ESPE Abstracts

Background: Duplication of the long arm of chromosome 4 has been described in more than 60 patients. The severity and specificity of associated symptoms depend on the size and location of the duplication, and which genes are involved.Reported features include developmental delay, intellectual disability, birth defects, hypotelorism, growth retardation, short neck, dysmorphism, and abnormalities to the extremities.

Objective: To report a two-year old child with complex chromosomal duplication involving the long arm of chromosome 4 and severe short stature due to GH deficiency.

Case history/Methods: We describe a case of a two-year old boy, born at 36 weeks of gestation. The patient was found to have the following: poor weigh gain, short stature (−3 S.D.S.) microcephaly, hypospadias, and horseshoe shaped kidneys. Biochemical evaluation revealed low level of growth hormone after stimulation test 1.45 mcg/L (reference >7 mcg/l) and normal cortisol and thyroid hormone levels. His head circumference was 43.9 cm (<3rd percentile) with normal CT head. Developmentally, he met the milestones of gross and fine motor activities and normal eye contact, with delayed speech. Urinary tract ultrasound showed horseshoe shaped kidneys. Genome wide oligonucleotide array-based comparative genomic hybridization (aCGH) analysis was performed with use of human genome CGH Microarray kit 44B (OGT technologies).

Results: aCGH analysis revealed a gain of approximately 38 MB in the long arm of chromosome 4 extending from cytogenetic band q28 and q32. Chromosomal analysis was performed to confirm the abnormal aCGH findings. G banding chromosome analysis of 11 metaphase cells from a peripheral blood sample revealed a duplication in the long arm of chromosome 4 at band q28.1 and q32.3. Several genes, MMAA (coding for methylmalonic aciduria), FGF2 (coding for fibroblast growth factor 2), NUDT6 (FGF2 antisense gene), NR3C2 (involved in minerlacorticoid regulation), and SFRP2 (Wnt signaling pathway) lay within the duplicated region seen in the patient. FGF2 is involved in limb development, angiogenesis, migration, and differentiation of neuronal cells and cardiogenic differentiation. Targeted overexpression of FGF2 isoforms in osteoblastic lineage cells in mice results in phenotypic changes, including dwarfism, rickets, hypophosphatemia.

Conclusion: Our patient carries a duplication of chromosome 4 with a cytogenetic band q28 and q32. The patient exhibited features related to growth hormone deficiency, short stature hypospadias, horseshoe kidney, and microcephaly. Our patient expands the spectrum of phenotypes associated with chromosome-4 long arm duplication and further work is on-going to undertand the phenotypic features in this patient.