Trisomy 9 mosaic syndrome: Sixteen additional patients with new and/or less commonly reported features, literature review, and suggested clinical guidelines

Abstract

Trisomy 9 mosaic syndrome (T9M) is a rare condition characterized by multiorgan system involvement including craniofacial dysmorphisms, cardiac, genitourinary (GU), skeletal, and central nervous system (CNS) abnormalities. Although more than 100 cases have been reported in the literature, a comprehensive review has not been performed nor have clinical guidelines been established. Therefore, we describe the clinical features of 16 additional patients, review features of previously reported individuals, and suggest clinical guidelines. Our findings expand the clinical phenotype of T9M, including novel features of amblyopia, astigmatism, corectopia of pupil, posterior embryotoxon, and diaphragmatic eventration. Most patients had prenatal and perinatal issues, particularly from respiratory, growth, and feeding standpoints. Although small birth parameters were common, long-term growth trends varied widely. An association with advanced parental ages was also identified. The spectrum of growth and development was wide, ranging from nonverbal patients to those able to participate in educational programs with age-appropriate peers. The severity of clinical outcomes was unrelated to blood lymphocyte mosaicism levels. Microarray analysis had a higher diagnostic rate compared to standard karyotype analysis and should be utilized if this diagnosis is suspected. Future longitudinal studies will be key to monitor long-term outcomes of individuals with T9M and determine best practices for clinical management.

1 ∣. INTRODUCTION

Trisomy 9 syndrome (T9) was first reported by Feingold and Atkins (Feingold & Atkins, 1973). T9 is an entire additional chromosome 9 in all cells and no evidence of mosaicism (Ferreres et al., 2008). Trisomy 9 mosaic syndrome (T9M) is the presence of both normal cells and cells with an additional copy of chromosome 9 (Mantagos et al., 1981). T9 typically occurs due to nondisjunction during meiosis (sometimes with subsequent trisomic rescue and possible uniparental disomy) or mitotic nondisjunction during somatic cell embryonic development (Moskovitz et al., 2006; Stipoljev et al., 2003). Of spontaneous abortions caused by autosomal trisomies, approximately 2.2% to 2.7% are due to T9 (Ferreres et al., 2008), and most spontaneously abort (Ferreres et al., 2008; Patil et al., 2012; Pinette et al., 1998). Prenatally reported cases are challenging because cytogenetic abnormalities can be limited to fetal membranes (Pfeiffer et al., 1984; Saura et al., 1995; Sutherland et al., 1976), and it may be difficult to distinguish between generalized and placental mosaicism (Van den Berg et al., 1997). Additionally, many individuals with T9 were diagnosed on limited cell numbers and/or did not have additional confirmatory tissue, so low-level mosaicism may not be excluded (Cantú et al., 1996).

Individuals with T9 and T9M have a wide spectrum of multiorgan system involvement (Saneto et al., 1998), most commonly craniofacial dysmorphisms, cardiac, genitourinary (GU), skeletal, and central nervous system (CNS) abnormalities (Wooldridge & Zunich, 1995). Global developmental delay is also commonly described (Patil et al., 2012; Chen et al., 2010; Chih-Ping Chen et al., 2011;Bruns, 2011; Bruns & Campbell, 2015). Patients with T9M are reported to have less complicated medical courses (Gniady et al., 2010) and longer survival (Wooldridge & Zunich, 1995) compared to liveborns with T9. Although approximately 40 patients with T9 and more than 100 patients with T9M have been described, there is still a lack of understanding about the associated major as well as the less commonly described features of T9M. Moreover, there are no management guidelines. There is limited information regarding the long-term outcome of these individuals, but three adults (19, 24, and 24 years old) with T9M have been described (Bruns, 2011; Bruns & Campbell, 2015). We describe 16 additional individuals with T9M who have classic as well as less common and/or novel features, review previously described patients, and provide suggestions for clinical management.

