Kagami-Ogata Syndrome: Case Series and Review of Literature

Abstract

Kagami-Ogata syndrome (KOS) (OMIM #608149) is a genetic imprinting disorder affecting chromosome 14 that results in a characteristic phenotype consisting of typical facial features, skeletal abnormalities including rib abnormalities described as "coat hanger ribs," respiratory distress, abdominal wall defects, polyhydramnios, and developmental delay. First identified by Wang et al in 1991, over 80 cases of KOS have been reported in the literature. KOS, however, continues to remain a rare and potentially underdiagnosed disorder. In this report, we describe two unrelated male infants with differing initial presentations who were both found to have the characteristic "coat hanger" rib appearance on chest X-ray, raising suspicion for KOS. Molecular testing confirmed KOS in each case. In addition to these new cases, we reviewed the existing cases reported in literature. Presence of polyhydramnios, small thorax, curved ribs, and abdominal wall defects must alert the perinatologist toward the possibility of KOS to facilitate appropriate molecular testing. The overall prognosis of KOS remains poor. Early diagnosis allows for counseling by a multidisciplinary team and enables parents to make informed decisions regarding both pregnancy management and postnatal care.

Keywords: 14q32.2; coat-hanger ribs; omphalocele; paternal UPD(14).

Fig. 1

Prenatal ultrasound of case 1 at 27.1 weeks of gestation showing ( A ) thoracic circumference at lower limit of normal, ( B ) large omphalocele, ( C ) rocker-bottom left foot, and ( D ) polyhydramnios.

Fig. 2

Chest radiograph of the patient 1 showing the classic “coat hanger” appearance of the ribs. Black arrows show the abnormally shaped thin ribs with cranial apex angulation. White arrows show “handlebar” clavicles.

Fig. 3

Chest radiograph of patient 2 at ( A ) 9 days of life and at ( B ) 3 years of life. Although the coat-hanger appearance of ribs is apparent in both X-rays, the mid-widest (M/W) thorax ratio normalized from 73% at 9 days of life to 98% at 3 years of life. Also note the “handlebar” clavicles in both the X-rays.

Fig. 4

Coat-hanger angle (CHA): The average of angles between the peak point (or the center in absence of peak point) of both 6th posterior ribs and the horizontal axis. CHA > 25% must raise suspicion for Kagami-Ogata syndrome (KOS).

Fig. 5

Relative frequencies of various features associated with Kagami-Ogata syndrome (KOS) reported in literature: ( n  = 77 for all features except cryptorchidism and hypospadias, where n  = 36). ( a ) After coat hanger-sign was defined in 2003, 95.7% of patients (67/70) with KOS were reported to have coat-hanger ribs. ( b ) 61% patients had diastasis recti, 27.3% patients had omphalocele, and 6.5% patients were reported to have umbilical hernia. ( c ) Atrial septal defects accounted for 31.5% of all cardiac diseases reported; ventricular septal defects for 5.2%, and persistent ductus arteriosus for 10.4%. Other cardiac diseases (6.5%) reported were pulmonic stenosis ( n  = 3), interrupted aortic arch ( n  = 1), and hypertrophic cardiomyopathy ( n  = 1).

Fig. 6

Schematic representation of physical map of the chromosome 14q32.2 imprinted region. RTL1 and DLK1 are paternally expressed genes (PEGs) and shown in blue. Maternally expressed genes (MEGs) including MEG3, MEG8, and RTL1as are shown in red. Differentially methylated regions (DMRs) (MEG3 and IG DMRs) are shown in green. (Courtesy of Ogata T, Kagami M. Kagami-Ogata syndrome: a clinically recognizable upd(14)pat and related disorder affecting the chromosome 14q32.2 imprinted region. J Hum Genet. 2016;61(2):87–94.)

Fig. 7

Pictographic representation of the methylation patterns of differentially methylated regions (DMRs) observed in Kagami-Ogata syndrome (KOS). Hypomethylated (functional DMRs) are shown in green and hypermethylated (nonfunctional) DMRs are shown in red. In normal individuals, paternal DMRs are hypermethylated and maternal DMRs are hypermethylated. In uniparental disomy of chromosome 14 (UPD(14)pat), DMRs of maternal origin are absent with two copies of paternal DMRs, all of which are hypermethylated with absence of hypomethylated DMRs. In case of epimutations derived maternally, both DMRs of maternal origin are hypermethylated. Maternally derived microdeletions (shown as checkered green box) involving the MEG3-DMR lead to inactivation of MEG3-DMR only. However, in those involving the IG-DMR, MEG3-DMR is hypermethylated. (Adapted from Ogata T, Kagami M. Kagami-Ogata syndrome: a clinically recognizable upd(14)pat and related disorder affecting the chromosome 14q32.2 imprinted region. J Hum Genet. 2016;61(2):87–94.)