1/16. Elective bone marrow transplantation in a child with X-linked hyper-IgM syndrome presenting with acute respiratory distress syndrome.We describe a 10-month-old boy diagnosed with X-linked hyper-IgM syndrome (XHIM) after suffering from life-threatening acute respiratory distress syndrome (ARDS) caused by pneumocystis carinii pneumonia (PCP), although his previous clinical history and first level laboratory tests investigating immunological function did not indicate immunodeficiency. When the patient's overall condition was good, elective bone marrow transplantation from an HLA-matched older brother was performed successfully. We describe how correct diagnosis and successful treatment were made possible thanks to the involvement of a network of specialists.- - - - - - - - - - ranking = 1keywords = life (Clic here for more details about this article) |
2/16. X-linked myotubular myopathy in a family with three adult survivors.We describe a family with an extremely mild form of X-linked myotubular myopathy. Three affected males survived to adulthood with sufficient muscle strength to enable them to carry out normal daily activities. The mildness of the myopathy in this family is highlighted by the following: no neonatal or infant mortality resulting from the myopathy; one affected male who did not have neonatal asphyxia and had normal early motor milestones - this affected male was able to increase his muscle bulk and strength to normal by weightlifting; and a 55-year-old male who still lives an independent life. dna sequencing identified a novel missense mutation - G469A (E157K) - in exon 7 of the MTM1 gene in this family. To our knowledge, this is the third X-linked myotubular myopathy family, with multiple adult survivors, to be reported in the literature.- - - - - - - - - - ranking = 1keywords = life (Clic here for more details about this article) |
3/16. Dermatologic and immunologic findings in the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome.BACKGROUND: The immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare genodermatosis associated with dermatitis, enteropathy, type 1 diabetes, thyroiditis, hemolytic anemia, and thrombocytopenia. IPEX results from mutations of FOXP3, a gene located on the x chromosome that encodes a dna-binding protein required for development of regulatory T cells. If untreated, affected males die early in life from malabsorption and other complications. To our knowledge, this syndrome has never been described in the dermatology literature. OBSERVATIONS: We studied an 11-year-old boy with IPEX. mutation analysis revealed a G-->A transition (1150G>A) in exon 11, resulting in a putative substitution of Ala-->Thr at residue 384, within the dna-binding site. Histopathologic examination of an active skin lesion revealed psoriasiform dermatitis. The lesions improved with clobetasol ointment. The patient also displayed alopecia universalis, which had been present since age 18 months, accompanied by longitudinal ridging of the nails. Lymphocyte challenge tests revealed a profound inability to synthesize interferon gamma (INF-gamma) and dysregulated production of other cytokines. CONCLUSIONS: IPEX is an often fatal genodermatosis associated with multiple autoimmune disorders. Cutaneous findings may include dermatitis, bullae, urticaria, alopecia universalis, and trachyonychia. Recognition of this life-threatening disorder is crucial for optimal treatment and genetic counseling.- - - - - - - - - - ranking = 2keywords = life (Clic here for more details about this article) |
4/16. Unusual late presentation of X-linked chronic granulomatous disease in an adult female with a somatic mosaic for a novel mutation in CYBB.Most patients with chronic granulomatous disease (CGD) have mutations in the X-linked CYBB gene that encodes gp91phox, a component of the phagocyte nadph oxidase. The resulting X-linked form of CGD is usually manifested in boys. Rarely, X-CGD is encountered in female carriers with extreme expression of the mutated gene. Here, we report on a woman with a novel mutation in CYBB (CCG[90-92]-->GGT), predicting Tyr30Arg31-->stop, Val in gp91phox, who presented with clinical symptoms at the age of 66. The mutation was present in heterozygous form in genomic dna from her leukocytes but was fully expressed in mRNA from these cells, indicating that in her leukocytes the x chromosome carrying the nonmutated CYBB allele had been inactivated. Indeed, only 0.4% to 2% of her neutrophils showed nadph oxidase activity. This extreme skewing of her X-chromosome inactivation was not found in her cheek mucosal cells and is thus not due to a general defect in gene methylation on one x chromosome. Moreover, the CYBB mutation was not present in the dna from her cheek cells and was barely detectable in the dna from her memory T lymphocytes. Thus, this patient shows a somatic mosaic for the CYBB mutation, which probably originated during her lifetime in her bone marrow.- - - - - - - - - - ranking = 1keywords = life (Clic here for more details about this article) |
5/16. Persistent hypogammaglobulinemia following mononucleosis in boys is highly suggestive of X-linked lymphoproliferative disease--report of three cases.Hypogammaglobulinemia is a common symptom in different immunodeficiencies. It is, however, not usually associated with Epstein-Barr virus (EBV) infections. The X-linked lymphoproliferative disease (XLP) on the other hand shows immunological changes in response to the EBV. Here we report three previously healthy boys, all of which developed persistent hypogammaglobulinemia following severe acute infectious mononucleosis. All three patients revealed T-cell abnormalities including inverted CD4/CD8 and increased CD8( ) T-cell numbers. The number of IFN-gamma-producing T cells were markedly increased in the two patients studied so far. In addition, patient 2 showed mainly T cells, instead of B cells, to be infected with the EBV. Apart from an uncle of patient 3, who died of malignant lymphoma, family history was unremarkable in all cases. All three patients exhibited mutations in the SH2D1A gene, establishing the diagnosis of XLP. Protein expression was found on immunoblot analysis in one patient with a missense mutation. Development of persistent hypogammaglobulinemia after severe primary EBV infection seems to be a specific diagnostic sign for XLP even in males with unremarkable family history.- - - - - - - - - - ranking = 5keywords = life (Clic here for more details about this article) |
