Infectious Disorders
Zika virus: neurologic complications
Oct. 08, 2024
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Incontinentia pigmenti is an X-linked dominant disorder characterized by distinct skin lesions and involving other ectodermal tissues, such as teeth, hair, nails, eyes, and the central nervous system. The most common identifiable abnormalities are the cutaneous lesions, which are described in four stages. Neurologic abnormalities are the most common morbidity of this disorder. The IKBKG (inhibitor of kappa B kinase gamma), previously named NEMO, gene located in the short arm of chromosome X is linked with this disorder. The severity of neurologic disease correlates with the severity of retinal disease, which is present in most patients.
• Cutaneous manifestations are diagnostic, and there are four overlapping and variable stages: vesicular, verrucous, hyperpigmented, and atrophic. | |
• Genetic inheritance is X-linked dominant, linked to the IKBKG gene. | |
• CNS manifestations are common and can include seizures, microcephaly, mental retardation, spasticity, delayed motor development, and ataxia. | |
• Patients with incontinentia pigmenti should have ongoing neurologic, ophthalmologic, and dental follow-ups. |
The term "incontinentia pigmenti” describes the characteristic leakage or "incontinence" of melanin, which appears outside melanocytes in the superficial dermis and basal layer of epidermis. This was first described by Garrod in 1906 but more clearly defined by Bardach in 1925, Block in 1926, Sulzberger in 1928, and Siemens in 1929 (50). However, it was Haber in 1952 who first described the multiphasic and multisystemic nature of this disorder and proposed Bloch-Sulzberger syndrome as its eponym. In 1959 Oldfelt believed this condition to be misnamed because there is no “incontinence of pigmentation,” but rather pigmentation occurring secondary to scarring in the ectoderm (71). He described incontinentia pigmenti as an “ecto-meso-dermal polydysplastic disease” and noted that it “mostly affects the female sex.” In 1961, Lenz first proposed the mode of inheritance of this disorder as X-linked dominant inheritance (53).
• Cutaneous manifestations are diagnostic, and there are four overlapping and variable stages: vesicular, verrucous, hyperpigmented, and atrophic. | |
• CNS manifestations are common, occurring in 30% of patients, and can include seizures, microcephaly, mental retardation, spasticity, delayed motor development, and ataxia. | |
• CNS manifestations present within the first year of life in 80% of patients with neurologic manifestations. |
Cutaneous manifestations, occurring in 96% of familial cases of incontinentia pigmenti, are diagnostic; however, its absence does not exclude the diagnosis. Four overlapping and variable stages have been defined: vesicular, verrucous, hyperpigmented, and atrophic (07). Stage 1 is characterized by a linear pattern of vesiculo-bullous lesions or pustules along the extremities occurring at or shortly after birth or circumferentially around the trunk. Although several phases of blister formation may occur in different areas and it may recur with febrile illnesses, most resolve by 4 months of age.
Stage 2, which can be identified in two thirds of patients (48), is characterized by hyperpigmented, hyperkeratotic papules occurring in the same distribution as earlier blisters. Linear verruciform lesions appear on the hands, feet, and scalp, but they may be subtle and easily overlooked. Although most lesions resolve by 6 months of age, they may recur throughout childhood (68). Late reactivation is most often associated with viral or bacterial infection and has also been reported after routine vaccination (74; 02).
Stage 3 occurs in 98% of patients and is characterized by the hallmark gray-brown, hyperpigmented macules of incontinentia pigment (13). These occur in streaks or whorls along Blaschko pigmentary lines, predominantly over the trunk in a distribution unrelated to that of earlier vesicles.
Macules become darker over weeks or months but fade during early adolescence. As many as 40% of patients with incontinentia pigmenti are born with verruciform or hyperpigmented lesions identified during stage 2 and 3. Stage 1, 2, and 3 lesions persist into adulthood in 16%, 17%, and 71%, respectively (81). Stage 4, identified in 14% to 28% of patients with incontinentia pigmenti, is characterized by pale streaks most prominent over the calves. These appear lighter in color because of absent hair follicles and reduced vascularity (65). Adults with incontinentia pigmenti often report hypohidrosis or heat intolerance (81).