2 ∣. METHODS

Sixteen individuals with confirmed diagnosis of T9M were evaluated at the Children's Hospital of Philadelphia and Cincinnati Children's Hospital Medical Center. Consent was obtained for participation. The Institutional Review Board at the Cincinnati Children's Hospital Medical Center approved this study. Retrospectively, available phenotypic information was manually reviewed and summarized (Table 1, Figures 1, 2, and Tables S1, S2). Literature reviews were conducted to identify previously described cases of T9 and T9M. Due to the possibility of discrepant results and pseudomosaicism, prenatal cases were only included for feature review in Table S2 if there was clear confirmatory postnatal or postmortem testing showing mosaic levels of Chromosome 9 in at least one tissue. Literature descriptions using older nomenclature were included in Elements of Morphology terminology categories wherever possible (Allanson et al., 2009).

TABLE 1.

Prenatal/birth history and genetic testing results of reported patients

Patient	Sex	Maternal age at birth	Paternal age at birth	Prenatal issues	Gestational age at birth	Neonatal issues	Birth growth parameters (% and ZSa based on WHOb growth charts)	Oldest reported age	Postnatal genetic testing (1 = karyotype, 2 = microarray, 3 = FISHc)
1	F	20 yeard	24 year	No	41 + 1weeke	No	Wf: 2473 g (1%, −2.2) Lg: 48.3 cm (18%, −0.9) HCh: NRi	6 year	1: 46, XX 2: arr cgh 9 (RP11-5906- > RP11-31 M4) × 3 3: nuc ish 9cen(D9Z3 × 3)[8]/ 9cen (D9Z3 × 2)[92]
2	M	31 year	31 year	Noted to be “small,” mild elevation in AFPj on maternal screening	35 + 6 week	Prematurity but no NICUk stay	W: 2427 g (72%, −0.6) L: NR HC: NR	14 year	1: 46, XY 2: arr snp 9p24q34 (rs10814410-rs12683496) × 3 [20%]
3	F	40 year	41 year	AMAl, Maternal gastroenteritis and PTLm at 34 week requiring hospitalization	38 week	NICU × 6 weeks and inpatient ward × 6 weeks for poor weight gain and feeding issues, jaundice	W: 2030 g (2%, −2) L: NR HC: NR	14 year	1: 46, XX 2: arr cgh 9(71 BAC) × 3 3: ish 9cen(D9Z3 × 3)[9/50]
4	F	25 year	30 year	IUGRn noted at 32–33 week, decreased fetal activity	35 week	Prematurity, NICU for several months for poor weight gain and feeding issues, jaundice, thrombocytopenia, 3 seizures (etiology not found, none since)	W: 1446 g (1%, −2.5) L: NR HC: NR	13 year	1: 46, XX 2: arr cgh 9(71 BAC) × 3 3: nuc ish 9cen(D9Z3 × 3)[4/30]
5	F	27 year	27 year	IUGR, maternal preeclampsia in final week of pregnancy	36 week	Prematurity, NICU × 12 days for poor weight gain	W: 1701g (2%, −2.1) L: NR HC: NR	3 year	1: 46, XX 2: arr snp 9p24.3q34.3 (rs10814410-rs12683496) [~40–60%] 3: ish 9q34.3(D9S325 × 3)[5]/ 9q34.3 (D9S325 × 2 [195] nuc ish 9q34.3 (D9S325 × 3) [96]/ 9q34.3 (D9S325 × 2)[304]
6	F	40 year	39 year	AMA, IUGR and oligohydramnios	36 + 6	Prematurity, NICU × 6 days for small size and hypoglycemia (resolved with IVF)o, jaundice	W: 2160 g (13%, −1.1) L: 47 cm (72%, 0.6) HC: 31.5 cm (33%, −0.4)	6 year	1: 47 XX +9[3]/ 46, XX [37]
