13.5.12  Social and Family Impact

GFS has an impact on families and patients affected with the disorder given its progressive course and poor visual prognosis. Fortunately, its autosomal recessive inheritance lessens the chance of affecting the children of an affected adult. Family screening and genetic counseling are needed [27].

the first year of life. Characteristic abnormalities in the teeth and developmental delay are common.

13.6.4  Classification

There is no classification system for IP.

13.6  Incontinentia Pigmenti (IP)

13.6.1  Introduction

Incontinentia pigmenti (IP) is a bilateral, X-linked dominant disorder, which can affect the skin, teeth, hair, eyes, heart, and central nervous system [65]. It is also known as Bloch-Sulzberger Syndrome.

13.6.2  Historical Context

Garrod first described the swirl-like dermatologic findings of IP in 1906 [66]. The term “IP” was first used to depict the clinical entity in 1926 [67, 68]. The unusual hereditary transmission (the disease is seen only in females) and the concept that IP was an ectodermal disorder were described by Salzberger in 1938 [69].

13.6.3  Overview with Clinical Significance

IP is an X-linked dominant systemic disorder, which is usually prenatally lethal in males. Skin changes in affected females classically occur in four stages including perinatal inflammatory vesicles, verrucous patches, a distinctive swirl-like pattern of hyperpigmentation, and dermal scarring [70, 71]. One-third of patients are affected with bilateral, although commonly asymmetric, cicatricial ocular disease that emerges from pathological retinal vascular changes that lead to fibrovascular retrolental membranes and retinal detachments as common findings in IP. These findings are present in the perinatal period and usually manifest themselves within

13.6.5  Genetics

IP is an X-linked dominant condition. An affected male fetus is normally not viable (embryonic lethality). Affected females have the clinical syndrome, which arises because of expression of the mutated gene by one of the X chromosomes. As lyonization occurs randomly in all cells, some cells will retain an X chromosome with the wild type allele, and some cells will retain an X chromosome with the mutant allele. Cells that fail to inactivate the mutant X chromosome will die by apoptosis around the time of birth and be replaced by cells with the normal X chromosome. This is known as an extremely skewed X-inactivation process. The molecular or cellular selection processes that could account for a severely skewed lyonization to a less random or nonrandom preferential inactivation of the mutated X chromosome are by no means clear. By restriction fragment-length polymorphism, inherited IP has been localized to the q28 region of the X chromosome [72]. Sporadic IP is associated with a translocation involving the breakpoint at the p11 region of the X chromosome [73]. Candidate gene analysis of these two regions, Xq28 and Xp11, was performed using cosmid clones [74]. Classical IP (IP2) maps to the region of Xp28 whereas the sporadic IP (IP1) maps to the region of Xp11. The sporadic condition is also known as hypomelanosis of Ito.

A family of transcription factors known as nuclear factor-kappa B (NF-kB) is important for regulating the response to immune challenges with essential roles in immune, inflammatory, and apoptotic pathways [75]. NF-kappaB essential modulator (NEMO), a 419 amino acid human protein, is required for the activation of the NFkB transcription factor, which regulates many signaling pathways. NEMO expression begins during embryogenesis and is ubiquitous throughout the body. The NFkB signaling pathway has two components of NFkB (p50 and relA) and two inhibitory components (IkB a and IkB b). The inhibitory components bind to

the NFkB factor in the cytoplasm and prevent its entry into the nucleus. Activation of NFkB comes about by phosphorylation by a high molecular weight kinase that contains three components (IKK1/a, IKK2/b, and IKK3/g; IKK3/g = NEMO). The a and b components of the kinase are catalytic units whereas the g component or NEMO appears to be purely regulatory. NEMO binds to the kinase complex and is fully required for activation of the kinase in response to signaling events (e.g., cytokines). In the absence of IKK3/gor NEMO, there is no kinase activation. In the resting state, the IkB inhibitor is bound to NFkB. Upon kinase activation, the inhibitory components are phosphorylated, which promotes their ubiquitination and degradation. Loss of the inhibitory influence allows NFkB to enter the nucleus and promote upregulation of transcription at target genes containing particular promoter sequence motifs (GGGRNTTTCC). NEMO is the convergence point for NFkB signaling as it is the only factor absolutely required for activation of the kinase by diverse stimuli.

Inherited IP is caused by mutations in NEMO with deletion of exons four through ten accounting for more than 80% of new mutations [76, 77]. This most common mutation, an 870 base pair deletion of the NEMO gene, occurs during paternal meiosis. This mutation arises due to a repeat sequence located in intron three and just downstream to exon ten of NEMO. Recombination between these regions occurs due to base pair hybridization leading to a deletion of exons four through ten of NEMO. This common mutation appears to arise in the paternal germline by intrachromosomal rearrangements during meiosis that is part of the process of sperm formation. This deletion leads to an inability of NEMO to modulate the NFkB pathway, and a state of extreme sensitivity to apoptosis arises. The latter feature explains the embryonic lethal effect in males.

In most cases, IP is X-linked dominant in males resulting in an embryonic lethality. This means that the single copy of the X chromosome was unable to support diverse cellular needs with a functional NEMO protein. The postnatal survival of males affected by IP has been explained by Kleinfelter (XXY) chromosomal arrangement or somatic mosaicism in the male infants (analysis shows both wild type and deleted copies of the NEMO gene) [78]. However, IP2 patients with Kleinfelter have also been identified. In addition to the Kleinfelter syndrome, other means of survival of males with IP due to NEMO mutations include hypomorphic alleles and somatic mosaicism.

