ABSTRACT
Hemophagocytic lymphohistiocytosis is a rare and fatal disorder of early infancy, which affects predominantly the mononuclear phagocyte system and is characterized by the presence of fever, hepatosplenomegaly and cytopenia. Neurological symptoms can be extremely variable, ranging from irritability, and convulsions to focal neurological signs. They often develop during disease progression, but can also be the leading initial symptoms. Early diagnosis is mandatory, because new treatments, including bone marrow transplantation, appear to be promising. Here we present the clinical, neuroradiological and histopathological findings from two children with progressive CNS disease as the main clinical manifestation of hemophagocytic lymphohistiocytosis. Both children died and diagnosis was only obtained in retrospect after careful review of the histopathological material.
Subject(s)
Central Nervous System Diseases/complications , Central Nervous System Diseases/pathology , Histiocytosis, Non-Langerhans-Cell/complications , Histiocytosis, Non-Langerhans-Cell/pathology , Child , Fatal Outcome , Female , Humans , Magnetic Resonance ImagingABSTRACT
Combined pituitary hormone deficiency (CPHD) has been linked with rare abnormalities in genes encoding transcription factors necessary for pituitary development. We have isolated LHX3, a gene involved in a new syndrome, using a candidate-gene approach developed on the basis of documented pituitary abnormalities of a recessive lethal mutation in mice generated by targeted disruption of Lhx3 (ref. 2). LHX3, encoding a member of the LIM class of homeodomain proteins, consists of at least six exons located at 9q34. We identified a homozygous LHX3 defect in patients of two unrelated consanguineous families displaying a complete deficit in all but one (adrenocorticotropin) anterior pituitary hormone and a rigid cervical spine leading to limited head rotation. Two of these patients also displayed a severe pituitary hypoplasia, whereas one patient presented secondarily with an enlarged anterior pituitary. These LHX3 mutations consist of a missense mutation (Y116C) in the LIM2 domain at a phylogenetically conserved residue and an intragenic deletion predicting a severely truncated protein lacking the entire homeodomain. These data are consistent with function of LHX3 in the proper development of all anterior pituitary cell types, except corticotropes, and extrapituitary structures.