Systemic manifestations of incontinentia pigmenti are common, but true prevalence of these manifestations may be underreported because subclinical cases are difficult to identify. Dental abnormalities occur in 60% of patients; these may include delayed, absent, or abnormal formation of teeth; teeth are typically peg-shaped or cone-shaped but have normal enamel (31; 30; 95). In addition, the presence of a gothic (high-arched) palate has been reported in a series (62).
Minor abnormalities of hair and nails are also seen. Almost 50% of patients with incontinentia pigmenti have alopecia and scarring or coarse, wiry hair near the vertex (13; 98). Whorled scalp lesions correspond to Blaschko lines of the scalp and may be associated with functional X chromosomal mosaicism (15). About 40% of patients have nail dystrophy, ranging from ridging or pitting to nail disruption or onychogryposis. Painful subungual, hyperkeratotic tumors and underlying deformities of the phalanges are occasionally seen (36; 87). Supernumerary nipples and nipple or breast hypoplasia have also been seen (50).
Significant neurologic problems occur in 30% of patients with incontinentia pigmenti, with 19% being classified as severe, and most frequently include seizures (40% to 42%), motor impairment (26%), and intellectual disability (20% to 30%) when present (64; 27). Eighty-eight percent of patients with incontinentia pigmenti who will develop neurologic manifestations will have symptoms present within the first year of life (64). Seizures can include infantile spasms (88). It has been reported that the presence of neonatal seizures is associated with a poor prognosis for normal development (68). Cognitive outcomes can range from mild to severe intellectual deficits to learning disabilities in specific areas, such as arithmetic reasoning and reading (78). However, patients with incontinentia pigmenti and neonatal seizures can have normal development despite the presence of white matter abnormalities on MRI (11).
Neuropathologic findings associated with seizures include polymicrogyria, neuronal heterotopia, and neuronal loss with microcephaly. Ischemic and hemorrhagic cerebral vascular changes are observed complications, though the exact pathology is unknown. Severe intellectual disability is seen in 15% of sporadic cases but in only 3% of familial cases (50). Spasticity occurs in 11% and delayed motor development in 7% (13), but others report motor impairment as high as 26% (64). Other CNS problems include dysgenesis of the corpus callosum, hydrocephalus, and ataxia (37; 92; 57; 40). There have been reports of cortical necrosis and subcortical white matter involvement in neonates and infants presenting with transient periods of acute encephalopathy and clusters of seizures, without evidence of central nervous system infection (100; 01). Although this is usually isolated to infancy, encephalopathy in the setting of arteriopathy has been reported in older children (46). Patients have also been reported with reversible CNS white matter lesions (102; 56), raising the question of whether CNS involvement occurs more often than previously reported.
Ocular abnormalities have been documented in 33% to 70% of patients with incontinentia pigmenti and in a large systemic review at a similar rate of 37% (79; 50; 42; 64). These abnormalities include cataracts, keratitis, strabismus, nystagmus, uveitis, retinal pigment epithelial abnormalities, foveal hypoplasia, vitreous hemorrhage, and optic atrophy (25; 52; 23). The most common problem is retinal ischemia, which produces extensive vascular remodeling, nonperfusion of retinal capillaries, and neovascular proliferation with subsequent hemorrhage and fibrosis (39). This process is typically self-limited but may progress to clinically significant scarring or retinal detachment (96). Serious visual impairment has been reported in up to 43% of patients with incontinentia pigmenti (42). Retinal vasculitis is a rare association with significant sequelae if not detected early (21).
Other less common anomalies documented in case reports include limb truncation, which is associated with a reduced expression of the IKBKG gene (formerly called NEMO) (49), primary pulmonary hypertension (38), immune dysfunction characterized by low serum level of IgG2 in a neonate (75), and an associated encephalocele in a neonate (17).
