org]

  Skeletal deformities affect up to 20% of patients and include scoliosis, hemivertebra, spina bifida, syndactyly, ear defects, and increased number of ribs, chondrodystrophy, clubfoot, short stature and dwarfism.1818. [scielo.br]

• Dental Caries

  1 Dental Caries in Children with Insulin – Dependent Diabetes Mellitus – An Epidemiological Study. [stomatolog.hr]

• Strabismus

  She also presented with strabismus, frontal bossing, and vertex alopecia. Figure 1: Profile photograph showing strabismus, frontal bossing and whorly pigmentation at the perioral region Click here to view Intra-oral examination revealed hypodontia. [jisppd.com]

  The retinal pigment epitheliopathy and the abnormalities of retinal vessels are thought to be the underlying pathognomonic findings, with all other ocular signs being secondary (cataract, leucocoria, optic atrophy, strabismus, nystagmus and microphthalmus [ncbi.nlm.nih.gov]

  […] intellectual disability ischemic strokes hydrocephaly anatomical abnormalities seizures are reported as consequence of these conditions 3 ocular lesions were observed only in patients with severe cerebral damage 3 and include: anophthalmia microphthalmia strabismus [radiopaedia.org]

• Retinal Pigmentation

  Abnormalities of the retinal pigment epithelium, including peripheral hypopigmented areas, have been reported occasionally in patients with IP. These have not been symmetric, and they have not involved the fovea. [ncbi.nlm.nih.gov]

  Study of this family shows that vascular abnormalities of the retina and disorders of the retinal pigment epithelium are the most important ocular lesions in the Bloch-Sulzberger syndrome. [bjo.bmj.com]

• Hyperpigmentation

  Stage 3: Hyperpigmentation Seen in 90-98% of patients. The degree of hyperpigmentation varies: from discreet pigmented bands in the folds to widespread pigmented lesions. Color: greenish gray to brown, typical lesions in the "mud-throwing" pattern. [vinmec.com]

  Over some months, the bullous lesions turned into verrucous lesions and then to residual hyperpigmentation in Blaschko's lines and few verrucous lesions ( Figure 3 ). [scielo.br]

  […] overlying an erythematous base in a pattern that follows the Blaschko lines (from birth to about four months of age),2.Verrucous: lesions are crusted and appear as wart-like rash (for several months),3.hyperpigmented: grey brown linear swirling macular hyperpigmentation [dailyrounds.org]

  Four clinical stages are recognized: blister, verrucous or wart like lesions, hyperpigmentation and atrophic lesions. [scielo.org.pe]

  It is characterized by swirled patterns of hyperpigmentation. In some cases, the condition is also associated with malformations of the teeth, nails, skeleton, hair, eyes, and the central nervous system. [ncbi.nlm.nih.gov]

• Cutaneous Manifestation

  Prognosis is good if the extra cutaneous manifestations are taken care off. [symptoma.com]

  Identification of characteristic cutaneous manifestation can lead to rapid diagnosis of IP even in the absence of family history, resulting in prompt management of systemic manifestations. [ijpd.in]

  In most patients, cutaneous manifestations are present at birth or occur within the first 2 weeks of life. The cutaneous manifestations usually appear in a characteristic, chronologic sequence. [skin.ern-net.eu]

  This scarring alopecia could be used as a marker to identify adult women affected with IP as older patients may have minimal cutaneous manifestations. [ijtrichology.com]

  Genetic alteration and presence of family members also affected by the disease should also be taken into consideration.10 The cutaneous manifestations do not need specific treatment; spontaneous resolution of lesions occurs normally. [ncbi.nlm.nih.gov]

• Hyperkeratosis

  In the first phase, differential diagnosis should be made with bullous systemic lupus erythematosus and juvenile bullous pemphigoid; in the second phase with epidermolytic hyperkeratosis, hyperkeratosis associated with skin infections and lichen striatus [scielo.br]

  The dermatologic features involve four stages: stage I is characterized by erythema, vesicles, and pustules; stage II by papules, verrucous lesions, and hyperkeratosis; stage III by hyperpigmentation; and stage IV by pallor, atrophy, and scarring. [medical-dictionary.thefreedictionary.com]

