Prenatal Diagnosis of CHOPS Syndrome: First Report of a Fetus Diagnosed In utero due to Shortened Limbs

Dear Editor, CHOPS syndrome, caused by AFF4 variants, is a rare genetic disorder that affects multiple organ systems. The “CHOPS” refers to the core clinical features associated with this condition, including cognitive impairment, coarse facial features, congenital heart defects, obesity, pulmonary complications, short stature, and skeletal abnormalities. First described in 2015, all confirmed diagnoses have been made in children or young adults.[1-3] We here describe a case of CHOPS syndrome diagnosed prenatally through fetal exome sequencing, following sonographic detection of shortened long bones. A 24-year-old female underwent a routine ultrasound at 12 weeks of gestation, revealing a nuchal translucency of 1.2 mm. The gestational age estimated from the crown-rump length was consistent with that calculated based on her last menstrual period. First-trimester screening using cell-free DNA analysis yielded negative results. The second-trimester ultrasound performed at 23 + 5 weeks demonstrated normal fetal morphology with biometric parameters: biparietal diameter of 58.7 mm (0.1 standard deviation [SD]), head circumference of 216.8 mm (−0.4 SD), abdominal circumference of 187.7 mm (−0.4 SD), femur length of 36.1 mm (−2.3 SD), and humerus length of 33.0 mm (−2.5 SD) [Figure 1a and b]. The estimated fetal weight was noted to be in the eighth centile range, while both umbilical artery Doppler and middle cerebral artery Doppler assessments were within normal limits. Given the suspicion of fetal growth restriction (FGR) alongside early shortened long bones, genetic counseling was provided regarding potential fetal genetic syndromes, particularly skeletal dysplasia concerns. In response to these findings, the patient requested further molecular evaluations. Amniocentesis was performed subsequently, and polymerase chain reaction testing for cytomegalovirus in amniotic fluid returned negative results. Due to the low likelihood of fetal chromosomal abnormalities as indicated by the prior negative cell-free DNA screening result, trio-exome sequencing was selected as the primary genetic approach. This analysis identified a heterozygous de novo missense variant c.778A>G (p. Met260Val) in the AFF4 gene [Figure 1c], classified as likely pathogenic according to the ACMG guidelines. No additional variants, particularly those associated with skeletal dysplasias, were identified in the exome data.Figure 1: A fetal case of CHOPS syndrome caused by an AFF4 variant. (a) A shortened femur length at 23 + 5 weeks; (b) a shortened humerus length at 23 + 5 weeks; (c) Schematic diagrams of the variant AFF4: c.778A>G, which was detected in the fetus, but not in parentsThe pregnancy was terminated at 27 weeks following the parents’ request after the genetic report became available. The aborted fetus exhibited short limbs and distinctive facial dysmorphisms, including hypertelorism, an upturned nasal tip, anteverted nares, and a coarse, full facial appearance. The identified AFF4 variant is considered to be responsible for the phenotypic abnormalities observed in the fetus. CHOPS syndrome has not yet been diagnosed in utero. We present the first reported fetal case of this syndrome. The phenotype observed in our case was characterized by short long bones, a feature consistently demonstrated in nearly all CHOPS patients. Raible et al.[2] noted that among their 11 cases, the average birth length, weight, and head circumference were approximately −2 to −3 SDs. Consequently, FGR appears to be the most prominent characteristic of CHOPS syndrome. In our case, short limbs may represent the sole significant finding on mid-pregnancy anatomical ultrasound. In prenatal diagnosis settings where structural fetal anomalies are present, exome sequencing demonstrates a yield of up to 31% for identifying unifying monogenic causes.[4] A recent systematic review revealed that prenatal sequencing substantially enhances incremental yield over chromosomal microarray testing in fetuses exhibiting short long bones or multisystem FGR.[5] Our case report underscores that in the era of exome sequencing, even nonspecific findings on prenatal ultrasound may justify pursuing exome sequencing. This approach has the potential to identify monogenic conditions, some features of which – such as neurodevelopmental delays – can only be recognized postnatally.Abbreviations ACMG American College of Medical Genetics and Genomics AFF4 Alf transcription elongation factor 4 CHOPS Cognitive impairment, coarse facial features, heart defects, obesity, pulmonary problems, short stature, and skeletal abnormalities DNA Deoxyribonucleic Acid FGR Fetal growth restriction SD Standard deviationEthics statement This study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki and its amendments. The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed. Financial support and sponsorship This study was supported by the School Management Scientific Research Project of Fujian University of Traditional Chinese Medicine (XB2024100). Conflicts of interest There are no conflicts of interest.