Patients with incontinentia pigmenti appear to be at increased risk of CNS infection (86; 18; 06), which may be related to defective neutrophil chemotaxis (61). Although infrequent, other reported CNS complications include hemorrhagic or necrotic encephalopathy (60; 86; 04; 85), recurrent encephalomyelitis and optic neuritis with depletion of T8 suppressor cells and increase in the T4:T8 ratio (10), and anterior horn cell degeneration (51). Risk of malignancy also appears to be increased in incontinentia pigmenti children under the age of 3 years (80). At an older age, the following may occur: slowing down of motor function, muscular weakness, mental retardation, and convulsions (12).
A 50-day-old girl presented to the emergency room with a chief complaint of intermittent facial and body twitching of 2 days’ duration. Her mother described the episodes of twitching as lasting 2 to 3 seconds, occurring primarily with crying and solely involving the right side of her face and right upper and lower extremities. There was no eye deviation, cyanosis, pallor, or apnea associated with the twitching. There was no recent fever or indications of illness. She had good oral intake and good urine output. Birth history was unremarkable. Family history was significant for the mother, with a rash during childhood that gradually resolved by adulthood and maternal history of two prior spontaneous abortions. In the emergency room, the patient was loaded with phenobarbital. Physical exam was significant for a linear hyperpigmented macular rash with surrounding macular erythema, primarily in the back, arms, and legs. No vesicles or bullae were noted. Head CT showed nonspecific mild patchy edema of the left cerebral hemisphere. An MRI showed multifocal areas of abnormal restrictive diffusion involving the left cerebral hemisphere and corpus callosum consistent with ischemic changes. MRA showed no aneurysms and no stenosis. Ophthalmologic examination was normal. PT and PTT were normal, and no further hypercoagulable workup was pursued. EEG showed a paucity of higher amplitude slow activity expected during the quiet sleep state. No seizures were observed during her hospitalization, and the patient was discharged with a diagnosis of incontinentia pigmenti.
• Genetic inheritance is X-linked dominant, linked to the inhibitor of kappa B kinase gamma (IKBKG) gene. | |
• The IKBKG gene is responsible for activating the transcription factor NF-kappaB, which is an important mediator in immune, inflammatory, and apoptotic pathways and possibly limb development. | |
• X-linked dominant IKBKG mutations are typically lethal in boys, except in cases of mosaicism. |
Incontinentia pigmenti is an X-linked dominant disorder, which is lethal to boys in the prenatal period (97). This pattern of inheritance explains the dramatically high female-to-male ratio, female-to-female transmission, and the increased incidence of spontaneous abortions in families of children with incontinentia pigmenti (98; 68; 83). Approximately half of the children with incontinentia pigmenti have a family history of the disorder (13); the remainder have sporadic mutations. Rarely, incontinentia pigmenti occurs in boys with Klinefelter syndrome (47,XXY) (72; 29). In some male patients, genetic mosaicism in which cells contain a normal and an abnormal X chromosome were observed (32). Father-to-daughter transmission is exceedingly rare (22) but can occur in the setting of the combination of somatic and germ-line mosaicism requiring sperm DNA genetic testing to provide proper genetic counseling (26).
Seminal genetic studies on incontinentia pigmenti showed two distinct loci in the X chromosome. Sporadic cases have been associated with autosomal translocations in the X-chromosomal breakpoints (Xp11) (08; 41; 45; 33; 09). However, data suggest that patients with this chromosomal translocation do not represent true cases of incontinentia pigmenti (07). Moreover, linkage analysis showed that the gene for familial incontinentia pigmenti is located in Xq28 (82; 83). It has also been suggested that in X-linked dominant disorders, cell selection exists against cells expressing the defective allele on their active X chromosome. Non-random (skewed) X inactivation has been documented in only 35% of patients with incontinentia pigmenti (35); however, it is present in the vast majority of individuals with Xq28-linked incontinentia pigmenti (73).
