Genotype/phenotype analysis in a patient with pure and complete trisomy 12p.

Reports on patients with pure and complete trisomy 12p are rare. Up to now, 12 cases have been described in the literature. Here, we report on the genotype/phenotype-correlation of a female patient with a pure trisomy 12p. Conventional cytogenetic studies on peripheral blood chromosomes as well as molecular cytogenetic (fluorescence in situ hybridization, FISH) techniques including whole chromosome painting (WCP), comparative genomic hybridization (CGH), multicolor-banding (MCB) detected a female karyotype with an abberant chromosome 12:46,XX,der(12).ish dup(12)(pter --> q24.3::p11.2 --> pter). In addition to the trisomy 12p specific clinical hallmarks, the patient showed some features of Pallister-Killian syndrome (PKS) such as sparse hair, macroglossia, and epilepsy. These findings contribute to the genotype/phenotype correlation in trisomy 12p patients.

Retrospective diagnosis and subsequent prenatal diagnosis of Nijmegen breakage syndrome.

OBJECTIVE: We report on the retrospective diagnosis of Nijmegen breakage syndrome (NBS) confirmed by molecular genetic analysis and consecutive prenatal diagnosis in the same family. METHOD: Thirteen years after the death of their daughter due to fatal recurrent infections, a couple presented in our genetic counselling unit asking for the recurrence risk of their daughter's disease. Retrospective analysis of the medical record suggested that the girl might have suffered from NBS. Therefore, molecular genetic analysis for NBS was performed in the parents. RESULTS: After the diagnosis, NBS could be indirectly proven by molecular genetic heterozygosity testing of the parents, and a reliable prenatal diagnosis for a new pregnancy could be offered. In a following pregnancy, a massive hydrocephalus was diagnosed by ultrasound investigation. Amniocentesis was performed, and molecular analysis of the fetal DNA revealed homozygosity for the NBS1 mutation 657del5. CONCLUSION: The analysis of this family allows a further delineation of the prenatal NBS phenotype including hydrocephalus and dystopic kidneys that are helpful parameters to recognise NBS prenatally, also by ultrasound investigations in pregnancy. Additionally, we conclude that hydrocephalus might be more common in NBS patients than previously suggested.

IGFs and IGF-binding proteins as diagnostic markers and biological modulators in brain tumors.

The insulin-like growth factors (IGFs) play a pivotal role in brain tumor growth and inhibition of apoptosis. Specific IGF binding proteins (IGFBPs) may enhance or inhibit tumor growth. Moreover, IGFBPs represent tumor markers and their expression correlates with tumor grading and patient survival. Understanding the role IGFs play for the proliferation of brain tumors is a prerequisite for modulating the biology of tumorigenesis. Novel antisense strategies targeting IGF-I or the Type I IGF receptor may offer additional options to patients suffering from malignant gliomas and other CNS malignancies. Clinical trials are currently underway that should demonstrate whether a beneficial effect is achievable in these patients.

The insulin-like growth factor system in hematopoietic cells.

The insulin-like growth factor (IGF) system regulates proliferation and differentiation of hematopoietic cells. IGFs exert their effects through specific receptors on growing and differentiating blood cells as they emerge from their small pool of ancestral stem cells. The IGF system is complex as both stimulating and inhibiting effects occur by interaction of IGFs and IGF-binding proteins (IGFBPs). IGFs stimulate erythrocytes and lymphocytes but also promote leukemic hematopoietic cell proliferation. IGF-I appears to be correlated with hemoglobin levels in anemia and could also be of benefit for patients with bone marrow aplasia after transplantation. Hypersensitivity to IGF-I has been implicated as an underlying cause of polycythemia vera. Loss of imprinting of IGF-II is found in acute myeloid leukemia and myelodysplastic syndrome. Apoptosis of hematopoietic cells is significantly reduced by IGF-I involving an intriguing signal transduction pathway. IGFs could therefore, although not classical hematopoietic growth factors, be of benefit for patients with diverse hematopoietic disorders.

Deletions of the homeobox gene SHOX (short stature homeobox) are an important cause of growth failure in children with short stature.

Short stature, with an incidence of 3 in 100, is a fairly frequent disorder in children. Idiopathic short stature refers to patients who are short due to various unknown reasons. Mutations of a human homeobox gene, SHOX (short stature homeobox), have recently been shown to be associated with the short stature phenotype in patients with Turner syndrome and most patients with Léri-Weill dyschondrosteosis. This study addresses the question of the incidence and type of SHOX mutations in patients with short stature. We analyzed the SHOX gene for intragenic mutations by single strand conformation polymorphism, followed by sequencing, in 750 patients and for complete gene deletions by fluorescence in situ hybridization in 150 patients (total, 900 patients). This is the largest group of patients with short stature studied to date for SHOX mutations. All patients had a normal karyotype, and their height for chronological age were below the third percentile or minus 2 SD of national height standards. All were without obvious skeletal features reminiscent of the Leri-Weill syndrome at the time of diagnosis. Silent, missense, and nonsense mutations and a small deletion in the coding region of SHOX were identified in 9 of the 750 patients analyzed for intragenic mutations. Complete gene deletions were detected in 3 of the 150 patients studied for gene deletions. At least 3 of the 9 intragenic mutations were judged to be functional based upon the genotype- phenotype relationship for the parents and normal control individuals. We conclude that SHOX mutations have been detected in 2.4% of children with short stature. The spectrum of SHOX mutations is biased, with the vast majority leading to complete gene deletions. The prevalence of short stature due to SHOX gene mutations among children with short stature appears to be similar to that of GH deficiency or Turner syndrome. Family studies of the children with SHOX mutations often reveal older family members with same mutation who exhibit mild skeletal features reminiscent of the Turner syndrome, such as high-arched palate, short neck, abnormal auricular development, cubitus valgus, genu valgum, short fourth metacarpals, and Madelung deformity.