ESPE Abstracts

CHOPS syndrome is a rare monogenic disorder caused by heterozygous gain-of-function variants in AFF4. The 13 patients reported to date share a highly recognizable phenotype: Coarse face, Cognitive impairment, Heart defects, Obesity, Pulmonary involvement, Short stature and Skeletal dysplasia. AFF4 encodes a scaffold protein involved in transcriptional elongation and critical for gene expression regulation during embryogenesis. Notably, it appears to regulate adipogenic differentiation via autophagy; his overexpression enhances adipogenesis in mice models. We report two additional cases of CHOPS syndrome. Patient 1 is 13 years old. During pregnancy, IUGR, polyhydramnios, and rhizomelic shortening were reported. At birth, weight was adequate (-0.92 SD); he showed patent ductus arteriosus, mild dilatation of ascending aorta, recurrent pulmonary infections, conductive hearing loss, strabismus and cataracts. He has moderate intellectual disability with speech impairment; mild, nonspecific anomalies were found at brain MRI. From the first months of life, he has displayed severe short stature (-4 SD) with adequate bone age; GH deficiency was ruled out. He underwent progressive weight gain due to hyperphagia; currently he shows severe obesity (BMI 32 kg/m2) and has been on liraglutide from the age of 12. Spine X-ray revealed decreased height and ovoidal shape of dorsal vertebral bodies. Patient 2 is 2 years old. Prenatal ultrasounds showed short femur length. Birth weight was 2700g (- 1.68 SD), length was 47 cm (-1.75 SD), OFC 32.5 cm (-1.72 SD). At birth, distal hypospadias, sensorineural hearing loss and cataracts were observed. He was diagnosed with multiple ventricular septal defects and underwent two heart surgeries. After the second surgery he developed chronic lung disease, probably multifactorial. He shows severely delayed neurodevelopment. At the last auxological evaluation at 2 years, short stature (-3.9 SD) and overweight (BMI 90th centile) were evident. Both patients share peculiar dysmorphic features: brachycephaly, thick and arched eyebrows with synophrys, long and curved eyelashes, anteverted nares, long philtrum, brachydactyly. In patient 1, WGS identified the AFF4 most recurrent variant c.772C>T (p. Arg258Trp). In patient 2 we performed targeted sequencing of AFF4 mutational hotspot, detecting another recurrent variant c.760A>G (p. Thr254Ala). Both mutations occurred de novo. Our patients share highly similar features to previously reported cases, confirming the presence of a core phenotype. Despite a partial overlap with CdLS, some distinct features (obesity, pulmonary involvement and skeletal findings) can lead to a targeted diagnosis. This condition should be kept in mind in differential diagnosis of syndromic obesity with hyperphagia.