Childhood overgrowth in patients with common NF1 microdeletions.

While growth retardation and short stature are well-known features of patients with classical neurofibromatosis type 1 (NF1), we found advanced height growth and accelerated carpal bone age in patients with an NF1 microdeletion. Our analysis is based on growth data of 21 patients with common 1.4/1.2 Mb microdeletions, including three patients with a Weaver-like appearance. Overgrowth was most evident in preschool children (2-6 years, n=10, P=0.02). We conclude that childhood overgrowth is part of the phenotypic spectrum in patients with the common 1.4/1.2 Mb NF1 microdeletions and assume that the chromosomal region comprised by the microdeletions contains a gene whose haploinsufficiency causes overgrowth.

Two new cases of analphoid marker chromosomes.

Supernumerary marker chromosomes (SMCs) without detectable alphoid DNA represent a rare and interesting class of rearranged marker chromosomes. These SMCs are predicted to have a neocentromere and have been referred to as neocentric marker chromosomes (NMCs). We report the molecular cytogenetic characterization of two new cases of neocentromere-containing chromosomes, one on 1q43-44 and one on 15q26. Both cases were examined using fluorescence in situ hybridization (FISH) with various alpha-satellite DNA probes, and no alphoid DNA was detected. In case 1, the NMC originated from the distal long arm of chromosome 1 by chromosomal microdissection and reverse painting. This marker lacked detectable chromosome 1q subtelomeric sequences, and therefore appeared to be a small ring chromosome. After genetic counseling with a high risk for a MCA/MR syndrome (trisomy 1q43 --> q44), the family continued the pregnancy. At age 6 months, the infant demonstrated no congenital or developmental anomalies. This is the first published example of a NMC derived from chromosome 1q. The marker may be one of the smallest, if not the smallest, human NMC reported to date. In case 2, fetal ultrasonography indicated a complex heart defect (abnormal return of lower vena cava, atrial septum malformation) and bilateral hydronephrosis. Molecular cytogenetic analysis showed an inverted duplication of the distal long arm of chromosome 15 (tetrasomy 15q24 --> qter). The pregnancy was terminated. Autopsy demonstrated polycystic left kidney and dysplastic right kidney. Case 2 represents the ninth report of a neocentromere on distal chromosome 15q, suggesting that this region may possibly especially support the formation of neocentromeres.

Tuberous sclerosis and polycystic kidney disease in a 3-month-old infant.

Tuberous sclerosis (TSC) is an autosomal dominantly inherited multisystemic disease characterized by the development of hamartomas predominantly in brain and kidneys. The TSC2 gene for tuberous sclerosis is localized on chromosome 16p13.3 immediately adjacent to PKD1, the gene for autosomal dominant polycystic kidney disease (ADPKD). A TSC2-PKD1 contiguous gene syndrome caused by chromosomal microdeletions disrupting both the TSC2 and PKD1 genes has been identified in patients with TSC and early-onset severe ADPKD. We report a 3-month-old Caucasian girl of non-consanguineous parents with TSC and early manifestation of ADPKD. She presented with right-sided focal seizures, two small hypopigmented areas on the left flank, and elevated blood pressure requiring antihypertensive treatment. Brain magnetic resonance imaging revealed typical signs of tuberous sclerosis and abdominal ultrasonography showed bilaterally enlarged kidneys with multiple cysts resembling those seen in ADPKD. There was no family history of renal disease or of tuberous sclerosis. Findings were highly suspicious of TSC2-PKD1 contiguous gene syndrome. Using fluorescence in situ hybridization and plasmid probe CW23, which spans the adjacent 3' regions of TSC2 and PKD1 genes, we identified a submicroscopic deletion on only one of the chromosomes 16p13.3, thus permitting the diagnosis of the TSC2-PKD1 contiguous gene syndrome.