Familial Pulmonary Hypertension

Melmon, Kenneth L.; Braunwald, Eugene

doi:10.1056/nejm196310102691502

Cited by 45 publications

(15 citation statements)

References 10 publications

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“…In 1995, we reported that genetic anticipation in HPAH appeared likely based on comparisons of age at death between two to three affected generations within families (4). The possibility of genetic anticipation had been suggested in earlier reports of familial primary pulmonary hypertension, now called HPAH (5,6). Other pulmonary hypertension registries have made similar observations (7,8).…”

mentioning

confidence: 91%

Longitudinal Analysis Casts Doubt on the Presence of Genetic Anticipation in Heritable Pulmonary Arterial Hypertension

Larkin

Newman

Austin

et al. 2012

Am J Respir Crit Care Med

189

145

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Rationale: Analysis of the age of onset in heritable pulmonary arterial hypertension (HPAH) has led to the hypothesis that genetic anticipation causes younger age of onset and death in subsequent generations. With accrual of pedigree data over multiple decades, we retested this hypothesis using analyses that eliminate the truncation of data that exists with shorter duration of follow-up. Objectives: To analyze the pedigrees of families with mutations in bone morphogenetic protein receptor type 2 (BMPR2), afflicted in two or more generations with HPAH, eliminating time truncation bias by including families for whom we have at least 57 years of data. Methods: We analyzed 355 individuals with BMPR2 mutations from 53 families in the Vanderbilt Pulmonary Hypertension Registry. We compared age at diagnosis or death in affected individuals (n ¼ 249) by generation within families with multigenerational disease. We performed linear mixed effects models and we limited time-truncation bias by restricting date of birth to before 1955. This allowed for 57 years of follow-up (1955-2012) for mutation carriers to develop disease. We also conducted Kaplan-Meier analysis to include currently unaffected mutation carriers (n ¼ 106). Measurements and Main Results: Differences in age at diagnosis by generation were found in a biased analysis that included all birth years to the present, but this finding was eliminated when the 57-year observation limit was imposed. By Kaplan-Meier analysis, inclusion of currently unaffected mutation carriers strengthens the observation that bias of ascertainment exists when recent generations are included. Conclusions: Genetic anticipation is likely an artifact of incomplete time of observation of kindreds with HPAH due to BMPR2 mutations.

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confidence: 91%

Longitudinal Analysis Casts Doubt on the Presence of Genetic Anticipation in Heritable Pulmonary Arterial Hypertension

Larkin

Newman

Austin

et al. 2012

Am J Respir Crit Care Med

189

145

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“…

Since Clarke et al (1927) described primary pulmonary hypertension in two sisters, several families with more than one member involved have been reported (Lange, 1948;Dresdale, Michtom, and Schultz, 1954;van Epps, 1957; Coleman, Edmunds, and Tregillus, 1959;Fleming, 1960;Cahen et al, 1961;van Bogaert et al, 1961;Boiteau and Libanoff, 1963;Melmon and Braunwald, 1963;Parry and Verel, 1966;Kingdon et al, 1966). The present family is interesting because its several members suffered from more than one disease in common.

CASE REPORTS

The family first came under our observation in 1962.

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mentioning

confidence: 66%

“…Recently, Melmon and Braunwald (1963) have reported upon the occurrence of this form of hypertension in 5 relatives over 3 generations. Kingdon et al (1966) have noticed the occurrence of genetic anticipation in their patients and also in the case of the mother and her two daughters described by Parry and Verel (1966).…”

Section: Discussionmentioning

confidence: 99%

Primary pulmonary hypertension, cerebrovascular malformation, and lymphoedema feet in a family.

