Neonatal Case Presentation - Nature

Perinatal/Neonatal Case Presentation Unusual Neonatal Presentation of Incontinentia Pigmenti with Persistent Pulmonary Hypertension of the Newborn: A Case Report Sunit Godambe, MRCPCH (UK) Patrick McNamara, MRCPCH (UK) Manju Rajguru, DNB Jonathan Hellmann, FRCPC

Incontinentia pigmenti (Bloch-Sulzberger syndrome) is a multisystem disorder with classical changing skin lesions. The other systems that are involved include the central nervous system, eye, hair, teeth, musculoskeletal system and, occasionally, the cardiovascular system. We report a neonate with a diagnosis of incontinentia pigmenti who presented at birth with pulmonary hypertension. This presentation has not been described in the literature. Journal of Perinatology (2005) 25, 289–292. doi:10.1038/sj.jp.7211250

INTRODUCTION Incontinentia pigmenti (IP), first described by Garrod in 1906,1 is a multisystem disorder inherited in an X-linked dominant fashion with lethality in males.2 The skin lesions are diagnostic and occur in four stages, all of which may not be observed in one patient. Other systems that may be involved include the central nervous system (mental deficiency, microcephaly, seizures); the eyes (ischemia of peripheral retinal field, retinal dysplasia, retinal detachment, pigment retinopathy, retrolental dysplasia); the hair (alopecia); the musculoskeletal system (hemivertebrae, kyphoscoliosis, syndactyly, hemiatrophy) and the teeth (hypodontia, microdontia and dysplasia).2–4 A few patients with IP have presented with cardiovascular anomalies including left ventricular endomyocardial fibrosis,5 acyanotic tetralogy of Fallot,6 triscupid insufficiency, anomalous connection of the right pulmonary vein into the superior vena

Department of Pediatrics (S.G., M.R.), Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; and Department of Pediatrics (P.M., J.H.), Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. Address correspondence and reprint requests to Patrick McNamara, MRCPCH, Department of Pediatrics, Hospital for Sick Children, 500 University Avenue, Toronto, Ontario, Canada M5G 1X8.

cava, and infantile pulmonary hypertension (presentation at 2 and 6 months of age).7,8 We report a neonate with IP who presented at birth with persistent pulmonary hypertension of the newborn (PPHN). This early presentation of PPHN, in the neonatal period, has not been described in the literature.

CASE REPORT A full-term female infant was born to a healthy 29-year-old primigravida mother of Asian origin with no history of consanguinity. There was no family history of skin disorders or neonatal deaths. The baby was born by spontaneous vaginal delivery at a level-2 nursery with normal Apgar scores. She was noted to have a large patch of alopecia on the scalp, and erythematous macular skin lesions that were localized on both knees and generalized over the abdomen in a linear distribution. She developed cyanosis immediately after birth and was placed on nasal CPAP. Her hypoxemia worsened over the next few hours and she required endotracheal intubation. She was started on a prostaglandin infusion and transferred to our level-3 NICU. On arrival to this institution, her oxygen saturations remained in the mid-eighties, despite an FiO2 of 1.0. Cardiovascular examination and chest radiograph were essentially normal. She developed systemic hypotension and inotropes were administered. The diagnosis of PPHN with right ventricular systemic pressure and a small atrial septal defect was confirmed by two-dimensional echocardiography. The prostaglandin infusion was discontinued, she was started on inhaled nitric oxide (NO) at 20 ppm and her condition improved over the next 48 hours, with normal oxygen saturations and PaO2. Inotropes and NO were weaned and she was extubated to room air. She continued, however, to have desaturation spells and was placed in low-flow oxygen. Despite this, her PaO2 remained low and she was reintubated and restarted on inhaled NO. On this occasion, there was only a transient response for the first 12 hours. A repeat echocardiogram showed a dilated right ventricle and pulmonary artery, marked tricuspid and pulmonary regurgitation, and bidirectional atrial and ductal shunting, confirming persistently elevated pulmonary vascular resistance. Intravenous infusions of Prostacyclin and subsequently Milrinone were added, but with no response in oxygenation, that is, FiO2 remained at 1.0.

