A Case of Mandibuloacral Dysplasia Progeroid Syndrome Presented as In Utero Growth Restriction

Dear Editor, Premature aging syndromes with features of accelerated aging are a heterogeneous group of rare genetic disorders.[1] Hutchinson–Gilford progeria syndrome (HGPS) is the best-characterized progeroid syndrome referred to as childhood progeria.[2] Recently, a newly defined syndrome with HGPS features, mandibuloacral dysplasia progeroid syndrome (MDPS), has been reported in pediatric patients.[3] Here, we first report a prenatal case of MDPS diagnosed by exome sequencing due to fetal growth restriction (FGR). A 30-year-old primigravida woman, 158 cm in height and 55.0 kg in weight, had a normal nuchal translucency scan at 12 weeks of gestation. She was healthy and had a nonsignificant medical history. The risk of developing preeclampsia was low based on a model combining body mass index, blood pressure, parity, uterine artery pulsatility index [Figure 1a], and maternal age. The cell-free DNA screening test was negative. The routine second trimester ultrasound at 24 weeks showed normal fetal morphology and biometrics. However, the third trimester ultrasound at 29 weeks, 3 days showed retarded fetal growth with head circumference of 264 mm (15.6p), abdominal circumference of 228 mm (3p), and femur length of 51 mm (11.4p). The amniotic fluid volume was normal. The umbilical artery Doppler and middle cerebral artery Doppler were both normal [Figure 1b and c]. After genetic counseling, the parents pursued advanced etiologic investigation via amniocentesis despite the fetus had a low risk of chromosomal abnormalities. Amniotic fluid cytomegalovirus polymerase chain reaction and chromosomal microarray were both negative. Rapid trio-exome sequencing revealed compound heterozygous variants c. 541_543delins (p.Q181Sfs*4) (pathogenic) and c. 378+1G>A (likely pathogenic) of the MTX2 (NM_006554.5) gene in the fetus [Supplemental Figure 1], inherited from the father and mother, respectively.Figure 1: A case of mandibuloacral dysplasia progeroid syndrome diagnosed in utero. (a) Uterine artery pulsatility index at 12 weeks; (b) umbilical artery Doppler at 29 weeks 3 days; (c) middle cerebral artery Doppler at 29 weeks 3 days; (d) picture of the patient at birthSupplemental Figure 1: Sanger sequencing data of the patient, showing the two MTX2 variants: c. 541_543delins (upper) and c.378+1G>A(lower)The pregnancy continued to 37 weeks with weekly normal color Doppler surveillance. A boy with “appearance of an old man” was delivered by cesarean section [Figure 1d]. The birth weight was 2000 g (2p), and the Apgar scores were 10 and 10 in the 1st and 5th min, respectively. The child had a normal physical and intellectual development until 1.5 years old [Supplemental Figure 2], when he developed the signs of HGPS. He died of hypertension, cardiac failure, and pneumonia at the age of 2.5 years.Supplemental Figure 2: Pictures of the patient at the age of 1 year, showing the clinical features of mandibuloacral dysplasia progeroid syndrome: an aging face with high forehead (a), mandibular recession (a), depressed nasal bridge (b), long philtrum (b), and alopecia (a)So far, only eight MDPS patients have been reported in two publications.[3,4] All of the eight cases were the products of consanguineous marriage, evidenced by homozygotes of six MTX2 variants. The present case is the ninth one, and the first one identified in a nonconsanguineous family with two different MTX2 variants. The distinctive feature is FGR, which had not been mentioned in the previous studies. The mother had no known causes of FGR, since normal fetal Doppler did not indicate placental insufficiency. In our clinical practice, patients with nonanomalous FGR are counseled by a genetic counselor, because parents are facing difficulties based on an incomplete phenotype on ultrasound or an inconclusive opinion from clinicians. If the patient chooses to undergo advanced genetic testing, exome sequencing is the option when microarray analysis is nondiagnostic. Our case report supports a previous finding that exome sequencing had a 12% incremental yield in isolated FGR over chromosomal microarray.[5] Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship This study was supported by the National Key Research and Development Program (2022YFC2702600). Conflicts of interest There are no conflicts of interest.