Alternative titles; symbols
SNOMEDCT: 772126000; ORPHA: 221046; DO: 0060551;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16q21 | Poikiloderma with neutropenia | 604173 | Autosomal recessive | 3 | USB1 | 613276 |
A number sign (#) is used with this entry because of evidence that poikiloderma with neutropenia (PN) is caused by homozygous or compound heterozygous mutation in the C16ORF57 gene (USB1; 613276) on chromosome 16q21.
Poikiloderma with neutropenia (PN) is an autosomal recessive syndrome characterized by poikiloderma, hyperkeratotic nails, generalized hyperkeratosis on palms and soles, noncyclic neutropenia, short stature, and recurrent pulmonary infections (Clericuzio et al., 1991).
Erickson (1999) provided a review of an apparently unique genodermatosis first described by Clericuzio et al. (1991) in patients of Athabaskan ancestry (Navajo and Apache). The disorder starts as a papular erythematous rash on the limbs during the first year of life. It gradually spreads centripetally and, as the papular rash resolves, hypo- and hyperpigmentation result, with development of telangiectases. Another skin manifestation is pachyonychia, but alopecia and leukoplakia are distinctively absent. That the disorder is not limited to skin is indicated by the fact that patients have recurrent pneumonias that usually result in reactive airway disease and/or chronic cough. Neutropenia has been variably present and may be cyclical. Autosomal recessive inheritance seemed clear because 8 of the 14 initial patients were sibs and none of the parents were affected. All of the patients were Navajo. There are some similarities to Rothmund-Thomson syndrome (RTS; 268400); however, the skin lesions of RTS primarily occur in sun-exposed areas, and the patients usually show marked alopecia of the head and eyebrows. In addition, RTS patients have skeletal manifestations, cataracts, and predisposition to malignancy, specifically osteosarcoma (Wang et al., 2001).
Wang et al. (2003) reported 2 Navajo sisters, ascertained in their teens, who had the classic rash of PN and neutropenia. They also reported a 2-year-old Turkish British girl who carried an initial diagnosis of probable RTS; however, her clinical findings were more consistent with PN. Her rash started at age 3 months on her lower legs, then spread to involve the arms, and eventually more centrally to involve her trunk and face. It began as a mottled pink/red rash with an eczematous component and over time became more hyperpigmented and poikilodermatous. She had pachyonychia, especially of the toenails. At age 20 months, she was found to have severe neutropenia that persisted and was noncyclical. Bone marrow exam was normal. In a Scottish kindred, 2-year-old male and female fraternal twins, born to nonconsanguineous parents, developed an eczematous rash on the arms and legs and subsequently on the face beginning at the age of 2 months. Gradually the eczema cleared and was replaced by poikiloderma; nail dystrophy started at 3 weeks of age with subungual hyperkeratosis. The nails were markedly thickened and difficult to cut. Both children had recurrent respiratory infections with prominent wheezing and recurrent otitis media. At age 20 months, they were both found to have isolated severe neutropenia.
Van Hove et al. (2005) reported 2 sibs from a consanguineous Turkish family with poikiloderma of the limbs and face, plantar keratoderma, toenail pachyonychia, and neutropenia and neutrophil dysfunction resulting in frequent respiratory infections. The proband died at 2 years of age from respiratory failure due to a bronchocentric granulomatous pneumonia. His brother had previously been diagnosed with RTS. Linkage analysis excluded the RECQL4 gene (603780) on chromosome 8q24. Van Hove et al. (2005) suggested that previously reported cases of RTS with myelodysplasia and neutropenia might represent PN rather than RTS.
Mostefai et al. (2008) reported 3 sibs from a consanguineous Moroccan family who presented with cutaneous poikiloderma following postnatal ichthyosiform lesions, associated with papillomatous lesions, palmoplantar keratoderma, pachyonychia of toenails, fragile carious teeth, and lachrymal duct obstruction. Photosensitivity and blistering improved with age. Atrophic scars were prominent on the limbs. Neutropenia developed in the first year secondary to dysmyelopoiesis affecting the granulocyte lineage, associated with a polyclonal hypergammaglobulinemia. Studies of neutrophils from 1 patient showed impaired production of reactive oxygen species. All patients had bronchopulmonary infections. The phenotype matched that described originally as poikiloderma with neutropenia-Clericuzio type in Navajo Indians. Mostefai et al. (2008) noted the phenotypic overlap with the group of the major hereditary poikiloderma disorders, including Rothmund-Thomson syndrome, dyskeratosis congenita (127550), and Kindler syndrome (173650).
