Kagami-Ogata Syndrome: Case Series and Review of Literature

Keywords

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

Wang et al first described paternal uniparental disomy of chromosome 14 (UPD(14)pat) in a 9-year-old girl.[1] In 2008, Kagami et al showed that microdeletions and epimutations affecting the maternally inherited 14q32.2 locus result in UPD(14) pat-like phenotype.[2] Recently, the European Network of Imprinting Disorders designated the term “Kagami-Ogata” (KOS) (OMIM #608149) to encompass UPD(14)pat and related methylation and epigenetic imprinting disorders.[3] With a reported prevalence of <1 in 1,000,000, KOS is a rare imprinting disorder of 14q32.2, which results in a classical phenotype.[4] [5] To date over 80 cases of KOS have been reported in the literature. Here we describe two new cases, a male infant born at 28^6/7 weeks with a large omphalocele and a second male infant born at 37^1/7 weeks of gestation with large diastasis recti, who were both subsequently diagnosed with KOS. We also reviewed 75 previously reported cases. We aim to review this rare and possibly underdiagnosed genetic condition to raise awareness of this condition among perinatologists, who will then be able to counsel parents regarding management options and promote informed decision making.

Case 1

A male infant was born at 28^6/7 weeks of gestation via C-section to a 21-year-old gravida 1 now para 1 female. Pregnancy was complicated by the presence of a large omphalocele, overlapping digits, rocker bottom feet and polyhydramnios, detected at 22 weeks of gestation ([Fig. 1]). Fetal echocardiogram was not performed. Patient's mother declined prenatal genetic testing. Prenatal screening tests for infections were negative.

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.

At birth, the infant was noted to have bradycardia with no respiratory effort, which improved with positive pressure ventilation. Apgar scores were 2, 4 and 6 at 1, 5 and 10 minutes, respectively. Physical exam was significant for anasarca, micrognathia, short neck, small dysplastic, low-set, posteriorly rotated ears, ocular hypertelorism, depressed nasal bridge, narrow bell-shaped chest, clenched hands, rocker bottom feet and large omphalocele containing part of the liver and the bladder. Chest X-ray showed narrow abnormally shaped ribs, “handlebar” clavicles and pronounced hypoplasia of the scapular necks ([Fig. 2]). The infant was placed on high frequency oscillatory ventilator within hours of birth due to severe respiratory acidosis and high oxygen requirement and was given surfactant. Echocardiogram on admission showed severe pulmonary hypertension, a small ventricular septal defect and a patent ductus arteriosus. Head ultrasound was significant for mild ventriculomegaly. Upper gastrointestinal contrast study for feeding intolerance showed midgut malrotation with failure of passage of barium beyond the duodenojejunal junction. Surgical correction of the malrotation was not possible due to the presence of large omphalocele. The infant required mechanical ventilation with oxygen throughout his stay. Due to initial suspicion of trisomy 18, blood was sent for chromosomal analysis that resulted a normal male karyotype. Chromosomal microarray (CMA) (Integrated Genetics, Cypress, CA) showed a 71Kb duplication at 10q24.2 of uncertain significance. After further discussion with the consulting geneticist, methylation studies for Beckwith–Wiedemann syndrome (Mayo Clinic Laboratories, Rochester, MN) were requested, which were negative. Abnormal cranial apex angulation of the ribs, representing the “coat-hanger sign,” was later identified on chest radiograph ([Fig. 2]) and the diagnosis of UPD(14)pat was suggested by the radiologist (SM). Subsequent methylation studies for UPD14 (EGL Genetics, Tucker, GA) showed absence of unmethylated MEG3 differentially methylated region (DMR). Only the methylated (paternal) copy of the MEG3 DMR was detected, consistent with a diagnosis of KOS. Confirmatory testing by microsatellite analysis to determine whether this infant had UPD(14)pat or an epimutation was not possible.

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.

