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Poikiloderma with Neutropenia

Synonym: Clericuzio-Type Poikiloderma with Neutropenia

, MD, , MD, and , MD.

Author Information

Initial Posting: .

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, prenatal testing for a pregnancy at increased risk, and preimplantation genetic diagnosis 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.

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 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

Table 1.

Molecular Genetic Testing Used in Poikiloderma with Neutropenia

Gene 1Test MethodProportion of Probands with Pathogenic Variants 2 Detectable by This Method
USB1Sequence analysis 3All probands reported to date 4
Gene-targeted deletion/duplication analysis 5Unknown 6
1.
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. 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.
5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used 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.

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:

In five additional persons with PN:

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.

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

DisorderGene(s)MOIFeatures
Overlapping with PNDistinguishing
In this disorderIn PN
Dyskeratosis congenitaACD
CTC1
DKC1
NHP2
NOP10
PARN
RTEL1
TERC
TERT
TINF2
WRAP53
XL
AD
AR
  • Poikiloderma
  • Nail dystrophy
  • Myelodysplasia
  • AML
  • Poikiloderma upper chest/neck
  • Oral leukoplakia
  • Pulmonary fibrosis
  • Short telomeres (on lab testing)
  • Generalized (extremities & central body) post-inflammatory poikiloderma in infancy/early childhood
  • Nail dystrophy
  • Congenital chronic moderate neutropenia
  • Recurrent upper-respiratory infections
Rothmund-Thomson syndromeRECQL4AR
  • Early-onset poikiloderma at extremities
  • Palmar/plantar hyperkeratosis
  • Nail dystrophy
  • Sparse hair & eyebrows/lashes
  • Dental abnormalities
  • Short stature
  • SCC skin
  • Early-onset facial poikiloderma
  • Skeletal defects (incl radial ray defects)
  • Gastrointestinal disturbance
  • Osteosarcoma
Hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP)FAM111BAD
  • Short stature
  • Sparse/absent eyelashes and/or eyebrows
  • Poikiloderma
  • Nail dysplasia
  • Palmar/plantar hyperkeratosis
  • Recurrent bronchitis
  • Thrombocytopenia, marrow hypocellularity
  • Poikiloderma localized to face
  • Hypohidrosis
  • Muscle contractures
  • Lymphedema of the extremities
  • Myopathy
  • Exocrine pancreatic insufficiency
  • Pulmonary fibrosis
ELANE-related neutropeniaELANEAD
  • Congenital neutropenia
  • Cyclic neutropenia
  • Severe neutropenia
  • Absence of poikiloderma

AML = acute myelogenous leukemia

SCC = squamous cell carcinoma

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 www.ClinicalTrialsRegister.eu 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Poikiloderma with neutropenia is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one USB1 pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • 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.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with poikiloderma with neutropenia are obligate heterozygotes (carriers) for a pathogenic variant in USB1.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of a USB1 pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the USB1 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the USB1 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for poikiloderma are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Neutropenia Network: North America Patient and Family Support Group
    PO Box 1693
    Brighton MI 48116
    Phone: 877-326-7117
    Email: kate@neutropenianet.org
  • Neutropenia Support Association Inc.: Canada Patient and Family Support Group
    971 Corydon Avenue
    P.O. Box 243
    Winnipeg Manitoba R3M 3SR
    Canada
    Phone: 204-489-8454; 800-663-8876 (within Canada and U.S.)
    Email: stevensl@neutropenia.ca
  • European Society for Immunodeficiencies (ESID) Registry
    Dr. Gerhard Kindle
    University Medical Center Freiburg Centre of Chronic Immunodeficiency
    Engesserstr. 4
    79106 Freiburg
    Germany
    Phone: 49-761-270-34450
    Email: esid-registry@uniklinik-freiburg.de
  • Severe Chronic Neutropenia International Registry: Australia, India, and Southeast Asia
    St. Vincent’s Hospital, Department of Medicine
    Fitzroy Victoria 3065
    Australia
    Phone: 61-3-9231-2574
    Email: ffirkin@bigpond.net.au
  • Severe Chronic Neutropenia International Registry: Europe, Africa, and Middle East
    Carl-Neuberg-Str., 30625
    Hannover
    Germany
    Phone: 49-511-546-0918
    Fax: 49-511-557-106
    Email: zeidler.cornelia@mh-hannover.de
  • Severe Chronic Neutropenia International Registry: North and South America
    1107 Northeast 45th Street
    Suite 345
    Seattle WA 98105
    Phone: 206-543-9749; 800-726-4463 (within U.S.)
    Fax: 206-543-3668
    Email: bolyard@uw.edu

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Poikiloderma with Neutropenia: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
USB116q21U6 snRNA phosphodiesteraseUSB1 databaseUSB1USB1

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Poikiloderma with Neutropenia (View All in OMIM)

604173POIKILODERMA WITH NEUTROPENIA; PN
613276U6 SMALL NUCLEAR RNA BIOGENESIS PHOSPHODIESTERASE 1; USB1

Gene structure. USB1 (previously known as C16orf57) is approximately 20 kb in size and comprises seven exons (NG_027698.1). The major transcript USB1-001 (ENST00000219281.7) encodes a 265-amino acid protein, called USB1 or hMPN1 (mutated in PN 1). Besides the canonic transcript, several isoforms are expressed, among which the alternative USB1-004 (ENST00000423271) transcript containing the first three exons and a fourth alternative exon 4, encodes a 186-amino acid protein that is expressed in keratinocytes, melanocytes, and fibroblasts [Arnold et al 2010]. See Table A, Gene for a detailed summary of gene and protein information.