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The infant demonstrated changing skin lesions over the course of her admission, from the initial macular rash on the knees and abdomen to a more generalized asymmetric erythematous rash over the trunk, axilla and groin on day 6 of life. The patch of alopecia was linear (3 cm 6 cm) and nonscarring, but had some areas of desquamation (Figure 1). A diagnosis of cutaneous candidiasis was entertained, and in the light of her poor general condition, she was started on amphotericin. All skin, blood and cerebrospinal cultures were however, negative for viruses, bacteriology and fungi. By day 9 the rash had become vesicular over the trunk and back. She was reviewed by the dermatologists on day 16 of life. They noted linear erythematous lesions on both knees, with some hypopigmented papules (Figure 2). The generalized macular rash on the trunk, axilla and groin had features of pseudovesiculation in a linear distribution. There were no obvious features of nail dystrophy. The diagnosis of IP was considered, however, the request for skin biopsy confirmation was declined by the parents. Cranial ultrasound performed on day 5 (for persistent hypoxemia) showed multiple echogenic foci in temporal and thalamic areas bilaterally, and a subsequent MRI showed

Figure 1. Image of the scalp demonstrating a linear, nonpigmented area of alopecia (2 cm 6 cm).

Figure 2. Linear erythematous and macular skin plaques, studded with hypopigmented papules and vesicles and early desquamation, are noted over the anteromedial aspect of the left thigh and knee. 290

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polymicrogyria in the perisylvian area with cortical dysplasia. Electroencephalogram and visual, somatosensory and auditoryevoked potentials were normal. Eye examination showed unilateral temporal avascular retina in zone III and bilateral peripheral straightened vessels and retinal hemorrhages. This was considered consistent with the diagnosis of IP. Chromosome analysis revealed a normal female karyotype F 46, XX. Molecular genetic testing of the NEMO gene revealed that the infant was heterozygous for a deletion encompassing exons 4–10 of the NEMO gene, confirming the clinical diagnosis of IP.9 The infant suffered a massive pulmonary hemorrhage and in view of her worsening clinical status and the confirmation of the diagnosis of IP, the parents were counseled regarding the poor short- and long-term prognosis. Lifesustaining medical therapy was withdrawn on day 26 of life. The parents declined a postmortem examination. DISCUSSION IP is a rare, inherited, neurocutaneous disorder characterized by classical skin lesions with frequent multisystem involvement. The other features described in the literature that were seen in our patient were the MRI findings of polymicrogyria and cortical dysplasia,2 the vascular retinal changes,10 and alopecia as described by Wiklund and Weston.11 Dermatology In most cases, the dermatological findings are the first observed features of IP. The skin lesions usually begin at birth or shortly after.7 The cutaneous features are present in nearly all cases and have been classified into four stages. Stage 1: Vesiculobullous/Inflammatory stage occurs in 90% of cases and is characterized by erythema and superficial vesicles in a linear distribution. The torso and extremities are affected in about 64% cases and, although the face is usually spared, scalp lesions are quite common.12 In 92% of cases, the characteristic lesions are present in the first 2 weeks of life. Stage 2: Verrucous stage occurs in 70% of patients with a peak age of onset between 2 and 6 weeks. The characteristic lesions include hyperkeratotic, linearly arranged papules and plaques limited to the distal limbs.12 Stage 3: (12 to 26 weeks of age) The majority of patients (98%) will progress to this stage characterized by whorls or streaks of brown to slate-gray pigmentation that follow the lines of Blaschko.13 Stage 4: (Atrophic Stage) This is the most difficult stage to identify as the features are subtle with pale, hairless, atrophic patches or areas of nontanning hypopigmentation without atrophy. Our patient presented with linear erythematous macules over her knees, linear alopecia and an erythematous, macular rash on the torso, which subsequently became vesicular, with some papules, during the first 3 weeks of life, suggestive of stage I skin disease. Journal of Perinatology 2005; 25:289–292


