Poikiloderma with neutropenia

Alternate names

Poikiloderma with neutropenia Clericuzio type; Clericuzio type poikiloderma with neutropenia

Definition

Poikiloderma with neutropenia is a rare, genetic hereditary poikiloderma disorder characterized by early-onset poikiloderma (which typically begins in the extremities, progresses centripetally and eventually involves the trunk, face and ears) associated with chronic neutropenia, recurrent infections, pachyonychia and palmoplantar keratoderma. Growth and/or develomental delay and hepato- and/or splenomegaly are additional reported features.

Epidemiology

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.

Cause

PN is caused by mutations in the USB1 gene. This gene provides instructions for making an enzyme that functions as an RNA exonuclease. RNA exonucleases cut off (cleave) building blocks called nucleotides one at a time from molecules of RNA (a chemical cousin of DNA). This process helps stabilize the 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.

Different versions (isoforms) of the USB1 enzyme are produced in different tissues, where they play various roles. In blood-forming tissues, the USB1 enzyme is thought to play a role in the maturation of neutrophils. In the skin, the enzyme is found in pigment-producing cells (melanocytes), cells in the outer layer of the skin calledkeratinocytes, and structural cells called fibroblasts. Its role in the function of these cells is unknown.

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 specific connection between USB1 gene mutations and the signs and symptoms of PN is unknown. However, the existence of tissue-specific isoforms of the enzyme could help explain why this disorder mainly affects the skin and immune system.

Inheritance

Autosomal recessive inheritance, a 25% chance

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.

Signs and symptoms

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; or sores (ulcers) that do not easily heal. Affected individuals also have fingernails and toenails that are thick and abnormally shaped (pachyonychia), fragile teeth, and low bone density. People with PN have chronic neutropenia, which is a persistent shortage (deficiency) 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 (bronchi) and can cause breathing problems. The infections become less frequent after early childhood, but throughout life affected individuals usually have a chronic cough or a reactive airway disease. This term describes asthma and other conditions in which the airways abnormally constrict in response to stimuli such as smoke or a viral infection, leading to wheezing and shortness of breath.

Researchers suggest that PN may increase the risk of cancer, although the level of risk is difficult to determine because only a small number of people have been diagnosed with PN. 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. These features include a prominent forehead (frontal bossing), widely spaced eyes (hypertelorism), a flat or sunken appearance of the middle of the face (midface hypoplasia), a small nose with a depressed nasal bridge, and a chin that protrudes (prognathism). Short stature and hypogonadotropic hypogonadism (a condition affecting the production of hormones that direct sexual development) can also occur in this disorder.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 5%-29% of people have these symptoms

• Hypertelorism(Wide-set eyes)
• Malar flattening(Zygomatic flattening)

1%-4% of people have these symptoms

• Elevated serum creatine kinase(Elevated blood creatine phosphokinase)
• Increased lactate dehydrogenase level
• Midface retrusion(Decreased size of midface)
• Neutropenia(Low blood neutrophil count)
• Plantar hyperkeratosis
• Poikiloderma
• Recurrent otitis media(Recurrent middle ear infection)
• Recurrent pneumonia
• Recurrent sinusitis
• Short stature(Decreased body height)
• Splenomegaly(Increased spleen size)

Diagnosis

Poikiloderma with neutropenia (PN) should be suspected in individuals with the following clinical findings and laboratory findings.

Clinical Skin

• Between ages six and 12 months, inflammatory eczematous rash appearing first on the limbs and progressing to the trunk, face, and on occasion the pinnae
• After age two years, post-inflammatory poikiloderma (areas of hyper- and hypopigmentation, atrophy, and telangiectasias) . Note: The telangiectasia may be subclinical and seen only on skin biopsy (which is not necessary for diagnosis).
• Recurrent infections (as evidence of neutropenia)

• In the first two years of life, recurrent sinopulmonary infections ‒ often complicated by bronchiectasis
• Adolescent- and adult-onset non-healing skin ulcers

Laboratory Congenital chronic noncyclic neutropenia that is moderate to severe: Moderate neutropenia: absolute neutrophil count (ANC)* 500-1000/µL Severe neutropenia: ANC <500/ µL

• ANC = white blood cell count (WBC) x % neutrophils

Treatment

Palmar/plantar hyperkeratosis if very pruritic ‒ and if there is no evidence of secondary dermatophyte infection ‒ can be treated for short periods with a strong topical steroid such as fluocinonide or clobetasol ointment two or three times a day. Other possible treatments include a topical keratolytic such as 40% urea, compounded salicylic acid mixed in cream, or propylene glycol.

Sinopulmonary, middle ear, and skin infections should be treated aggressively with antibioticsuntil clinical resolution and normalization of inflammatory markers.

For individuals with recurrent sinopulmonary infections, use of prophylactic antibiotics during the winter may decrease frequency of infections Neutropenia. Although administration of granulocyte-colony stimulating factor (G-CSF) to patients with PN increases the absolute neutrophil count (ANC), no reports to date have indicated definitive benefit . Based on lack of evidence of definitive benefit, G-CSF use may be considered only in patients with severe infections associated to very low neutrophil count. Bone marrow abnormalities (e.g., premyelodysplastic changes) should be followed and managed by the consulting hematologist/oncologist. Management of myelodysplastic syndrome and acute myelogenous leukemia is per routine.

Delayed puberty caused by hypogonadotropic hypogonadism should be managed by an endocrinologist specialized in this condition and may include hormone replacement therapy.

Growth. There is no evidence that growth hormone therapy increases linear growth.

NIH genetic and rare disease info

• NIH info on Poikiloderma with neutropenia

Poikiloderma with neutropenia is a rare disease.

Poikiloderma with neutropenia Resources
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