Poikiloderma With Neutropenia
Summary
Clinical characteristics.
Poikiloderma with neutropenia (PN) is characterized by an inflammatory eczematous rash (ages 6-12 months) followed by post-inflammatory poikiloderma (age >2 years) and chronic noncyclic neutropenia typically associated with recurrent sinopulmonary infections in the first two years of life and (often) bronchiectasis. There is increased risk for myelodysplastic syndrome and, rarely, acute myelogenous leukemia. Other ectodermal findings include nail dystrophy and palmar/plantar hyperkeratosis. Most affected individuals also have reactive airway disease and some have short stature, hypogonadotropic hypogonadism, midfacial retrusion, calcinosis cutis, and non-healing skin ulcers.
Diagnosis/testing.
Often the diagnosis of PN can be established in a proband based on clinical findings (post-inflammatory poikiloderma and congenital chronic neutropenia). Unequivocal confirmation of the diagnosis of PN relies on detection of biallelic USB1 pathogenic variants on molecular genetic testing.
Management.
Treatment of manifestations: Dermatologic manifestations are treated with gentle skin care using bland emollients and diligent sun protection; very pruritic palmar/plantar hyperkeratosis can be treated with a strong topical steroid or a topical keratolytic if secondary dermatophyte infection has been ruled out. Although use of granulocyte-colony stimulating factor (G-CSF) increases the absolute neutrophil count, there is little evidence of its clinical effect (such as decreased frequency of infections). Myelodysplastic syndrome and acute myelogenous leukemia are treated in the usual manner. Sinopulmonary, middle ear, and skin infections require aggressive treatment with antibiotics. Reactive airway disease and hypogonadotropic hypogonadism are treated in the usual manner.
Prevention of secondary complications: Annual influenza vaccine; dental cleaning and evaluation for gingivitis/caries every three to six months; liberal use of sunscreens with both UVA and UVB protection to reduce the risk of skin cancer.
Surveillance: Annual evaluation:
- By a physician familiar with PN of CBC with differential and platelet count (for evidence of anemia and/or thrombocytopenia ‒ signs of possible myelodysplastic syndrome);
- By a pulmonologist for those with bronchiectasis, chronic cough, and/or reactive airway disease;
- By a dermatologist (starting at age 10 years) for skin cancer screening.
In children: routine monitoring of growth, developmental milestones, school progress, and pubertal development.
Agents/circumstances to avoid: Excessive sun exposure (to decrease risk of skin cancer); exposure to second-hand cigarette or wood smoke and persons with respiratory illnesses (to decrease the risk of respiratory infections).
Evaluation of relatives at risk: It is appropriate to evaluate apparently asymptomatic older and younger sibs of a proband in order to identify as early as possible those who would benefit from prompt initiation of treatment and surveillance for potential complications.
Genetic counseling.
PN is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the USB1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.
Diagnosis
Suggestive Findings
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) (Figure 1). Note: The telangiectasia may be subclinical and seen only on skin biopsy (which is not necessary for diagnosis).
Figure 1.
Post-inflammatory poikiloderma in a boy age ten years; note hypo- and hyperpigmentation.
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
Establishing the Diagnosis
In many instances, the diagnosis of poikiloderma with neutropenia (PN) is established clinically in a proband with post-inflammatory poikiloderma and congenital chronic neutropenia. Unequivocal confirmation of the diagnosis of PN in individuals with a suspected clinical diagnosis or findings consistent with PN relies on molecular genetic testing demonstrating biallelic USB1 pathogenic variants (Table 1) [Colombo et al 2012, Piard et al 2012, Larizza et al 2013].
Molecular genetic testing approaches depend on the phenotype and can include a combination of gene-targeted testing (single-gene testing or a multigene panel) and genomic testing (exome or genome sequencing).
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Persons with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing, whereas those in whom a specific diagnosis has been elusive are more likely to be diagnosed using genomic testing.
Gene-targeted testing
- Single-gene testing. Sequence analysis of USB1 (formerly C16orf57) is performed first. To date sequence analysis has detected biallelic pathogenic variants in all tested individuals with a clinical diagnosis of poikiloderma with neutropenia. To date, no USB1 exon or whole-gene deletions have been reported.
