- Email: [email protected]
Sudden death of a preschool child diagnosed by postmortem examination
Journal of Forensic and Legal Medicine 66 (2019) 144–146
Contents lists available at ScienceDirect
Journal of Forensic and Legal Medicine journal homepage: www.elsevier.com/locate/yjflm
Sudden death of a preschool child diagnosed by postmortem examination ∗
T
Shuji Kozawa , Masayuki Nata Department of Forensic Medicine and Sciences, Mie University Graduate School of Medicine, Japan
A R T I C LE I N FO
A B S T R A C T
Keywords: Pulmonary hypertension Histopathological examination Genetic examination Unexpected sudden death Autopsy
An autopsy case of sudden death due to pulmonary arterial hypertension (PAH) in a 5-year-old boy whose cause of death was not determined during autopsy, but was later determined by postmortem examination, is presented. The boy developed convulsions that subsequently stopped, but remained unconscious. He was transported to hospital by ambulance, but died soon after. The boy had been found to have right ventricular overload on ECG 2 weeks earlier. A plan had been made to consult a doctor for a specialist visit 2 months later. During autopsy, significant abnormalities or injuries were not observed on the body's external surface. Internal examination showed congested organs, and the blood remaining in the body was dark red with fluidity. The heart was significantly enlarged (146 g), with nearly equivalent thickness of the left and right ventricles, showing right ventricular hypertrophy. Obvious macroscopic abnormalities were not observed at the origin and main trunk of the pulmonary artery. The lungs were slightly swollen (right lung 100 g, left lung 95 g), severely congested, and edematous. A postmortem CT scan displayed some patchy shadows in both lungs; however, no significant abnormalities were detected. Histopathological examination suggested a diagnosis of PAH. Three genes (BMPR2, ALK1, and ENG) were tested, revealing a heterozygous insertion of five nucleotides, TTTCC, between nucleotides 2677 and 2678 within exon 12 of the BMPR2 gene. Therefore, the subject was considered to have had heritable PAH due to a BMPR2 gene mutation.
1. Introduction
2. Case report
Unexpected sudden death is a tragedy at any age, but particularly in childhood and adolescence, although sudden death in childhood is rare.1 While many of the causes of sudden death in childhood are known, in other cases, this is difficult to assess. Population-based reports present an age-specific rate of sudden unexpected death of 1.3–4.3/year per 100,000 population. Between 1 and 20 years of age, 40% of deaths are not sudden and are due to medical causes, the most common of which are epilepsy and asthma.2 Pulmonary arterial hypertension (PAH) is a rare disease characterized by high pulmonary vascular resistance and arterial pressure, which can lead to right heart failure and death.3 PAH is a serious disease with a grave prognosis. Linkage analysis and positional cloning have identified mutations in the bone morphogenetic protein type 2 receptor (BMPR2) gene as a cause of familial PAH cases.4 This paper presents an autopsy case of sudden death due to PAH in a 5-year-old boy whose cause of death was not determined at autopsy, but was later determined by postmortem examination.
2.1. Clinical history Seven months before his death, a 5-year-old boy presented with convulsions, for which he was examined at the hospital. No notable findings were observed on brain examination, but he was administered valproic acid under the diagnosis of epilepsy. Twenty-six days before his death, the convulsions reappeared, and he was found to have right ventricular overload on electrocardiogram; thus, a consultation with a specialist was scheduled for 2 months later. At around 11:25 a.m. on the day of his death, the patient developed convulsions, which eventually stopped; however, he remained unconscious. Ten minutes later, an ambulance arrived, but his condition deteriorated, and he developed cardiopulmonary arrest. He was transported to our hospital by ambulance, but was declared dead at 2:09 p.m. 2.2. Autopsy and postmortem radiological findings The patient was 108 cm in height and weighed 17.6 kg. No significant abnormalities or injuries were observed on the body's external
∗
Corresponding author. Department of Forensic Medicine and Sciences, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan. E-mail address: [email protected] (S. Kozawa).
https://doi.org/10.1016/j.jflm.2019.07.004 Received 12 February 2019; Received in revised form 28 June 2019; Accepted 10 July 2019 Available online 10 July 2019 1752-928X/ © 2019 Published by Elsevier Ltd.