Pathogenic variants. To date, 23 pathogenic variants have been reported. They include frameshifts (7) and nonsense (7), splicing (6), and missense (3) variants (see Figure 4) [Larizza et al 2013, Suter et al 2016, Walne et al 2016, Aglaguel et al 2017].

Figure 4. . Schematic of reported USB1 pathogenic variants (exons are shown as numbered boxes).

Figure 4.

Schematic of reported USB1 pathogenic variants (exons are shown as numbered boxes). Nonsense variants are in black, frameshift in blue, splicing in violet, and missense variants in red. Note: The asterisked (*) missense (red) variant is – by transcript (more...)

To date, all reported pathogenic variants appear to act by a loss-of-function mechanism. This applies also to the p.His208Arg missense variant that affects the "signature" histidine of the second motif His208-Leu-Ser210-Leu, altering the catalytic site, and to the c.502A>G variant, which interferes with splicing and induces exon skipping.

Due to the high rate of consanguinity observed in parents of individuals with PN, most affected individuals (50/56; 89%) were homozygous for USB1 pathogenic variants and only a few (6/56; 11%) were compound heterozygous. This finding reflects the geographic clustering of variants driven by a founder effect and should be considered in the molecular diagnostics of different populations.

Indeed, several pathogenic variants have been identified in multiple families of specific ethnicity:

Table 3.

USB1 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide Change 1Predicted Protein Change 1Reference Sequences
c.179delCp.(Pro60LeufsTer55)NM_024598​.3
NP_078874​.2
c.243G>Ap.(Trp81Ter)
c.499delAp.(Thr167ProfsTer98)
c.502A>G 2p.(Phe151_Arg168del)
c.504-2A>Cp.(Thr169IlefsTer61)
c.531delAp.(His179MetfsTer86)
c.541C>Tp.(Gln181Ter)
c.623A>Gp.(His208Arg)
c.673C>Tp.(Gln225Ter)
c.683_693+1del12 3p.(Asp204_Gln231del)
c.693+1G>Tp.(Asp204_Gln231del)
1.

See Figure 4 for the other 12 "private" pathogenic variants that are not listed here.

2.

Apparent missense variation identified by transcript analysis as affecting splicing [Volpi et al 2010]

3.

Apparent frameshift variation identified by transcript analysis as affecting splicing [Volpi et al 2010]

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. USB1 encodes a protein of 265 amino acids called USB1 (Mpn1), a recognized member of the 2H-phosphodiesterase family owing to its twofold-pseudosymmetric structure with a central active site, and its two conserved tetrapeptid motifs (His120LeuSer122Leu and His208LeuSer210Leu) that frame the catalytic site [Colombo et al 2012].

USB1 is a 3'-5'RNA-exonuclease able to cleave and protect from exosome damage the 3' end of U6, a small highly conserved nuclear RNA involved in the splicing process [Mroczek et al 2012, Shchepachev et al 2012, Hilcenko et al 2013].

A key role of USB1 in normal hematopoiesis has been suggested by modeling poikiloderma with neutropenia in zebrafish, as USB1-depleted embryos showed impaired commitment and differentiation of neutrophil progenitors [Colombo et al 2015] and defective splicing of "myeloid" genes [Patil et al 2015].

Abnormal gene product. USB1 pathogenic variants cause disease through a loss-of-function mechanism. Transcripts from abnormal USB1 alleles, including those resulting from early truncating variants, are detectable and thus both relatively stable and translatable [Volpi et al 2010, Clericuzio et al 2011, Colombo et al 2012, Unpublished data].

All reported pathogenic variants directly or indirectly affect the enzymatic domain of the protein by either deleting one or both key histidine-serine motifs (His120/208 -X-Ser122/210 –X, where X indicates a hydrophobic residue) or destroying the native fold and the pseudosymmetrical structure of the protein.

The mechanistic basis of poikiloderma with neutropenia (i.e., the cascade of events primed by the aberrant oligoadenylation of U6 snRNA) remains to be elucidated [Mason & Bessler 2013]. Tissue-specific isoforms could be an adjunct key to discerning the differential sensitivity of the skin and the hematopoietic tissues, possibly revealing their contribution to constitutional disease and cancer.

Transient thrombocytopenia and variable anemia have been recapitulated in zebrafish Usb1 morphants [Colombo et al 2015], suggesting that PN has more global bone marrow involvement.

References

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Chapter Notes

Author Notes

Dr Wang is a pediatric oncologist at Texas Children's Cancer Center with particular interest in treating children with solid tumors, particularly osteosarcoma. She has a longstanding interest in Rothmund-Thomson syndrome and related disorders.

Dr Clericuzio is a clinical geneticist/dysmorphologist at University of New Mexico Health Sciences Center with an interest in cancer syndromes. She was the first to identify PN as a unique disorder in 1991.

Dr Larizza is a former professor of Medical Genetics at the University of Milan with a long-lasting interest in rare diseases, particularly cancer-predisposing syndromes. In 2010 her group identified C16orf57/USB1 as the gene involved in Clericuzio-type poikiloderma with neutropenia.

Acknowledgments

We thank Dr D Concolino for providing the patient photographs in Figure 3 and the families who have generously shared their information.

We thank Dr EA Colombo (curator of the USB1 LOVD) for assistance in updating the USB1 pathogenic variants.

Revision History

  • 26 October 2017 (bp) Review posted live
  • 19 December 2016 (lw) Original submission
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