Absence of RECQL4 mutations in poikiloderma with neutropenia in Navajo and non-Navajo patients.

Poikiloderma with neutropenia (PN), previously referred to as Navajo poikiloderma (MIM #604173) is a rare, autosomal recessive disorder first described by Clericuzio et al. [1991] in the Navajo American Indian population [Erickson, 1999]. It is characterized by a distinctive poikilodermatous rash, noncyclical neutropenia, small stature, pachyonychia, and pulmonary disease (reactive airway disease and recurrent pulmonary infections). Themolecular defect in this disorder has not been identified. PN shares some overlapping clinical features with Rothmund-Thomson syndrome (RTS, MIM #268400), another autosomal recessive disorder characterized by poikiloderma, small stature, and nail abnormalities. In addition, RTS patients have skeletal manifestations, sparse hair, cataracts, and predisposition to malignancy, specifically osteosarcoma [Wang et al., 2001], not reported in PN. Both disorders are defined by poikilodermatous skin changes, but the pattern of the rash differs. InRTS, the rash typically starts in infancyon the cheeks as macular erythema (acute phase) and then spreads to involve the extremities, rarely affecting the trunk and abdomen. The rash of PN tends to start more peripherally as papular eczematous erythema which then spreads centrally to involve the trunk and face. The skin changes of both disorders ultimately evolve into a more chronic phase of poikiloderma. Whereas neutropenia is classically associated with PN but not RTS, an increasing number of cases of hematologic abnormalities are being reported in RTS, including isolated neutropenia [Welch et al., 1984], myelodysplastic syndrome [Rizzari et al., 1996], leukemia [Porter et al., 1999], and aplastic anemia [Knoell et al., 1999]. Mutations in the RECQL4 gene at 8q24.3 encoding a DNA helicase have been detected in approximately two-thirds of RTS patients [Kitao et al., 1999; Lindor et al., 2000; Wang et al., 2002]. To examinewhether PN could be due to homozygosity for a particular allele at the RTS locus, we performed sequence analysis of the RECQL4 gene in three kindredswith the PNphenotype. One kindred included two affectedNavajo siblings; the secondkindredhada single affected child of Turkish and British descent; and the third kindred consisted of affected fraternal twins of Scottish descent. All subjects or their parents provided informed consent to participate in a research protocol approved by the Institutional Review Board for Human Subjects Research of Baylor College of Medicine, Houston, TX. The two Navajo subjects were sisters (ages 15 and 13 years at time of ascertainment) who had the classic rash of PN and neutropenia. Other findings included frequent infections in the first year of life, such as recurrent pneumonia with associated wheezing and recurrent otitismedia. Theyhadmarked thickening and excessive curving of the fingernails and toenails. The Turkish/British subject was a 2-year-old female 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 extremities, then spread to involve upper extremities, 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. She was found at age 20 months to have severe neutropenia (ANC 0.3 10/ul) that persisted and was noncyclical. Bone marrow examination was normal. Her growth (25th centile for weight and height) and development have been without delay. Chromosome analysis was normal (46, XX). The third kindred consisted of 2-year-old male (sibling A) and female (sibling B) fraternal twins from Scotland who were born at 36 weeks gestation to nonconsanguineous parents. At the age of 2 months they developed an eczematous rash initially on the arms and legs and subsequently on the face. Gradually the eczema cleared and was replaced by poikiloderma (Fig. 1A and B). They also exhibited nail dystrophy starting at 3 weeks of age with subungual hyperkeratosis (Fig. 2). The nails were markedly thickened and difficult to cut. Both children had recurrent respiratory Grant sponsor: National Institutes of Health; Grant numbers: HD24064, K12 HD41648-01, K08 HD42136-01.