Journal of Forensic and Legal Medicine 66 (2019) 144–146
S. Kozawa and M. Nata
Fig. 2. Macroscopic and histological findings of the lung. (A) The lungs. (B) Cross section of the lung. (C) Elastica van Gieson (EVG) stain staining, ×200 magnification. (D) H-E staining, ×200 magnification. *Medial hypertrophy, ● Plexiform lesion, ■Thrombi filling the pulmonary artery.
Fig. 1. Macroscopic and histological findings of the heart. (A) The heart. (B) Cross section of the heart. (C) Hematoxylin-Eosin (H-E) staining, ×40 magnification. (D) H-E staining, ×100 magnification. The right ventricle(upper side of Figure B) is markedly enlarged, and its wall is thickened (0.9 cm). Myocardial fiber narrowing and interstitial edema were observed (C and D).
3. Discussion PAH is a progressive disease involving high pulmonary pressure caused by increased vascular resistance. Its estimated prevalence is 15–50 cases per million people.8 A mean pulmonary artery pressure of at least 25 mmHg at rest is one of the requirements for diagnosing PAH.12 This condition presents as functional vascular endothelial cell injury in the early stages, but results in hyperplasia of smooth muscle cells, fibroblasts, and extracellular matrix as the disease progresses.13 With such progression, pulmonary artery plexiform lesions form, and the capacity of the pulmonary vascular bed decreases, leading to right ventricular hypertrophy and right heart failure caused by pulmonary hypertension.7 In the World Health Organization's clinical classification system for pulmonary hypertension (2013), PAH is classified into five groups: (i) idiopathic PAH (IPAH; completely unknown cause), (ii) heritable PAH (HPAH; BMPR2, ALK1, ENG, SMAD9, CAV1, and KCNK3 genes have been shown to be involved in the onset of disease (Table 1), but their mechanisms of involvement are unknown), (iii) drug- and (iv) toxininduced PAH (particular orally administered drugs such as appetite suppressants are involved in the onset), and (v) PAH associated with another condition (e.g., connective tissue disease).14 In the case reported here, the PAH of the subject appeared unlikely to have been caused by drugs or other substances. Therefore, IPAH or HPAH was conceivable. IPAH is one of the more common types of PAH, accounting for approximately 40% of cases15; although the cause of IPAH is still unknown, it is known to develop in a hereditary manner, suggesting the involvement of genetic elements. Recently, the involvement of several gene aberrations in this condition was reported, and the number of cases with disease states classified as HPAH has increased, accounting for 6% of cases of PAH. Therefore, genetic testing was performed in the case reported here, in order to obtain a definitive diagnosis.
surface. Internal examination showed that the organs were congested and the blood remaining in the body was dark red with fluidity. The heart was enlarged, weighing 146 g (reference value 92.6 ± 11.5 g). The dissected surface of the heart showed nearly equivalent thickness of the left and right ventricles, and right ventricular hypertrophy was observed. No obvious macroscopic abnormalities were observed at the origin and main trunk of the pulmonary artery. The lungs were slightly swollen, with the right and left lungs weighing 100 and 95 g, respectively. The dissected surfaces showed that the lungs were severely congested and edematous. Caffeine and diazepam were detected in the serum in toxicological analysis using gas chromatography-mass spectrometry. A postmortem computed tomography (CT) scan was performed at the hospital. It displayed some patchy shadows in both lungs, but no significant abnormalities were detected.
2.3. Histopathology The results of histopathological examination with hematoxylin–eosin staining of the heart tissue are displayed in Fig. 1. Myocardial fiber narrowing and interstitial edema were observed. However, lesions that caused these conditions or ones that resulted in the patient's death, including myocarditis, were not detected in immunohistochemical investigations (data not shown). The findings of histopathological examination of the lung tissue are displayed in Fig. 2. In the lungs, pulmonary artery remodeling that involved concentric fibrosis of the pulmonary arteriole intima was observed, as well as plexiform lesions accompanied by the destruction of vascular lumens and existing structures. There were also some thrombi filling the pulmonary artery. These findings suggested a diagnosis of PAH.
Table 1 Gene mutations in pulmonary arterial hypertension (PAH).
2.4. Gene analysis of PAH
Gene
Prevalence in I/H-PAH 5
Three genes (BMPR2, ALK1, and ENG) were screened for mutation via direct DNA sequencing from blood. A heterozygous insertion of five nucleotides, TTTCC, was identified between nucleotides 2677 and 2678 within exon 12 of the BMPR2 gene. No mutations in the ALK1 and ENG genes were identified.