7	F	39 year	39 year	AMA	40 + 3	NICU × 3 weeks for respiratory distress, ROSp, concern for seizures (not confirmed)	W: 2948 g (20%, −0.8)  L: 50 cm (58%, 0.2) HC: 32.5 cm (8%, −1.4)	6 year	1: 46, XX 2: arr snp 9p24.3q34.3 (203,861-141,020,389) × 2-3 (hg19) [60–70%]
8	F	35 year	31 year	AMA	38	None	W: 2950 g (26%, −0.63) L:50 cm (68%, 0.46) HC: 34.5 cm (70%, 0.52)	14 year	1: 46,XX 2: arr cgh 9pterqter(RP11-5906->CTB-135I17) × 3 3: ish(LSI p16,CEP9) × 3[3/25] nuc ish (LSI p16,CEP9)x3[11/100]
9	M	43 year	NR	AMA, IUGR	36 + 2	4 months in NICU, during which tracheostomy and G tube were placed	W: 1815 g (<1%, −3.77) L: 43 cm (<1%, −3.64) HC: 30 cm (<1%, −3.51)	11 year	1: 46,XY 2: arr cgh 9 (RP11-5906->RP11-378H7) × 3 arr 9(rsl0814410-> rs11559363) × 3 3: ish(p16,CEP9) × 3[2/10} nuc ish (p16,CEP9) × 3[16/120]
10	F	43 year	40 year	AMA, oligohydramnios	34	Hospitalized 6 days for weight gain and jaundice requiring phototherapy	W: 1360 g (<1%, −5.2) L: NR HC: NR	9 year	1: 47,XX,+9[2]/46,XX[18] 2: arr 9p24.3q34.3(590–140,222,916) × 2-3 3: ish(q34,ABL1) × 3[2/10] nuc ish (q34,ABL1) × 3[10/50]
11	F	33 year	NR	IUGR, oligohydramnios, placental insufficiency, premature rupture of membranes	29 + 2	NICU for IUGR, prematurity, central apnea, and dysmorphic features	W: 798 g (<1%, −7.65) L: 34.5 cm (<1%, −7.86) HC: 23.5 cm (<1%, −8.76)	6 year	1:47.XX.+9[11]/46,XX[9] 2: arr[hg19] 9p24.3q24.3 (46,587-141,066,491) × 2-3 3: nuc ish (LSI p16,CEP9) × 3 [116/200]
12	M	NR	NR	IUGR and skeletal abnormalities on ultrasound	37	NICU for pulmonary hypertension leading to respiratory failure and death at 8 weeks	W: 1740 (<1%, −4.0) L: 40 cm (<1%, −5.22) HC: 31 cm (<1%, −2.73)	2 months	1:47,XY,+9[16]/46,XY[4] Previous cell free fetal DNA (Materniti21) had indicated 47,XXY
13	F	44 year	NR	AMA, IUGR, single umbilical artery	41	Apnea and primary pulmonary hypertension leading to death at 7 days	W: 1735 g (<1%, −3.91) L: 45 cm (1%, −2.23) HC: 31 cm (1%, −2.43)	7 days	1: 47,XX,+9[10]/46,XX[10]
14	F	29 year	NR	None	37	Tachypnea and required 1 day of supplemental oxygen	W: 2650 g (9%, −1.35) L: 46 cm (5%, −1.69) HC: NR	5 year	1: Trisomy 9 in 16% of cells
15	F	39 year	39 year	AMA, measured “small” but growth caught up by 1 year, an “aortic anomaly,” oligohydramnios at 36 week	37	NICU for 1 day observation only due to uncertainty regarding diagnosis, then transferred to well-baby without further concerns	W: 2466 g (40%, −0.27) L: 46 cm (51%, 0.02) HC: NR	10 year	1. 46, XX Note: amniocentesis karyotype was 47,XX,+9 [7]/46,XX,[8]
16	F	43 year	49 year	Weight dropped from 50th centile to 15th centile in third trimester but birth weight was AGA	39 1/7	NICU for 2 week due to blood in stool and feeding issues	W: 3120 g (38%, −0.30) L: NR HC: NR	7 months	1. 47,XY,+9[2]/46,XX[48]

Note: Chromosome 9 pter is 9p24.3; qter is 9q34.3.

^aZ-score.

^bWorld Health Organization.

^cFlourescence in situ hybridization.

^dYear.

^eWeek.