Concolino et al. (2010) provided clinical details on a brother and 2 sisters with poikiloderma and neutropenia from the highly consanguineous Italian family previously studied by Volpi et al. (2010). All 3 sibs had poikiloderma, neutropenia, short stature, dystrophic nails, and hypermobile fingers with a 'beak of swan' appearance. The sibs also displayed facial dysmorphism, including hypoplasia of eyebrows, frontal bossing, widely spaced eyes, midface hypoplasia, small nose, depressed nasal bridge, and prognathism. Concolino et al. (2010) reviewed previously reported cases and noted that although dysmorphic features have not always been described, the male patient studied by Van Hove et al. (2005) showed photographic evidence of midface hypoplasia very similar to their male patient.
Concolino et al. (2019) reported a 10-year follow-up on the brother and 2 sisters reported by Volpi et al. (2010) and Concolino et al. (2010). The authors noted the stability of the intrafamilial heterogeneity of clinical manifestations. None of the patients, currently in their second and third decades of life, had developed skin cancer or myelodysplastic disorders. In both sisters, a small posterior lens opacity was seen; these were not visually significant. The frequency of acute sinopulmonary infections decreased during later years, despite a persistent noncyclic neutropenia. In one of the patients, normal neutrophil values and an absence of signs or symptoms of acute infection were seen. A substantially elevated ferritin value was noted in one of the sisters; no specific cause of the increased level was identified.
Arnold et al. (2010) reported a 4-year-old proband and his cousin with poikiloderma and neutropenia. The proband had a history of light brown macules on his arms and legs from age 5 months. At examination at 3 years of age, he had hyper- and hypopigmented spots mainly on extremities, spreading over the trunk and face, with telangiectases on the cheeks. The sun-exposed areas were predominantly affected, but there was no acute blistering. The hands and feet showed keratoderma, and the great toes showed pachyonychia. The patient's height was between the 3rd and 8th centile. Since birth he had recurrent viral and bacterial infections. He had elevated lactate dehydrogenase (LDH) and ferritin levels. Skin biopsy of a hyperpigmented macule showed slight interface dermatitis with lymphocytes and histiocytes leading to pigmentary incontinence. The affected cousin had a similar clinical presentation.
Suter et al. (2016) reported a patient with poikiloderma, neutropenia, short stature, hypogonadism, and noncaseating granuloma involving the lungs with interstitial lung disease and bronchiectasis who was found to have a homozygous mutation in the USB1 gene.
Colombo et al. (2018) reported 3 unrelated patients with PN. Patient 32 was a 2.5-year-old Turkish boy with a history of poikiloderma that began at 4 months of age. He had thin hair, photosensitivity, palmoplantar hyperkeratosis, and nail dystrophy. He experienced recurrent infections, and laboratory testing demonstrated leukopenia and neutropenia. Patient 48 was a 36-year-old Italian man with a history of poikiloderma, photosensitivity, thin and sparse hair, dental defects, palmoplantar hyperkeratosis, and nail dystrophy. He had bone defects including osteopenia and sclerosis of the distal phalanges. Dysmorphic facial features included macrocephaly, hypertelorism, depressed nasal bridge, and midface retrusion. He had a history of recurrent infections, and laboratory testing demonstrated leukopenia and neutropenia. Bone marrow evaluation demonstrated hypocellularity. Other features included hypotonia, growth delay, short stature, hypogonadism, and delayed puberty. Patient 49 was a 6-year-old Italian boy who presented with poikiloderma at 6 months of age. He had sparse hair and nail dystrophy. Facial features included frontal bossing, saddle nose, and malar hypoplasia. He had a history of recurrent infections, and laboratory testing demonstrated leukopenia and neutropenia. Bone marrow evaluation demonstrated hypocellularity. He also had hepatosplenomegaly detected at 5 years of age.
Piccolo et al. (2021) reported a patient with a history of premature birth, neonatal hypocalcemia, jaundice, and an atrial septal defect, who presented with neutropenia and recurrent pneumonia at 6 months of age. Dermatologic examination demonstrated diffuse, scaly hyperpigmentation, 2 brownish infiltrated macules, and pachyonychia of the toenails. Biopsy of one of the macules demonstrated features of cutaneous mastocytosis. At 8 months of age he had motor delay, persistent mild elevation of liver transaminases, and splenomegaly. Examination at 2 years and 10 months of age demonstrated growth delay and absent speech.
In a highly consanguineous Italian family with poikiloderma and neutropenia, Volpi et al. (2010) performed linkage analysis and identified a 3.4-Mb candidate region on 16q between rs16954293 and rs9939133, containing more than 80 known and predicted genes. Using array capture-mediated next-generation sequencing, Volpi et al. (2010) identified an A-C SNP at 56,608,737 Mb within the highly conserved C16ORF57 gene (613276) that appeared to be a strong candidate.
The transmission pattern of PN in the families studied by Mostefai et al. (2008), Volpi et al. (2010), and others was consistent with autosomal recessive inheritance.
