151 Journal of Neonatal-Perinatal Medicine 7 (2014) 151–155 DOI 10.3233/NPM-1475413 IOS Press Case Report Neonatal presentation of incontinentia pigmenti with a family history extending over four generations – A case report R. Ojhaa,b,∗ , D. Villarreala and H. Coughtreya a Sydney Medical School – Nepean, The University of Sydney, Discipline of Pediatrics, Nepean Hospital, NSW, Australia b Suchlich School of Medicine & Dentistry, Discipline of Pediatrics, Western University, London, ON, Canada Received 10 October 2013 Revised 19 February 2014 Accepted 25 March 2014 Abstract. We report a case of Incontinentia pigmenti (IP). A day 2 female presented to the special care nursery with seizures. EEG showed multifocal epileptiform discharges and cranial MRI revealed extensive cerebral infarction. A rash appeared shortly after birth. Eye examination revealed changes of IP. There is a strong family history of IP. Genetic testing excluded the most common mutation. Follow-up reveals significant development delay. Keywords: Incontinentia pigmenti, hypermalinosis of Ito, Bloch-Sulzberger syndrome, skin rashes 1. Introduction Incontinentia pigmenti (IP) is a rare X-linked dominant disease with estimated prevalence 0.2/100,000 in which changes of skin and skin appendages are usually combined with anomalies of other organs: teeth, eyes, and central nervous system (CNS). IP was first described in 1906 by Garrod. IP appears almost exclusively in females and is usually lethal in males.The absence of IKBKG (inhibitor of kappa B kinase gamma previously NEMO), protein ∗ Corresponding author: Dr. Rahul Ojha, Sydney Medical School – Nepean, The University of Sydney, Discipline of Pediatrics, Nepean Hospital, Derby Street Penrith, 2750 NSW, Australia. Tel.: +61 247342155; Fax: +61 247343610; E-mail: ojha.rahul1@ yahoo.com.au. makes the cells sensitive to apoptosis, leading to the IPassociated male lethality and skewed X-inactivation. It is currently believed that the highly heterogeneous and often severe clinical presentation of IP might be due to the pleiotropic role of IKBKG. Mutations of the IKBKG gene, localized on the X-chromosome, locus Xq28, are responsible for IP. According to a recently published report which looked at mutation analysis on clinically diagnosed IP patients, the IKBKG gene mutation (exon 4–10 deletion) was most common. The level of highest IKBKG expression was noted in CNS. CNS anomalies usually occur from the neonatal through the early infantile period and represent the most important threat to the normal life span of patients with IP. The CNS anomalies include seizures, mental retardation, hemiplegia, hemiparesis, spasticity, microcephaly, and cerebellar ataxia [1–6]. 1934-5798/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved 152 R. Ojha et al. / Neonatal presentation of incontinentia pigmenti 2. Case report A day 2 female term baby was referred from Blacktown hospital’s postnatal ward to the Special Care Nursery with jitteriness. The delivery was to have occurred elsewhere and little was known of the family history at that point. She was born to a 30 year old mother by normal vaginal delivery without complications. Her birth weight was 3010gm, length was 49 cm and head circumference was 34.2 cm (all above the 50th centile). Her mother’s medical history revealed Incontinentia pigmenti, cognitive difficulties and depression. The parents were non consanguineous, have 3 previous children, all girls, 4, 3 and 2 years old. Of the three, one has IP with seizure disorder and spasticity; another has skin changes though not the formal diagnosis of IP. The third child is normal. On further questioning, it was revealed that there is a very strong family history of IP and also of miscarriages. IP is present in all 4 generation as evident in the genogram (Fig. 1). The patient’s grandmother has been diagnosed with IP and has seizure disorder, rashes and eye changes (blind in 1 eye); her sister also has IP. The patient’s mother has rashes, nail changes and intellectual delay. Her sister (baby’s aunt) has a history of miscarriages with no living children. On day 2 the infant had twitching of left side of face with lip smacking. Soon these became left sided seizures lasting for 2-3 minutes. She also had apneas which were presumed to be clinical seizures. Several clonic seizures (2–5 minute duration) continued over next few hours which were not responsive to intravenous midazolam and phenobarbitone. Partial septic work up was done and intravenous antibiotics were commenced. A lumbar puncture was contemplated but not done because of the patient’s worsening clinical condition. Seizures continued so Phenytoin was added. However, the seizures became more pronounced and generalized tonic/clonic in nature. She required ventilatory support and a Midazolam infusion and then was transferred to a tertiary center for ongoing management and investigations. Seizures were controlled by day 6 of life. 2.1. Physical examination She had no obvious dysmorphic features. Her anterior fontanel was not bulging, pupillary reaction was normal. Her tone and reflexes in upper and lower limb were brisk with an upward plantar response. She was noted to have an evolving linear, confluent erythematous macular rash on her forearms and legs as well as patches of alopecia. 2.2. Investigations Blood: normal results for hematology, biochemistry and liver function tests. Plasma amino acids, ammonia and lactate were also normal. Urine: baby’s urine for drug screen was negative. EEG: Multifocal epileptiform discharges most prominent in the left central region with some brief periods of suppression. MRI: Extensive areas of cerebral infarction involving deep and sub cortical white matter in occipital, parietal, temporal and frontal lobes and occasional areas in basal ganglia with sparing of brain stem and cerebellum. The corpus callosum was thought hypoplastic (Fig. 2). DNA Mutation testing excluded the most common form of mutation causing IP. However, approximately 20% of patients with IP carry a mutation unable to be detected by direct PCR test. Eyes revealed changes consistent with IP.She had avascular areas in the periphery of her right retina and cherry red spot at the macula suggesting infarction or vascular occlusion. The optic disc was swollen and prognosis of vision in this eye was poor. There were also avascular areas in the periphery of her left retina. No retinal detachment was seen in either eye. At 6 weeks and 3 months follow-up, she was noted to be delayed in early milestones, had minimal social smile, poor head control and poor suck, still requiring tube feeds. On her central nervous examination she had evidence of upper motor neuron involvement with increased tone of upper and lower limbs with brisk reflexes. She continued on Phenobarbitone and had had no further seizures. 