Comparison of Two Congenital Myotonic Dystrophy Groups According to the Number of CTG Trinucleotide Copies on Clinical Characteristics and Outcomes

In Ji Hwang; Hyun Ok Lee; Ha Jin Oh; Eun Song Song; Young Youn Choi

doi:10.14734/PN.2017.28.2.59

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Hwang, Lee, Oh, Song, and Choi: Comparison of Two Congenital Myotonic Dystrophy Groups According to the Number of CTG Trinucleotide Copies on Clinical Characteristics and Outcomes

Original Article

Perinatology 2017;28(2):59-68.

Published online: 19 June 2017

DOI: https://doi.org/10.14734/PN.2017.28.2.59

Comparison of Two Congenital Myotonic Dystrophy Groups According to the Number of CTG Trinucleotide Copies on Clinical Characteristics and Outcomes

In Ji Hwang, MD¹, Hyun Ok Lee, MD¹, Ha Jin Oh, MD¹, Eun Song Song, MD^1,^2,, Young Youn Choi, MD^1,²

¹Department of Pediatrics, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea

²Department of Pediatrics, Chonnam National University Medical School, Gwangju, Korea

Correspondence to Eun Song Song, MD Department of Pediatrics, Chonnam National University Medical School, 160 Baekseo-ro, Dong-gu, Gwangju 61469, Korea Tel: +82-62-220-6641 Fax: +82-62-222-6103 E-mail: essong@jnu.ac.kr

Received 7 February 201718 May 2017 Accepted 19 June 2017

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Objective

The aims of this study were to compare clinical characteristics and outcome of neonates with congenital myotonic dystrophy (CMD) according to the number of cytosine, thymine, guanine (CTG) copies and to analyze the relating factors for survival.

Methods

The patients were divided into two groups; less than or equal to 1,000 CTG copies (group A) and above 1,000 CTG copies (group B). This study compared the maternal CTG copies, obstetric characteristics, and patients’ clinical characteristics, morbidity, hospital course, and long term outcome between group A and B, and also analyzed the relating factors for survival.

Results

The twenty-three patients were confirmed by gene analysis in the neonatal period. Nine patients (39.1%) were included in group A and fourteen patients (60.9%) in group B. There was no correlation between the number of CTG copies of the mothers and their babies. There were no significant differences in maternal obstetric characteristics, patient's clinical findings, morbidities, hospital course and mortality between group A and B. Seven patients died before discharge and six patients among 16 who survived died after discharge. Analyzing the relating factors for survival, Apgar score at 1 and 5 minute were significantly higher in patients who survived than those who expired (P=0.0001, P=0.01, respectively). All survived patients showed developmental delay and 7 patients (58.3%) failed to thrive.

Conclusion

There was no correlation between the number of CTG copies of the mothers and their babies. There were no statistical differences in maternal obstetric characteristics, patient's clinical findings, morbidities, hospital course, and mortality between the two groups. Apgar score at 1 minute and 5 minute were the relating factors for survival.

Keywords: Myotonic dystrophy, CTG trinucleotide copies number, Outcomes

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Fig. 1

Southern blot of long-range PCR products from the CTG copies in the DMPK gene. (A) More than 1,000 CTG copies expansion (patient of case 12), (B) 75 of CTG copies expansion (mother of case 12). The arrow indicate subject's strand of PCR products. PCR, polymerase chain reaction; CTG, cytosine, thymine, guanine; M, gene ruler-size marker; NC, normal control; PC, positive control; Sub, subject.

Fig. 2

Flow diagram of subjects. CMD, congenital myotonic dystrophy; CTG, cytosine, thymine, guanine.

Fig. 3

The relationship between CTG copies of patients and their mothers. CTG, cytosine, thymine, guanine.

Table 1.

The Number of CTG Copies in Patients and Their Mothers

Case	CTG copies of patient	CTG copies of mother
1	>1,000	400
2	>1,000	200
3	>1,000	300
4	>1,000	150
5	>1,000	Not checked
6	>1,000	150
7	>1,000	Not checked
8	>1,000	400
9	>1,000	150
10	>1,000	Not checked
11	>1,000	150
12	>1,000	75
13	>1,000	100
14	>1,000	Not checked
15	400	Not checked
16	400	Not checked
17∗	400	80
18	700	85
19	650	500
20∗	300	80
21	550	Not checked
22	900	Not checked
23	400	90

Abbreviation: CTG, cytosine, thymine, guanine.

^∗ Case 17 and 20 were sibling.

Table 2.

Maternal Obstetric Characteristics between Group A and B

	Mothers of patients with		P-value
	CTG≤1,000 copies (group A, n=9)	CTG>1,000 copies (group B, n=14)	P-value
Age (yr)	31.9±5.2	32.0±3.0	0.98
IVF-ET	1 (11.1)	2 (14.3)	1.00
Multipara	6 (66.7)	7 (50.0)	0.67
Polyhydramnios	6 (66.7)	13 (92.9)	0.26
AFI	26.2±7.8	29.8±8.5	0.28
Amniotic fluid reduction	2 (22.2)	2 (14.3)	1.00
Abnormal presentation	1 (11.1)	2 (14.3)	1.00
Decreased fetal movement	2 (22.2)	3 (21.4)	1.00
Preterm labor	5 (55.6)	10 (71.4)	0.66
PROMs	3 (33.3)	5 (35.7)	1.00
Cesarean section	8 (88.9)	12 (85.7)	1.00
Emergency operation	7 (77.8)	11 (78.6)	1.00

Values are presented as mean±standard deviation or number (%). Abbreviations: CTG, cytosine, thymine, guanine; IVF-ET, in vitro fertilizationembryo transfer; AFI, amniotic fluid index; PROMs, premature rupture of membranes.

