Chromosome 15q26-Qter Deletion Syndrome

A number sign (#) is used with this entry because it represents a contiguous gene deletion syndrome.

Clinical Features

Drayer et al. (1977) reported 2 sibs with mental retardation and multiple congenital anomalies, including facial dysmorphism, and skeletal abnormalities. Rump et al. (2008) provided a follow-up of the patients reported by Drayer et al. (1977). Both patients were born with microcephaly and showed growth retardation with failure to thrive. The older sister had excessive scalp hair, a broad nasal bridge, epicanthal folds, blepharophimosis, strabismus, low-set dysplastic ears, hyperextensible joints, and perceptive hearing loss. The younger brother had broad nasal bridge, epicanthal folds, blepharophimosis, divergent strabismus, low-set dysplastic ears, bilateral hearing loss, and an atrial septal defect. Both had moderate to severe mental retardation. Both also had brachydactyly characterized by short second and fifth fingers, small thumbs, and talipes equinovarus. Nails were normal. Radiographs showed absence of the middle phalanges of the second and fifth fingers, short middle phalanges of the third and fourth fingers, and short proximal phalanges of the thumbs. The toes also showed absent phalanges. There were no obvious anomalies of the internal organs.

Roback et al. (1991) described a patient with a chromosome 15q26.1-qter deletion and monozygosity for the insulin-like growth factor I receptor gene (IGF1R; 147370). Clinical features included intrauterine growth retardation (IUGR), microcephaly, micrognathia, renal anomalies, lung hypoplasia, and delayed growth and development. The authors reviewed the clinical findings in patients with similar chromosome 15 deletions and speculated that the loss of an IGF1R allele may be related to the severe IUGR and postnatal growth deficiency observed in their patient and other patients with distal 15q deletions.

Tonnies et al. (2001) reported a girl with IUGR, microcephaly, micrognathia, low-set ears, broad nasal bridge, and a complex congenital heart malformation including atrial and ventricular septal defects and coarctation of the aorta. Renal ultrasound showed slight ectasia of the left renal pelvis. FISH analysis showed a de novo terminal deletion of 15q26.1.

Okubo et al. (2003) reported a girl had intrauterine growth retardation, postnatal growth failure, and recurrent hypoglycemia. Karyotype analysis identified a deletion on 15q26.2, and a FISH study using IGF1R probes showed only a single IGF1R gene.

Walenkamp et al. (2008) reported a 15-year-old girl with heterozygous deletion of 15q26.2-qter, including the IGF1R gene, who had been small for gestational age and who showed persistent postnatal growth retardation, microcephaly, and elevated IGF1 (147440) levels. She had been treated with growth hormone since the age of 5 years, which resulted in a good growth response and normal adult height.

Veenma et al. (2010) studied a 3-generation Dutch family segregating moderate to severe short stature. The proband, a boy with a history of minor developmental delay in early childhood, presented at age 12 years due to short stature. Examination revealed small but normal-for-height head circumference, triangular facies, flat occiput, upward-slanting palpebral fissures, flat philtrum, and thin upper lip. He also had a normally shaped but low-implanted thumb and mild clinodactyly, as well as numerous cafe-au-lait spots on his thorax. At age 14, the proband underwent treatment with combined growth hormone (GH1; 139250) and luteinizing hormone-releasing hormone (LHRH; 152760), with overall catch-up growth of +32.3 cm at 4.6 years after treatment start. His 3 affected sibs, affected mother and maternal aunt, and affected maternal grandfather all shared some of the proband's mild facial and skeletal dysmorphic features, with the proximally implanted thumb being the most common characteristic in addition to short stature. Endocrine evaluation revealed variable but normal serum IGF1 levels in all family members without a consistent sign of peripheral IGF1 resistance (see 270450).

Mapping

In the 2 sibs reported by Drayer et al. (1977), Rump et al. (2008) identified a heterozygous apparently de novo 5.8-Mb deletion of chromosome 15q26.2-qter on the maternal chromosome. The proximal breakpoint was located at position 94.52 Mb from 15pter. As neither parent was affected, the authors postulated germline mosaicism for the deletion in the mother. Rump et al. (2008) noted that the deleted region includes IGF1R, haploinsufficiency of which may be responsible for the growth retardation.

Cytogenetics

By MLPA screening in the proband of a 3-generation Dutch family segregating autosomal dominant short stature, Veenma et al. (2010) identified an intragenic IGF1R deletion involving exons 11 to 21. Genomewide microarray analysis confirmed the deletion and showed that in addition to the 3-prime end of the IGF1R gene, the deletion included the more distal putative gene locus LOC145814; no other pathogenic copy number variations were detected. The proximal breakpoint of the 95-kb interstitial deletion on chromosome 15q was at 97,295 bp (rs2715449) and the distal breakpoint at 97,390 bp (rs3890115). Veenma et al. (2010) summarized the proband's karyotype as 46,XY.ish del(15)(q26.3q26.3)(rs2715449-rs3890115). Screening of 12 family members by MLPA and FISH confirmed the segregation of the deletion with short stature in all 7 affected family members. Veenma et al. (2010) stated that this was the smallest pure 15q26.3 interstitial deletion reported to that time and noted that the phenotype in this family overlapped the characteristics of patients with chromosome 15q deletions and patients with mutations in IGF1R.