Genome analysis identified the putative genes called IKBKG (inhibitor of kappa B kinase gamma, previously named NEMO) and IKK gamma (IkappaB kinase-gamma) located 200 kilobases proximal to the factor VIII gene in the Xq28 region. The IKBKG gene activates the transcription factor NF-kappaB, which is an important mediator in immune, inflammatory, and apoptotic pathways and possibly limb development (49). Ninety percent of cases were attributed to an identical genomic deletion (exons 4 to 10), resulting in genomic rearrangements at the IKBKG locus (89; 93; 03). Partial mutations of IKBKG, which do not abolish NF-kappaB activity totally, permit male survival, causing an allelic variant of incontinentia pigmenti called hypohidrotic ectodermal dysplasia and immunodeficiency (HED-ID) (59). Intrafamilial phenotypic variability often occurs even among family members with the same genetic mutation (58).
One study found significant changes in cytokine expression (specifically TNF-α) during the first year of life in a patient with IKBKG mutation, which may lead to the prominent inflammatory processes evidenced by skin findings (55). It has been suggested that the apoptosis function associated with NF-kappaB accounts for much of the incontinentia pigmenti phenotype, including the retinal and central nervous system manifestations, and failure of these cells to resist apoptosis results in early cell death. Limb truncation likely related to the defect in NF-kappa B gene, which is responsible for the formation of the apical ectodermal ridge at the tip of limb buds (38). Cytokines, growth factor, and modulators also interact with NF-kappa B and may explain the primary pulmonary hypertension documented in the literature (38). The modulation of immune function by NF-kappaB is likely related to the immune dysfunction reported in the literature (75).
Special interest has also been paid to eotaxin, an eosinophil-selective chemokine that has been isolated from the blister fluid of incontinentia pigmenti lesions. The expression of eotaxin is influenced by NF-kappaB through binding to the promoter region of the Eotaxin gene; immunohistochemical staining of skin lesions from patients with incontinentia pigmenti demonstrated strong expression of eotaxin throughout most of the epidermal layers (07). Serum markers of thrombocytopenia and eosinophilia are often reported (91). Cerebrospinal fluid studies have implicated markers of oxidative stress more than elevated cytokine levels (70). Others have postulated that clinical findings result from an autoimmune attack on ectodermal cells, which express a surface antigen controlled by the mutant X chromosome gene (76). Additionally, the X-inactivation status in female individuals contributes to the wide variety of phenotypes associated with this single common deletion (03).
MR imaging suggests the possibility of perinatal ischemic injury as a mechanism for incontinentia pigmenti-related structural changes in the CNS (57). Progressive microvascular changes may be a common pathogenesis of retinal and some CNS abnormalities (52). MRI may demonstrate multiple scattered foci of restricted diffusion and decreased T2 signal within the periventricular white matter consistent with microvascular hemorrhagic infarcts. Susceptibility-weighted imaging may also be useful for identifying and differentiating hemorrhagic components (90). These abnormalities may progress to hemorrhagic necrosis. MRA may reveal decreased branching and poor filling of the distal middle and posterior cerebral arteries (40). These abnormalities have been postulated to relate to cerebral or cerebrovascular anomalies similar to those in the retina (24).
Vascular abnormalities and occlusion of the retinal vessels are well documented, and it is thought that the retinal and cerebral vasculature share the same vulnerability due to inflammation or a hypersensitivity reaction to an abnormal protein expressed by a mutant gene (52). Retinal pathology occurs in 74% of patients and is best detected using fluorescein angiography. The severity of detected retinal disease may correlate with the severity of neurologic disease (16). Additionally, a microangiopathic process in the lungs may result in primary pulmonary hypertension (38).
Incontinentia pigmenti is rare and the prevalence is uncertain, however, it has been estimated at approximately 1 in 50,000 newborns (03). The IKBKG gene deletion has been found in 80% to 90% of newborn patients (77).
There is no known prevention of incontinentia pigmenti.