  Histopathological examination of the dorsum of the right great toe revealed severe hyperkeratosis and acanthosis with epidermal edema. In the upper dermis there were heavy perivascular infiltrations of lymphocytes, including eosinophils. [jstage.jst.go.jp]

• Papule

  Figure 6: Verrucous or inflammatory Stage 1: Presence of Hyperaemic papule and vesicles lesions on anterior Portion of the thorax and Abdomen, and on medial face of left Arm. [peertechz.com]

  It can present as patches, papules, ulcers, scars, ichthyosis, and alopecia. The development of cutaneous sarcoidosis can be idiopathic or iatrogenic, particularly in patients using anti-TNF therapy. [mdedge.com]

  The dermatologic features involve four stages: stage I is characterized by erythema, vesicles, and pustules; stage II by papules, verrucous lesions, and hyperkeratosis; stage III by hyperpigmentation; and stage IV by pallor, atrophy, and scarring. [medical-dictionary.thefreedictionary.com]

  Further examination showed hyperkeratotic lesions on her calves, and a hyperkeratotic papule and blister which had been present on her hand since birth. Her mother had a history of two spontaneous abortions. [adc.bmj.com]

• Macula

  She had microaneurysms temporal to the macula, with an abnormal branch of inferior temporal vein. There was extensive retinitis proliferans in the upper temporal equatorial region, which showed leakage on fluorescein angiography. [ncbi.nlm.nih.gov]

  Note the presence of characteristic brown-grayish maculae following the Lines of Blaschko]]. Français : Macules brunâtres visibles dans la région axillaire gauche ; Noter que certaines tâches suivent les lignes de Blaschko. [commons.wikimedia.org]

  Two twin girls were observed at birth with a characteristic whorling pattern of erythema, patch, and plaques, and were later found to have dental anomalies and eye findings consisting of black pigment granules around the macula and optic nerve head. [researchwithrutgers.com]

  During investigation of her medical, dental and familial history, the mother reported the presence of maculae in various regions of the child's body. [jmedicalcasereports.biomedcentral.com]

• Suggestibility

  Genetics The majority of evidence suggests that this is an X-linked dominant disorder with lethality in males although sporadic cases occur. [disorders.eyes.arizona.edu]

  Pedigree review suggests X-linked dominance with lethality in affected males. Presentation in female carriers is variable. [ncbi.nlm.nih.gov]

• Stroke

  CNS microcephaly cerebral atrophy hypoplasia of corpus callosum periventricular white matter damage strokes hydrocephalus porencephalic cysts neuronal heterotopias Head and face optic atrophy anophthalmia (absence of eye) microphthalmia hypodontia (small [radiopaedia.org]

  There is blockage in the arteries of the retina and the brain which lead to further complications like blindness and stroke etc. The dental and oral changes are seen more as abnormal growth of teeth and enamel. [symptoma.com]

  Central nervous system: seizures, strokes, intellectual disability, and CNS structural abnormalities have been reported in approximately 30% of the individuals with IP. [epilepsy.com]

  Neurological Disorders and Stroke » [brainfacts.org]

• Nystagmus

  The retinal pigment epitheliopathy and the abnormalities of retinal vessels are thought to be the underlying pathognomonic findings, with all other ocular signs being secondary (cataract, leucocoria, optic atrophy, strabismus, nystagmus and microphthalmus [ncbi.nlm.nih.gov]

  Syndromes and diseases associated with exophthalmos, ptosis, strabismus, nystagmus, glaucoma, cataracts, uveitis and optic atrophy are discussed in detail. [books.google.com]

  Nystagmus, strabismus, and limited vision are often present. The majority (up to 90%) of individuals have significant retinal disease. The retinal vascular pattern is anomalous with tortuosity in some areas and absence of vessels in others. [disorders.eyes.arizona.edu]

  Microphthalmos, cataract, glaucoma, optic atrophy, strabismus, and nystagmus occur occasionally, representing secondary consequences of end-stage retinopathy in most if not all cases. [aao.org]