Table 3.

Neonatal Demographic and Clinical Findings between Group A and B

	CTG≤1,000 copies (group A, n=9)	CTG>1,000 copies (group B, n=14)	P-value
Demographic findings
Birth weight (g)	2,071.1±519.2	2,435.7±701.9	0.22
SGA∗	1 (11.1)	0	0.39
LGA^†	0	1 (9.1)	1.00
Gestational weeks	33.7±2.9	34.5±2.6	0.60
Female	4 (44.4)	9 (64.3)	0.42
Inborn	8 (88.8)	8 (72.7)	0.62
Apgar score
1 minute	3.3±2.4	3.0±2.4	0.78
5 minute	5.2±3.0	5.5±2.6	0.73
Resuscitation at delivery room
Intubation	6 (66.7)	11 (78.6)	1.00
Cardiac massage	2 (22.2)	2 (14.3)	1.00
Clinical findings
Typical facial appearance	9 (100.0)	14 (100.0)	1.00
Hypotonia	9 (100.0)	14 (100.0)	1.00
Club foot	5 (55.6)	5 (35.7)	0.42
Diaphragm elevation	5 (55.6)	10 (71.4)	0.66
Feeding problems	9 (100.0)	14 (100.0)	1.00

Values are presented as mean±standard deviation or number (%). Abbreviations: CTG, cytosine, thymine, guanine; SGA, small for gestational age; LGA, large for gestational age.

^† Weight above the 90th percentile for the gestational age.

^∗ Weight below the 10th percentile for the gestational age.

Table 4.

Neonatal Morbidity between Group A and B

	CTG≤1,000 copies (group A, n=9)	CTG>1,000 copies (group B, n=14)	P-value
Respiratory
RDS	7 (77.8)	9 (64.3)	0.66
BPD	5 (55.6)	8 (57.1)	1.00
PPHN	1 (11.1)	4 (28.6)	0.61
Atelectasis	6 (66.7)	5 (35.7)	0.21
Aspiration pneumonia	6 (66.7)	4 (28.6)	0.10
Pleural effusion	2 (22.2)	4 (28.6)	1.00
Pulmonary hemorrhage	0	3 (21.4)	0.25
Cardiovascular
PDA	5 (55.6)	9 (64.3)	1.00
Surgical ligation	0	1 (7.1)	1.00
Medically closed	5 (55.6)	5 (35.7)	0.42
Hypotension	3 (33.3)	7 (50.0)	0.67
Inotropics	3 (33.3)	7 (50.0)	0.67
Steroid	0	2 (14.3)	0.50
Cranial
IVH (≥grade II)∗	2 (22.2)	0	0.14
PVL	0	0	-
Ventriculomegaly	7 (77.8)	10 (71.4)	1.00
Gastrointestinal
Ascites	0	4 (28.6)	0.13
NEC (≥stage IIa)^†	0	1 (7.1)	1.00
TPN induced cholestasis	1 (11.1)	2 (14.3)	1.00
Infection
Sepsis (culture-proven)	2 (22.2)	4 (28.6)	1.00

Values are presented as number (%). Abbreviations: CTG, cytosine, thymine, guanine; RDS, respiratory distress syndrome; BPD, bronchopulmonary dysplasia; PPHN, persistent pulmonary hypertension of newborn; PDA, patent ductus arteriosus; IVH, intraventricular hemorrhage; PVL, periventricular leukomalacia; NEC, necrotizing enterocolitis; TPN, total parenteral nutrition.

^∗ Intraventricular hemorrhage with ventricular dilatation (based on Papile grading system).¹⁵

^† Signs of temperature instability, apnea, bradycardia, elevated pregavage residuals, mild abdominal distension, occult blood in stool, absent bowel sounds, abdominal tenderness, ileus and pneumatosis intestinalis (based on Modified Bell's staging criteria).¹⁶

Table 5.

Hospital Course between Group A and B

	CTG≤1,000 copies (group A, n=9)	CTG>1,000 copies (group B, n=14)	P-valu
Hospital stay (days)	56.2±44.4	59.8±56.1	0.8
O2 supplement (days)	50.6±48.4	51.9±52.4	0.8
Ventilatory support (days)
Invasive mechanical ventila-	40.4±49.0	41.1±49.1	0.8
tion
Non-invasive mechanical	0.2±0.2	4.1±3.0	0.2
ventilation
Enteral feeding
Number of full enteral feed-	6 (66.7)	10 (71.4)	1.0
ing at discharge
Number of full oral feeding	3 (33.3)	5 (35.7)	1.0
at discharge
Postnatal days of full oral	15.8±9.0	32.4±15.1	0.6
feeding
Mortality	2 (22.2)	5 (35.7)	0.66
Cause of death
Respiratory failure	2	1
Hydrops fetalis with pul-		1
monary hemorrhage
Large PDA with congestive		1
heart failure
Intestinal perforation		1
Necrotizing enterocolitis		1

Values are presented as mean±standard deviation or number (%). Abbreviations: CTG, cytosine, thymine, guanine; PDA, patent ductus arteriosus.