Avasthey¹,

Roy²

1968

Heart

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Since Clarke et al. (1927) described primary pulmonary hypertension in two sisters, several families with more than one member involved have been reported (Lange, 1948;Dresdale, Michtom, and Schultz, 1954;van Epps, 1957; Coleman, Edmunds, and Tregillus, 1959;Fleming, 1960;Cahen et al., 1961;van Bogaert et al., 1961;Boiteau and Libanoff, 1963;Melmon and Braunwald, 1963;Parry and Verel, 1966;Kingdon et al., 1966). The present family is interesting because its several members suffered from more than one disease in common. CASE REPORTSThe family first came under our observation in 1962. The grandparents were not known to have suffered from heart disease or lymphoedema. Sibs of the parents were described by them to be healthy. The family tree is shown in Fig. 1. Case 1. This 38-year-old woman, the mother of the other patients to be described, had had two episodes of high fever, and redness and swelling over both feet and legs, at the ages of 13 and 15 years, respectively. Both attacks lasted two days each. Ever since then she had noticed swelling over both feet. Physical examination showed her to be a healthy-looking woman with nonpitting oedema over both feet and some pitting oedema over the shins. There was no clubbing or cyanosis. Peripheral pulses were normal. A loud systolic bruit was audible over both temporal regions of the skull and was conducted down the carotids. Fundi and the central nervous system were normal. Cardiovascular and respiratory systems and abdomen were normal. Skiagram of the chest showed a rounded small shadow in the left infraclavicular region, which was thought to be an arrested Koch's lesion. Heart was normal in size. Urinalysis and routine blood investigations were normal, as was a 12-lead electrocardiogram. No acid-fast organisms were grown from the laryngeal swab. Case 2. The eldest child of Case 1 was 20 at the time of emination. His parents thought he had always been of low intelligence. He gave a history of repeated attacks of painful red swelling over both feet since the age of 8. He was a well-developed boy of subnormal intelligence; slight non-pitting oedema was present over the feet; heart, lungs, and abdomen were normal. A loud systolic bruit was heard all over the head and along the carotid vessels. Optic fundi were normal and there was no neurological deficit. Thoracic x-ray examination and electrocardiogram were normal. A right-sided carotid angiogram revealed a large extracranial arteriovenous malformation over the postero-superior parietal region (Fig. 2). The superficial temporal and occipital branches of the external carotid artery were tortuous and dilated and fed the malformation. No dye was seen in the internal carotid artery or its branches.Case 3. He was 16 years of age and had a history of attacks of fever and redness and swelling over the feet since the age of 8. He was found to have lymphoedema over both feet. The heart was clinically enlarged, with

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“…Primary or idiopathic PAH (IPAH) was noted to occur in a familial form by Melmon and Braunwald [130] and was reported to transmit in families as an autosomal dominant disease before the identification of genetic mutations, suggesting that a heterozygous mutation might be responsible for the disease [116,117]. However, not all individuals at risk develop PAH, due to reduced penetrance of approximately 20-30 % [116,117].…”

Section: Discovery Of Bmpr2 Mutationsmentioning

confidence: 99%

Bone Morphogenetic Protein Signaling in Pulmonary Arterial Hypertension

Yang

2017

Bone Morphogenetic Proteins: Systems Biology Regulators

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A wealth of evidence from human genetics, developmental and cell biology, and translational science has implicated members of the bone morphogenetic protein (BMP) and transforming growth factor-β (TGF-β ) signaling family in the pathogenesis of pulmonary arterial hypertension (PAH). The discovery of loss-offunction germline mutations in BMPR2 and in functionally related BMP/TGF-β signal transduction molecules as causes of heritable PAH and several overlapping congenital vascular syndromes has catalyzed work to elucidate how BMP signals critically regulate vascular development, vascular homeostasis, inflammation, metabolism and pathogenic remodeling. This work in vascular biology and experimental medicine has in turn led to a more nuanced understanding by which the structurally diverse family of BMP ligands and receptors achieve their tissue-specific and context-dependent functions. Recently this work has shed light on promising new strategies by which dysregulated BMP/TGF-β might be modulated for therapeutic benefit in PAH and related conditions. BMP Signaling in the Cardiopulmonary SystemBMP signaling plays a fundamental role in the development and homeostasis of the heart and the systemic and pulmonary circulation. Spatiotemporal specificity of BMP signaling in the cardiopulmonary system is achieved by selective expression

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Familial Pulmonary Hypertension

Cited by 45 publications

References 10 publications

Longitudinal Analysis Casts Doubt on the Presence of Genetic Anticipation in Heritable Pulmonary Arterial Hypertension

Longitudinal Analysis Casts Doubt on the Presence of Genetic Anticipation in Heritable Pulmonary Arterial Hypertension

Primary pulmonary hypertension, cerebrovascular malformation, and lymphoedema feet in a family.

Bone Morphogenetic Protein Signaling in Pulmonary Arterial Hypertension

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