Compound heterozygosity for MSH6 mutations in a pediatric lymphoma patient.

An 8-year-old male with lymphoblastic lymphoma was noted to have multiple café-au-lait macules and possible Lisch nodules. Work-up revealed the child as compound heterozygous for mutations in the DNA mismatch repair gene, MSH6. This case emphasizes many clinical issues regarding individuals with biallelic mismatch repair mutations, a rare and easily missed hereditary predisposition to childhood cancer. The issues include the need for high clinical suspicion based on skin examination findings and family history, the phenotypic similarity to neurofibromatosis type 1 with possibility of misdiagnosis, the high risk for subsequent malignances, and the need for further research of possible treatment resistance.

The overlapping spectrum of rett and angelman syndromes: a clinical review.

Rett and Angelman syndromes comprise part of the spectrum of neurologic disorders associated with autism. Their clinical presentations overlap, with both presenting in later infancy with global developmental delays, severe speech and communication impairments, progressive microcephaly, seizures, autistic behaviors, and characteristic albeit different movement disorders and stereotypic hand movements. Although other features can help differentiate these disorders, significant phenotypic overlap and variation in severity sometimes cloud the underlying diagnosis. Rett syndrome is caused by a mutation in the MECP2 gene located on Xq28, whereas Angelman syndrome results from the loss of UBE3A function on chromosomal region 15q11-q13 related to a variety of molecular genetic mechanisms. Recent advances have uncovered interactions between these and other genes that affect the function and structure of neurons in the brain. The reversal of symptoms of Rett syndrome in a mature mouse model suggests the possibility for treatment of these and perhaps other autism-related disorders in the future.

MRX42: two linkage intervals, one in the pericentromeric region and one in Xq26, and the impact for carrier risk estimation.

A nonspecific X-linked mental retardation (MRX) family is reported with four mild to moderately affected males and no intellectual impairment in their obligate carrier mothers. Linkage analysis obtained the same multipoint lod score of 2.08 for two intervals on the X chromosome already reported to be linked to other MRX and syndromic X-linked mental retardation (XLMR) families: one pericentromeric and the other at Xq26. Since the responsible gene is not yet characterized, haplotyping is presently the only means available for carrier and prenatal testing for this form of MRX. Carrier risk estimation using pedigree and haplotype data for five females at risk is presented, and the difficulties of prenatal diagnosis given linkage to two different regions is discussed.