- A multigene panel that includes USB1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost while limiting identification of pathogenic variants in genes that do not explain the underlying phenotype. Of note, given the rarity of poikiloderma with neutropenia many custom panels for pigmentary skin disorders and neutropenia may not include USB1.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Genomic testing
- Comprehensive genomic testing includes exome sequencing and genome sequencing.For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Poikiloderma with Neutropenia
| Gene 1 | Method | Proportion of Probands with Pathogenic Variants 2 Detectable by Method |
|---|---|---|
| USB1 | Sequence analysis 3 | All probands reported to date 4 |
| Gene-targeted deletion/duplication analysis 5 | Unknown 6 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Arnold et al [2010], Tanaka et al [2010], Volpi et al [2010], Walne et al [2010], Clericuzio et al [2011], Colombo et al [2012], Piard et al [2012], Farruggia et al [2014], Koparir et al [2014], Patiroglu & Akar [2015], Kilic & Cekic [2016], Suter et al [2016], Walne et al [2016], Aglaguel et al [2017]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
To date, no USB1 exon or whole-gene deletions have been reported.
Clinical Characteristics
Clinical Description
Poikiloderma with neutropenia (PN) is characterized by post-inflammatory poikiloderma and chronic noncyclic neutropenia typically associated with recurrent sinopulmonary infections and (often) bronchiectasis. There is increased risk for myelodysplastic syndrome and, rarely, acute myelogenous leukemia. Other ectodermal findings include nail dystrophy (typically, thickened nails) and palmar/plantar hyperkeratosis. Most affected individuals also have reactive airway disease and some have short stature, hypogonadotropic hypogonadism, midfacial retrusion, calcinosis cutis, and non-healing skin ulcers [Colombo et al 2012].
Intrafamilial clinical variability of findings of midfacial hypoplasia, poikiloderma, and neutropenia [Concolino et al 2010] and pulmonary involvement [Patiroglu & Akar 2015] has been observed ‒ the most significant instance being acute myelogenous leukemia observed in one of two sibs [Porter et al 1999].
The clinical information that follows is based on more than 70 individuals (published and unpublished to date) with a clinical diagnosis of PN.
Ectodermal Features
Skin. The skin is normal at birth. At age six to 12 months, a nonpruritic acral eczematous-like rash develops which progresses to the trunk and face. Over the next year or so the inflammatory rash resolves, the skin becomes dry, and poikiloderma becomes evident as areas of hyper- and hypopigmentation, atrophy, and telangiectasias (Figure 1).
Poikiloderma persists throughout life and may be more noticeable in individuals who have constitutionally darker skin.
Palmar/plantar hyperkeratosis is common.
Calcinosis cutis – small nodules that may be localized to the elbows, knees, and pinnae or more diffuse – may develop in childhood [Chantorn & Shwayder 2012].
Children and adults are prone to cellulitis (a manifestation of neutropenia) that may progress to non-healing skin ulcers.
Photosensitivity has been reported in some.
Squamous cell carcinoma of the skin was reported in two individuals: one age 14 years [Rodgers et al 2013] and the other "at a young age" [Walne et al 2010].
Nails. Thickened, hyperkeratotic toenails are common; dystrophic nails which can slough may also be seen (Figure 2).
Figure 2
A. Nail dystrophy in a girl age five years B. Dysplastic toenails and squamous cell carcinoma (blue arrow) in a girl age 14 years
Hair. Eyebrows and eyelashes can be sparse; hair can be dry and thin.
Teeth. Delayed dental eruption and abscesses have been observed. Gingivitis and dental caries leading to tooth loss are common.
Hematologic Findings
Neutropenia. Neutropenia is usually identified in early infancy associated with recurrent sinopulmonary infections, often complicated by bronchiectasis.
Most individuals with PN who are not acutely ill have moderate neutropenia; although some have severe neutropenia [Van Hove et al 2005, Farruggia et al 2014]. While the absolute neutrophil count (ANC) may rise to the low-normal range during acute infection, it is always inappropriately low and with resolution of the infection reverts to baseline neutropenia.