BMPR2 ALK16 ENG7 SMAD98 CAV19 KCNK310 EIF2AK411
145
80% 2%–6% ∼1% ∼1% ∼1% 1.3%–3.2% N/Ain
Journal of Forensic and Legal Medicine 66 (2019) 144–146
S. Kozawa and M. Nata
the significance of the results of this study.
Three genes were tested, which revealed a heterozygous insertion of five nucleotides, TTTCC, between nucleotides 2677 and 2678 within exon 12 of the BMPR2 gene. While this mutation has not previously been reported, it results in a frameshift, replacing amino acid 893 from Arg to Leu and encoding a stop codon four amino acids later. In 2000, PAH development was found to be associated with a mutation in the BMPR2 gene.16 This mutation strengthens the signal transduction of the TGF-β system, resulting in smooth muscle cell proliferation of the pulmonary artery and excessive apoptosis of pulmonary artery endothelial cells.17 It has been reported that 50%–100% of familial PAH cases and about 25% of sporadic IPAH cases are positive for BMPR2 gene aberrations. In contrast, only 10%–20% of those with this gene aberration develop PAH. Therefore, the onset is probably caused by some type of trigger, such as an environmental factor, in addition to these genetic factors. Based on these observations, PAH in the present case was most likely caused by a mutation in this BMPR2 gene. This was supported by the absence of mutations in the ALK1 and ENG genes, which are known to be mutated more frequently among genes that are associated with the onset of PAH. Therefore, it was concluded that this case involved heritable PAH that appeared due to a BMPR2 gene mutation. Reports on hypertrophic systemic vasculature being a key factor in the etiology of PAH with BMPR mutations18,19 have garnered attention.20 BMPR2 and its related signaling pathways have now been recognized as key regulators of pulmonary vascular homeostasis. Although, traditionally, the phenotypic consequences of BMPR2 deficiency in PAH have been thought to be limited to the pulmonary vasculature, there is evidence that abnormalities in BMPR2 signaling may affect many other organ systems and cellular compartments, such as the heart, immune system, and bone marrow. Although analyses of histopathological examination were performed in the preserved organs, no lesions were found in them. However, some of the organs considered to be affected by abnormalities in BMPR2 signaling, including the bone marrow and thymus, were unfortunately not preserved.
References 1. Molander NI. Sudden natural death in later childhood and adolescence. Arch Dis Child. 1982;57:572–576https://doi.org/10.1136/adc.57.8.572. 2. Wren C, O'sullivan JJ, Wright C. Sudden death in children and adolescents. Heart. 2000;83:410–413https://doi.org/10.1136/heart.83.4.410. 3. Igari Y, Hosoya T, Hayashizaki Y, et al. Sudden, unexpected infant death due to pulmonary arterial hypertension. Leg Med (Tokyo). 2014;16:44–47https://doi.org/ 10.1016/j.legalmed.2013.11.001. 4. Gamou S, Kataoka M, Aimi Y, et al. Genetics in pulmonary arterial hypertension in a large homogeneous Japanese population. Clin Genet. 2018;94:70–80https://doi.org/ 10.1111/cge.13154. 5. Lane KB, Machado RD, Pauciulo MW, et al. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nat Genet. 2000;26:81–84https://doi.org/10.1038/79226. 6. Abdalla SA, Pece-Barbara N, Vera S, et al. Analysis of ALK-1 and endoglin in newborns from families with hereditary hemorrhagic telangiectasia type 2. Hum Mol Genet. 2000;9:1227–1237https://doi.org/10.1093/hmg/9.8.1227. 7. Widlitz A, Barst RJ. Pulmonary arterial hypertension in children. Eur Respir J. 2003;21:155–176https://doi.org/10.1183/09031936.03.00088302. 8. Badesch DB, Champion HC, Sanchez MA, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54:S55–S66https://doi.org/ 10.1016/j.jacc.2009.04.011. 9. Austin ED, Ma L, LeDuc C, et al. Whole exome sequencing to identify a novel gene (caveolin-1) associated with human pulmonary arterial hypertension. Circ Cardiovasc Genet. 2012;5:336–343https://doi.org/10.1161/CIRCGENETICS.111.961888. 10. Ma L, Roman-Campos D, Austin ED, et al. A novel channelopathy in pulmonary arterial hypertension. N Engl J Med. 2013;369:351–361https://doi.org/10.1056/ NEJMoa1211097. 