Due to lack of improvement in the infant's clinical status and the poor prognosis associated with KOS, after discussion with the patient's mother, life-sustaining measures were discontinued at 2.5 months of life. The family declined autopsy.

Case 2

A male was born at 37.1 week of gestation with birth weight of 3.09 kg. Pregnancy was complicated by polyhydramnios and suspected omphalocele. He was intubated in the delivery room due to absent respiratory effort and was admitted to the neonatal intensive care unit (NICU). Apgar scores were 3, 6, and 7 at 1, 5, and 10 minutes of life, respectively. Physical exam on admission was significant for large diastasis recti, flattened nasal bridge, narrow chest, short limbs, hypermobile fingers, prominent cheeks, cryptorchidism, and hypotonia. Echocardiogram was normal. He was extubated on day of life 2 and transitioned to room air on day of life 9. Initial chest X-ray ([Fig. 3A]) with narrow bell-shaped thorax and “handlebar” clavicles was suggestive of Jeune syndrome. He was reintubated ∼ 1 month of life for G-tube placement due to poor feeding. After multiple failed extubation attempts, tracheostomy tube was placed at ∼2 months of life. Chest computed tomography was not consistent with classical Jeune syndrome. CMA (CombiMatrix, Irvine, CA) revealed a male profile with 2.6 Mb duplication on chromosome 12q14.1 of uncertain clinical significance. A skeletal dysplasia ciliopathy panel (Connective Tissue Gene Tests, Allentown, PA) detected heterozygous variants of unknown significance in WDR35 (c.1624C > G; p.Leu542Val) and IFT80 (c.880G > A; p.Val294Ile). WDR35 deletion/duplication analysis via high-density targeted array (Connective Tissue Gene Tests, Allentown, PA) was negative. He was discharged from the NICU at 7 months of life on a home ventilator and weaned off the ventilator ∼ 16 months of life. He was readmitted multiple times due to respiratory distress associated with respiratory infections. After coat-hanger appearance of the ribs was noted on chest X-ray at the age of 28 months, molecular testing for KOS was initiated. Microsatellite analysis for UPD14 (The University of Chicago Genetic Services Laboratory, Chicago, IL) revealed biparental origin of chromosome 14. Methylation analysis for UPD14 (Emory Genetics Laboratory, Decatur, GA) requested a month later detected the paternally methylated MEG3 gene with absence of maternal unmethylated MEG3 DMR, consistent with the diagnosis of KOS. Alpha fetoprotein (AFP) level was 10.3 ng/mL at 33 months of life (within normal limits), and abdominal ultrasound was negative for hepatoblastoma. The patient died at 39 months of age due to cardiac arrest following dislodgement of the tracheostomy tube.

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.

Methods

A systematic search was performed on PubMed using the key words: “Kagami Ogata Syndrome,” “Coat Hanger,” “UPD(14),” “UPD14,” and “Uniparental Disomy 14.” Only case reports/case studies/reviews involving original cases of KOS were considered. Forty-three articles were identified consisting of 77 patients. One report consisting of two patients was excluded as the publication was in German language and translation could not be obtained. Seventy-seven patients including the two new cases above were reviewed.

Discussion

KOS is a rare imprinting disorder that can be caused by paternal UPD14 or microdeletions and epimutations involving the DMRs at 14q32.2.[3] Here, we describe two new cases of KOS, one in a premature male infant who was initially suspected to have trisomy 18 and the other in a term male suspected to have Jeune syndrome. Both infants had characteristic facial features, abdominal wall defects, and abnormal appearance of the ribs. In both patients, the diagnosis of KOS was suspected subsequent to the identification of the coat-hanger sign on chest X-ray. The coat-hanger sign (described below) is pathognomonic of KOS.[6] KOS is associated with an overall poor prognosis. Early diagnosis is key to the management of affected patients and allows for parental decision making. However, diagnosis may be complicated by the phenotypic overlap between KOS and other genetic conditions such as Jeune syndrome, Beckwith–Wiedemann syndrome, and trisomy 18. In the two cases above, diagnosis was delayed until recognition of the coat-hanger sign prompted evaluation for KOS. Perinatal providers caring for infants with multiple congenital anomalies should be aware of the classic features of KOS, as well as those features overlapping with more common genetic conditions, to promptly identify patients with KOS and initiate diagnostic work up in collaboration with radiology and genetics colleagues.