^fWeight.

^gLength.

^hHead circumference.

ⁱNot recorded or not known.

^jAlpha-fetoprotein.

^kNeonatal intensive care unit.

^lAdvanced maternal age.

^mPreterm labor.

ⁿIntrauterine growth retardation.

^oIntravenous fluids.

^pRule out sepsis.

FIGURE 1.

Clinical features of individuals with trisomy 9 mosaic syndrome

FIGURE 2.

Genetics of trisomy 9 mosaicism cohort

3 ∣. RESULTS

3.1 ∣. Demographics and parental ages

Our cohort had 16 individuals, 13 females and three males, ranging from 7 days to 14 years old (Table 1). Maternal age at birth ranged from 20 to 44 years, with a mean of 35.4 years and median of 39 years (data available for 15 mothers). Paternal age at birth ranged from 24 to 49 years, with a mean of 35.5 years and median of 39 years (data available for 11 fathers).

3.2 ∣. Prenatal histories and neonatal growth

Prenatal complications were noted in all but three individuals (Table 1). Intrauterine growth retardation (IUGR) and/or “small” size was the most common reported feature seen in nine individuals. Gestational age (GA) ranged from 29 + 2/7 weeks to 41 + 1/7 weeks, with prematurity (<37 weeks GA) occurring in seven individuals. Ten individuals had birth weights (BW) less than 10th centile for GA. Birth lengths (BL) were unavailable for six individuals, but five out of the 10 individuals reported were less than 10th centile for GA and the remaining individuals were normal. Of the seven birth head (BH) circumferences documented, five were less than 10th centile for GA. All except for four individuals had postnatal complications requiring prolonged hospitalization, most commonly due to prematurity, respiratory problems, and feeding/growing difficulties.

3.3 ∣. Growth beyond neonatal period

The most recent available growth parameters showed that 10 individuals had weights less than 10th centile and 10 individuals had lengths less than 10th centile. Of the seven available postnatal head circumference (HC) measurements reported beyond 2 years, three measured less than third centile, one was greater than 97% centile, and remaining were within normal limits for age.

When comparing individual growth trends with their birth parameters, there was a wide variation. Nine individuals who started with BW less than 10th centile continued postnatally, but one individual (pt. 5) improved from weight less than 10th centile at birth to normal. Conversely, there was an individual who started with normal BW and decreased to less than 10th centile. Three had BL less than 10th centile and continued postnatally. Two individuals did not survive beyond infancy so comparisons could not be made. Three individuals had normal BL and continued to have age-appropriate growth, while two other patients had normal BL that decreased to less than 10th centile beyond infancy. For those individuals with available BH and HC beyond 2 years, one had postnatal microcephaly, one had BH less than 10% then later normal HC, and one had normal BH then became macrocephalic. For this individual, additional workup for secondary causes of macrocephaly was not documented.

3.4 ∣. Clinical features

The most common previously described clinical features in T9M are outlined in Figure 1(a), (b). Craniofacial abnormalities, cardiac abnormalities, feeding and respiratory difficulties, cryptorchidism, hip dysplasia, seizures, and developmental delay were the most frequently reported features. The majority of previously reported findings were found in our cohort. In particular, developmental delay was noted in all individuals, but the range of severity varied significantly. A number of previously less commonly reported features were also seen in our cohort (Figure 1(c)) including craniosynostosis (2/16), hearing loss (6/16), ptosis (5/16), iris colobomas (2/16), iris hypoplasia (1/16), dextrocardia (1/16), aortic dilation (1/16), malrotation (2/16), tethered cord (3/16), and double ureter (1/16). There were additional common features previously reported including microphthalmia, short neck, and rocker bottom feet that were not seen in our cohort. Novel features included astigmatism (4/16), hyperopia (3/16), amblyopia (2/16), corectopia of pupil (1/16), diaphragmatic eventration (1/16), and posterior embryotoxon (1/16) (Figure 1(c)).