6/16. De Novo incontinentia pigmenti in female twins.The cutaneous lesions of incontinentia pigmenti classically evolve in stages, beginning with erythematous vesicular rash and bullae, followed by verrucose lesions, with an eventual macular pattern of splashed or whorled hyperpigmentation. We describe female twins presenting with the classic form of cutaneous expression. Ophthalmologic examination revealed abnormal vascular proliferations in the peripheral retinas in twin B. Several studies have confirmed linkage of familial incontinentia pigmenti to chromosome Xq28, with the factor viii gene in Xq28 identified as the locus for incontinentia pigmenti. Two-hundred kilobases proximal to this locus, the gene for NEMO (NF-kappaB essential modulator)/IKKgamma (I kappaB kinase-gamma) has been mapped. We describe herein female twins with incontinentia pigmenti caused by a de novo mutation of this locus, as demonstrated by diagnostic polymerase chain reaction.- - - - - - - - - - ranking = 1keywords = life (Clic here for more details about this article) |
7/16. Failure of SCID-X1 gene therapy in older patients.Gene therapy has been shown to be a highly effective treatment for infants with typical X-linked severe combined immunodeficiency (SCID-X1, gammac-deficiency). For patients in whom previous allogeneic transplantation has failed, and others with attenuated disease who may present later in life, the optimal treatment strategy in the absence of human leukocyte antigen (HLA)-matched donors is unclear. Here we report the failure of gene therapy in 2 such patients, despite effective gene transfer to bone marrow CD34( ) cells, suggesting that there are intrinsic host-dependent restrictions to efficacy. In particular, there is likely to be a limitation to initiation of normal thymopoiesis, and we therefore suggest that intervention for these patients should be considered as early as possible.- - - - - - - - - - ranking = 1keywords = life (Clic here for more details about this article) |
8/16. NEMO mutations in 2 unrelated boys with severe infections and conical teeth.X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency is a developmental and immunologic disorder caused by mutations in nuclear factor-kappaB essential modulator (NEMO), which is essential for nuclear factor-kappaB activation. Early in life, affected boys present a typical appearance, with hypotrichosis or atrichosis, hypohidrosis or anhidrosis, and hypodontia or anodontia with conical incisors. They are also susceptible to various microorganisms, mostly pyogenic bacteria and mycobacteria. Here we report 2 unrelated boys, aged 6 and 11 years, who have novel mutations in NEMO and present conical incisors and hypodontia as their sole and long-unrecognized developmental anomaly. One child had isolated recurrent pneumococcal disease, whereas the other had multiple infections. Our observations indicate that conical incisors should prompt the search for NEMO mutations in boys with unusual infectious diseases.- - - - - - - - - - ranking = 1keywords = life (Clic here for more details about this article) |
9/16. Cryptococcal meningitis in a patient with X-linked hyper-IgM1 syndrome.A case is reported of cryptococcal meningitis in a 27-y-old male suffering from X-linked hyper-IgM1 syndrome. This congenital disorder is characterized by multiple infections of the respiratory and gastrointestinal tracts, but also opportunistic infections commonly seen in patients with cell-mediated immunity. His clinical recovery was good but the need for life-long secondary chemoprophylaxis to prevent relapses is unknown.- - - - - - - - - - ranking = 1keywords = life (Clic here for more details about this article) |
10/16. Importance of genetic diagnosis of DAX-1 deficiency: example from a large, multigenerational family.BACKGROUND: Inactivating mutations of DAX-1 give rise to the X-linked form of adrenal hypoplasia congenita (AHC). Affected fetuses are at risk of early postnatal Addisonian crisis, but the variable phenotypic expression of DAX-1 insufficiency renders this diagnosis challenging. methods: We describe the familial transmission of AHC over several generations. The proband was diagnosed with adrenal insufficiency at age 3.5 years: molecular analysis revealed a novel, 373-bp deletion including the second exon of DAX-1. Given the familial history of several unexplained deaths in male infants related to the proband via his maternal great-grandmother, we hypothesized that all these boys had been affected with AHC. Another female member of the family being pregnant with a male fetus at the time, we performed DAX-1 analysis on the mother and the newborn. The mother was heterozygous for the deletion, and the newborn hemizygous: he presented an adrenal crisis at 10 days of life, and is now doing well on hormone replacement therapy. CONCLUSION: The unfortunate deaths of male infants at each generation of this family underlie the importance of early and precise diagnosis of this rare condition, stressing the value of genetic diagnosis in six potential female carriers of this family entering their reproductive years.- - - - - - - - - - ranking = 1keywords = life (Clic here for more details about this article) |
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