3. Discussion IP is familial in 10–25% cases [7]. The diagnosis is also aided by family history and history of miscarriages of male gender fetuses. In most cases affected males do not survive beyond the second trimester. In one study, where 653 IP patients were reviewed, 55.4% had definitive family history of IP [8]. In this case, there is a strong family history of IP extending over four generations. The index case is one of the 2 affected children of the 4 siblings born to mother with confirmed IP with no h/o miscarriages although the maternal aunt and grand maternal aunt have histories of miscarriages. R. Ojha et al. / Neonatal presentation of incontinentia pigmenti 153 Fig. 1. IP: Incontinentia pigmenti. Yr.-Years. Alphabets- R, D, S, J, A, L, K, A, B and J are initials and represents name in this genogram. In this disorder the risk of recurrence depends on the mutation status of the parents. If the parents have a deletion in the IKBKG gene, risk is 50% to all offspring’s (male or female). Without this deletion the risk in the next pregnancy is low (about 1%) [7]. In this case the baby’s mother has IP but we could not determine whether there is a deletion on the IKBKG gene. Neurological manifestations are found in 30% of IP patients, forming one of the major causes of morbidity and mortality. According to one recent published report reviewing clinical and brain imaging data of 45 IP patients, several clinical presentations could be identified comprised of seizures, infantile encephalopathy, acute disseminated encephalomyelitis and ischemic 154 R. Ojha et al. / Neonatal presentation of incontinentia pigmenti Fig. 2. MRI scans demonstrating extensive areas of cerebral infarction. stroke. Most neurological features presented during the neonatal period [9]. Brain MRI findings in IP include periventricular and subcortical white matter disease, hemorrhagic changes, corpus callosum hypoplasia, cerebral atrophy and cerebellar hypoplasia [9, 10]. The timing of CNS involvement in IP has not been clearly defined. CNS symptoms, particularly seizures, have been documented in the first week of life. A more diffuse encephalopathy has been observed in neonatal period [9, 11, 12]. The CNS involvement is a very important indicator for predicting the prognosis in patients with IP [13]. These patients should be regularly followed up for possible neurological handicaps such as seizures disorder, hemiplegia and other similar complications of various intensities and degrees. One study reported a long term follow-up case of a 12-year-old male with IP. The patient showed severe ophthalmic abnormalities and neurological manifestations characterized by mild cerebellar ataxia and a history of epilepsy that was severe at the beginning with West syndrome, become moderate overtime and gradually resolved. Despite these neurological manifestations the longterm follow-up in this patient as reported by the authors, demonstrated good neurological and cognitive outcome [14]. It should be noted here that not all IP patients may have such an outcome. The infant in our case we report had seizures on day 2 which were initially focal but later became generalized requiring 3 antiepileptic drugs. The Cerebral MRI revealed extensive areas of infarction. As mentioned above, this infant had significant neuro-developmental issues. It is also well known that patients with IP have eye and skin changes of varying degree. Ocular findings occur in 20–30% of patients comprising a range of retinal vascular changes and optic atrophy, but also developmental defects like microphthalmia and cataract. Most findings may reflect changes following brain injury. Both (ischemic) vascular and inflammatory components may play a role in the cerebral and ocular phenotype. However, a role of disturbed apoptosis during development may also be a contributing factor. Loss of visual acuity and blindness are significant complications. Blindness has been reported in about 7% of IP patients [9, 15]. In the case presented, the infant had significant retinal disease and prognosis for vision was poor. The skin lesion in IP manifest in four stages that evolve sequentially. The onset and duration of each stage vary among individuals; not all individuals experience all the four stages. Skin lesions usually begin at birth or soon after.Stage 1 (Vesicular) - develops in the first 2 weeks of life characterized by development of red papule and vesicles in linear distribution. The Stage 2 (Verrucous stage): develops in first few weeks to months of life, characterized by thick warty-appearing linear and whorled plaques. The Stage 3 is Hyperpigmented lesions noted usually over trunk, extremities, and skin folds, characterized by streaks and whorls of brown or slate-grey pigmentation. While Stage 4 is R. Ojha et al. / Neonatal presentation of incontinentia pigmenti Atrophic Stage: develops during adolescence, persisting into adulthood, characterized by hypopigmented, atrophic patches. On day 3 the infant in our case had erythematous macules over the elbow, forearms and lower limbs which soon became more florid and vesiculopapular with prominent erythematous bases, suggestive of stage I skin disease. [2] [3] [4] [5] 4. Conclusion IP is a rare genetic condition with serious multisystem involvement. This case shows classical presentation of IP, yet is amongst the 20% of IP unable to be detected by direct PCR. The interesting aspect in this case is the strong family history extending over four generations (few such cases reported in the literature). The importance of a detailed family history especially in such a rare condition presenting with common symptoms is stressed as a key to diagnosis, further management and follow up. [6] [7] [8] [9] [10] [11] [12] Financial disclosure statement An informed consent regarding publication of personal material in the medical journal was taken from the mother of this infant and was provided a copy of manuscript. [13] [14] [15] References [1] Minić S, Dušan Trpinac D, Obradović M. Systematic review of central nervous system anomalies in incontinentia pigmenti. Orphanet J Rare Dis 2013;8:25. 155 Fusco F, Paciolla M, Napolitano F. 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