Table 6.

Differences in Demographics and Morbidities between Survivors and Mortality Cases

	Alive at discharge (n=16)	Died at discharge (n=7)	P-value
Demographics
Gestational weeks	34.7±2.7	33.0±2.5	0.15
Birth weight (g)	2,347.5±626.6	2,168.6±735.4	0.67
Female	9 (56.3)	4 (57.1)	1.00
Inborn	14 (87.5)	4 (57.1)	0.14
Apgar score
1 minute	4.1±2.2	0.9±0.7	0.0001
5 minute	6.3±2.5	3.3±1.9	0.01
Resuscitation at delivery room
Intubation	10 (62.5)	7 (100.0)	0.12
Cardiac massage	0	2 (28.6)	0.08
Morbidity
RDS	9 (56.3)	7 (100.0)	0.06
BPD	9 (56.3)	4 (57.1)	1.00
PPHN	4 (25.0)	1 (14.3)	1.00
Atelectasis	8 (50.0)	3 (42.9)	1.00
Aspiration pneumonia	7 (43.8)	3 (42.9)	1.00
Pleural effusion	3 (18.8)	3 (42.9)	0.32
Pulmonary hemorrhage	1 (6.3)	2 (28.6)	0.21
PDA	9 (56.3)	5 (71.4)	0.66
Hypotension	5 (31.3)	5 (71.4)	0.17
Ventriculomegaly	12 (75.0)	5 (71.4)	1.00
IVH (≥grade III)∗	1 (6.3)	1 (14.3)	0.53
Ascites	2 (12.5)	2 (28.6)	0.56
NEC (≥stage IIa)^†	0	1 (14.3)	0.30
Sepsis (culture proven)	4 (25.0)	2 (28.6)	1.00

Values are presented as mean±standard deviation or number (%). Abbreviations: RDS, respiratory distress syndrome; BPD, bronchopulmonary dysplasia; PPHN, persistent pulmonary hypertension of newborn; PDA, patient ductus arteriosus; IVH, intraventricular hemorrhage; NEC, necrotizing enterocolitis.

^∗ Intraventricular hemorrhage with ventricular dilatation (based on Papile grading system).¹⁵

Table 7.

Long Term Outcomes of Survivors after Discharge

Case	CTG copies	Condition at discharge	Age of last follow-up	Death after discharge	Development	Growth status
5	>1,000	GF, O2, monitor	7 y 1 m	No	Delayed	BW 25-50 p, LT 50-75 p, HC <3 p
6	>1,000	OF	4 y 9 m (CA 4 y 7 m)	No	Delayed	BW <3 p, LT <3 p, HC 10-25 p
7	>1,000	GF	4 y 10 m	No	Delayed	BW 5-10 p, LT 50-75 p, HC <3 p
8	>1,000	OF+GF, O2, monitor	4 y 5 m (CA 4 y 4 m)	No	Delayed	BW 25-50 p, LT 25-50 p, HC 25-50 p
9	>1,000	OF	2 y 11 m (CA 2 y 9 m)	No	Delayed	BW 75-90 p, LT 50-75 p, HC 25-50 p
10	>1,000	OF	-	Yes	-	-
11	>1,000	GF, O2, monitor	7 m (CA 5 m)	Yes	Delayed	BW <3 p, LT <3 p, HC <3 p
12	>1,000	OF	1 y 8 m	No	Delayed	BW 50-75 p, LT 50-75 p, HC 95-97 p
13	>1,000	OF, O2, monitor	1 y 2 m (CA 1 y)	No	Delayed	BW <3 p, LT <3 p, HC <3 p
17	400	GF, Home ventilator	-	Yes	-	-
18	700	GF, O2, monitor	10 y 11 m (CA 10 y 10 m)	Yes	Delayed	BW 10-25 p, LT 10-25 p
19	650	GF, O2, monitor	-	Yes	-	-
20	300	OF	9 y 7 m (CA 9 y 5 m)	No	Delayed	BW 75-90 p, LT 75-90 p
21	550	OF	9 y 6 m (CA 9 y 5 m)	No	Delayed	BW <3 p, LT <3 p
22	900	GF, tracheostomy, home ventilator, mo	onitor 3 y 11 m (CA 3 y 9 m)	No	Delayed	BW <3 p, LT <3 p, HC <3 p
23	400	OF, O2, monitor	-	Yes	-	-

Abbreviations: CTG, cytosine, thymine, guanine; GF, gavage feeding; y, years; m, months; BW, body weight; LT, length; HC, head circumference; p, percentile; OF, oral feeding; CA, corrected age.

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