Kagami-Ogata syndrome is characterized by developmental delay, intellectual disability, feeding difficulty with impaired swallowing, full cheeks, prominent and deep philtrum, small bell-shaped thorax with coat-hanger appearance of the ribs, and abdominal wall defects (omphalocele and diastasis recti). Additional common features include joint contractures, kyphoscoliosis, coxa valga, and laryngomalacia. Cardiac disease and hepatoblastoma have also been reported. The diagnosis of Kagami-Ogata syndrome is established in a proband with suggestive findings and findings on molecular genetic testing that suggest deficient expression of the RTL1 antisense (RTL1as) allele of maternal origin due to one of the following: paternal uniparental disomy of chromosome 14; epimutation (hypermethylation) affecting the normally unmethylated MEG3/DLK1 intergenic differentially methylated region (MEG3/DLK1:IG-DMR) and MEG3 transcription start site DMR (MEG3:TSS-DMR) on the maternal allele; deletion of the maternally inherited 14q32.2 region that includes MEG3/DLK1:IG-DMR and/or MEG3:TSS-DMR, and may include RTL1as; deletion of the maternally inherited RTL1as but not MEG3/DLK1:IG-DMR or MEG3:TSS-DMR; translocation (or inversion) disrupting the integrity between the maternally inherited MEG3 promoter at the MEG3:TSS-DMR and RTL1as. Treatment of manifestations: Developmental and educational support; mechanical ventilation and oxygen therapy as needed after birth; tracheostomy as required; monitor and treat upper and lower respiratory tract infections; treatment of scoliosis per orthopedist; treatment of joint contractures per rehabilitation medicine specialist; tube feeding typically required for poor weight gain; gastrostomy tube feeding as needed; feeding training; treatment of cardiac disease per cardiologist; standard treatment of hepatoblastoma with surgery and chemotherapy; social work and family support. Surveillance: Monitor developmental progress, educational needs, for evidence of aspiration or respiratory insufficiency, progression of kyphoscoliosis and joint contractures, nutritional status, safety of oral intake, constipation, and family and care coordination needs at each visit. Echocardiogram annually; abdominal ultrasound and serum alpha-fetoprotein every three months until age three to four years. Agents/circumstances to avoid: Avoid exposure to respiratory infections; individuals with Kagami-Ogata syndrome may develop respiratory failure with respiratory infections, especially during infancy. The recurrence risk of Kagami-Ogata syndrome is dependent on the genetic mechanism underlying deficient expression of the maternal RTL1as allele in the proband. In most affected individuals, the underlying genetic mechanism occurs as a de novo event and the recurrence risk to sibs is not increased. Less commonly, a parent of a proband has a predisposing genetic alteration associated with an increased recurrence risk to sibs. Recurrence of Kagami-Ogata syndrome has been reported in sibs with maternally derived deletions. If a deletion or translocation involving the chromosome 14q32.2 imprinted region has been identified in the proband, prenatal testing and preimplantation genetic testing are possible. Methylation testing of fetal DNA to examine abnormal methylation patterns of the DMRs (MEG3/DLK1:IG-DMR and MEG3:TSS-DMR) is not recommended; while DNA extracted from amniotic fluid is currently believed to provide the most reliable tissue source for evaluating fetal methylation status, false negative findings have been reported.

Multi-locus imprinting disturbance (MLID) with methylation defects in various differentially methylated regions (DMRs) has recently been identified in approximately 150 cases with imprinting disorders (IDs), and deleterious variants have been found in genes related to methylation maintenance of DMRs, such as those encoding proteins constructing the subcortical maternal complex (SCMC), in a small fraction of patients and/or their mothers. However, integrated methylation analysis for DMRs and sequence analysis for MLID-causative genes in MLID cases and their mothers have been performed only in a single study focusing on Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS) phenotypes. Of 783 patients with various IDs we have identified to date, we examined a total of 386 patients with confirmed epimutation and 71 patients with epimutation or uniparental disomy. Consequently, we identified MLID in 29 patients with epimutation confirmed by methylation analysis for multiple ID-associated DMRs using pyrosequencing and/or methylation-specific multiple ligation-dependent probe amplification. MLID was detected in approximately 12% of patients with BWS phenotype and approximately 5% of patients with SRS phenotype, but not in patients with Kagami-Ogata syndrome, Prader-Willi syndrome, or Angelman syndrome phenotypes. We next conducted array-based methylation analysis for 78 DMRs and whole-exome sequencing in the 29 patients, revealing hypomethylation-dominant aberrant methylation patterns in various DMRs of all the patients, eight probably deleterious variants in genes for SCMC in the mothers of patients, and one homozygous deleterious variant in ZNF445 in one patient. These variants did not show gene-specific methylation disturbance patterns. Clinically, neurodevelopmental delay and/or intellectual developmental disorder (ND/IDD) was observed in about half of the MLID patients, with no association with the identified methylation disturbance patterns and genetic variants. Notably, seven patients with BWS phenotype were conceived by assisted reproductive technology (ART). The frequency of MLID was 7.5% (29/386) in IDs caused by confirmed epimutation. Furthermore, we revealed diverse patterns of hypomethylation-dominant methylation defects, nine deleterious variants, ND/IDD complications in about half of the MLID patients, and a high frequency of MLID in ART-conceived patients.

