Fanconi anemia with sun-sensitivity caused by a Xeroderma pigmentosum-associated missense mutation in XPF.

BACKGROUND: Fanconi anemia (FA) is an inherited genomic instability disorder with congenital and developmental abnormalities, bone marrow failure and predisposition to cancer early in life, and cellular sensitivity to DNA interstrand crosslinks. CASE PRESENTATION: A fifty-one-year old female patient, initially diagnosed with FA in childhood on the basis of classic features and increased chromosomal breakage, and remarkable sun-sensitivity is described. She only ever had mild haematological abnormalities and no history of malignancy. To identify and characterise the genetic defect in this lady, who is one of the oldest reported FA patients, we used whole-exome sequencing for identification of causative mutations, and functionally characterized the cellular phenotype. Detection of the novel splice site mutation c.793-2A > G and the previously described missense mutation c.1765C > T (p.Arg589Trp) in XPF/ERCC4/FANCQ assign her as the third individual of complementation group FA-Q. Ectopic expression of wildtype, but not mutant, XPF/ERCC4/FANCQ, in patient-derived fibroblasts rescued cellular resistance to DNA interstrand-crosslinking agents. Patient derived FA-Q cells showed impaired nuclear excision repair capacity. However, mutated XPF/ERCC4/FANCQ protein in our patient's cells, as in the two other patients with FA-Q, was detectable on chromatin, in contrast to XP-F cells, where missense-mutant protein failed to properly translocate to the nucleus. CONCLUSIONS: Patients with FA characteristics and UV sensitivity should be tested for mutations in XPF/ERCC4/FANCQ. The missense mutation p.Arg589Trp was previously detected in patients diagnosed with Xeroderma pigmentosum or Cockayne syndrome. Hence, phenotypic manifestations associated with this XPF/ERCC4/ FANCQ mutation are highly variable.

Central nervous system abnormalities in Fanconi anaemia: patterns and frequency on magnetic resonance imaging.

OBJECTIVE: Fanconi anaemia (FA) is an inherited disease associated with congenital and developmental abnormalities resulting from the disruption of a multigenic DNA damage response pathway. This study aimed to define the MRI appearances of the brain in patients with FA in correlation with their genetic and clinical features. METHODS: A review of the brain MRI in 20 patients with FA was performed. Pituitary size and frequencies of the radiological findings of individuals with FA and age-matched controls were determined. RESULTS: Abnormalities were identified in 18 (90%) patients with FA, the commonest being a small pituitary (68%, p < 0.01 females and p < 0.001 males). In five cases (25%, p = 0.02), the pituitary morphology was also abnormal. Posterior fossa abnormalities were seen in six cases (30%, p = 0.01) including Chiari I malformation (n = 3), Dandy-Walker variant (n = 2) and cerebellar atrophy (n = 2). Six patients (30%, p = 0.01) had morphological structural variation of the corpus callosum (CC). CONCLUSION: The incidence of central nervous system (CNS) abnormalities in FA is higher than previously reported, with a midline predominance that points to impact in the early stages of CNS development. MRI brain imaging is important for endocrine assessment and pre-transplant evaluation and can make an important contribution to clinical decision-making. ADVANCES IN KNOWLEDGE: The incidence of brain structural abnormalities in FA is higher than previously reported, with abnormalities of the posterior fossa, CC and pituitary being common. There is an association with gender and reduction in pituitary size which does not strongly correlate with biochemically evident endocrine abnormality.

Optimizing the management of patients with spinal myeloma disease.

Myeloma is one of the most common malignancies that results in osteolytic lesions of the spine. Complications, including pathological fractures of the vertebrae and spinal cord compression, may cause severe pain, deformity and neurological sequelae. They may also have significant consequences for quality of life and prognosis for patients. For patients with known or newly diagnosed myeloma presenting with persistent back or radicular pain/weakness, early diagnosis of spinal myeloma disease is therefore essential to treat and prevent further deterioration. Magnetic resonance imaging is the initial imaging modality of choice for the evaluation of spinal disease. Treatment of the underlying malignancy with systemic chemotherapy together with supportive bisphosphonate treatment reduces further vertebral damage. Additional interventions such as cement augmentation, radiotherapy, or surgery are often necessary to prevent, treat and control spinal complications. However, optimal management is dependent on the individual nature of the spinal involvement and requires careful assessment and appropriate intervention throughout. This article reviews the treatment and management options for spinal myeloma disease and highlights the value of defined pathways to enable the proper management of patients affected by it.