Transient thrombocytopenia and variable anemia have been reported [Van Hove et al 2005, Walne et al 2010, Clericuzio et al 2011, Farruggia et al 2014].
Myelodysplasia and Hematologic Malignancies
Of 26 persons with PN without a known malignancy, bone marrow studies showed:
- 24 with premyelodysplastic changes (often defined as <10% abnormal cells) including increased number of immature cells and myeloid maturation defects [Van Hove et al 2005, Mostefai et al 2008, Concolino et al 2010, Tanaka et al 2010, Walne et al 2010, Clericuzio et al 2011, Farruggia et al 2014, Patiroglu & Akar 2015, Walne et al 2016];
- Two with a normal pattern.
In five additional persons with PN:
- Three had myelodysplastic syndrome [Pianigiani et al 2001, Colombo et al 2012, Walne et al 2016];
- Two had acute myelogenous leukemia [Porter et al 1999, Walne et al 2010].
Infection
Almost 90% of individuals with PN have recurrent pulmonary infections including bronchiectasis, lung abscesses, and lung granulomas. Chronic recurrent otitis media and sinusitis are common in childhood.
After age five to ten years, the frequency of acute sinopulmonary infections decreases, but most individuals continue to have bronchiectasis, chronic non-productive cough, and reactive airway disease.
Quantitative immunoglobulins and lymphocyte subset panels are normal.
Facial Features
Facial features are normal at birth; however, over time characteristic craniofacial features of prominent forehead, depressed nasal bridge, and midface retrusion usually develop (Figure 3) [Concolino et al 2010, Colombo et al 2012, Koparir et al 2014].
Figure 3.
Three Italian sibs with typical midfacial hypoplasia
Other Findings
Common. Birth length and weight are usually normal; however, intrauterine growth restriction (IUGR) can be seen. Postnatal-onset short stature not associated with growth hormone deficiency is common. One individual was reported to be unresponsive to growth hormone therapy [Koparir et al 2014].
Virtually all individuals have elevated serum lactate dehydrogenase of unknown etiology; some have nonspecific mild elevation of aminotransferases, aspartate aminotransferase, ferritin, and creatine phosphokinase.
Hypogonadotropic hypogonadism causing delayed puberty is common.
Both osteopenia and increased bone density have been reported [Migliaccio et al 1999, Porter et al 1999, Wang et al 2003, Walne et al 2010, Colombo et al 2012, Koparir et al 2014]. Associated features include increased bone fragility and osteoporosis. Two individuals who are older than age 30 years have been followed long term for poorly healing long bone fractures [Volpi et al 2010, Colombo et al 2012].
Although early developmental delays (possibly related to chronic illness) have been reported, intellectual disability has not been reported.
Several patients with muscle weakness had normal muscle biopsies.
Rare
- Epiphora due to lacrimal duct obstruction and vocal cord nodules with hyperkeratinization, resulting in high-pitched voice [Koparir et al 2014]
- Macrocephaly and microcephaly
- Hepatosplenomegaly
- Hypermobile fingers with "swan neck deformity"
Genotype-Phenotype Correlations
Genotype-phenotype correlations have not been established to date.
Nomenclature
Poikiloderma with neutropenia was termed "immune-deficient poikiloderma" in the publication by Clericuzio et al [1991], who first described the condition in the Navajo population. When it was subsequently reported in non-Navajo individuals, the condition was renamed poikiloderma with neutropenia [Wang et al 2003].
In 2005 Van Hove proposed renaming the disorder Clericuzio-type poikiloderma with neutropenia [Van Hove et al 2005].
Prevalence
First described in the Navajo native American population [Clericuzio et al 1991], poikiloderma with neutropenia has since been identified in non-Navajos worldwide, including a substantial number of individuals of Turkish ancestry.
Differential Diagnosis
Table 2 summarizes inherited disorders with either poikiloderma or neutropenia in the differential diagnosis of poikiloderma with neutropenia (PN). While there is clinical overlap between PN and dyskeratosis congenita (DC) and Rothmund-Thomson syndrome (RTS), PN is clinically distinguishable from these two disorders (Table 2).
