Letter to the Editor Severe persistent pulmonary hypertension in a neonate with RubinsteineTaybi syndrome accompanied by triple X syndrome RubinsteineTaybi syndrome (RTS) is a genetic disorder characterized by broad thumbs and toes, distinctive facial features, and mental delays, and often compli- cated by congenital heart defects (CHDs). 1 Mutations in the gene located on chromosome 16p13.3, encoding cyclic-AMP-response element-binding protein (CREB) binding protein (CREBBP), contribute to the development of RTS. 1 Herein, we describe a rare case of RTS associ- ated to severe pulmonary hypertension (PH) without CHDs, multiple genetic abnormalities of the CREBBP , and triple X syndrome. A Japanese full-term female was born via vaginal de- livery with a birth weight of 2290 g. The Apgar score was 3 and 9 at 1 and 5 min, respectively. Umbilical cord arterial pH was 7.29. The patient was suspected to have RTS based on findings, namely broad thumbs and toes and distinctive facial features (Fig. 1). The patient’s mother was a healthy 29-year-old woman who had an uneventful pregnancy. There was no relevant finding in the patient’s family his- tory. The patient was admitted to our hospital and gradu- ally started to present signs of respiratory insufficiency. Pre- and postductal percutaneous oxygen saturation (SpO 2 ) were 80% and 60% on room air, respectively. Chest radio- graph showed decreased pulmonary vascular shadow. Echocardiogram showed moderate tricuspid regurgitation, and an estimated right ventricular pressure of 54 mmHg (systolic blood pressure: 58 mmHg [pulmonary/systolic pressure ratio 0.93]); no complex cardiac anomaly was detected. On day of life (DOL) 1, the patient was intubated and underwent inhaled nitric oxide (iNO) therapy with 20 ppm of NO for PH. The SpO 2 dissociation and elevated estimated right ventricular pressure improved soon after iNO therapy. iNO was gradually tapered and stopped on DOL 5. The patient was discharged from our hospital on DOL 28. After discharge, she presented motor, mental, and speech delays. G-banding revealed her karyotype of 47,XXX. Additionally, she had a CREBBP mutation (c. 3307C > T; p. Arg1103*). There was no evidence of obstructive sleep apnea or related malformation that might be involved in PH. CREBBP , a major gene responsible for RTS, encodes the CREBBP. 1 CREB possesses intrinsic histone acetyltransferase activities and is a major regulatory nuclear protein. 1 In lung tissues, CREB is activated in response to alveolar hypoxia; it is essential for maintaining low pulmonary vascular resis- tance. 2 Mutations and deletions of CREBBP decrease acet- ylation of histones, close the chromatin structure, and impair gene expression. 1 Correspondingly, a nonsense mu- tation of CREBBP might lead to a functional defect of CREB followed by high pulmonary vascular resistance. Another concern is the presence of triple X in the pa- tient. According to a previous report, deletion or skewed inactivation of the X chromosome might contribute to the progression of PH. 3 Accordingly, inactivation of two of three X chromosomes might also be involved in the devel- opment of severe PH in the present patient. However, we could not verify the speculation, and this was one of the limitations of our study. Available online at www.sciencedirect.com ScienceDirect journal homepage: http://www.pediatr-neonatol.com Pediatrics and Neonatology 63 (2022) 200e201 https://doi.org/10.1016/j.pedneo.2021.08.006 1875-9572/Copyright ª 2021, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY- NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Severe persistent pulmonary hypertension in a neonate with RubinsteineTaybi syndrome accompanied by triple X syndrome
Nov 07, 2022
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Severe persistent pulmonary hypertension in a neonate with Rubinstein-Taybi syndrome accompanied by triple X syndromeAvailable online at www.sciencedirect.com
Letter to the Editor
Severe persistent pulmonary hypertension in a neonate with RubinsteineTaybi syndrome accompanied by triple X syndrome
RubinsteineTaybi syndrome (RTS) is a genetic disorder characterized by broad thumbs and toes, distinctive facial features, and mental delays, and often compli- cated by congenital heart defects (CHDs).1 Mutations in the gene located on chromosome 16p13.3, encoding cyclic-AMP-response element-binding protein (CREB) binding protein (CREBBP), contribute to the development of RTS.1 Herein, we describe a rare case of RTS associ- ated to severe pulmonary hypertension (PH) without CHDs, multiple genetic abnormalities of the CREBBP, and triple X syndrome.
