Chromosomal IGF1R Deletion: Array Characterization in Two Patients with Structural Abnormalities in Chromosome 15

KESELMAN, ANA; FERNÁNDEZ, MARÍA DEL CARMEN; DE BELLIS, RODOLFO; REY, RODOLFO A.; VILLEGAS, FLORENCIA; ARMANDO, ROMINA; DEL REY, GRACIELA; ROPELATO, MARÍA GABRIELA; CASALI, BÁRBARA; SANGUINETI, NORA; BOWITT, ADRIANA; ARBERAS, CLAUDIA; BERGADÁ, IGNACIO

Florianópolis

Congreso; Congreso anual Sociedad Latinoamericana de Endocrinología Pediátrica (SLEP); 2019

Type 1 insulin-like growth factor receptor gene (IGF1R) (chromosome 15q26.3) is essential for normal fetal and postnatalgrowth. Its haploinsufficiency is associated with severe growth retardation, microcephaly and developmental delay. We describetwo patients with IGF1R deletion as a consequence of structuralabnormalities in chromosome (chr)15: one patient with stable dicentric chr15 originated in maternal paracentric inversion with aconcomitant duplication 15q11-q15 and terminal deletion ofchr15 and a second patient with ring chr15. Array CGH and FISHanalysis were performed to characterize deletion/duplication regions, determine the breakpoints and identify the gene content.Patient 1 (male) consulted at 1.3 yr for short stature (-5.3 SD), developmental delay and microcephaly (-4.6 SD). He was born atterm with low weight (-2.7 SD) and height (-2.6 SD). He presenteddysmorphic features (triangular face, wide forehead, high nasalbridge, microretrognathia, low-set dysplastic ears, thin upper lip,pectus excavatum, brachydactyly and joint hypermobility), persistent ductus arteriosus. IGF1, IGFBP3 and basal GH levels werenormal. His array CGH analysis accurately defined a large 15.8Mbtriplication of 15q11.2q14 region and 4.2 Mb loss in 15q26.2q26.3region. Patient 2 (female) consulted at 10 months of age for shortstature (-7 SD) and microcephaly (-4.3 SD). She was born at termwith weight at -3.1 SD, height -5.4 SDS and microcephaly (-2.4SD). She presented dysmorphic features (prominent and highforehead, upslanted palpebral fissures, thin lip, retrognathia, lowset ears, short neck and bilateral clinodactyly), bicuspid aorticvalve. IGF1, IGFBP3 and basal GH levels were normal. FISH analysis of 200 cells showed 15.5% of cells with loss of the ring. ArrayCGH analysis specified a deletion of 5.2Mb in 15q26.2q26.3 region. In both patients, the deletions encompassed a total of 46genes, including the IGF1R. Six of these genes are associated withMendelian phenotypes: MEF2A, ADAMTS17, CERS3, LINS1,ALDH1A3, and CHSY1 involving cardiac, skeletal and neurological abnormalities. The two patients described here help to betterdefine the clinical spectrum of 15q26 terminal deletions. Althoughpatients with r(15) share some of the features with 15q terminaldeletion, growth delay is more marked due to the dynamic mosaicism. This report emphasizes the important role of analyzed structural abnormali