Prenatal diagnosis of recurrent Kagami–Ogata syndrome inherited from a mother affected by Temple syndrome: a case report and literature review

Abstract

Background

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.

Case presentation

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.

Conclusions

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.

Background

Genomic imprinting is an epigenetic mechanism in which the expression pattern of a parental allele influences phenotypic expression [1]. Imprinted genes are generally found in clusters and are regulated by imprinting control regions (ICRs), which exhibit parent-specific DNA methylation during germline development. Gamete-specific DNA methylation at ICRs can be retained despite extensive postfertilization epigenetic reprogramming [2, 3].

Kagami–Ogata syndrome (KOS, OMIM #608149) and Temple syndrome (TS, OMIM #616222) are rare imprinting disorders caused by genetic or epigenetic alterations of an imprinted gene cluster in the chromosome 14q32 region. This locus encompasses paternally expressed protein-coding genes (DLK1, RTL1 and DIO3), maternally expressed long noncoding RNAs (MEG3/GTL2, RTL1as and MEG8) and short noncoding RNAs. The absence or reduced expression of maternal or paternal genes results in KOS or TS, respectively [4,5,6].

More than 60% of KOS cases are caused by paternal uniparental disomy 14, approximately 25% are caused by microdeletions, and nearly 10% are caused by epimutations of the chromosome 14q32 imprinted region [7]. The major clinical features of KOS include polyhydramnios, omphalocele, placentomegaly and macrosomia during the prenatal period [4]. KOS, which has a mortality rate of approximately 30%, is also characterized by a small bell-shaped thorax, coat-hanger ribs and a narrow chest wall postnatally, leading to significant respiratory distress upon delivery [8,9,10]. Therefore, prenatal diagnosis is crucial not only for prenatal counseling but also for the management of KOS newborns. However, prenatal identification of KOS is challenging, possibly due to insufficient recognition of this rare disease and its associated imprinted regions.

Here, we present a prenatally diagnosed case of recurrent KOS caused by a deletion in the chromosome 14q32 imprinted region inherited from a mother who was affected by TS. We provide a review of previous cases involving maternal allele deletions associated with KOS, with the objective of improving awareness of rare imprinted disorders within the realm of prenatal diagnosis.

Case presentation

We present the case of a healthy 33-year-old pregnant woman, gravida 3, para 0. She had an ectopic pregnancy, and her second pregnancy ended in stillbirth at 27 weeks gestation, with fetal omphalocele and polyhydramnios indicated by prenatal ultrasound. The miscarried tissues obtained during the second pregnancy were analyzed by single-nucleotide polymorphism (SNP) array (Affymetrix GeneChip 3000Dx, 25 kb 25 marker loss & 25 kb 25 marker gain), and no abnormalities were found. In the third pregnancy, prenatal ultrasound at 23⁺⁵weeks of gestation revealed polyhydramnios and clenched hands with overlapping fingers. Additionally, head circumference (226 mm, 92nd percentile for gestational age according to reference data of the Asian population provided by the National Institute of Child Health and Development), abdominal circumference (232.1 mm, 100th percentile for gestational age) and weight (820 g, 99th percentile for gestational age) were above the normal range for a fetus at the corresponding gestational week [11]. The ultrasound abnormalities of the fetus are presented in Fig. 1. Given the woman’s multiple fetal ultrasound abnormalities, gestational age, and adverse pregnancy history, amniocentesis was performed at 27 weeks after the she was provided informed consent. Standard chromosome analyses, SNP array (Affymetrix GeneChip 3000Dx, 25 kb 25 marker loss and 25 kb 25 marker gain) analysis and trio whole exome sequencing (WES) were carried out.

Fig. 1

Pedigree of the family and abnormalities of the fetus detected by prenatal ultrasound. A Pedigree of the family: members affected by KOS are colored in black and the member affected by TS is colored in dark gray. ECT, ectopic pregnancy; SB, still birth. B Ultrasound image showing clenched hands with overlapping fingers and polyhydramnios with a deepest vertical pocket of 12.98 cm. B Fetal growth trajectories of head circumference, abdominal circumference and estimated fetal weight, NICHD Fetal Growth Studies—Singletons

Neither aneuploidy nor structural rearrangements of the chromosomes were detected by karyotype analysis. Both SNP array and trio WES revealed a maternal allele deletion of 268.2 kb in the chromosome 14q32 imprinted region, as illustrated in Fig. 2. In light of the abnormalities detected by ultrasound and the results of the genetic tests, KOS was diagnosed prenatally. The diagnosis prompted a review of the SNP array analysis of the previously affected pregnancy, and the same deletion was detected.

Fig. 2

SNP array and WES results for the fetus. A A deletion of 268.2 kb at 14q32.2 was detected by SNP array (highlighted in the red frame). B A deletion including DLK1, exons 1–7 of MEG3, IG-DMR and MEG3-DMR was detected by WES (highlighted in a red shadow)

The woman experienced preterm labor at 30 weeks of gestation and delivered a male fetus weighing 2045 g (99th percentile for gestational age) with a head circumference of 30 cm (97th percentile for gestational age), a length of 40 cm (62nd percentile for gestational age), a placental volume of 18 cm × 14 cm × 3 cm and a weight of 500 g [12]. The fetus had facial dysmorphism (small dysplastic ears, small palpebral fissures, full cheeks, tented upper lip, depressed nasal bridge and micrognathia), short neck, thin and slack abdominal wall with abdominal distension, and clenched fist. Chest X-ray revealed a small bell-shaped thorax with distinctive coat-hanger ribs, which are representative features of KOS, as illustrated in Fig. 3 [4]. In addition to feeding difficulties, infections and calcium deficiency, the most prominent symptom of the newborn was respiratory deficiency. The newborn continued to depend on high-frequency oscillatory ventilation with high-quality respiratory support even at one month of age.

