Analphoid de novo marker chromosome inv dup(3)(q28qter) with neocentromere in a dysmorphic and developmentally retarded girl.

CASE REPORT The marker was ascertained during cytogenetic diagnosis of a 5 year old girl with marked developmental delay and mild facial dysmorphism. Body measurements were birth length 49 cm, birth weight 2965 g, and OFC 34 cm. At the age of 8.5 years, height was 131 cm, and weight was 37 kg (>97th centile) as a result of hyperphagia which developed two years ago. Dysmorphic signs included hypognathia, broad and flat nasal root, and abnormally shaped alae nasi (fig 1). The median upper lids showed atypical epicanthus. Furthermore, the girl showed slight hirsutism and a bilateral ichthyosiform hyperkeratosis of the palms and soles. On clinical investigation at the age of 5 years our proband presented with slight muscular hypotonia and hyporeflexia. Perceptive skills and visuomotor coordination were retarded corresponding to a developmetal age of 3-3.5 years. At the age of 8.5 years the girl attends a special school for mentally handicapped children. She cannot speak properly, searching for words, can recognise only between 10 and 15 letters, and is still not able to write. Standard cytogenetic investigation showed a very small, nearly metacentric supernumerary de novo marker chromosome (fig 2), which was C band negative (not shown) but appeared mitotically stable in cultured lymphocytes, since it was present in all metaphases investigated. FISH with an alpha satellite probe detecting all human centromeres (fig 3) gave hybridisation signals on all chromosomes of the proband, except the marker chromosome. This finding implies that it is an analphoid marker. The chromosomal origin of the marker was clarified by reverse painting. Twenty copies of the marker chromosome were collected by microdissection, subsequently amplified, and labelled by DOP-PCR, 3 and the resulting FISH probe was hybridised to metaphase spreads of a male control (results not shown) and of the proband, respectively. DNA from this microdissection library hybridised exclusively on the marker and on distal 3q (fig 4). FISH with the Vysis subtelomeric probe 3QTEL05 of chromosome 3q showed two terminal signals on the marker chromosome (fig 5). In order to characterise the extent of the marker chromosome along distal 3q, FISH with mapped YAC or BAC clones was performed (table 1). All clones tested gave either no FISH signal on the marker chromosome or a double signal, a finding which suggests a (presumably inverted) duplication of the terminal chromosome 3q segment (with no monosomic segment in between). Therefore, one can assume that this chromosome belongs to the expanding category of analphoid