Early cutaneous findings must be distinguished from vesicular or bullous lesions common at birth. Noninfectious causes include erythema toxicum neonatorum, epidermolysis bullosa, dermatitis herpetiformis, drug eruptions, erythema multiforme, and neonatal lupus, whereas common infectious causes include bullous impetigo, herpes simplex, and varicella zoster. Disorders that exhibit linear cutaneous lesions lines must also be distinguished from incontinentia pigmenti. One of these is hypomelanosis of Ito, which is also called incontinentia pigmenti achromians. Clinical findings in hypomelanosis of Ito include mental retardation, seizures, skeletal dysplasia, and depigmentation following Blaschko lines, resulting from a decrease in melanin in the basal layer of epidermis. Chondrodysplasia punctata is another diagnosis that can be differentiated by its linear scarring with follicular pitting, skeletal dysplasia, and congenital cataracts. Finally, disorders of hyperpigmentation must be differentiated from incontinentia pigmenti. Examples include multisystem disorders with café-au-lait or brown spots, such as neurofibromatosis, Silver-Russell syndrome, tuberous sclerosis, and Albright syndrome. The differential diagnosis of vesicular and linear lesions is broad, and a dermatologist should be consulted if diagnostic questions remain. However, the presence of primary skeletal abnormalities or severe neurologic impairment in early stages makes the diagnosis of incontinentia pigmenti less likely.
• In the newborn period, clinical diagnosis is possible based on the vesicular lesions in a whorling or linear pattern, especially in the setting of a family history. However, alternative etiologies for vesicular lesions should be evaluated for as clinically indicated. | |
• In older patients, clinical diagnosis based on the hallmark hyperpigmented lesions in whorling or linear patterns is often possible without biopsy. | |
• IKBKG gene testing can be confirmatory and should be conducted, especially in inconclusive cases. |
Clinical diagnosis on the basis of the hallmark hyperpigmented lesions in whorling or linear patterns is often possible without biopsy. However, during the vesicular or verruciform stages, skin biopsy and direct immunofluorescence is diagnostic. In stage 1, histologic studies show intraepidermal infiltration of eosinophils. In stage 2, the epidermis is acanthotic and hyperkeratotic with papillomatosis (54). In stage 3, melanin is seen in the papillary dermis, and vacuoles are seen in the basal cell layer. Electron microscopy shows gaps in the basement membrane where fetal nerves enter the epidermis (101). In stage 4, there is epidermal atrophy with reduced melanocytes and absence of adnexal structures (54; 66; 103). Colloid bodies similar to Civatte bodies of lichen planus and lupus erythematosus have also been identified in the upper dermis by means of electron microscopy (07). Histologic examination is especially important with atypical symptoms that may suggest chromosomal mosaicism. Biopsy may also be helpful with older children or adults in whom cutaneous findings may be minimal. Bedside diagnosis in neonates may be facilitated by unroofing a vesicle and observing eosinophils in the fluid under light microscopy. A Tzanck preparation, bacterial and viral cultures, and complete blood count may further narrow the differential diagnosis, as significant leukocytosis with eosinophilia is seen during the vesicular stage of incontinentia pigmenti (13). The presence of cone-shaped teeth, nail dysplasia, patchy alopecia, or retinal dysplasia may further suggest the need for biopsy in children who do not have typical cutaneous involvement.
A detailed examination of the skin, MRI of the brain, and ophthalmologic examination should be performed. Minic and colleagues have proposed that major and minor criteria be evaluated in the diagnosis: major criteria being the hallmark cutaneous findings, and minor criteria to include the dental, ocular, CNS, hair, nail, palate, breast and nipple anomalies, multiple male miscarriages, and pathohistologic findings (63). Genetic testing can be confirmatory and should be conducted in inconclusive cases as necessary.
•There is no specific treatment for incontinentia pigmenti; treatment is based on symptoms (ie, treatment of seizures and spasticity, treatment of retinal neovascularization, and genetic counseling). | |
• Although inflammatory skin lesions in incontinentia pigmenti have been reported to respond to corticosteroids and tacrolimus, further research is needed to understand the long-term benefits of anti-inflammatory agents, especially regarding neuroinflammation. |
There is no specific treatment for incontinentia pigmenti. However, early lesions characterized histopathologically by eosinophilic inflammation, such as the initial vesiculobullous stage, have been shown to respond to corticosteroids (47). Tacrolimus, a calcineurin inhibitor, has also been shown to be successful in a case of incontinentia pigmenti in its vesicular stage (44). Subungual tumors in incontinentia pigmenti have been treated with retinoic acid. Donati and colleagues reported a case in which after 1 month of 0.05% retinoic acid cream twice a day, there was an improvement of the painful sensation, and after 6 months, a definitive clinical resolution (20). The long-term implications of these treatments have not been studied, however.