Clinical Features

Patients with KOS typically present with a classical phenotype consisting of polyhydramnios, characteristic facial appearance, small narrow bell-shaped thorax, abnormally shaped ribs (described as coat-hanger appearance of the ribs on chest radiograph-see [Fig. 4]), abdominal wall defects, and placentomegaly. Facial dysmorphism includes frontal bossing, hirsute forehead, depressed nasal bridge, micro/retrognathia, full cheeks, webbed neck, blepharophimosis/short palpebral fissures, protruding philtrum, small ears, anteverted nares, and puckered lips.[3] Almost all patients have developmental delay. [Fig. 5] shows the relative frequencies of various features associated with KOS in patients previously reported in the literature.

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).

Other infrequently reported findings include subarachnoid hygroma, single transverse palmar crease, H-shaped skin crease below lower lip, short limbs, camptodactyly, and syndactyly. Male patients with KOS have also been reported to have cryptorchidism, hypospadias, bilateral scrotum (scrotal fission), and penile scrotal transposition.[1] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] It is unknown whether KOS affects fertility. To date only four adult cases of KOS have been described and no comments regarding their fertility were made by the authors.[18]

Genetics

The human chromosome 14 consists of an imprinted region at 14q32.2 that includes the paternally expressed genes (PEGs) DLK1 and RTL1 and maternally expressed genes (MEGs) MEG3 (also known as GTL2), RTL1as (RTL1 antisense), and MEG8.[22] This region also encompasses the DMRs IG-DMR and MEG3-DMR ([Fig. 6]).[23] [24] [25] Both DMRs are methylated after paternal transmission and unmethylated after maternal transmission in the body, whereas, in the placenta, the IG-DMR remains as a DMR and the MEG3-DMR is hypomethylated regardless of parental origin.[2] [25] KOS occurs due to various molecular mechanisms, the most common being UPD(14)pat in ∼2/3rd of the cases followed by microdeletions and epimutations. Both inherited and de novo Robertsonian translocations involving chromosome 14 increase risk of KOS due to trisomy and monosomy rescue. Excessive RTL1 expression due to absence of RTL1as expression without the involvement of the 2 DMRs might also lead to development of the UPD(14)pat-like phenotype.[2] [26] Paternally inherited Robertsonian translocations and maternally inherited microdeletions are associated with increased recurrence risk in future pregnancies.[17] [25] [26] [27]

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.)

Only two cases of UPD(14)pat mosaicism have been reported to date.[11] [28] Our review found that the reported frequency of KOS due to epimutations was lower (8.4% compared with 15.4%) than previously reported.[29] All cases of epimutations previously reported were from Japan. Our second case is the first patient with KOS due to epimutation reported from outside Japan. There is an almost equal incidence in males and females (n = 36 vs. n = 41). [Table 1] summarizes the previously reported cases of KOS.

Table 1 Summary of previously reported cases of KOS included in this literature review