13.6.6  Pathophysiology

Examination of the various mutations and proposed mutated gene products may help elucidate the mechanism causing the various manifestations of this disorder [77]. IP2 is a disease affecting the retina and causing peripheral retinal vascular nonperfusion, preretinal neovascularization, retrolental fibroplasias, infantile retinal detachment, and foveal hypoplasia. These clinical findings are similar to the diseases presenting as FEVR, ND, and ROP, as discussed above. In fact, IP2 has been demonstrated to cause an avascular temporal retina, with arteriovenous shunting, and suggesting an arrest in vascular development that is associated with pigmentary degeneration, persistence of the primary vitreous, fibrovascular membranes, and retinal detachments (Francois 1984; Spallone 1987; Mayer et al. 2003). It is natural to consider that a substantial component of the retinal pathology in IP2 arises because of a primary developmental retinal vascular anomaly. This could then lead to regional ischemia, pathological angiogenesis, exudation from leaky vessels, and cicatricial changes that lead to the resultant phenotype. IP2 is known to be caused by mutations in the NEMO gene. Given the essential role of NEMO in promoting NFkB activation, the pathological features of the retinal vasculature in IP2 may be a result of disruption of the critical pathways of cell survival (antiapoptosis), inflammation, and angiogenesis. Is NFkB signaling involved in angiogenesis?

NFkB signaling is known to promote or upregulate expression from several genes in vascular endothelial cells that are involved in normal or pathological angiogenic processes. These include genes that are involved in cell proliferation, regulation of apoptosis, cell migration, and the promotion of angiogenesis. Genes specifically involved in angiogenesis include the following: E-selectin, VCAM, ICAM, VEGF, IL-8, MMP2, MMP9, and COX2 (Lee et al. 2007). Therefore, it is feasible that NEMO mutations could directly impact the retinal angiogenic process.

13.6.7  Incidence

IP is extremely rare. There are less than 700 reported cases of IP in the ophthalmic and dermatologic literature combined [68].

13.6.8  Natural History and Prognosis

(Signs, Symptoms, Timing, etc.)

Skin lesions are the hallmark of the disease occurring in four stages in the postnatal period. Infants present with inflammatory vesicles within the first 2 weeks of life. These are usually found on the extremities and torso and may disappear and reappear. In the first month of life, the skin findings become hypertrophic with verrucous patches and papules, which may persist on the feet. After 3 months, the distinctive swirl-like pattern of hyperpigmentation is apparent, and dermal scarring is notable on the extremities and torso leaving the face unaffected [70, 71]. The characteristic dermal hyperpigmentation may fade in adulthood. Other ectodermal findings can be noted in patients with IP. Alopecia, or loss of hair, and abnormal tooth eruption including late, missing, or pegged teeth are common in IP.

Ocular disease is found in about one third of patients and almost always presents itself within the first year of life [65]. Findings can include strabismus, nystagmus, congenital cataract, corneal opacities, conjunctival pigmentation, pigmentary changes of the RPE, foveal hypoplasia, and peripheral vascular abnormalities with peripheral fibrovascular proliferation leading to tractional retinal detachment. Persistence of fetal vasculature has been reported in patients with IP [65]. Progression of ocular disease beyond infancy is rare.

Central nervous system involvement is found in about one third of patients. Patients with IP can manifest spastic paralysis, convulsive disorders, developmental delay, and mental retardation; however, 84% of patients have normal or above normal intelligence [70].

The overall clinical course for most patients with IP is benign. The ocular and central nervous system findings can result in significant morbidity, but the ectodermal findings are cosmetic.

13.6.9  Diagnosis and Diagnostic Aids

Diagnosis is based on clinical examination of the skin, eyes, family members, and a high index of suspicion. Patients may be referred by neonatologists, pediatricians, or dermatologists for a thorough

ophthalmic evaluation. Infants with a known family history­ of IP need to be screened for retinal abnormalities. Careful observation and/or treatment may be warranted.

13.6.10  Treatment

TheocularfindingsinIPmayneedtreatment.Therapeutic laser or cryotherapy to peripheral avascular retina has been reported to cause regression of the proliferative vasculopathy found in IP patients [79, 80]. Although laser may cause regression of the peripheral vascular abnormality, tractional retinal detachment may still occur. Peripheral retinal detachment can be treated with a standard scleral buckling procedure [81]. Surgical intervention should be considered in patients with peripheral tractional retinal detachment encroaching on the macula or persistent vitreous hemorrhage.

13.6.11  Complications and Associations

Ocular complications include tractional or exudative retinal detachment and vitreous hemorrhage leading to strabismus and amblyopia. Careful observation and diagnosis of these complications within the first year of life are important for timely intervention.

Skin and dental abnormalities are not dangerous. Central nervous system changes, including develop­­ mental delay and spastic paralysis, can be significant.

13.6.12  Social and Family Impact

Patients diagnosed with IP should undergo a thorough ophthalmic exam in the postnatal period. Appropriate ophthalmic follow-up is essential since blindness in at least one eye due to retinal disease is common [82]. Genetic counseling is imperative in families with IP. Females affected with IP have a 25% rate of spontaneous miscarriage, 50% rate of male miscarriage, and a 50% rate of transmission of IP to their female offspring. A healthy child born to a female with IP cannot transmit the disease.