Incontinentia Pigmenti

Synonyms

Bloch-Sulberger Syndrome

Incontinentia pigmenti (IP) is an X-linked dominant disorder and is usually lethal before birth in males.  In affected females, it causes highly variable abnormalities of the skin, hair, nails, teeth, eyes, and central nervous system.

Incontinentia Pigmenti (IP Syndrome) is a Rare Genetic Condition Characterized by


Growth

  • Short stature

Eyes

  • Abnormally small eyes (if the retinal damage is extensive and leads to total retinal detachment early in life)
  • Retinal vascular proliferation (one of the vessels carrying blood to or from the retina to become blocked or have a blood clot.)  The retina is the inner coat of the eye which is a light-sensitive layer of tissue.
  • Optic atrophy (the loss of some or most of the nerve fibers in the optic nerve, if the retinal vascular disease is severe and early onset.  The effects range from visual change to severe visual loss.)
  • Eyes do not properly align with each other as a secondary event following poor vision when the retinal damage is severe. (strabismus)
  • Retinal bleeding from the abnormally formed blood vessels in early life
  • Formation of excess fibrous connective tissue (retinal fibrosis)
  • Separation of the retina from its attachments to the underlying tissue within the eye (retinal detachment) caused by the scarring after the growth of extensive new blood vessel formation in some females
  • Abnormality of the center part of the retina (foveal hypoplasia) if the blood flow and capillary development in that zone is damaged early in life

Teeth

  • Fewer than the normal number of teeth (hypodontia)
  • Wide spacing between teeth (diastema)
  • Delayed tooth eruption
  • Cone shaped
  • Accessory points on some teeth

Chest

  • Extra ribs

Breasts

  • Extra nipples
  • Small, underdeveloped breasts and nipples
  • Lack of breast tissue

Skeletal

  • A type of vertebral anomaly that results from a lack of formation of one half of a vertebral body. It can be a common cause of early onset scoliosis. (hemivertebrae)
  • A combination of outward curvature (kyphosis) and lateral curvature (scoliosis) of the spine  (kyphoscoliosis)

Skin Manifestations of IPSkin

Skin manifestations occur in four stages.

Stage 1

  • Onset birth-newborn period
  • Skin erythema, vesicles, pustules
  • Affects limbs and trund
  • Occurs in linear distribution

Stage 2

  • Skin papules
  • Verrucous lesions
  • Hyperkeratosis
  • Affects distal limbs and scalp

Stage 3

The third stage persists for several years and usually disappears at about age 20 years.

  • Skin hyperpigmentation
  • Primarily affects trunk
  • Follows Blaschko’s lines
  • Streaks and whorls
  • Fades in adolescence

Stage 4

  • Skin pallor, atrophy, and scarring,
  • Reduction of hair in the involved areas, both on the limbs and scalp
  • Most evident on lower legs

Nails

  • Lose shape or gets partially or completely damaged. (nail dystrophy)
  • Ridging
  • Pitting
  • Thickening that may produce nails resembling claws or a ram’s horn (onychogryposis; also known as ram’s horn nails)
  • Painful tumors under the nail bed (subungual keratotic tumors)

Hair

  • Patchy alopecia and hair loss (vertex/ crown of head) following the early blisters in the skin
  • Wiry, coarse in childhood
  • Thin, sparse in childhood with missing patches where the blisters were in infancy

Central Nervous System

  • Stroke-like episodes in the first few months of life
  • Seizures, depending on the severity of the loss of brain tissue from the early onset strokes
  • Intellectual disability depending on the severity of the strokes
  • Spasticity (unusual “tightness”, stiffness, or “pull” of muscles.) or “cerebral palsy”

Hematology

  • Leukocytosis with eosinophilia during stage 1 

 

Diagnosing IP Syndrome

A physician may suspect IP syndrome on the basis of physical features listed above especially if the mother has a formal diagnosis of IP.  However, in the isolated case, the skin manifestations are often mistaken for a viral exanthema and the baby is placed in isolation and treated with antiviral drugs until either a skin biopsy or preferably a genetic test confirms the correct diagnosis.

Diagnostic Criteria for the Disorder

Major criteria including any of the four stages of skin lesions described by Landy and Donnai (1993), and minor criteria including dental, ocular, central nervous system, hair, nail, palate, breast, and nipple anomalies, as well as multiple male miscarriages in the affected mother, the histopathologic skin findings at biopsy, or preferably the molecular confirmation for the causal gene.

Causes of IP Syndrome

Incontinentia Pigmenti (IP) is caused by mutation in the IKK-gamma gene (IKBKG), also called NEMO, on chromosome Xq28.

An affected mother may pass the gene to a female child with one chance in three for each pregnancy. The other two surviving possibilities include an unaffected male and an unaffected female. Affected male conceptions almost never complete the pregnancy and usually die in utero. Infrequently, the gene can mutate in a female child without the mother having IP.  Extremely rarely, a male child may be affected if some of his cells mutated after his conception, making him a mosaic.  If he survives to adulthood, rare cases of transmission from a mosaic father to an affected female have been documented with molecular confirmation.

Genetic Testing

Testing is available for IP syndrome.

IP Inheritance

X-linked dominant “lethal”: In X-linked dominant lethal inheritance, when the mother alone has a copy of a mutated, or defective gene associated with a disorder; she herself will be affected with the disorder. Her children will inherit the disorder as follows:

Of her surviving daughters and sons, each female offspring has one chance in two (50:50) to inherit the X-chromosome with the normal copy of the gene on it and one chance in two to inherit the X-chromosome with the mutated IP gene on it.

Every female with the normal X-chromosome from mother and the normal X-chromosome from the father will be normal for this trait.

However, every female who inherits the X-chromosome with the IP copy on it from the mother and the normal X-chromosome from the father (thus being female) will be affected with IP.

Every male child who inherits the normal X-chromosome from mother and the normal Y-chromosome from the father (thus being a male) will be normal.  However, every conception that inherits the X-chromosome with the mutated IP gene from mother and the Y-chromosome from the father will be an affected male. Virtually no males with that combination survive the complete pregnancy and are spontaneously aborted.

Learn more about IP from the Online Mendelian Inheritance in Man or the Incontinentia Pigmenti International Foundation.