ESPE Abstracts

Introduction: I. was born at term by emergency caesarean delivery due to foetal distress, by unrelated parents. Birth weight: 2160 g (-3.18 SD), length 41.5 cm (-4.47 SD), head circumference 35.4 cm (0.57 SD). He was admitted in the neonatal intensive care unit (NICU) for the severe growth retardation associated to dysmorphic features. Neonatal screening, echocardiography and brain ultrasound normal. Karyotype: 46,XY.

Case presentation: I. came to our observation for the first time when he was 12.88 years old for obesity associated with severe short stature. Height: 124.3 cm (-4.07 SDS), weight: 51.1 kg (1.04 SDS), BMI: 25.6 kg/m2 (3.15 SDS). Bone age: 12 years; Tanner pubertal stage: I. At physical examination he presented harmonic short stature, dysmorphic features such as lunar lunar-freckled face, prominent eyebrows, depressed nasal bridge, large ears and earlobes, anteverted nares and full lips. He also had short broad neck chubby, small hands with brachydactyly, cubitus valgus and knee valgus. His parents reported behavioural problems such as easy loss of self-control, impulsiveness, hyperactivity and aggressiveness with a progressive tendency to worsen. His academic performance was poor. Blood count, lipid profile, electrolytes, renal, hepatic and thyroid function were normal. In consideration of the severe obesity associated to acanthosis nigricans, an oral glucose tolerance test was performed with evidence of marked hyperinsulinism associated with normal glucose tolerance. The patient was tested through a NGS panel including genes involved in short stature and genetic obesity. The analysis revealed the novel pathogenic variant c.2494-1G>T at the homozygous state in the CUL7 gene, at the splicing consensus site, predicted to produce an aberrant transcript. Moreover, a heterozygous missense mutation in the PHIP gene, namely c.494T>A, that causes the aminoacidic change p.Val165Asp, classified as variant of uncertain significance, was identified.

Discussion: Mutations in the CUL7 gene are associated to the 3M syndrome, an autosomal recessive disorder characterized by characteristic facial features, severe pre- and postnatal growth restriction and normal mental development whereas mutations in PHIP gene are associated to the Chung-Jansen syndrome, an autosomal dominant disorder, mainly characterized by developmental delay, learning difficulties, behavioural abnormalities, facial dysmorphism and obesity.

Conclusion: I. presents a phenotype resulting from the overlap of 3M and Chung-Jansen syndrome, both very rare and caused in this patient by novel genetic variants. Co-occurrence of genetic disorders should be kept in mind especially in the presence of very complex phenotype.