Kagami-Ogata syndrome (KOS) and Temple syndrome (TS) are two imprinting disorders characterized by the absence or reduced expression of maternal or paternal genes in the chromosome 14q32 region, respectively. We present a rare prenatally diagnosed case of recurrent KOS inherited from a mother affected by TS. The woman's two affected pregnancies exhibited recurrent manifestations of prenatal overgrowth, polyhydramnios, and omphalocele, as well as a small bell-shaped thorax with coat-hanger ribs postnatally. Prenatal genetic testing using a single-nucleotide polymorphism array detected a 268.2-kb deletion in the chromosome 14q32 imprinted region inherited from the mother, leading to the diagnosis of KOS. Additionally, the woman carried a de novo deletion in the paternal chromosome 14q32 imprinted region and presented with short stature and small hands and feet, indicating a diagnosis of TS. Given the rarity of KOS as an imprinting disorder, accurate prenatal diagnosis of this rare imprinting disorder depends on two factors: (1) increasing clinician recognition of the clinical phenotype and related genetic mechanism, and (2) emphasizing the importance of imprinted regions in the CMA workflow for laboratory analysis.

Kagami-Ogata syndrome (KOS) is a clinically recognizable syndrome in the neonatal period. It is characterized by specific skeletal anomalies and facial dysmorphisms. It is typically caused by paternal uniparental disomy of chromosome 14, while epimutations and microdeletions are less commonly reported causes. In the pediatric setting, KOS is a well delineated syndrome. However, there is a dearth of literature describing the natural history of the condition in adults. Herein, we describe a 35-year-old man, the first adult with KOS reported due to paternal uniparental disomy 14, and review reports of KOS in other affected adults. This highlights the variability in neurocognitive phenotypes, the presence of connective tissue abnormalities, and the uncertainties around long-term cancer risk.

We present two genetic causes of polyhydramnios that were challenging to diagnose due to their rarity and complexity. In view of the severe implications, we wish to highlight these rare genetic conditions when obstetricians consider differential diagnoses of polyhydramnios in the third trimester. Patient 1 is a 34-year-old Asian woman who was diagnosed with polyhydramnios at 28 weeks' gestation. First trimester testing, fetal anomaly scan, and intrauterine infection screen were normal. Subsequent antenatal ultrasound scans revealed macroglossia, raising the suspicion for Beckwith-Wiedemann syndrome. Chromosomal microarray analysis revealed a female profile with no pathological copy number variants. The patient underwent amnioreduction twice in the pregnancy. The patient presented in preterm labor at 34 weeks' gestation but elected for an emergency caesarean section. Postnatally, the baby was noted to have a bell-shaped thorax, coat hanger ribs, hypotonia, abdominal distension, and facial dysmorphisms suggestive of Kagami-Ogata syndrome. Patient 2 is a 30-year-old Asian woman who was diagnosed with polyhydramnios at 30 weeks' gestation. She had a high-risk first trimester screen but declined invasive testing; non-invasive prenatal testing was low risk. Ultrasound examination revealed a macrosomic fetus with grade 1 echogenic bowels but no other abnormalities. Intrauterine infection screen was negative, and there was no sonographic evidence of fetal anemia. She had spontaneous rupture of membranes at 37 + 3 weeks but subsequently delivered by caesarean section in view of pathological cardiotocography. The baby was noted to have inspiratory stridor, hypotonia, low-set ears, and bilateral toe polysyndactyly. Further genetic testing revealed a female profile with a pathogenic variant of the GLI3 gene, confirming a diagnosis of Greig cephalopolysyndactyly syndrome. These cases illustrate the importance of considering rare genetic causes of polyhydramnios in the differential diagnosis, particularly when fetal anomalies are not apparent at the 20-week structural scan. We would like to raise awareness for these rare conditions, as a high index of suspicion enables appropriate counseling, prenatal testing, and timely referral to pediatricians and geneticists. Early identification and diagnosis allow planning of perinatal care and birth in a tertiary center managed by a multidisciplinary team.