Reference (year)	Pts (n)	Genetic cause of KOS	Facial gestalt	Mechanical ventilation	Develop-mental delay	At the time of report			Cause(s) of death
						Age	Alive	Dead
Wang et al[1] (1991)	1	UPD(14) with RT [45,XX,t(13q14q)]	1	Not specified	1	9 y	1	0	n/a
Papenhausen et al[43] (1995)	1	UPD(14) with RT [45,XX,t(14q14q)]	1	1	1	20 mo	1	0	n/a
Walter et al[7] (1996)	1	UPD(14) with RT [45,XY,idic(14)(p11)]	1	1	0	6 mo	1	0	n/a
Cotter et al[9] (1997)	1	UPD(14) with RT [45,XX,der(13;14)(q10;q10)]	1	1	1	6 mo	0	1	Pulmonary complications
Yano et al[44] (2001)	1	UPD(14)pat with RT [45,XX,der(14;14)(q10;q10)]	1	Not specified	Not specified	Not specified	Not specified	Not specified
McGowan et al[45] (2002)	1	UPD(14) with RT [45,XX,der(14;14)(q10;q10)]	1	1	n/a	6 wk	0	1	Care withdrawn
Coveler et al[8] (2002)/Towner et al[41] (2001)	1	UPD(14)pat without RT	1	1	1	19 mo (vegetative state)	1	0	n/a
Offiah et al[6] (2003)	1	UPD(14)pat without RT	1	1	n/a	6 wk	0	1	Care withdrawn
Chu et al[13] (2004)	1	UPD(14)pat without RT	1	1	1	3 mo	0	1	Respiratory infection
Stevenson et al[46] (2004)	1	UPD(14) with RT [45,XX,inv(9)(p11q13),dic(14;14)(p11.1;p11.1)]	1	1	1	7 mo	1	0	n/a
Curtis et al[35] (2006)	1	UPD(14)pat without RT	1	1	1	9 mo	0	1	Care withdrawn
Mattes et al[11] (2007)	1	UPD(14)mosaic 47,XX + mar(14)[44]/46,XX[6]	1	1	1	5 mo	0	1	Respiratory infection
Irving et al[14] (2010)	1	UPD(14)pat without RT	1	1	n/a	9 wk	0	1	Care withdrawn
Sargar et al[15] (2014)	1	UPD(14)pat without RT	1	1	Not specified	4 mo	0	1	Comfort care only
Suzumori et al[33] (2010)	1	UPD(14)pat without RT	1	1	1	8 mo	1	0	n/a
Yamanaka et al[32] (2010)	2[a]	UPD(14)pat without RT	Not specified	2/2	1/2[a]	4 mo–1 y	1	1	Hepatic failure (4 mo)
Boiffard et al[17] (2014)	1	Not reported	1	Not specified	0	2 y	1	0	n/a
Beygo et al[47] (2015)	1	Microdeletion [de novo]	Not specified	1	1	27 mo	1	0	n/a
	2	Microdeletion [maternally inherited]	2	1/2	1/2	10 mo–5.5 y	2	0	n/a
Watanabe et al[34] (2015)	1	Epimutation	1	Not specified	Not specified	Not specified	Not specified	Not specified
Kagami et al[3] (2015)	2	2 UPD(14)pat with RT [45,XX,rob(13;14)(q10;q10) and 45,XX,rob(14;21)(q10;q10)]	2/2	1/2	1/2[b]	8 mo–1 y, 8 mo	1	1	Hepatoblastoma (8 mo)
	20	UPD(14)pat without RT	20/20	19/20	20/20	6 mo–15 y	17	3	Influenza (3 y, 2 mo), NEC (6 mo), hemophagocytic syndrome (17 mo)
	1	UPD(14)pat with karyotype unknown	1/1	1/1	n/a	2 h	0	1	Respiratory failure
	5	Epimutation	5/5	5/5	5/5	9 mo–5.5 y	5	0	n/a
	2	Microdeletion [de novo]	2/2	2/2	1/2[c]	4 d–3 y, 10 mo	0	2	Intracranial hemorrhage (4 d), care withdrawn (3 y, 11 mo)
	4	Microdeletion [maternally inherited]	4/4	4/4	4/4	9 mo–8 y, 11 mo	3	1	Sudden death due to URI (9 mo)
Schmeh et al[12] (2016)	1	Not reported	1	1	Not specified	4 mo	0	1	Care withdrawn
Yuan et al[21] (2016)	1	UPD(14)pat without RT	1	0	1	2 y	1	0	n/a
Vecchio and Giuffrè[48] (2016)	1	UPD(14)pat without RT	1	0	Not specified	35 d	1	0	n/a
van der Werf et al[18] (2016)	4	Microdeletions [maternally inherited]	4/4	2/4	4/4	3–32 y	4	0	n/a
Haug et al[28] (2017)	1	UPD(14)pat Mosaicism [46,XX/46,XX upd(14)pat]	1	0	0	13 y	1	0	n/a
Chen et al[30] (2019)	1	UPD(14)pat without RT	1	n/a	n/a	n/a	0	1	Termination of pregnancy at 21.5 wk of gestation
Huang et al[49] (2019)	1	Microdeletion [de novo]	1	1	1	2.5 y	1	0	n/a
Luk[27] (2017)	2	Microdeletion [maternally inherited]	2/2	2/2	2/2	3–5 y	2	0	n/a
Yamagata et al[19] (2018)	1	Not reported	Not specified	1	Not specified	2 y	1	0	n/a
Igreja da Silva et al[16] (2019)	1	UPD(14)pat with RT [45,XX,der(13;14)(q10;q10)]	Not specified	n/a	n/a	3 h	0	1	Comfort care only
Wang et al[20] (2020)	1	UPD(14)pat with RT [45,XY,der(13;14)(q10;q10)]	1	Not specified	1	20 mo	1	0	n/a
Altmann et al[40] (2020)	1	Microdeletion	1	1	1	15 mo	1	0	n/a
Al-Mudares and Fernandes[50] (2020)	1	Not reported	Not specified	1	n/a	4 wk	0	1	Omphalocele and septic shock
Jung et al[10] (2018)	1	Microdeletion [maternally inherited]	1	1	1	2 mo	1	0	n/a
Corsello et al[26] (2015)	1	Microdeletion [de novo, not involving the 2 DMRs]	1	1	Not specified	5 mo	1	0	n/a
This report (2021)	2	1 Epimutation 1 Unknown	2/2	2/2	2/2	2.5 mo–3 y, 3 mo	0	2	Care withdrawn (2.5 mo), cardiac arrest (3 y, 3 mo)