11. Eyries M, Montani D, Girerd B, et al. EIF2AK4 mutations cause pulmonary venoocclusive disease, a recessive form of pulmonary hypertension. Nat Genet. 2014;46:65–69https://doi.org/10.1038/ng.2844. 12. Runo JR, Loyd JE. Primary pulmonary hypertension. Lancet. 2003;361:1533–1544https://doi.org/10.1016/S0140-6736(98)02111-4. 13. Sysol JR, Machado RF. Classification and pathophysiology of pulmonary hypertension. Contin Cardiol Educ. 2018;4:2–12https://doi.org/10.1002/cce2.71. 14. Foshat M, Boroumand N. The evolving classification of pulmonary hypertension. Arch Pathol Lab Med. 2017;141:696–703https://doi.org/10.5858/arpa.20160035-RA. 15. Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med. 2006;173:1023–1030https://doi.org/10.1164/rccm.200510-1668OC. 16. Evans JDW, Giered B, Montani D, et al. BMPR2 mutation and survival in pulmonary arterial hypertension: an individual participant data meta-analysis. Lancet Repir Med. 2016;4:129–137https://doi.org/10.1016/S2213-2600(15)00544-5. 17. International PPH Consortium, Lane KB, Machado RD, et al. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nat Genet. 2000;26:81–84https://doi.org/10.1038/79226. 18. Ghihna M-R, Guignabert C, Montani D, et al. BMPR2 mutation status influences bronchial vascular changes in pulmonary arterial hypertension. Eur Resipr J. 2016;48:1668–1681https://doi.org/10.1183/13993003.00464-2016. 19. Humbert M, Guignarbert C, Bonnet S, et al. Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives. Eur Respir J. 2019;53:1801887https://doi.org/10.1183/13993003.01887-2018. 20. Andruska A, Spiekerkoetter E. Consequences of BMPR2 deficiency in the pulmonary vasculature and beyond: contributions to pulmonary arterial hypertension. Int J Mol Sci. 2018;19:2499https://doi.org/10.3390/ijms19092499.
Funding None. Conflicts of interest All Authors declare no conflict of Interest. Acknowledgment The authors wish to thank Dr. Hiroyuki Ohashi, Dr. Hirofumi Sawada and Prof. Masahiro Hirayama, Department of Pediatrics, Mie University Graduate School of Medicine, for their help in interpreting
146
Contents lists available at ScienceDirect
Journal of Forensic and Legal Medicine journal homepage: www.elsevier.com/locate/yjflm
Sudden death of a preschool child diagnosed by postmortem examination ∗
T
Shuji Kozawa , Masayuki Nata Department of Forensic Medicine and Sciences, Mie University Graduate School of Medicine, Japan
A R T I C LE I N FO
A B S T R A C T
Keywords: Pulmonary hypertension Histopathological examination Genetic examination Unexpected sudden death Autopsy
An autopsy case of sudden death due to pulmonary arterial hypertension (PAH) in a 5-year-old boy whose cause of death was not determined during autopsy, but was later determined by postmortem examination, is presented. The boy developed convulsions that subsequently stopped, but remained unconscious. He was transported to hospital by ambulance, but died soon after. The boy had been found to have right ventricular overload on ECG 2 weeks earlier. A plan had been made to consult a doctor for a specialist visit 2 months later. During autopsy, significant abnormalities or injuries were not observed on the body's external surface. Internal examination showed congested organs, and the blood remaining in the body was dark red with fluidity. The heart was significantly enlarged (146 g), with nearly equivalent thickness of the left and right ventricles, showing right ventricular hypertrophy. Obvious macroscopic abnormalities were not observed at the origin and main trunk of the pulmonary artery. The lungs were slightly swollen (right lung 100 g, left lung 95 g), severely congested, and edematous. A postmortem CT scan displayed some patchy shadows in both lungs; however, no significant abnormalities were detected. Histopathological examination suggested a diagnosis of PAH. Three genes (BMPR2, ALK1, and ENG) were tested, revealing a heterozygous insertion of five nucleotides, TTTCC, between nucleotides 2677 and 2678 within exon 12 of the BMPR2 gene. Therefore, the subject was considered to have had heritable PAH due to a BMPR2 gene mutation.