In 3 affected sibs from a highly consanguineous Italian family with poikiloderma and neutropenia, who were known to be negative for mutation in the Rothmund-Thomson syndrome (RTS; 268400)-associated gene RECQL4 (603780), Volpi et al. (2010) identified homozygosity for a splice site mutation in the C16ORF57 gene (613276.0001). Analysis of the C16ORF57 gene in 5 patients diagnosed with 'atypical' RTS revealed compound heterozygosity for mutations in C16ORF57 (613276.0002-613276.0003) in an unrelated Italian female patient with neutropenia, who had previously been reported by Pianigiani et al. (2001) with a diagnosis of RTS and myelodysplasia but who was found to be negative for mutation in the RECQL4 gene by Volpi et al. (2010).
In 3 affected sibs from the consanguineous Moroccan family with poikiloderma and neutropenia, previously studied by Mostefai et al. (2008), Tanaka et al. (2010) identified homozygosity for a 1-bp deletion in the C16ORF57 gene (613276.0004). The unaffected parents were heterozygous for the mutation, which was not found in an unaffected sister.
In a proband and his cousin with PN, Arnold et al. (2010) identified a homozygous nonsense mutation in the C16ORF57 gene (W81X; 613276.0005). Both sets of parents were heterozygous for the mutation.
In 11 patients from 8 kindreds with PN, including 4 families of Athabaskan ancestry, Clericuzio et al. (2011) identified homozygous and compound heterozygous mutations in the C16ORF57 gene (see, e.g., 613276.0006-613276.0008). All patients in the Athabaskan families (Navajo or Apache) carried the same deletion (c.496delA; 613276.0006), indicating a founder mutation.
In a patient with PN, Suter et al. (2016) identified homozygosity for a frameshift mutation in exon 3 of the USB1 gene (613276.0009). No functional studies were reported.
By sequencing of the USB1 gene in 3 unrelated patients with PN, Colombo et al. (2018) identified homozygous and compound heterozygous mutations in the USB1 gene (613276.0002; 613276.0005; 613276.0010-613276.0011).
In a Serbian patient with PN, Piccolo et al. (2021) identified homozygosity for the previously identified nonsense mutation (W81X; 613276.0011) in the USB1 gene. The mutation, which was identified by trio whole-exome sequencing and confirmed by Sanger sequencing was present in heterozygous state in the parents.
Exclusion Studies
Because of phenotypic overlap between PN and RTS, Wang et al. (2003) performed a mutation screen of the RECQL4 gene, which is mutant in RTS, in 1 Navajo and 2 non-Navajo kindreds with the PN phenotype. No mutations were found in any of the patients.
Arnold, A. W., Itin, P. H., Pigors, M., Kohlhase, J., Bruckner-Tuderman, L., Has, C. Poikiloderma with neutropenia: a novel C16orf57 mutation and clinical diagnostic criteria. Brit. J. Derm. 163: 866-869, 2010. [PubMed: 20618321] [Full Text: https://doi.org/10.1111/j.1365-2133.2010.09929.x]
Clericuzio, C., Harutyunyan, K., Jin, W., Erickson, R. P., Irvine, A. D., McLean, W. H. I., Wen, Y., Bagatell, R., Griffin, T. A., Shwayder, T. A., Plon, S. E., Wang, L. L. Identification of a novel C16ORF57 mutation in Athabaskan patients with poikiloderma with neutropenia. Am. J. Med. Genet. 155A: 337-342, 2011. [PubMed: 21271650] [Full Text: https://doi.org/10.1002/ajmg.a.33807]
Clericuzio, C., Hoyme, H. E., Aase, J. M. Immune deficient poikiloderma: a new genodermatosis. (Abstract) Am. J. Hum. Genet. 49 (suppl.): 131 only, 1991. [PubMed: 2063865]
Colombo, E. A., Elcioglu, N. H., Graziano, C., Farinelli, P., Di Fede, E., Neri, I., Facchini, E. Greco, M., Gervasini, C., Larizza, L. Insights into mutation effect in three poikiloderma with neutropenia patients by transcript analysis and disease evolution of reported patients with the same pathogenic variants. J. Clin. Immun. 38: 494-502, 2018. [PubMed: 29770900] [Full Text: https://doi.org/10.1007/s10875-018-0508-9]