A Japanese full-term female was born via vaginal de- livery with a birth weight of 2290 g. The Apgar score was 3 and 9 at 1 and 5 min, respectively. Umbilical cord arterial pH was 7.29. The patient was suspected to have RTS based on findings, namely broad thumbs and toes and distinctive facial features (Fig. 1). The patient’s mother was a healthy 29-year-old woman who had an uneventful pregnancy. There was no relevant finding in the patient’s family his- tory. The patient was admitted to our hospital and gradu- ally started to present signs of respiratory insufficiency. Pre- and postductal percutaneous oxygen saturation (SpO2) were 80% and 60% on room air, respectively. Chest radio- graph showed decreased pulmonary vascular shadow. Echocardiogram showed moderate tricuspid regurgitation, and an estimated right ventricular pressure of 54 mmHg (systolic blood pressure: 58 mmHg [pulmonary/systolic pressure ratio 0.93]); no complex cardiac anomaly was detected. On day of life (DOL) 1, the patient was intubated
https://doi.org/10.1016/j.pedneo.2021.08.006 1875-9572/Copyrightª 2021, Taiwan Pediatric Association. Published by NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
and underwent inhaled nitric oxide (iNO) therapy with 20 ppm of NO for PH. The SpO2 dissociation and elevated estimated right ventricular pressure improved soon after iNO therapy. iNO was gradually tapered and stopped on DOL 5. The patient was discharged from our hospital on DOL 28. After discharge, she presented motor, mental, and speech delays. G-banding revealed her karyotype of 47,XXX. Additionally, she had a CREBBP mutation (c. 3307C > T; p. Arg1103*). There was no evidence of obstructive sleep apnea or related malformation that might be involved in PH.
CREBBP, a major gene responsible for RTS, encodes the CREBBP.1 CREB possesses intrinsic histone acetyltransferase activities and is a major regulatory nuclear protein.1 In lung tissues, CREB is activated in response to alveolar hypoxia; it is essential for maintaining low pulmonary vascular resis- tance.2 Mutations and deletions of CREBBP decrease acet- ylation of histones, close the chromatin structure, and impair gene expression.1 Correspondingly, a nonsense mu- tation of CREBBP might lead to a functional defect of CREB followed by high pulmonary vascular resistance.
Another concern is the presence of triple X in the pa- tient. According to a previous report, deletion or skewed inactivation of the X chromosome might contribute to the progression of PH.3 Accordingly, inactivation of two of three X chromosomes might also be involved in the devel- opment of severe PH in the present patient. However, we could not verify the speculation, and this was one of the limitations of our study.
Elsevier Taiwan LLC. This is an open access article under the CC BY-
Pediatrics and Neonatology 63 (2022) 200e201
In conclusion, the genetic conditions might be involved in the development of severe PH in our patient. We should be aware of the possibility of occurrence of severe PH in a patient with RTS, regardless of their CHDs.
Declaration of competing interest
The authors have no conflicts of interest relevant to this article.
References
1. Stevens CA. Rubinstein-taybi syndrome. In: GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993e2021.
2. Li L, Howell K, Sands M, Banahan M, Frohlich S, Rowan SC, et al. The a and D isoforms of CREB1 are required to maintain normal pulmonary vascular resistance. PLoS One 2013;8: e80637.
201
3. Aldred MA, Comhair SA, Varella-Garcia M, Asosingh K, Xu W, Noon GP, et al. Somatic chromosome abnormalities in the lungs of patients with pulmonary arterial hypertension. Am J Respir Crit Care Med 2010;182:1153e60.
Chie Matsuguma Kazumasa Takahashi*,1
Seigo Okada1
School of Medicine, Ube, Japan
*Corresponding author. Department of Pediatrics, Yama- guchi University Graduate School of Medicine, 1-1-1 Mina-
mikogushi, Ube, Yamaguchi, 755-8505, Japan. E-mail address: [email protected] (K. Takahashi)
Jan 13, 2021
1 K. Takahashi and S. Okada contributed equally to this paper.
Declaration of competing interest
Declaration of competing interest
Letter to the Editor
Severe persistent pulmonary hypertension in a neonate with RubinsteineTaybi syndrome accompanied by triple X syndrome
RubinsteineTaybi syndrome (RTS) is a genetic disorder characterized by broad thumbs and toes, distinctive facial features, and mental delays, and often compli- cated by congenital heart defects (CHDs).1 Mutations in the gene located on chromosome 16p13.3, encoding cyclic-AMP-response element-binding protein (CREB) binding protein (CREBBP), contribute to the development of RTS.1 Herein, we describe a rare case of RTS associ- ated to severe pulmonary hypertension (PH) without CHDs, multiple genetic abnormalities of the CREBBP, and triple X syndrome.