Abbreviations: DMRs, differentially methylated regions; KOS, Kagami-Ogata syndrome; n/a, not applicable; NEC, necrotizing enterocolitis; Pts, patients; RT, Robertsonian translocation; UPD(14)pat, uniparental disomy of chromosome 14; URI, upper respiratory infection.

^a Four cases were reported by Yamanaka et al, of which two cases were also reported by Kagami et al (2015) more comprehensively and have been included below. Developmental status of the infant who died at 4 months of age has not been specified.

^b Developmental status in one patient not specified.

^c Developmental delay assessment not possible in infant who died at 4 days of life.

Prenatal Diagnosis

Accurate diagnosis of KOS may be difficult to establish in the prenatal period. To date, only few cases of prenatal diagnosis have been reported in literature.[16] [17] [30] [31] [32] Although polyhydramnios is present in nearly all patients with KOS ([Fig. 5]), the presence of polyhydramnios is nonspecific. Facial dysmorphism may or may not be seen on fetal ultrasound. Small thorax on fetal ultrasound, although very sensitive for KOS, has been reported in only 19.5% of the cases. In our first case, the thorax size was at the lower limit of normal ([Fig. 1]). However, presence of characteristic facial findings or omphalocele with/without small thorax with/without absent/small stomach should raise suspicion for KOS.[32] [33]

Three-dimensional ultrasound, fetal X-ray, or fetal magnetic resonance imaging to look for coat-hanger ribs/bell shaped thorax has been used in the past to aid the diagnosis of KOS.[32] [33] [34] The coat-hanger sign (usually identified on postnatal chest radiographs) could be visible as early as 23 weeks of gestation by prenatal ultrasound.[35]

