Bone Marrow Failure in Fanconi Anemia: Clinical and Genetic Spectrum in a Cohort of 20 Pediatric Patients.

Prognostic refinement in Fanconi anemia (FA) is needed, especially when considering allogeneic hematopoietic stem cell transplantation (HCT). We studied 20 children with FA and bone marrow failure from a single center. According to Hôpital Saint-Louis risk classification for FA, patients were classified in stage A (no or mild cytopenia/dysplasia), B (single non-high-risk cytogenetic abnormality), C (severe cytopenia and/or significant dysplasia and/or high-risk cytogenetic abnormality), and D (myelodysplastic syndrome with excess of blasts/acute myeloid leukemia) in 4, 2, 13, and 0 cases, respectively. Nine patients received androgens +/- steroids, with a response rate of 30%, and 11 patients underwent HCT. Ten-year cumulative incidence (CI) of myelodysplastic syndrome/acute myeloid leukemia and overall survival (OS) were 21.9% and 45.3%, respectively, in the entire cohort, whereas cumulative incidence of transplantation-related mortality and OS were 27% and 63%, respectively, in patients who underwent HCT. Patients with significant dysplasia at diagnosis (stages C and D) had significantly shorter OS post-HCT as compared with patients without dysplasia. All patients in stages C and D at diagnosis or during evolution died from their disease. HCT in recent years was associated with more favorable outcomes. Larger cohorts could validate homogenous reporting of risk and help decision-making, particularly for HCT.

Androgen insensitivity syndrome: clinical features and molecular defects.

The end-organ resistance to androgens has been designated as androgen insensitivity syndrome (AIS), an X-linked disorder caused by mutations in the androgen receptor (AR) gene. It is generally accepted that defects in the AR gene prevent the normal development of both internal and external genital structures in 46,XY individuals, causing a variety of phenotypes ranging from male infertility to completely normal female external genitalia. Precise diagnosis requires clinical, hormonal and molecular investigation and is of great importance for appropriate gender assignment and management in general. The complexity of phenotypic presentation of AIS with genotype-phenotype variability of identical mutations complicates both the diagnostic procedure and genetic counseling of the affected families. More than 400 different AR gene mutations have thus far been reported but the receptor structure-function relationship and its phenotypic outcome is not yet fully understood. This review focuses on the clinical features and molecular pathophysiology of AIS and explores the relationship of the molecular defects in the AR gene to their clinical expression.

Short stature and dysmorphology associated with defects in the SHOX gene.

Since its discovery in 1997, knowledge about the SHOX gene ( Short stature HOmeoboX-containing gene) has rapidly advanced. Although originally described as causing idiopathic short stature, SHOX mutations are also responsible for growth retardation in Léri-Weill dyschondrosteosis, Langer mesomelic dysplasia and Turner syndrome. Furthermore, SHOX has a broad functional scope and leads to a variety of different morphological-skeletal stigmata associated with these syndromes. This article reviews clinical and molecular data associated SHOX gene defects. Functional ongoing studies are expected to improve our understanding of the SHOX gene as comprising part of a genetic process responsible for normal growth and bone development.

Sex-reversed phenotype in association with two novel mutations c.2494delA and c.T3004C in the ligand-binding domain of the androgen receptor gene.

OBJECTIVE: To establish the diagnosis of complete androgen insensitivity syndrome (CAIS) in two patients with characteristic clinical and hormonal findings, relative family history in one of them, and unusual Müllerian remnants in the other. DESIGN: Case report. SETTING: Research laboratory in the Department of Medical Genetics at a university children's hospital. PATIENT(S): Two patients with 46,XY sex reversal and two maternal aunts of the first patient with the same clinical condition were tested. INTERVENTION(S): Bilateral gonadectomy was performed on both patients. MAIN OUTCOME MEASURE(S): Genetic counseling, cancer prophylaxis, hormone substitution therapy. RESULT(S): Molecular analysis revealed two novel mutations, a frameshift familial (c.2494delA) in patient 1 and a missense sporadic (c.T3004C) in patient 2. The c.2494delA mutation was also detected in two of the three affected maternal aunts of patient 1. Patient 2 presents an unusual persistence of Müllerian structures. CONCLUSION(S): Genetic counseling of potential women carriers of androgen receptor (AR) mutations is crucial for the early diagnosis of the affected offspring. The presence of Müllerian remnants, although rare, should not exclude the diagnosis of CAIS. Both identified mutations are novel and provide further evidence for the correlation between specific AR mutations and phenotype.