A novel X-linked trichothiodystrophy associated with a nonsense mutation in RNF113A.

BACKGROUND: Trichothiodystrophy (TTD) is a group of rare autosomal recessive disorders that variably affect a wide range of organs derived from the neuroectoderm. The key diagnostic feature is sparse, brittle, sulfur deficient hair that has a 'tiger-tail' banding pattern under polarising light microscopy. PATIENTS AND METHODS: We describe two male cousins affected by TTD associated with microcephaly, profound intellectual disability, sparse brittle hair, aged appearance, short stature, facial dysmorphism, seizures, an immunoglobulin deficiency, multiple endocrine abnormalities, cerebellar hypoplasia and partial absence of the corpus callosum, in the absence of cellular photosensitivity and ichthyosis. Obligate female carriers showed 100% skewed X-chromosome inactivation. Linkage analysis and Sanger sequencing of 737 X-chromosome exons and whole exome sequencing was used to find the responsible gene and mutation. RESULTS: Linkage analysis localised the disease allele to a 7.75 Mb interval from Xq23-q25. We identified a nonsense mutation in the highly conserved RNF113A gene (c.901 C>T, p.Q301*). The mutation segregated with the disease in the family and was not observed in over 100,000 control X chromosomes. The mutation markedly reduced RNF113A protein expression in extracts from lymphoblastoid cell lines derived from the affected individuals. CONCLUSIONS: The association of RNF113A mutation with non-photosensitive TTD identifies a new locus for these disorders on the X chromosome. The extended phenotype within this family includes panhypopituitarism, cutis marmorata and congenital short oesophagus.

An unusual cause of fever.

A 5-month old infant presented with a short history of fever of unknown origin. He initially appeared well although there was a resting tachycardia during periods of normal temperature, and pancytopenia. He remained febrile in spite of antibiotic therapy and by 48 h he had developed marked hepatosplenomegaly and coagulopathy. At 72 h a bone marrow aspirate and trephine biopsy showed haemophagocytosis. By this time the infant was encephalopathic and haemodynamically unstable with multi-organ dysfunction. Treatment with high-dose methylprednisolone and cyclosporin was commenced with an initial good response. Unfortunately the patient ultimately died of infective complications of treatment and reactivation of the underlying disease process. Haemophagocytic lymphohistiocytosis (HLH) is a rare disorder of the mononuclear phagocyte system characterised by proliferation of morphologically benign histiocytes resulting in hypercytokinaemia and uncontrolled activation of immune cells. The diagnosis of familial HLH should be considered in any infant with fever, splenomegaly and cytopenia of at least two cell lines. HLH may be cured by immunosuppressive therapy and eventual stem cell transplantation but rapid disease progression to multi-organ failure results in a high mortality.

Case report: consumptive hypothyroidism consequent to multiple infantile hepatic haemangiomas.

A 10-month-old infant with multiple infantile hepatic hemangiomas and developmental delay is reported. He was found to be profoundly hypothyroid. Evaluation and management issues are discussed. This case emphasizes the importance of screening for hypothyroidism in patients with hemangiomas and the potential therapeutic benefit of prednisolone therapy in this condition.

Allogeneic bone marrow transplantation: cure for familial Mediterranean fever.

We describe data on a 7-year-old girl with congenital dyserythropoietic anemia (CDA), who also had familial Mediterranean fever (FMF). Repeated transfusions required since the age of 6 months to treat her CDA led to iron overload and a persistently high ferritin level. Her relapsing FMF made effective iron chelation therapy very difficult. Consequently, at the age of 4 years, she underwent allogeneic, sibling bone marrow transplantation (BMT). During conditioning for her BMT, symptoms of FMF, including splenomegaly, arthritis, and recurrent abdominal pain, began to resolve and she was gradually weaned off colchicine. Now, 2 years after the transplantation, she remains free from FMF symptomatology and is off all immunosuppressants. This case demonstrates that symptoms of FMF can be alleviated by the therapy used during allogeneic BMT. In this patient it is likely that the missing factor in FMF is now being provided by granulocytes derived from the stem cells within transplanted bone marrow.