If KOS is suspected in a fetus, parents should be offered amniocentesis for karyotype, CMA, and methylation analysis. Methylation analysis to detect the hypermethylation of IG-DMR and MEG3-DMR has been proposed as the first-tier test in the evaluation of suspected KOS ([Fig. 7]).[25] Hypermethylation of the IG-DMR and/or MEG3-DMR is diagnostic for KOS; however, in absence of KOS, other genetic etiologies of the fetal malformations will be missed by methylation analysis alone. CMA is indicated in the workup of fetuses or infants with multiple congenital anomalies.[36] Balanced Robertsonian translocations involving chromosome 14 or supernumerary marker chromosome 14 identified on karyotype as well as deletions involving chromosome 14q identified on CMA may point toward the diagnosis of KOS.[11] [16] [31] Karyotype and CMA may also help identify the other possible genetic etiologies for the malformations detected prenatally. CMA may detect UPD due to isodisomy but will not detect heterodisomy. Single nucleotide polymorphisms-based microarray has been used for prenatal diagnosis of KOS in the past.[16] [30]

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.)

Even though prenatal diagnosis is possible, often the clinical features are not seen on ultrasound until 19 to 20 weeks of gestation and the definitive diagnosis requires access to a tertiary genetic testing facility that may further delay diagnosis. Hence, by the time diagnosis is established, termination of pregnancy may not be possible depending on the abortion laws of the country. However, prenatal diagnosis of KOS may aid the neonatologists and the obstetricians to better counsel parents and may enable the parents to make informed decisions regarding the escalation of care after delivery.

Genetic testing should also be offered to parents who had previous children with KOS if the affected child was found to have a deletion of the maternally inherited chromosome 14 or a paternally inherited Robertsonian translocation. In pregnant females with known microdeletions involving chromosome 14q32, chorionic villous sampling for CMA or SNP-microarray may aid in the early detection of KOS in the fetus.[37]

Postnatal Diagnosis

KOS must be suspected in newborns that present with the facial gestalt described above as well as the classic “coat hanger” appearance of the ribs on chest radiographs and should be confirmed with genetic testing. In both our cases, recognition of the “coat-hanger sign” on chest X-ray prompted the genetic testing for diagnosis of KOS.

Coat Hanger Sign and M/W Ratio

Offiah et al first introduced the term “coat-hanger sign” for the short abnormally curved ribs seen in patients with KOS.[6] After its initial description, the coat-hanger sign has been recognized in 95.7% patients with KOS ([Fig. 5]). In 2011, Miyazaki et al introduced the coat-hanger angle or 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) and the mid-widest thorax ratio (M/W ratio) ([Fig. 4]).[38] A CHA of > 25 degree with/without M/W ratio of ≤ 80% should raise a suspicion for KOS. Chest radiographs often normalize with age.[3] [18] [38] [39] [Fig. 3] shows the chest X-rays of our second patient at 9 days and at 3 years of life.

KOS must also be considered in the differential diagnosis of a patient with omphalocele or other abdominal wall defects along with other phenotypical features of KOS.[40] [41] According to the diagnostic flowchart proposed by Ogata and Kagami, methylation analysis should be the first-tier diagnostic testing. Positive methylation analysis (hypermethylation of MEG3/IG DMR with absence of respective hypomethylated DMR) ([Fig. 7]) is diagnostic of KOS and must be followed by parent-of-origin analysis to determine biparental inheritance versus UPD(14)pat. In cases where biparental inheritance is confirmed, deletion analysis should be done to distinguish between KOS caused by microdeletions versus epimutations. In cases with confirmed UPD(14)pat, karyotype should be performed to evaluate for Robertsonian translocations or isochromosome 14. If methylation analysis is negative, diagnosis must be reconsidered, and CMA and testing for other genetic conditions should be considered.[25] However, UPD14 methylation analysis may take weeks to result and it might be reasonable to order CMA and/or karyotype earlier, as they may aid in the early detection of KOS as well as detect other genetic abnormalities in the absence of KOS. Of note, patients with KOS due to small deletions involving only RTL1as, MEG3, MEG8, snoRNAs, and/or miRNAs, but not the DMRs, or mutations of RTL1as leading to excessive RTL1 expression may be missed by methylation analysis.[25] [26]

Unfortunately, in our first case, we were unable to perform the parent-of-origin analysis, as parents declined further testing. Both our patients had unrelated nondiagnostic segmental abnormalities in a different chromosome and karyotype was normal, thus pointing toward either UPD(14)pat without Robertsonian translocation or KOS due to epimutations. UPD(14) microsatellite analysis was negative in our second case, thus confirming KOS due to epimutation.