A Japanese full-term female was born via vaginal de- livery with a birth weight of 2290 g. The Apgar score was 3 and 9 at 1 and 5 min, respectively. Umbilical cord arterial pH was 7.29. The patient was suspected to have RTS based on findings, namely broad thumbs and toes and distinctive facial features (Fig. 1). The patient’s mother was a healthy 29-year-old woman who had an uneventful pregnancy. There was no relevant finding in the patient’s family his- tory. The patient was admitted to our hospital and gradu- ally started to present signs of respiratory insufficiency. Pre- and postductal percutaneous oxygen saturation (SpO2) were 80% and 60% on room air, respectively. Chest radio- graph showed decreased pulmonary vascular shadow. Echocardiogram showed moderate tricuspid regurgitation, and an estimated right ventricular pressure of 54 mmHg (systolic blood pressure: 58 mmHg [pulmonary/systolic pressure ratio 0.93]); no complex cardiac anomaly was detected. On day of life (DOL) 1, the patient was intubated
https://doi.org/10.1016/j.pedneo.2021.08.006 1875-9572/Copyrightª 2021, Taiwan Pediatric Association. Published by NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
and underwent inhaled nitric oxide (iNO) therapy with 20 ppm of NO for PH. The SpO2 dissociation and elevated estimated right ventricular pressure improved soon after iNO therapy. iNO was gradually tapered and stopped on DOL 5. The patient was discharged from our hospital on DOL 28. After discharge, she presented motor, mental, and speech delays. G-banding revealed her karyotype of 47,XXX. Additionally, she had a CREBBP mutation (c. 3307C > T; p. Arg1103*). There was no evidence of obstructive sleep apnea or related malformation that might be involved in PH.
CREBBP, a major gene responsible for RTS, encodes the CREBBP.1 CREB possesses intrinsic histone acetyltransferase activities and is a major regulatory nuclear protein.1 In lung tissues, CREB is activated in response to alveolar hypoxia; it is essential for maintaining low pulmonary vascular resis- tance.2 Mutations and deletions of CREBBP decrease acet- ylation of histones, close the chromatin structure, and impair gene expression.1 Correspondingly, a nonsense mu- tation of CREBBP might lead to a functional defect of CREB followed by high pulmonary vascular resistance.
Another concern is the presence of triple X in the pa- tient. According to a previous report, deletion or skewed inactivation of the X chromosome might contribute to the progression of PH.3 Accordingly, inactivation of two of three X chromosomes might also be involved in the devel- opment of severe PH in the present patient. However, we could not verify the speculation, and this was one of the limitations of our study.
Elsevier Taiwan LLC. This is an open access article under the CC BY-
Pediatrics and Neonatology 63 (2022) 200e201
In conclusion, the genetic conditions might be involved in the development of severe PH in our patient. We should be aware of the possibility of occurrence of severe PH in a patient with RTS, regardless of their CHDs.
Declaration of competing interest
The authors have no conflicts of interest relevant to this article.
References
1. Stevens CA. Rubinstein-taybi syndrome. In: GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993e2021.
2. Li L, Howell K, Sands M, Banahan M, Frohlich S, Rowan SC, et al. The a and D isoforms of CREB1 are required to maintain normal pulmonary vascular resistance. PLoS One 2013;8: e80637.
201
3. Aldred MA, Comhair SA, Varella-Garcia M, Asosingh K, Xu W, Noon GP, et al. Somatic chromosome abnormalities in the lungs of patients with pulmonary arterial hypertension. Am J Respir Crit Care Med 2010;182:1153e60.
Chie Matsuguma Kazumasa Takahashi*,1
Seigo Okada1
School of Medicine, Ube, Japan
*Corresponding author. Department of Pediatrics, Yama- guchi University Graduate School of Medicine, 1-1-1 Mina-
mikogushi, Ube, Yamaguchi, 755-8505, Japan. E-mail address: [email protected] (K. Takahashi)
Jan 13, 2021
1 K. Takahashi and S. Okada contributed equally to this paper.
Declaration of competing interest
Declaration of competing interest
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