• Convulsions

  A female newborn presented with emerging skin lesions, systemic eosinophilia, and eosinophilic reaction in the skin, liver, lungs, spleen, lymphatic nodes, porencephalia, convulsions, and disorders of thermoregulation. [ncbi.nlm.nih.gov]

  660X Keywords [eng] Incontinentia pigmenti ; Eosinophilia ; Female Abstract [eng] A female newborn presented with emerging skin lesions, systemic eosinophilia, and eosinophilic reaction in the skin, liver, lungs, spleen, lymphatic nodes, porencephalia, convulsions [publications.lsmuni.lt]

  We, there-fore, feel that this should be brought more directly to neurologists' attention, since it can be recognized at different stages in early life and needs to be included in the differential diagnosis of neonatal convulsions. [jamanetwork.com]

  The most common are: dental anomaly (dentin deficiency or absence of a teeth row); visual organs disorders (cataract, vascular anomalies and profound changes of retina epithelium); CNS injury (spastic paralysis, convulsive disorder, mental retardation [program.eventact.com]

The diagnosis is made on the following diagnostic criteria:

• If NEMO mutation is unconfirmed, and incontinent pigmenti is absent in first-degree female relatives, 2 major or 1 major + 1 minor criteria need to be satisfied.
• If NEMO mutation status is unconfirmed but condition is confirmed in a 1st degree female relative, then 1 major criteria or 2 minor criteria need to be satisfied.
• If NEMO mutation status is confirmed, then any 1 major or 1 minor criteria needs to be confirmed.

Major critera include typical cutaneous manifestations while minor criteria include dental, CNS, breast, nipple, palate and ocular anomalies, alopecia/abnormal hair, abnormal nails, history of multiple spontaneous abortions and typical histological skin findings.

Laboratory studies

The blood investigations show raised eosinophil counts which are commonly seen in most of the skin disorders. In patients whom Bloch Sulzberger syndrome is strongly suspected, karyotyping and genetic studies should be performed. Also, if a skin biopsy is done in the earlier stages then diagnosis of incontinentia pigmenti is confirmed. The histologic findings of every stage of skin eruption are different but extremely informative as regards the diagnosis.

Imaging studies

If we perform a CT scan and a MRI in view of the neurological and ophthalmic manifestations, we will notice decreased blood supply and other ischemic changes. There will be seen areas of infarcts in the brain.

Complications like secondary bacterial infections should be prevented aggressively. Treatment of the symptomatic complaints is the only relief. As the disease is the result of a genetic mutation, there can be no reversal.

Use of anticonvulsants for seizure control is recommended. Pediatric periodontist must be visited regularly for prevention of further damage to the oral cavity. Ophthalmologist consultation at regular intervals is necessary for management of retinal damage. Cryosurgery might help treat retinal proliferation [11].

Dermatologists and neurologists are indispensable in throughout life for recurrent symptomatic relief and management.

The prognosis of the syndrome is good as death may occur only if the neurological and opthalmological changes are deteriorating. If complications are avoided then the prognosis is fairly good.

Bloch Sulzberger syndrome is caused due to a genetic mutation in the X sex chromosome and hence, it is a dominant X-linked disorder.

It is the result of a mutation in the NEMO/IKK-gamma gene located on the sex chromosome Xq28. The gene is necessary for activation of a transcription factor NF-kappaB that is key to regulate immunity, apoptosis and inflammation.

A single mutation in the gene is the cause for almost 80% of the cases. Recently, 21 point mutations have been discovered that lead to incontinent pigmenti [2]. The condition when occurring in males is also called as ‘male lethal syndrome’.

It is an X-linked disorder and hence most commonly seen in females at the prenatal age. In rare cases, it may be seen in males manifesting Klinefelter Syndrome or due to mosaicism/hypomorphic mutations in the gene called NEMO [1].

Its manifestations are seen in children at birth or develop during infancy in about 90% patients. The skin manifestations are characteristic and remain for lifetime. After the skin eruptions show up, there may be neurological manifestations and also dental changes seen in early childhood.

Morbidity and mortality depend on the age and severity of the cutaneous as well as extracutaneous signs and symptoms. It is more commonly seen in whites than blacks.

Uptill 1987, just 700 cases of this rare disease had been reported in literature. The underreporting is probably due to many cases going undiagnosed or misdiagnosed.

