Erickson (1999) provided a review of an apparently unique genodermatosis first described by Clericuzio et al. (1991). The disorder starts as a papular erythematous rash on the limbs during the first year of life. It gradually spreads centripetally ... Erickson (1999) provided a review of an apparently unique genodermatosis first described by Clericuzio et al. (1991). 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 telangiectasias. 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 that of the brother reported here.
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 ... 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. - 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.