Fig. 3

Postnatal features of the neonate. A Thin and soft abdominal wall, clenched hands, full cheeks, tented upper lip and micrognathia. B Chest X-ray image showing a typical bell-shaped thorax with coat-hanger ribs

Further clinical evaluations of the mother revealed features of a short stature with a height of 158 cm and small hands and feet. Genetic analysis indicated that the woman carried a de novo deletion in the paternal chromosome 14q32 imprinted region, leading to the diagnosis of TS [13].

Discussion

Herein, we described a case with a prenatal diagnosis of recurrent KOS caused by a 268.2-kb deletion in the chromosome 14q32 imprinted region inherited from the mother who was affected by TS due to a de novo deletion in the paternal chromosome.

Among the three differentially methylated regions (DMRs) in the chromosome 14q32 imprinted region, IG-DMR and MEG3-DMR are hypomethylated, and MEG8-DMR is regulated to be methylated in the maternal chromosome, resulting in the maternal expression of MEG3, RTL1as and MEG8. In contrast, the paternal IG-DMR and the MEG3-DMR are methylated, and the MEG8-DMR is demethylated, regulating the paternal expression of DLK1 and RTL1 [4,5,6]. In our case, the woman carried a de novo deletion in the paternal chromosome. The deleted locus contained DLK1, exons 1-7 of MEG3, IG-DMR and MEG3-DMR. The absence of paternally expressed genes results in TS [4, 13]. When transmitted to the fetus, this deletion was of maternal origin and therefore caused KOS [14]. Preimplantation or prenatal genetic diagnosis was recommended for the next pregnancy due to a recurrence risk of 50%.

KOS is characterized by serial prenatal overgrowth of the fetus and placenta and a narrow chest in the infant. On the other hand, TS is characterized by pre- and postnatal growth restriction, as well as other features, including small hands and feet, short stature, hypotonia, early onset of puberty, and mild dysmorphism of the face. In our case, the recurrent manifestations of two affected pregnancies were consistent with the clinical phenotypes of KOS. The woman had TS features of short stature and small hands and feet. The clinical–genetic diagnoses of TS in the woman and KOS in her offsprings were confirmed by molecular cytogenetics and imprinting mechanisms.

We reviewed 27 previous cases of KOS caused by maternal allele deletions of varying sizes in the literature, as shown in Table 1. Among these cases, there was only one prenatal diagnosis [14], while in most postnatal cases, the diagnosis was performed during infancy and early childhood (20/27 cases). Prenatally, the majority of cases had polyhydramnios (25/27 cases), while omphalocele and placentomegaly were reported in 6 and 5 cases, respectively. Three infants died due to respiratory infection or intracranial hemorrhage [5, 16, 17]. Notably, chromosomal microarray analysis (CMA), including array comparative genomic hybridization (aCGH) and SNP array techniques, detected 18 cases, three of which were attributed to deletions inherited from the mother affected by TS [15, 18, 19]. Furthermore, next-generation sequencing methods such as whole genome sequence (WGS) and copy number variant sequencing (CNV-seq) have also been employed for diagnosing KOS [20, 21].

Table 1 Kagami–Ogata syndrome cases with maternal allele deletions on chromosome 14q32

SNP array-based CMA is routinely utilized as a first-line test in the prenatal diagnosis of fetuses with ultrasound abnormalities [20, 28,29,30]. However, in the application of SNP arrays to detect KOS caused by maternal allele deletions, two important points should be noted. First, copy number variations (CNVs) below the resolution could not be detected. The smallest deletion associated with KOS was only 203 bp, which was far below the detection threshold of the SNP array. However, this deletion was detected by WGS [21]. Second, SNP array analysis workflow primarily focuses on CNVs that contain genes causing human diseases, particularly those dosage-sensitive genes within the OMIM morbid map. In contrast, CNVs that lack OMIM-morbid genes and dosage-sensitive genes may be underestimated. In our case, despite the presence of an imprinting region in the 14q32 deletion CNV, it does not include any OMIM-morbid genes or dosage-sensitive genes. Therefore, the CNV was missed during the CMA-SNP analysis in the second pregnancy. During the analysis in the third pregnancy, recurrent phenotypes prompted a thorough investigation into the imprinting region, subsequently leading to the detection of the CNV.

Currently, some regions associated with imprinting disorders, such as 15q11.2q13 (related to Prader–Willi syndrome and Angelman syndrome), have received ample attention in CMA analysis [31, 32]. However, regions associated with much rarer imprinting disorders, such as KOS, with an estimated incidence of less than 1 in 1 million [33], tend to be underestimated in CMA analysis.

Conclusions

The absence or reduced expression of maternal genes in the 14q32 imprinted region is associated with KOS. 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 analysts.