Familial Kleefstra syndrome due to maternal somatic mosaicism for interstitial 9q34.3 microdeletions.

The Kleefstra syndrome (Online Mendelian Inheritance in Man 607001) is caused by a submicroscopic 9q34.3 deletion or by intragenic euchromatin histone methyl transferase 1 (EHMT1) mutations. So far only de novo occurrence of mutations has been reported, whereas 9q34.3 deletions can be either de novo or caused by complex chromosomal rearrangements or translocations. Here we give the first descriptions of affected parent-to-child transmission of Kleefstra syndrome caused by small interstitial deletions, approximately 200 kb, involving part of the EHMT1 gene. Additional genome-wide array studies in the parents showed the presence of similar deletions in both mothers who only had mild learning difficulties and minor facial characteristics suggesting either variable clinical expression or somatic mosaicism for these deletions. Further studies showed only one of the maternal deletions resulted in significantly quantitative differences in signal intensity on the array between the mother and her child. But by investigating different tissues with additional fluorescent in situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA) analyses, we confirmed somatic mosaicism in both mothers. Careful clinical and cytogenetic assessments of parents of an affected proband with an (interstitial) 9q34.3 microdeletion are merited for accurate estimation of recurrence risk.

Variable phenotypes associated with 10q23 microdeletions involving the PTEN and BMPR1A genes.

Infantile juvenile polyposis is a rare disease with severe gastrointestinal symptoms and a grave clinical course. Recently, 10q23 microdeletions involving the PTEN and BMPR1A genes were found in four patients with infantile juvenile polyposis. It was hypothesized that a combined and synergistic effect of the deletion of both genes would explain the condition. Subsequently, however, a patient with a larger 10q23 deletion including the same genes but with a mild clinical phenotype was identified. Here, we present four additional patients with 10q23 microdeletions involving the PTEN and BMPR1A genes. The sizes of the deletions were analyzed using single nucleotide polymorphism array analysis. All patients had macrocephaly, dysmorphic features, retardation and congenital abnormalities. One patient developed colorectal cancer. However, only one case had disease onset before 2 years of age and severe symptoms requiring colectomy. No clear correlation was found between ages at onset or severity of gastrointestinal symptoms and the sizes of the deletions. We conclude that patients with 10q23 microdeletions involving the PTEN and BMPR1A genes have variable clinical phenotypes, which cannot be explained merely by the deletion sizes. The phenotypes are not restricted to severe infantile juvenile polyposis but include childhood-onset cases with macrocephaly, retardation, mild gastrointestinal symptoms and possibly early-onset colorectal cancer.

Aberrant marker expression patterns on the CD34+CD38- stem cell compartment in acute myeloid leukemia allows to distinguish the malignant from the normal stem cell compartment both at diagnosis and in remission.

Acute myeloid leukemia (AML) is generally regarded as a stem cell disease. In CD34-positive AML, the leukemic stem cell has been recognized as CD38 negative. This CD34+CD38- population survives chemotherapy and is most probable the cause of minimal residual disease (MRD). The outgrowth of MRD causes relapse and MRD can therefore serve as a prognostic marker. The key role of leukemogenic CD34+CD38- cells led us to investigate whether they can be detected under MRD conditions. Various markers were identified to be aberrantly expressed on the CD34+CD38- population in AML and high-risk MDS samples at diagnosis, including C-type lectin-like molecule-1 and several lineage markers/marker-combinations. Fluorescent in situ hybridization analysis revealed that marker-positive cells were indeed of malignant origin. The markers were neither expressed on normal CD34+CD38- cells in steady-state bone marrow (BM) nor in BM after chemotherapy. We found that these markers were indeed expressed in part of the patients on malignant CD34+CD38- cells in complete remission, indicating the presence of malignant CD34+CD38- cells. Thus, by identifying residual malignant CD34+CD38- cells after chemotherapy, MRD detection at the stem cell level turned out to be possible. This might facilitate characterization of these chemotherapy-resistant leukemogenic cells, thereby being of help to identify new targets for therapy.

Interstitial deletion in 3q in a patient with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) and microcephaly, mild mental retardation and growth delay: clinical report and review of the literature.

We present a boy with blepharophimosis, ptosis, epicanthus inversus, microcephaly, mild mental retardation, and growth delay. Chromosomal analysis revealed a male karyotype with an interstitial deletion in the long arm of chromosome 3. DNA-analysis showed that the deletion is of maternal origin and encompasses the region between markers D3S1535 and D3S1593. The deletion contains not only the FOXL2 gene, but also the gene encoding ataxia-telangiectasia and Rad3-related protein (ATR). Mutations in FOXL2 have been shown to cause blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). ATR has been identified as a candidate gene for Seckel syndrome, an autosomal recessive syndrome that comprises growth retardation, microcephaly, and mental retardation. We hypothesize that our patient has a contiguous gene syndrome and that the non-BPES-associated abnormalities (microcephaly, mild mental retardation, and growth delay) are the result of the deletion of the maternal ATR gene. However, it has not yet been excluded that haploinsufficiency of some other gene in this region plays a role.

Atypical progeroid syndrome: an unknown helicase gene defect?

We describe a boy with chromosomal breakage syndrome, who died of hepatocellular carcinoma at the age of 17 years. Other findings included growth retardation, bilateral cataracts, premature graying of hair and elevated levels of urinary hyaluronic acid. Intellectual functions were normal. Although some manifestations were suggestive of Werner syndrome, the diagnosis could not be confirmed by molecular investigations. Therefore, this patient probably represents a provisionally unique syndrome, perhaps due to a mutation in a related (helicase) gene.