Periodic neurologic and psychoeducational evaluations of patients with incontinentia pigmenti should be performed to identify motor, developmental, or cognitive problems. MR imaging is recommended to document dysplastic or ischemic brain malformations. Standard strategies for treatment of infantile spasms or other seizures are required in some patients. Subclinical epileptiform discharges may be seen in others (09). Neuroinflammation may cause neonatal seizures in incontinentia pigmenti. There may be a role for systemic glucocorticoids in the treatment of neonatal seizures and encephalopathy, based on case reports, but further research is needed (99; 94; 69). Providing hope for future research, brain endothelial-targeted gene therapy has shown initial promise in an animal model of incontinentia pigmenti (19).
Increased use of MR angiography and spectroscopy has permitted the identification of acute or chronic cerebrovascular disease not previously recognized.
MR findings reported in patients with incontinentia pigmenti include small vessel occlusions, hypoplasia of the corpus callosum, enlargement of the lateral ventricles, and periventricular white matter disease (52; 05). Because neuroimaging has not been routinely ordered in incontinentia pigmenti, the frequency of cerebrovascular accidents may be underestimated (24). Recurrent stroke despite treatment with antiplatelet therapy has been reported (14).
Because of ocular anomalies associated with incontinentia pigmenti, serial retinal examination is recommended during the first year of life. Fluorescein angiography may be recommended to further evaluate occult areas of neovascularization and leakage that may progress to retinal detachment and decreased vision (84). Retinal neovascularization may be treated with xenon photocoagulation (67) or cryotherapy (79). Retinal detachment may require vitreous surgery (96). There may also be a role for optical coherence tomography to define and characterize the outer plexiform layer of the macula (43). The prognosis for normal vision is excellent if incontinentia pigmenti children do not have retinal abnormalities during the first year of life (79). Finally, regular dental evaluations are important to plan for orthodontic treatment in selected patients.
Comprehensive genetic counseling is essential. It is important to obtain a family history, including a history of spontaneous abortions, and to examine all female members of the family as potential gene carriers. Because girls with sporadic incontinentia pigmenti are often severely affected, chromosome analysis is indicated for patients with atypical or severe symptoms and all presumably affected boys (32). Genetic testing for the common IKBKG gene mutation is available in the United States at the Baylor College of Medicine DNA Diagnostic Laboratory (Houston, Texas; phone: 800-BCM-DNA4; Web site: BCM Medical Genetics Laboratories).
Support groups and additional educational information for patients and their families is available through the Incontinentia Pigmenti International Foundation (30 East 72nd St, 16th Floor, New York, NY 10021; phone: 212-452-1231) and the Incontinentia Pigmenti Support Network (34929 Elm, Wayne, MI 48184; phone: 313-729-7912) (07). The Incontinentia Pigmenti Genetic Biobank project has established a large collection deposit of biological samples, providing clinical information to facilitate research (28).
A woman with incontinentia pigmenti has a 50% chance of contributing a normal X chromosome and a 50% chance of contributing an abnormal X chromosome to each child. The daughter or son receiving a normal X chromosome will be unaffected. The daughter receiving an abnormal X chromosome from the mother and a normal X chromosome from the father will have incontinentia pigmenti. The son receiving an abnormal X chromosome from the mother and a normal Y chromosome from the father will also have incontinentia pigmenti but will likely die in utero. The frequency of spontaneous abortions in familial incontinentia pigmenti is 23%, corresponding to the one in four chance of a child receiving the incontinentia pigmenti-mutated X chromosome from the mother and a Y chromosome from the father (97). A case of incontinentia pigmenti has occurred via in vitro fertilization (34).
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David T Hsieh MD
Dr. Hsieh of the Uniformed Services University of the Health Sciences has no relevant financial relationships to disclose.
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Dr. Maria of Thomas Jefferson University has no relevant financial relationships to disclose.
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