Postnatal Management

The management of KOS remains largely supportive and requires a multidisciplinary approach involving the neonatologist, pulmonologist, cardiologist, neurologist, pediatric surgeon, speech therapist, physical therapist, and developmental therapist. Genetic specialists must be consulted to aid in the molecular evaluation and provide pretest counseling, anticipatory guidance, and posttest counseling that should include discussion of recurrence risks and testing of family members when indicated.

Respiratory distress developing due to abnormally shaped ribs and small thorax with/without hypotonia is usually the first sign for which the patient is admitted to the NICU, and most patients require mechanical ventilation ([Fig. 5]). Endotracheal intubation in patients with KOS can be complicated by the presence of micrognathia, short neck, kyphoscoliosis, and tracheal deviation.[1] Echocardiogram to evaluate for congenital heart diseases must be performed given a more than normal incidence of septal defects associated with this syndrome ([Fig. 5]). Some patients may require gastrostomy and/or tracheostomy tube placement. Male patients with KOS must be evaluated for the presence of cryptorchidism and hypospadias, and if present, urology must be consulted. Due to the possibility of hepatoblastoma and the high mortality associated with this tumor, we recommend regular abdominal ultrasounds and serum AFP levels (every 3 months, until 48 months of age).[3] [42] Patients should also be monitored for seizure disorders and must receive appropriate speech, physical and developmental therapy.

Prognosis

Respiratory distress is the primary cause of morbidity and mortality in patients with KOS. In our review, mortality was reported to be 29.7% at the time of report (22 out of 74; 1 medical termination and outcomes of 2 patients were unknown). Most deaths occurred between 2 hours and 9 months (n = 18, mean = 3.7 months). However, four deaths occurred after infancy: one at 17 months due to hemophagocytic syndrome in a patient with hepatoblastoma (of note, infant was ventilator-dependent during her life and had a tracheostomy), two others at 3 years, 2 months and 3 years, 10 months, respectively, due to respiratory infections in patients who were successfully weaned off the ventilator, and the fourth (our 2nd case) due to respiratory failure secondary to tracheostomy tube dislodgement at 3 years, 3 months of age.[2] [29] [42] Consistent with reports by Ogata and Kagami, no deaths occurred in patients > 4 years of age.[25] Of the 52 patients who were alive at the time of report in the literature, 6 were still on mechanical ventilation and ranged in age from 6 months to 55 months.

Most patients with KOS invariably have developmental delay and feeding difficulties. Other long-term complications may include seizure disorder and the need for tracheostomy and/or gastrostomy tubes.

Conclusion

KOS is a rare imprinting disorder associated with a severe phenotype and poor long-term prognosis. The diagnosis of KOS is often delayed due to the significant overlap with Beckwith–Wiedemann syndrome, trisomy 18, Jeune syndrome, and other congenital thoracic dysplasias. Presence of omphalocele and/or small thorax on fetal ultrasound along with polyhydramnios must alert the perinatologist toward the possibility of KOS. The coat-hanger sign on fetal ultrasound or on chest X-ray is specific to KOS. Recognition of these key findings is integral to early diagnosis of patients and enables parents to make an informed decision regarding management. Genetic evaluation is complicated and should be performed in collaboration with medical genetics professional. Our cases demonstrate the need to recognize KOS in the differential and collaborate with appropriate specialists to come to timely diagnosis.

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