Of note, several individuals who were clinically misdiagnosed as either DC or RTS in the past have been correctly diagnosed as having PN following identification of biallelic USB1 variants on molecular genetic testing [Volpi et al 2010, Walne et al 2010, Walne et al 2016].
Table 2.
Disorders to Consider in the Differential Diagnosis of Poikiloderma with Neutropenia
| Disorder | Gene(s) | MOI | Features | ||
|---|---|---|---|---|---|
| Overlapping with PN | Distinguishing | ||||
| In this disorder | In PN | ||||
| Dyskeratosis congenita | ACD CTC1 DKC1 NHP2 NOP10 PARN RTEL1 TERC TERT TINF2 WRAP53 | XL AD AR |
|
|
|
| Rothmund-Thomson syndrome | RECQL4 | AR |
|
| |
| Hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) | FAM111B | AD |
|
| |
| ELANE-related neutropenia | ELANE | AD |
|
| |
AD = autosomal dominant; AML = acute myelogenous leukemia; AR = autosomal recessive; MOI = mode of inheritance; SCC = squamous cell carcinoma; XL = X-linked
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with poikiloderma with neutropenia, the following evaluations are recommended:
- Dermatologic evaluation to confirm poikiloderma, assess calcinosis cutis and palmar/plantar hyperkeratosis, and screen for skin cancer
- Baseline complete blood count with differential and platelet count, if not done at the time of diagnosis
- Hematology/oncology consultation to evaluate need for bone marrow examination (e.g., if more than one cell line is involved)
- Baseline pulmonary evaluation to include evaluation for bronchiectasis and granulomas and to manage reactive airway disease
- Otolaryngology evaluation to evaluate complications of chronic otitis media
- For children, pediatric endocrinology evaluation to assess growth and pubertal development
- Gastrointestinal evaluation if hepatosplenomegaly and/or elevated liver transaminases are present
- Dental evaluation for evidence of gingivitis and/or caries
- Consideration of dual-energy x-ray absorptiometry (DXA) to evaluate for low bone density in adults
- Developmental evaluation for children younger than age five years
- Consultation with a clinical geneticist familiar with poikiloderma with neutropenia
Treatment of Manifestations
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 antibiotics until 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 [Author, personal observation].
There is no rationale for immunoglobulin therapy in the absence of low immunoglobulin levels.
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 [Migliaccio et al 1999, Van Hove et al 2005, Colombo et al 2012, Rodgers et al 2013]. 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.
Prevention of Secondary Complications
The following are appropriate:
- Annual influenza vaccine as per standard of care
- Dental cleaning and evaluation for gingivitis/caries every 3-6 months
- Use of sunscreens with both UVA and UVB protection to reduce the risk of skin cancer
Surveillance
The following are appropriate:
- Annual evaluation
- By a physician familiar with poikiloderma with neutropenia
- Of CBC with differential and platelet count for evidence of anemia and/or thrombocytopenia (signs of possible myelodysplastic syndrome) which would prompt a referral to a hematologist/oncologist for consideration of bone marrow examination
- By a pulmonologist for patients with bronchiectasis, chronic cough, and/or reactive airway disease
- By a dermatologist (starting at age 10 years) for skin cancer screening
- Routine monitoring in children. Growth, developmental milestones, school progress, and pubertal development
Agents/Circumstances to Avoid
Avoid the following:
- Excessive sun exposure (to decrease the risk for skin cancer)
- Exposure to second-hand cigarette or wood smoke and persons with respiratory illnesses (to decrease the risk of respiratory infections)
Evaluation of Relatives at Risk
It is appropriate to evaluate apparently asymptomatic older and younger sibs of a proband in order to identify as early as possible those who would benefit from prompt initiation of treatment and surveillance for potential complications.
Evaluations can include:
- Molecular genetic testing if the USB1 pathogenic variants in the family are known;
- The following if the pathogenic variants in the family are not known:
- Examination by a clinician familiar with poikiloderma with neutropenia to evaluate for the characteristic skin changes
- CBC with differential and platelet count especially in newborn sibs who have not manifested a skin rash
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.