Concolino, D., Roversi, G., Muzzi, G. L., Sestito, S., Colombo, E. A., Volpi, L., Larizza, L., Strisciuglio, P. Clericuzio-type poikiloderma with neutropenia syndrome in three sibs with mutations in the C16orf57 gene: delineation of the phenotype. Am. J. Med. Genet. 152A: 2588-2594, 2010. [PubMed: 20734427] [Full Text: https://doi.org/10.1002/ajmg.a.33600]
Concolino, D., Sestito, S., Falvo, F., Romano, G., Ceravolo, M., Anastasio, E., Pensabene, L., Colombo, E. A., Larizza, L. Assessment of intrafamilial clinical variability of poikiloderma with neutropenia by a 10-year follow-up of three affected siblings. Europ. J. Med. Genet. 62: 73-76, 2019. [PubMed: 29753917] [Full Text: https://doi.org/10.1016/j.ejmg.2018.05.007]
Erickson, R. P. Southwestern Athabaskan (Navajo and Apache) genetic diseases. Genet. Med. 1: 151-157, 1999. [PubMed: 11258351] [Full Text: https://doi.org/10.1097/00125817-199905000-00007]
Mostefai, R., Morice-Picard, F., Boralevi, F., Sautarel, M., Lacombe, D., Stasia, M. J., McGrath, J., Taieb, A. Poikiloderma with neutropenia, Clericuzio type, in a family from Morocco. Am. J. Med. Genet. 146A: 2762-2769, 2008. [PubMed: 18925663] [Full Text: https://doi.org/10.1002/ajmg.a.32524]
Pianigiani, E., De Aloe, G., Andreassi, A., Rubegni, P., Fimiani, M. Rothmund-Thomson syndrome (Thomson-type) and myelodysplasia. Pediat. Derm. 18: 422-425, 2001. [PubMed: 11737690] [Full Text: https://doi.org/10.1046/j.1525-1470.2001.01971.x]
Piccolo, V., Russo, T., Di Pinto, D., Pota, E., Di Martino, M., Piluso, G., Ronchi, A., Argenziano, G., Di Brizzi, E. V., Santoro, C. Poikiloderma with neutropenia and mastocytosis: a case report and a review of dermatological signs. Front. Med. (Lausanne) 8: 680363, 2021. [PubMed: 34179048] [Full Text: https://doi.org/10.3389/fmed.2021.680363]
Suter, A.-A., Itin, P., Heinimann, K., Ahmed, M., Ashraf, T., Fryssira, H., Kini, U., Lapunzina, P., Miny, P., Sommerlund, M., Suri, M., Vaeth, S., Vasudevan, P., Gallati, S. Rothmund-Thomson syndrome: novel pathogenic mutations and frequencies of variants in the RECQL4 and USB1 (C16orf57) gene. Molec. Genet. Genomic Med. 4: 359-366, 2016. [PubMed: 27247962] [Full Text: https://doi.org/10.1002/mgg3.209]
Tanaka, A., Morice-Picard, F., Lacombe, D., Nagy, N., Hide, M., Taieb, A., McGrath, J. Identification of a homozygous deletion mutation in C16orf57 in a family with Clericuzio-type poikiloderma with neutropenia. Am. J. Med. Genet. 152A: 1347-1348, 2010. [PubMed: 20503306] [Full Text: https://doi.org/10.1002/ajmg.a.33455]
Van Hove, J. L. K., Jaeken, J., Proesmans, M., De Boeck, K., Minner, K., Matthijs, G., Verbeken, E., Demunter, A., Boogaerts, M. Clericuzio type poikiloderma with neutropenia is distinct from Rothmund-Thomson syndrome. Am. J. Med. Genet. 132A: 152-158, 2005. [PubMed: 15558713] [Full Text: https://doi.org/10.1002/ajmg.a.30430]
Volpi, L., Roversi, G., Colombo, E. A., Leijsten, N., Concolino, D., Calabria, A., Mencarelli, M. A., Fimiani, M., Macciardi, F., Pfundt, R., Schoenmakers, E. F. P. M., Larizza, L. Targeted next-generation sequencing appoints C16orf57 as Clericuzio-type poikiloderma with neutropenia gene. Am. J. Hum. Genet. 86: 72-76, 2010. Note: Erratum: Am. J. Hum. Genet. 87: 445 only, 2010. [PubMed: 20004881] [Full Text: https://doi.org/10.1016/j.ajhg.2009.11.014]
Wang, L. L., Gannavarapu, A., Clericuzio, C. L., Erickson, R. P., Irvine, A. D., Plon, S. E. Absence of RECQL4 mutations in poikiloderma with neutropenia in Navajo and non-Navajo patients. (Letter) Am. J. Med. Genet. 118A: 299-301, 2003. [PubMed: 12673665] [Full Text: https://doi.org/10.1002/ajmg.a.10057]
Wang, L. L., Levy, M. L., Lewis, R. A., Chintagumpala, M. M., Lev, D., Rogers, M., Plon, S. E. Clinical manifestations in a cohort of 41 Rothmund-Thomson syndrome patients. Am. J. Med. Genet. 102: 11-17, 2001. [PubMed: 11471165] [Full Text: https://doi.org/10.1002/1096-8628(20010722)102:1<11::aid-ajmg1413>3.0.co;2-a]