1. Introduction
2. Case report
Unexpected sudden death is a tragedy at any age, but particularly in childhood and adolescence, although sudden death in childhood is rare.1 While many of the causes of sudden death in childhood are known, in other cases, this is difficult to assess. Population-based reports present an age-specific rate of sudden unexpected death of 1.3–4.3/year per 100,000 population. Between 1 and 20 years of age, 40% of deaths are not sudden and are due to medical causes, the most common of which are epilepsy and asthma.2 Pulmonary arterial hypertension (PAH) is a rare disease characterized by high pulmonary vascular resistance and arterial pressure, which can lead to right heart failure and death.3 PAH is a serious disease with a grave prognosis. Linkage analysis and positional cloning have identified mutations in the bone morphogenetic protein type 2 receptor (BMPR2) gene as a cause of familial PAH cases.4 This paper presents an autopsy case of sudden death due to PAH in a 5-year-old boy whose cause of death was not determined at autopsy, but was later determined by postmortem examination.
2.1. Clinical history Seven months before his death, a 5-year-old boy presented with convulsions, for which he was examined at the hospital. No notable findings were observed on brain examination, but he was administered valproic acid under the diagnosis of epilepsy. Twenty-six days before his death, the convulsions reappeared, and he was found to have right ventricular overload on electrocardiogram; thus, a consultation with a specialist was scheduled for 2 months later. At around 11:25 a.m. on the day of his death, the patient developed convulsions, which eventually stopped; however, he remained unconscious. Ten minutes later, an ambulance arrived, but his condition deteriorated, and he developed cardiopulmonary arrest. He was transported to our hospital by ambulance, but was declared dead at 2:09 p.m. 2.2. Autopsy and postmortem radiological findings The patient was 108 cm in height and weighed 17.6 kg. No significant abnormalities or injuries were observed on the body's external
∗
Corresponding author. Department of Forensic Medicine and Sciences, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan. E-mail address: [email protected] (S. Kozawa).
https://doi.org/10.1016/j.jflm.2019.07.004 Received 12 February 2019; Received in revised form 28 June 2019; Accepted 10 July 2019 Available online 10 July 2019 1752-928X/ © 2019 Published by Elsevier Ltd.
Journal of Forensic and Legal Medicine 66 (2019) 144–146
S. Kozawa and M. Nata
Fig. 2. Macroscopic and histological findings of the lung. (A) The lungs. (B) Cross section of the lung. (C) Elastica van Gieson (EVG) stain staining, ×200 magnification. (D) H-E staining, ×200 magnification. *Medial hypertrophy, ● Plexiform lesion, ■Thrombi filling the pulmonary artery.
Fig. 1. Macroscopic and histological findings of the heart. (A) The heart. (B) Cross section of the heart. (C) Hematoxylin-Eosin (H-E) staining, ×40 magnification. (D) H-E staining, ×100 magnification. The right ventricle(upper side of Figure B) is markedly enlarged, and its wall is thickened (0.9 cm). Myocardial fiber narrowing and interstitial edema were observed (C and D).
3. Discussion PAH is a progressive disease involving high pulmonary pressure caused by increased vascular resistance. Its estimated prevalence is 15–50 cases per million people.8 A mean pulmonary artery pressure of at least 25 mmHg at rest is one of the requirements for diagnosing PAH.12 This condition presents as functional vascular endothelial cell injury in the early stages, but results in hyperplasia of smooth muscle cells, fibroblasts, and extracellular matrix as the disease progresses.13 With such progression, pulmonary artery plexiform lesions form, and the capacity of the pulmonary vascular bed decreases, leading to right ventricular hypertrophy and right heart failure caused by pulmonary hypertension.7 In the World Health Organization's clinical classification system for pulmonary hypertension (2013), PAH is classified into five groups: (i) idiopathic PAH (IPAH; completely unknown cause), (ii) heritable PAH (HPAH; BMPR2, ALK1, ENG, SMAD9, CAV1, and KCNK3 genes have been shown to be involved in the onset of disease (Table 1), but their mechanisms of involvement are unknown), (iii) drug- and (iv) toxininduced PAH (particular orally administered drugs such as appetite suppressants are involved in the onset), and (v) PAH associated with another condition (e.g., connective tissue disease).14 In the case reported here, the PAH of the subject appeared unlikely to have been caused by drugs or other substances. Therefore, IPAH or HPAH was conceivable. IPAH is one of the more common types of PAH, accounting for approximately 40% of cases15; although the cause of IPAH is still unknown, it is known to develop in a hereditary manner, suggesting the involvement of genetic elements. Recently, the involvement of several gene aberrations in this condition was reported, and the number of cases with disease states classified as HPAH has increased, accounting for 6% of cases of PAH. Therefore, genetic testing was performed in the case reported here, in order to obtain a definitive diagnosis.