The diagnosis of IP is usually definitively confirmed by skin biopsy although this was not feasible in our case. The molecular genetic studies confirmed the diagnosis in our case. The classicial early histopathological features include spongiotic dermatitis with intraepidermal and dermal spongiosis.14 With disease progression, there is hyperkeratosis (papule development), melanin deposition within melanophages (pigmentation)15 and finally atrophic dermatitis.16 Genetics IP exhibits an X-linked pattern of transmission and the gene has recently been mapped to the Xq28 locus.17,18 Subsequently, the gene encoding nuclear factor kappa b (NF-kb) essential modulator (NEMO), also known as the g-subunit of the inhibitor kb (IKKg), has also been mapped to Xq28.19 Mutations in the NEMO/IKKg gene, which maps in close proximity to the factor VIII locus, result in the IP phenotype.20 NF-kb is a transcription factor that regulates the expression of multiple genes, including cytokines, chemokines and adhesion molecules.9 In the majority of cells, NF-kb is inactivated by cytoplasmic sequestration, through interaction with an inhibitory molecule of the Ikb family. In patients with IP, who have mutations in the NEMO/IKKg gene levels of Ikb are increased, and NF-kb is not translocated to the nucleus.21 The genes downstream of NF-kb that are essential for immune-responsiveness are not activated, increasing cellular sensitivity to proapoptotic signals. Makris et al.22 propose that cells in IKKg deficient females undergo rapid hyperproliferation, leading to increased apoptosis and chemokine production in neighboring NF-kb-positive cells.22 There is a marked influx of granulocytes into this area and cells become necrotic, releasing their contents, and trigger an immune/inflammatory response in the affected tissue. Pulmonary Hypertension and Incontinentia Pigmenti Pulmonary hypertension in IP has only been previously reported in two infants, one who also died at 2 months of age.8 In the other infant, the diagnosis was made at 6 months of age.7 No pulmonary pathology was described at autopsy in either of the infants. It is tempting to speculate that the unusual early neonatal presentation of severe PPHN in our case, with an initial improvement, followed by unresponsiveness to all medical treatment later, was due to a progressive pulmonary vasculopathy, similar to that described in the central nervous system and retinal vessels. Hennel et al.23 suggested an evolving microvascular involvement for the cerebral lesions seen in IP. They reported a neonate with IP who presented with seizures on day 4 of life, in which serial MRI scans demonstrated changing findings of microvascular hemorrhagic infarcts in the periventricular white matter and associated angiographic changes of intracerebral vessels indicative of a progressive microangiopathic process. Macular and retinal vasculopathy and ischemia have also been documented early in IP, Journal of Perinatology 2005; 25:289–292

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with subsequent development of neovascularization, in a prospective cohort study.11 The relationship of the specific IP mutation to the development of severe pulmonary hypertension is unclear, although there is some evidence that the NF-kb signaling pathway, outlined above, is involved in pulmonary vascular development and regulation. NF-kb is responsible for the activation of several cytokines and growth factor genes associated with primary pulmonary hypertension (PPH). Specifically, there is increased NF-kb activation in alveolar macrophages of PPH patients compared to controls, which is reversed by inhaled NO.24 Bleomycin induced activation of NF-kb and activator protein (AP)-1, leading to lung injury and pulmonary hypertension in mice, is inhibited by treatment with Enalapralil, an angiotensinconverting enzyme (ACE) inhibitor.25 Unfortunately, the parents did not provide consent for a lung biopsy, so the histological, biochemical and molecular/genetic details of this case could not be delineated. There is insufficient evidence to confirm a mechanistic link between IP to pulmonary hypertension in our case. The expression of these mediators in lung aspirates and the pulmonary vasoreactivity of patients with IP, particularly those patients who present with respiratory distress or pulmonary hypertension, need prospective evaluation. In conclusion, we report an infant with IP presenting with early PPHN, which initially improved and then became progressively unremitting and unresponsive. We speculate that a progressive pulmonary vasculopathy may account for this clinical presentation in our patient. The relationship to the IP mutation, and specifically the role of the NF-kb signaling pathway, needs further investigation.

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18. Smahi A, Hyden-Granskog C, Peterlin B, et al. The gene for the familial form of incontinentia pigmenti (IP2) maps to the distal part of Xq28. Hum Mol Genet 1994;3:273–8. 19. Jin DY, Jeang KT. Isolation of full-length cDNA and chromosomal localization of human NF-kappaB modulator NEMO to Xq28. J Biomed Sci 1999;6:115–20. 20. Baldwin Jr AS. The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol 1996;14:649–83. 21. Verma IM, Stevenson JK, Schwarz EM, Van Antwerp D, Miyamoto S. Rel/NFkappa B/I kappa B family: intimate tales of association and dissociation. Genes Dev 1995;9:2723–35. 22. Makris C, Godfrey VL, Krahn-Senftleben G, et al. Female mice heterozygous for IKK gamma/NEMO deficiencies develop a dermatopathy similar to the human X-linked disorder incontinentia pigmenti. Mol Cell 2000;5:969–79. 23. Raychaudhuri B, Dweik R, Connors MJ, et al. Nitric oxide blocks nuclear factor-kappaB activation in alveolar macrophages. Am J Respir Cell Mol Biol 1999;21:311–6. 24. Ortiz LA, Champion HC, Lasky JA, et al. Enalapril protects mice from pulmonary hypertension by inhibiting TNF-mediated activation of NFkappaB and AP-1. Am J Physiol Lung Cell Mol Physiol 2002;282:L1209–21. 25. Hennel SJ, Ekert PG, Volpe JJ, Inder TE. Insights into the pathogenesis of cerebral lesions in incontinentia pigmenti. Pediatr Neurol 2003;29:148–50.

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