Incontinentia pigmenti

Rare X-linked dominant genetic disorder

Not to be confused with Incontinentia pigmenti achromians.

Incontinentia pigmenti
Synonyms	Bloch–Siemens syndrome, Bloch–Sulzberger disease, Bloch–Sulzberger syndrome, nelanoblastosis cutis, nevus pigmentosus systematicus
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Symptoms	N/A
Complications
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Incontinentia pigmenti (IP) is a rare X-linked dominant genetic disorder that affects the skin, hair, teeth, nails and central nervous system. It is named from its appearance under a microscope.

Incontinentia pigmenti forming along Blaschko's lines in a 3-year-old girl

The disease is characterized by skin abnormalities that begin in childhood, usually a blistering rash which heals, followed by the development of harder skin growths. The skin may develop grey or brown patches which fade with time. Other symptoms can include hair loss, dental abnormalities, eye abnormalities that can lead to vision loss and lined or pitted fingernails and toenails. Associated problems can include delayed development, intellectual disability, seizures and other neurological problems. Most males with the disease do not survive to childbirth.

Incontinentia pigmenti is caused by a mutation in the IKBKG gene, which encodes the NEMO protein, which serves to protect cells against TNF-alpha-induced apoptosis. A lack of IKBKG therefore makes cells more prone to apoptosis.

There is no specific treatment; individual conditions must be managed by specialists.

Presentation

Incontinentia pigmenti forming along Blaschko's lines in a 3-year-old girl The skin lesions evolve through characteristic stages:

• blistering (from birth to about four months of age),
• a wart-like rash (for several months),
• swirling macular hyperpigmentation (from about six months of age into adulthood), followed by
• linear hypopigmentation.
• Alopecia, dental anomalies, and dystrophic nails are observed. Some patients have retinal vascular abnormalities predisposing to retinal detachment in early childhood. Cognitive delays or intellectual disability are occasionally seen.

The discolored skin is caused by excessive deposits of melanin (normal skin pigment). Most newborns with IP will develop discolored skin within the first two weeks. The pigmentation involves the trunk and extremities, is slate-grey, blue or brown, and is distributed in irregular marbled or wavy lines. The discoloration sometimes fades with age.

Neurological problems can include cerebral atrophy, the formation of small cavities in the central white matter of the brain, and the loss of neurons in the cerebellar cortex. About 20% of children with IP will have slow motor development, muscle weakness in one or both sides of the body, intellectual disability, and seizures. They are also likely to have visual problems, which can include: crossed eyes, cataracts, and severe visual loss. Dental problems are also common, and can include hypodontia, abnormally shaped teeth, and delayed tooth eruption.

Breast anomalies can occur in 1% of patients and can include hypoplasia or supernumerary nipples.

Skeletal and structural anomalies can occur in approximately 14% of patients, including:

• Somatic asymmetry
• Hemivertebrae
• Scoliosis
• Spina bifida
• Syndactyly
• Acheiria (congenital absence of the hands - note: other limbs may be affected)
• Ear anomalies
• Extra ribs
• Skull deformities

Genetics

IP is inherited in an X-linked dominant manner. IP is lethal in most, but not all, males. A female with IP may have inherited the IKBKG mutation from either parent or have a new gene mutation. Parents may either be clinically affected or have germline mosaicism. Affected women have a 50% risk of transmitting the mutant IKBKG allele at conception; however, most affected male conceptuses miscarry. Thus, the effective ratio for liveborn children from a mother carrying the mutation is 33% unaffected females, 33% affected females, and 33% unaffected males. Genetic counseling, prenatal testing, and preimplantation genetic diagnosis is available.

In females, the cells expressing the mutated IKBKG gene due to lyonization selectively die around the time of birth, so the X-inactivation is extremely skewed.

IP is caused by mutations in a gene called NEMO (NF-κB essential modulator). Diagnosis The diagnosis of IP is established by clinical findings and occasionally by corroborative skin biopsy. Molecular genetic testing of the NEMO IKBKG gene (chromosomal locus Xq28) reveals disease-causing mutations in about 80% of probands. Such testing is available clinically.

In addition, females with IP have skewed X-chromosome inactivation; testing for this can be used to support the diagnosis.

Many people in the past were misdiagnosed with a second type of IP, formerly known as IP1. This has now been given its own name - 'Hypomelanosis of Ito' (incontinentia pigmenti achromians). This has a slightly different presentation: swirls or streaks of hypopigmentation and depigmentation. It is not inherited and does not involve skin stages 1 or 2. Some 33–50% of patients have multisystem involvement — eye, skeletal, and neurological abnormalities. Its chromosomal locus is at Xp11, rather than Xq28.

Treatment

There does not yet exist a specific treatment for IP. Treatment can only address the individual symptoms.

Management and Prognosis

• Skin Manifestations: The blistering phase usually requires wound care similar to that used for burns. As the condition evolves, the skin manifestations may become less noticeable and may not require specific treatment. Dermatological consultation is advised for proper management.
• Neurological Manifestations: Seizures and other neurological symptoms should be addressed with a neurologist. Antiepileptic drugs may be prescribed for seizure management. Any developmental delays or intellectual disabilities may require early intervention services, physical therapy, occupational therapy, and special education services.
• Ophthalmological Manifestations: Regular eye exams, preferably by a pediatric ophthalmologist, are recommended to monitor for potential visual problems and to address them as soon as possible. Retinal detachment or vascular anomalies can lead to blindness if not treated promptly.
• Dental Manifestations: Regular dental check-ups are crucial. Orthodontic treatment or dental implants may be necessary for missing or misshapen teeth.
• Breast, Skeletal, and Structural Anomalies: Regular check-ups with a pediatrician or relevant specialist (e.g., orthopedic surgeon) are essential to address and manage these anomalies.
• Genetic Counseling: Families affected by IP would benefit from genetic counseling to understand the risk of recurrence in future pregnancies and the potential outcomes for affected offspring. It provides information to families regarding the genetic nature of the disease, risks to other family members, and reproductive options.

Prognosis

The prognosis for individuals with IP varies widely and is primarily dependent on the presence and severity of systemic symptoms. While skin manifestations can be cosmetically concerning, they usually don't result in functional problems. However, neurological, ophthalmological, and dental issues can lead to significant morbidity. Regular monitoring and early interventions can help optimize outcomes for affected individuals.

Regular follow-up with specialists (dermatologist, neurologist, ophthalmologist, dentist, and genetic counselor) is essential to ensure that any emerging symptoms are addressed promptly.

In conclusion, while Incontinentia Pigmenti is a multi-system disorder with a wide range of presentations, multidisciplinary care can help manage and mitigate many of the associated complications.

External links

Classification	ICD-10: Q82.3 OMIM: 308300 MeSH: D007184 DiseasesDB: 29600
External resources	MedlinePlus: 001583 eMedicine: article/1114205 Orphanet: 464

• GeneReview/NIH/UW entry on Incontinentia Pigmenti

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