IMPE Abstracts

Introduction: Noonan syndrome-like is a developmental disorder with heterogenic phenotype (macrocephaly, dysmorphic facial features, congenital heart disease, motor delay, short stature in 31% of cases etc.). These patients carry rare heterozygous mutations in the CBL gene, with an increased risk of malignancies, particularly juvenile myelomonocytic leukemia.

Methods: A 2.5-year-old boy, born in term with intrauterine growth retardation (IUGR) (birth weight 1650gr, –5.18 SDS and birth length 50cm, -0.38 SDS), has dysmorphic facial features, dolichocephaly and microcephaly (46cm, -2.23 SDS), short neck and short stature, height (84cm, -2.3 SDS) and weight (9.8kg, -2.7 SDS). His motor development is delayed, he does not sit or stand on his own, yet. The diagnostic assessment included a clinical examination, biochemical and hormonal investigations, followed by imaging studies and cytogenetic and molecular analyses.

Results: The evaluation has shown normal values of serum biochemical analyses and thyroid hormone, ACTH, and cortisol concentrations, while his IGF1 (29.7 ng/ml) and IGF BP3 (2.79 μg/ml) serum concentrations were low, as well as two tests of pituitary reserve (peak 6.9 ng/ml). The performed abdominal ultrasound was uneventful. The heart ultrasound revealed mitral valve insufficiency and an uncompact left ventricular wall with normal motion. There are no signs of hematologic malignancy. Karyotype was normal male, 46, XY. An array comparative genomic hybridization did not show any deletion or duplication. The targeted resequencing analysis revealed a heterozygous (nonsense) pathogenic variant, c.1675C>T, p. (Arg559Ter) in exon 11 of the CBL gene. Unfortunately, our patient is an orphan living with foster carers and the evaluation of his ancestors is unavailable.

Conclusions: Herein we present an IUGR born child with a microcephaly, growth hormone deficiency and a very rare CBL mutation. The Whole Exome Sequencing enables us the correct diagnosis of the Noonan syndrome-like disorder and the possibility of monitoring the development of malignancy.

Key words: Noonan syndrome-like disorder, microcephaly, growth hormone deficiency, motor development delay, CBL gene mutation