Bloch Sulzberger syndrome is an X-linked dominant disorder and affects those tissues that arise from the ectoderm and neuroectoderm.

Involvement of skin, central nervous system and dental tissues is a part of this syndrome. It manifests as an ectodermal dysplasia affecting even the hair, teeth and nails.

In females, lionization produces functional mosaicism of the X-linked genes. This is manifested as blaschkoid distribution of skin [3]. Normal chromosomes are active in the areas where the skin is unaffected whereas the abnormal mutated X chromosome is active in the skin lesions which are affected by the disease.

There are no guidelines for prevention of Bloch Sulzberger syndrome.

Bloch Sulzberger syndrome is also called as Incontinentia Pigmenti. It is a dominant X-linked disorder affecting the skin, central nervous system, eyes and teeth.

The first case was seen in 1906 by Garrod and later on the condition was redefined in 1926 and 1928 by Bloch and Sulzberger as a syndrome with multi-systemic affections.

Bloch Sulzberger syndrome is a dominant X linked disorder due to genetic changes. A lot of symptoms are seen in various systems in the individual. The symptoms are seen at birth or within 2 weeks of birth. The most dominant skin manifestations are excellent for diagnosis of the syndrome.

There are four stages of skin eruptions described as vesicular, verruceous, hyperpigmentation and hypopigmentation stage. Apart from the cutaneous manifestations there occur changes in the central nervous system, eyes, hair, nails, teeth and oral changes. There is blockage in the arteries of the retina and the brain which lead to further complications like blindness and stroke etc. The dental and oral changes are seen more as abnormal growth of teeth and enamel. There is lack of enamel and pegged teeth are seen along with delayed dental development. Alopecia is seen as the hair change and there is nail ridging.

To investigate the condition one must carefully take the history, notice the skin eruptions and send in for histologic findings, blood tests which shows eosinophilia, CT scan and MRI scan which reveal infarction and ischemic changes. As the disease is genetic in nature one must conduct karyotyping and genetic study report.

There are no specific drugs which help in recovery; only symptomatic relief can be given. Prognosis is good if the extra cutaneous manifestations are taken care off.

1. Kenwrick S, Woffendin H, Jakins T, 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. Dec 2001;69(6):1210-7.
2. 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. Feb 2014;35(2):165-77
3. Maingay-de Groof F, Lequin MH, Roofthooft DW, et al. Extensive cerebral infarction in the newborn due to incontinentia pigmenti. Eur J Paediatr Neurol. Jul 2008;12(4):284-9.
4. Alikhan A, Lee AD, Swing D, Carroll C, Yosipovitch G. Vaccination as a probable cause of incontinentia pigmenti reactivation. Pediatr Dermatol. Jan 1 2010;27(1):62-4
5. van Leeuwen RL, Wintzen M, van Praag MC. Incontinentia pigmenti: an extensive second episode of a "first-stage" vesicobullous eruption. Pediatr Dermatol. Jan-Feb 2000;17
6. Macey-Dare LV, Goodman JR. Incontinentia pigmenti: seven cases with dental manifestations. Int J Paediatr Dent. Dec 1999;9(4):293-7.
7. Meuwissen ME, Mancini GM. Neurological findings in incontinentia pigmenti; a review. Eur J Med Genet. May 4 2012
8. Turkmen M, Eliacik K, Temocin K, Savk E, Tosun A, Dikicioglu E. A rare cause of neonatal seizure: incontinentia pigmenti. Turk J Pediatr. Jul-Sep 2007;49(3):327-30.
9. Cartwright MS, White DL, Miller LM 3rd, Roach ES. Recurrent stroke in a child with incontinentia pigmenti. J Child Neurol. May 2009;24(5):603-5.
10. Nicolaou N, Graham-Brown RA. Nail dystrophy, an unusual presentation of incontinentia pigmenti. Br J Dermatol. Dec 2003;149(6):1286-8.
11. Nguyen JK, Brady-Mccreery KM. Laser photocoagulation in preproliferative retinopathy of incontinentia pigmenti. J AAPOS. Aug 2001;5(4):258-9