surface. Internal examination showed that the organs were congested and the blood remaining in the body was dark red with fluidity. The heart was enlarged, weighing 146 g (reference value 92.6 ± 11.5 g). The dissected surface of the heart showed nearly equivalent thickness of the left and right ventricles, and right ventricular hypertrophy was observed. No obvious macroscopic abnormalities were observed at the origin and main trunk of the pulmonary artery. The lungs were slightly swollen, with the right and left lungs weighing 100 and 95 g, respectively. The dissected surfaces showed that the lungs were severely congested and edematous. Caffeine and diazepam were detected in the serum in toxicological analysis using gas chromatography-mass spectrometry. A postmortem computed tomography (CT) scan was performed at the hospital. It displayed some patchy shadows in both lungs, but no significant abnormalities were detected.
2.3. Histopathology The results of histopathological examination with hematoxylin–eosin staining of the heart tissue are displayed in Fig. 1. Myocardial fiber narrowing and interstitial edema were observed. However, lesions that caused these conditions or ones that resulted in the patient's death, including myocarditis, were not detected in immunohistochemical investigations (data not shown). The findings of histopathological examination of the lung tissue are displayed in Fig. 2. In the lungs, pulmonary artery remodeling that involved concentric fibrosis of the pulmonary arteriole intima was observed, as well as plexiform lesions accompanied by the destruction of vascular lumens and existing structures. There were also some thrombi filling the pulmonary artery. These findings suggested a diagnosis of PAH.
Table 1 Gene mutations in pulmonary arterial hypertension (PAH).
2.4. Gene analysis of PAH
Gene
Prevalence in I/H-PAH 5
Three genes (BMPR2, ALK1, and ENG) were screened for mutation via direct DNA sequencing from blood. A heterozygous insertion of five nucleotides, TTTCC, was identified between nucleotides 2677 and 2678 within exon 12 of the BMPR2 gene. No mutations in the ALK1 and ENG genes were identified.
BMPR2 ALK16 ENG7 SMAD98 CAV19 KCNK310 EIF2AK411
145
80% 2%–6% ∼1% ∼1% ∼1% 1.3%–3.2% N/Ain
Journal of Forensic and Legal Medicine 66 (2019) 144–146
S. Kozawa and M. Nata
the significance of the results of this study.
Three genes were tested, which revealed a heterozygous insertion of five nucleotides, TTTCC, between nucleotides 2677 and 2678 within exon 12 of the BMPR2 gene. While this mutation has not previously been reported, it results in a frameshift, replacing amino acid 893 from Arg to Leu and encoding a stop codon four amino acids later. In 2000, PAH development was found to be associated with a mutation in the BMPR2 gene.16 This mutation strengthens the signal transduction of the TGF-β system, resulting in smooth muscle cell proliferation of the pulmonary artery and excessive apoptosis of pulmonary artery endothelial cells.17 It has been reported that 50%–100% of familial PAH cases and about 25% of sporadic IPAH cases are positive for BMPR2 gene aberrations. In contrast, only 10%–20% of those with this gene aberration develop PAH. Therefore, the onset is probably caused by some type of trigger, such as an environmental factor, in addition to these genetic factors. Based on these observations, PAH in the present case was most likely caused by a mutation in this BMPR2 gene. This was supported by the absence of mutations in the ALK1 and ENG genes, which are known to be mutated more frequently among genes that are associated with the onset of PAH. Therefore, it was concluded that this case involved heritable PAH that appeared due to a BMPR2 gene mutation. Reports on hypertrophic systemic vasculature being a key factor in the etiology of PAH with BMPR mutations18,19 have garnered attention.20 BMPR2 and its related signaling pathways have now been recognized as key regulators of pulmonary vascular homeostasis. Although, traditionally, the phenotypic consequences of BMPR2 deficiency in PAH have been thought to be limited to the pulmonary vasculature, there is evidence that abnormalities in BMPR2 signaling may affect many other organ systems and cellular compartments, such as the heart, immune system, and bone marrow. Although analyses of histopathological examination were performed in the preserved organs, no lesions were found in them. However, some of the organs considered to be affected by abnormalities in BMPR2 signaling, including the bone marrow and thymus, were unfortunately not preserved.
