Poikiloderma with neutropenia
Poikiloderma with neutropenia (PN) is a rare genetic disorder characterized by distinctive skin changes and a persistent deficiency of infection-fighting white blood cells.
Description
Poikiloderma with neutropenia (PN) is a disorder that mainly affects the skin and the immune system. This condition begins with a bumpy rash that usually appears between the ages of 6 and 12 months, gradually spreading from the arms and legs to the torso and face. At about age 2, the rash fades, and the affected child is left with darker and lighter patches of skin coloring (hyperpigmentation and hypopigmentation) and small clusters of blood vessels just under the skin (telangiectases); this combination is known as poikiloderma.
Other skin problems include:
- Unusually thick skin on the palms of the hands and soles of the feet (palmoplantar keratoderma)
- Calcium deposits that form small nodules (calcinosis cutis), especially on the knees, elbows, or ears
- Sores (ulcers) that do not easily heal
Affected individuals also have fingernails and toenails that are thick and abnormally shaped, fragile teeth, and low bone density.
Immune System and Respiratory Health
People with PN have chronic neutropenia, which is a persistent shortage of neutrophils. Neutrophils are a type of white blood cell that plays a role in inflammation and in fighting infection. Neutropenia makes it more difficult for the body to fight off pathogens such as bacteria and viruses. As a result, people with PN experience recurrent sinus infections and pneumonia, especially in the first few years of life. They often develop a condition called bronchiectasis, which damages the passages leading from the windpipe to the lungs and can cause breathing problems. Throughout life, affected individuals usually have a chronic cough or a reactive airway disease, such as asthma, which leads to wheezing and shortness of breath.
Cancer Risk and Physical Features
Researchers suggest that PN may increase the risk of cancer. A type of skin cancer called squamous cell carcinoma, a precancerous blood disorder known as myelodysplastic syndrome (MDS), and a blood cancer called acute myelogenous leukemia that often follows MDS have occurred in a few people with PN.
Some individuals with PN also develop unusual facial features as they grow, including a prominent forehead, widely spaced eyes, a flat or sunken appearance of the middle of the face, a small nose, and a protruding chin. Short stature and hypogonadotropic hypogonadism (a condition affecting the production of hormones that direct sexual development) can also occur.
Frequency
The prevalence of PN is unknown; only about 100 affected individuals have been described in the medical literature. Although it was first described in the Navajo population of the southwestern United States, it has since been identified in other individuals worldwide.
Causes
PN is caused by mutations in the USB1 gene. This gene provides instructions for making an enzyme that functions as an RNA exonuclease. This enzyme helps stabilize RNA and protects it from damage. Specifically, the USB1 enzyme protects a small RNA molecule called U6, which helps in the assembly of the blueprints for protein production.
Mutations in the USB1 gene are thought to lead to an enzyme whose function is impaired. As a result of the dysfunctional USB1 exonuclease, the U6 RNA is not protected from damage. The existence of tissue-specific isoforms of the enzyme may help explain why this disorder mainly affects the skin and immune system.
Inheritance
This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.