3.5 ∣. Brain imaging

Fourteen individuals had brain magnetic resonance imaging (MRI), which showed a range of abnormalities including decreased white matter volume and prominences of ventricles (Table S1). There were no definitive unifying features, but the most common finding reported on brain MRI was ventriculomegaly in six individuals. An additional individual did not have imaging but had an autopsy that confirmed agenesis of the corpus callosum and colpocephaly.

3.6 ∣. Development

Global developmental delay was universal, with speech delays being especially prominent in all. Developmental milestones and abilities of individuals are described as reported by parents, though most had individualized education plans (IEPs) and school assessments. At least three individuals were reported as essentially nonverbal. However, receptive understanding and ability to communicate by signs or gestures was common. Developmental regression was not reported in our cohort. Specific milestones were only reported in five individuals. Rolling ranged from 7 to 9 months, sitting 7 to 11 months, crawling 11 to 12 months, pulling to stand at 17 months in one individual, and walking at 18 to 25 months. Speaking was reported at 2 years in one individual.

Our cohort contained four adolescents. At 14 years old, one individual was described as functioning at fifth-grade level with moderate learning/intellectual disability. A second individual at 13 years was nonverbal and required maximal assistance for daily self-care skills but could use an augmentative and alternative communication (AAC) device. A third individual at 13 years could recognize letters with an AAC device and was working on self-care skills such as dressing. An additional individual was nonverbal in the seventh grade but used some signs and was working on self-care skills such as toilet training. The school-aged children in our cohort were behind their peers and required IEPs.

3.7 ∣. Genetic testing

The patients had genetic confirmation of their diagnosis with mosaicism levels ranging from 4% to 80%, mean of 31%, and median of 20% (Figure 2(a)). Karyotypes were completed in all individuals. In addition, 10 patients had a microarray (five had comparative genomic hybridization or microarray CGH, five had single nucleotide polymorphism [SNP] microarray), and eight had fluorescence in situ hybridization (FISH) for Chromosome 9 (Figure 2(b)). Karyotype led to diagnosis in 44% of the cohort. Conversely, every microarray or FISH showed abnormal results consistent with T9M (Figure 2(c)).

4 ∣. DISCUSSION

This study is the most comprehensive review to date of all reported T9M individuals and, with the additional reported patients, expands the phenotype of this condition significantly. Most individuals in this cohort had prenatal and birth complications and developed multisystemic medical concerns. Respiratory and feeding difficulties were especially common, and growth trends varied significantly among individuals. Neonatal size was not necessarily reflective of postneonatal growth. Long-term growth predictions are challenging due to this finding, so enhanced growth monitoring prenatally and postnatally would be beneficial.

The individuals in our cohort have many classic features consistent with findings in previously described individuals with T9M (Figure 1(a),(b), Table S2). However, there were a number of features previously less commonly reported that were seen as well as a number of novel features (Figure 1(c)). Of the less common features, craniosynostosis, coloboma of iris, iris hypoplasia, malrotation, and double ureter have been previously reported in individuals with T9 reflecting phenotypic overlap. The novel reported features do not overlap with reported T9 patients except for one prenatal case of diaphragmatic eventration that was not confirmed postnatally (Ferreres et al.,2008). Certain eye abnormalities and hearing loss were noted in especially high numbers in our cohort compared to previous reports (Figure 1(c)), which is significant as vision and hearing deficits can directly impact early development if not identified early. A possible explanation for this difference is these clinical features were present in prior reported patients but were not identified or specifically evaluated for and therefore not previously described. Although these findings may also be present in the general population, in combination with intellectual disability and described dysmorphic facial features, T9M should be considered in the differential diagnosis. Early clinical screening is key in this population to maximize developmental and health outcomes. Given the high frequency of medical complications affecting multiple organ systems in these individuals, suggested clinical recommendations are detailed in Table 2.

TABLE 2.

