Further phenotypic delineation of subtelomeric (terminal) 4q deletion with emphasis on intracranial and reproductive anatomy

Orphanet Journal of Rare Diseases Further phenotypic delineation of subtelomeric (terminal) 4q deletion with emphasis on intracranial and reproductive anatomy Eric Scott Sills 2 MJ Burns 1 Laurinda D Parker 1 Lisa P Carroll 1 Lisa L Kephart 1 CS Dyer 1 Peter R Papenhausen 0 Jessica G Davis 3 0 Cytogenetics Laboratory, Laboratory Corporation of America, Research Triangle Park , North Carolina , USA 1 Murphy Women's Center , Murphy, North Carolina , USA 2 Reproductive Medicine Associates at Vassar Brothers , Fishkill, New York , USA 3 Division of Human Genetics, Department of Pediatrics, Weill Medical College, Cornell University , New York, New York , USA Objective: To describe selected morphological and developmental features associated with subtelomeric deletion at chromosome 4q. Materials and methods: A 21-year old female was brought for gynecologic evaluation of menorrhagia. High-resolution metaphase karyotype and subtelomere fluorescent in-situ hybridization (FISH) analysis were used for genotype determination. Pelvic anatomy was characterized via CT and laparoscopy; MR and CT were used for intracranial imaging. Results: A de novo deletion [46,XX del(4)(q32)] was identified cytogenetically and confirmed as a terminal loss via subtelomere FISH. Hand/foot malformation characteristic of deletion at this segment was present. Pelvic CT and laparoscopy revealed normal uterine anatomy. Fallopian tubes appeared grossly unremarkable, and a right ovarian cyst was excised without difficulty. Bilateral broad ligament fibroadipose nodularities were noted adjacent to the uterus between round ligament and fallopian tube. Neurological exam revealed no focal defects, although brain MR identified an abnormal signal intensity at the inferior margin of the globus pallidus, consistent with old lacunar infarct and gliosis. Developmental delay was supported by an observed level of general intellectual function estimated at age seven. Conclusion: Terminal deletion of the long arm of chromosome 4 is a rare genetic event associated with a distinctive phenotype dependent on the size of the deletion. Chromosomal losses that span the 4q32 band include mental retardation and mild craniofacial anomalies. Here, further characterization of this disorder is offered including precise quantification of the DNA loss, information on brain morphology and pelvic anatomy. Additional studies will be required to characterize the full developmental and physiologic implications of this unusual genetic disorder. - Background The incidence of terminal deletion of chromosome 4q is believed to be very low but is not known with certainty. Indeed only a limited number of reports describing such deletions exist [1] and very few of these have specifically addressed reproductive and intracranial morphology in affected individuals. Here we present an analysis of the impact of this unusual autosomal deletion on pelvic and brain anatomy. Materials and methods A 21 year-old Caucasian female nonsmoker G0 was brought by family for gynecologic evaluation to assess irregular menses and menorrhagia. She was fully ambulatory but from an early age demonstrated developmental delay; she resided in an institutional setting for several months prior to presentation. The patient was in good general health and had no specific medical complaint except occasional headache and irregular vaginal bleeding. Review of neonatal records described coarse facial features, temporal narrowing, anteverted nose, posteriorly rotated ears, broad philtrum, hypoplastic left fifth digit, and 3rd toe overriding 4th toe (bilaterally). Although inborn errors of metabolism were considered, the diagnosis of "deletion of the long arm of the fourth chromosome" was made a few days after delivery. The parents underwent testing and normal karyotypes were confirmed for both. The patient underwent an uncomplicated right inguinal hernia repair at age 4 months, but there was no other surgery. Although no recent formal developmental testing had been performed, careful history provided by the patient's caregivers revealed that by age 21 the patient had a level of basic cognitive function normally seen in a 7-year old child. Specifically, the patient was able to attend to her own toilet needs and even follow simple instructions to prepare meals. She knew the alphabet and could correctly identify numerals but was unable to read or write, except printing her own name. Arithmetic was not possible. Primary colors were recognized but the patient had no concept of interpreting calendars, clocks, or counting money. No particular affinity to music or other artistic expression was noted. There was never any hearing or visual impairment and the patient mastered good communication skills. From our center, genotype was confirmed by karyotype of PHA-stimulated peripheral metaphase leukocytes (n = 5) by GTG banding at 550 cM resolution. Subtelomere FISH was performed with TelVysion Probes (Vysis/Abbott Molecular, Des Plains, IL). Denaturation of metaphase chromosomes, hybridization, and washing was according to manufacturers recommendations. After DAPI counterstaining, microscopy and photography was performed under epifluorescence. (PFaeirgrriuoprwhee)r1al GTG banded metaphase karyotype for 46,XX del(4)(q32) proband indicating region of deleted chromosome 4 Peripheral GTG banded metaphase karyotype for 46,XX del(4)(q32) proband indicating region of deleted chromosome 4 (arrow). FdFliiusgtouarlreleoscn2egnatrimnsoitfuchyrobrmidoiszoatmioen4study indicating deletion of Fluorescent in situ hybridization study indicating deletion of distal long arm of chromosome 4. (Green = 4p, Red = 4q [unpaired signal]; chromosome 21 = control). Liquid-based Papanicolau test was performed for cervical cytology. Pelvic anatomy was evaluated by transvaginal ultrasound and CT. When an echolucent 45 mm right ovarian cyst was identified on ultrasound, surgery was planned for excision. Triple-puncture 5 mm laparoscopy was undertaken as described previously [2]. Using a 1.5 Tesla instrument, intracranial anatomy was elucidated via axial T1, T2, FLAIR DW1 and ADC magnetic resonance images with T1 sagittal pulse sequence including post-contrast axial/coronal T1-weighted sequences. Standard radiographs of both hands were also obtained. Results Genetic assessment showed 46,XX, del(4)32q [Figure 1]; a terminal deletion was confirmed by FISH analysis [Figure 2]. Both parents had a normal karyotype. Exterior uterine contour appeared normal without evidence of serosal myomas. No gross peritoneal hyperpigmentation, adhesive disease, or puckering was present to suggest endometriosis. However, the surface of the broad ligament demonstrated multiple 12 mm vesicle-like punctations [Figure 3] in random distribution which, when biopsied, showed benign peritoneal calcification. Spheroid aggregations of fibroadipose tissue were noted between the round ligament and fallopian tube, especially prominent on t (...truncated)