References 1. Molander NI. Sudden natural death in later childhood and adolescence. Arch Dis Child. 1982;57:572–576https://doi.org/10.1136/adc.57.8.572. 2. Wren C, O'sullivan JJ, Wright C. Sudden death in children and adolescents. Heart. 2000;83:410–413https://doi.org/10.1136/heart.83.4.410. 3. Igari Y, Hosoya T, Hayashizaki Y, et al. Sudden, unexpected infant death due to pulmonary arterial hypertension. Leg Med (Tokyo). 2014;16:44–47https://doi.org/ 10.1016/j.legalmed.2013.11.001. 4. Gamou S, Kataoka M, Aimi Y, et al. Genetics in pulmonary arterial hypertension in a large homogeneous Japanese population. Clin Genet. 2018;94:70–80https://doi.org/ 10.1111/cge.13154. 5. Lane KB, Machado RD, Pauciulo MW, et al. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nat Genet. 2000;26:81–84https://doi.org/10.1038/79226. 6. Abdalla SA, Pece-Barbara N, Vera S, et al. Analysis of ALK-1 and endoglin in newborns from families with hereditary hemorrhagic telangiectasia type 2. Hum Mol Genet. 2000;9:1227–1237https://doi.org/10.1093/hmg/9.8.1227. 7. Widlitz A, Barst RJ. Pulmonary arterial hypertension in children. Eur Respir J. 2003;21:155–176https://doi.org/10.1183/09031936.03.00088302. 8. Badesch DB, Champion HC, Sanchez MA, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54:S55–S66https://doi.org/ 10.1016/j.jacc.2009.04.011. 9. Austin ED, Ma L, LeDuc C, et al. Whole exome sequencing to identify a novel gene (caveolin-1) associated with human pulmonary arterial hypertension. Circ Cardiovasc Genet. 2012;5:336–343https://doi.org/10.1161/CIRCGENETICS.111.961888. 10. Ma L, Roman-Campos D, Austin ED, et al. A novel channelopathy in pulmonary arterial hypertension. N Engl J Med. 2013;369:351–361https://doi.org/10.1056/ NEJMoa1211097. 11. Eyries M, Montani D, Girerd B, et al. EIF2AK4 mutations cause pulmonary venoocclusive disease, a recessive form of pulmonary hypertension. Nat Genet. 2014;46:65–69https://doi.org/10.1038/ng.2844. 12. Runo JR, Loyd JE. Primary pulmonary hypertension. Lancet. 2003;361:1533–1544https://doi.org/10.1016/S0140-6736(98)02111-4. 13. Sysol JR, Machado RF. Classification and pathophysiology of pulmonary hypertension. Contin Cardiol Educ. 2018;4:2–12https://doi.org/10.1002/cce2.71. 14. Foshat M, Boroumand N. The evolving classification of pulmonary hypertension. Arch Pathol Lab Med. 2017;141:696–703https://doi.org/10.5858/arpa.20160035-RA. 15. Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med. 2006;173:1023–1030https://doi.org/10.1164/rccm.200510-1668OC. 16. Evans JDW, Giered B, Montani D, et al. BMPR2 mutation and survival in pulmonary arterial hypertension: an individual participant data meta-analysis. Lancet Repir Med. 2016;4:129–137https://doi.org/10.1016/S2213-2600(15)00544-5. 17. International PPH Consortium, Lane KB, Machado RD, et al. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nat Genet. 2000;26:81–84https://doi.org/10.1038/79226. 18. Ghihna M-R, Guignabert C, Montani D, et al. BMPR2 mutation status influences bronchial vascular changes in pulmonary arterial hypertension. Eur Resipr J. 2016;48:1668–1681https://doi.org/10.1183/13993003.00464-2016. 19. Humbert M, Guignarbert C, Bonnet S, et al. Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives. Eur Respir J. 2019;53:1801887https://doi.org/10.1183/13993003.01887-2018. 20. Andruska A, Spiekerkoetter E. Consequences of BMPR2 deficiency in the pulmonary vasculature and beyond: contributions to pulmonary arterial hypertension. Int J Mol Sci. 2018;19:2499https://doi.org/10.3390/ijms19092499.
Funding None. Conflicts of interest All Authors declare no conflict of Interest. Acknowledgment The authors wish to thank Dr. Hiroyuki Ohashi, Dr. Hirofumi Sawada and Prof. Masahiro Hirayama, Department of Pediatrics, Mie University Graduate School of Medicine, for their help in interpreting
146