Clinical recommendations for individuals with trisomy 9 mosaic syndrome

	Evaluation at diagnosis	Frequency of evaluation after diagnosis
Growth	If diagnosed prenatally, increased surveillance for intrauterine growth restriction Monitoring of weight, length, and head circumference	Checks during standard neonatal, childhood, and adolescent well visits with additional growth checks as needed if growth is not progressing
Cranial	Monitoring for craniosynostosis and abnormal head shape	As needed if concerns regarding abnormal head shape occur
Vision/hearing	Audiology evaluation	Neonates: newborn hearing screen, at 6 months, 1 year, then annually, sooner as needed if hearing concerns Non-neonates: at diagnosis then annually, sooner as needed if hearing concerns
	Ophthalmologic evaluation	Neonates: after initial evaluation, at 6 months, 1 year, then annually, sooner as needed if vision concerns Non-neonates: at diagnosis then annually, sooner as needed if vision concerns
Cardiovascular	Baseline echocardiogram	As needed if cardiac symptoms occur
Gastrointestinal	Monitoring of feeding and growth Evaluate if concern for malrotation Referral to gastroenterology as needed	Annually, sooner as needed if gastrointestinal symptoms occur
Musculoskeletal	Hip ultrasound (if neonate)	As needed if musculoskeletal symptoms occur
Respiratory	Monitoring of respiratory system (after birth if neonate)	As needed if respiratory symptoms occur
Genitourinary	Baseline renal ultrasound	As needed if renal symptoms occur
	Monitoring for cryptorchidism (if male)	As needed if testes do not descend within first year of life
Neurologic	Neurologic evaluation Consideration of brain and spine magnetic resonance imaging	As needed if neurologic symptoms occur
	Evaluation of need for supportive therapy services	Annually, sooner as needed if no progress with assigned therapies
	Educational services such as individualized education plans	Annually when entering school, sooner as needed if no progress with initial plan

The majority of individuals with T9M are reported to have developmental delay, particularly speech delays, though a couple have been described with normal or only mild issues (Saneto et al., 1998; Zen et al., 2012). A study by Bruns and Campbell (2015) also noted despite reported delays that individuals with T9M do display some developmental strengths. Developmental delay was seen in all individuals reported here but varied significantly from patients who were nonverbal to those able to participate unassisted in educational programs with age-appropriate peers (Table S1). Additionally, many individuals displayed multiple nonverbal communication skills. The range of milestones is limited to only a subset of our cohort, and we suspect the range is likely wider than that reported in our data. This variation should be noted when providing counseling regarding the diagnosis. Results showed no correlation between blood lymphocytes' mosaicism levels and severity of developmental and medical complications, and this finding is supported by previous studies (Arnold et al., 1995; Merino et al., 1993; Moskovitz et al., 2006).

There has also been conflicting data regarding the association of T9M with advanced maternal age. Wooldridge and Zunich (1995) suggested a positive association; however, Williams et al. (1985) did not report an association, and McDuffie (1994) reported 80% of cases occurred in mothers younger than 35 years. In this cohort, the mean and median ranges were above 35 years for reported mothers and fathers, which likely reflects the increased risks of aneuploidy with age.

From a genetic testing standpoint, the diagnostic rates in our cohort were significantly better with chromosomal microarray than with karyotype analysis (Figure 2(c)). This is consistent with prior reports noting higher diagnostic rates with microarray-based technologies than with standard cytogenetics (Cheung et al., 2007). Although diagnosis is possible via karyotype, especially with increased cell counts, chromosomal microarray analysis is recommended when this condition is suspected.

5 ∣. CONCLUSIONS

T9M is a rare, multisystemic disorder, and the clinical phenotype of individuals with T9M is broader than previously described. Chromosomal microarray analysis should be utilized if this diagnosis is suspected. There is an increased risk of prenatal and perinatal issues, and there was also an association with advanced parental ages in our cohort. Although low birth growth parameters were common and warrant monitoring prenatally, long-term trends are difficult to predict given significant individual variability. With near-universal reporting of developmental delay, all individuals with this diagnosis should receive supportive therapy evaluations and educational support. These individuals are at higher risk for multiorgan involvement, warranting clinical screenings as suggested in Table 2. Future longitudinal studies will be key to monitor long-term outcomes of individuals with T9M and continue to determine best practices for clinical management.

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study.