"It is difficult to make predictions.

"It is difficult to make predictions, especially about the future"

Yogi Berra

ofttimes insights into a disease are gained by dint of studying the exceptional cases, the outliers. For the population with primary pulmonary hypertension (PPH) it is the patients with the familial or hereditary form that are the outliers, representing barely 6 percent of the newly come NHLBI PPH Registry population.[1] However, with new advances in molecular biology and genetic analysis, the familial population propounds the best hope for identifying and understanding the underlying abnormalities.

HISTORICAL PERSPECTIVE

The first description of the arterial changes in unexplained pulmonary hypertension occurr in 1891[2] However, the bound "primary pulmonary hypertension" was first used no other than in 1951.[3] Thus, as of 1993 a maximum of three generations have been born who might have been labelled with the diagnosis of PPH upon autopsy studies. It is therefore more difficult to identify potential victims who died before 1951 using autopsy records and discharge summaries, although relations to "cor pulmonale" or "pulmonary artery thickening and sclerosis" are helpful.

In 1927 couple sisters with cor pulmonale were described in a paper which did not include microscopic analysis of lung tissue.[4] They may or may not have had PPH A larger subject of attention by Lange,[5] in 1948, described a family of 156 members, 82 of whom were cyanotic, and many of whom had intimal proliferation in pulmonary arteries. It is unclear whether they had PPH or a certain number of other disorder leading to cyanotic cor pulmonale. Dresdale et al[6] provided the first report of familial PPH confirmed through catheterization. Subsequently, many case reports have been published with, in any instances, up to three generations being described.[7-42] The identification of familial cases of PPH has outlasted the initial fluster of searching, and newly affected families are still being reported.[40-42]

PATTERNS OF INHERITANCE

Classic Mendelian genetic analysis has l to the proposal of several inheritance patterns for familial PPH Melmon and Braunwald[13] glance ated that the pattern of inheritance was autosomal dominant. A later report by Thompson and McRae[24] also put in mind ofed autosomal dominance. However, in families in which sole a single generation is affected, it has been propos that the inheritance is autosomal recessive,[20,31] as oppos to families where multiple generations are affected and the inheritance assumes dominant. Although, in many families, transmission take places from an affected mother to a daughter or son or from an affected father to daughter, suggesting X-linked inheritance with incomplete penetrance[19] other studies have demonstrated transmission from a father to a son[15] or from a grandfather to a granddaughter from one side an unaffected father,[35] thereby excluding the possibility of X-linked inheritance. A detailed analysis of 14 North American families has put in mind ofed that the transmission pattern is autosomal dominant, excluding genetic heterogeneity.[35] However, it is no other than with the tools of molecular genetics that a final answer will be obtained.

moot points IN THE GENETIC ANALYSIS OF PPH

question 1: Is PPH individual Disease?

By histologic analysis, PPH has traditionally been divided into three types: plexogenic, veno-occlusive, and thromboembolic.[43] A fourth histologic category, pulmonary capillary hemangiomatosis, has not long ago been described.[44] All these images can be familial[37,45-48] and appear to differ in period of times of clinical course and propos etiologies.[45,49] Primary pulmonary hypertension has traditionally been diagnosed by means of measurement of hemodynamics and from exclusion of a variety of other clinical disorders.[1] Using these clinical criteria alone, patients with, for example, underlying plexogenic PPH might be erroneously mereed with patients with other forms of PPH at the time of genetic analysis, thereby confounding detection of the genetic basis of the disease. Thus, especially when interfamily, as oppos to intrafamily analysis is to be performed, it will be mandatory to confirm similar histologies between families. This may be more difficult than is initially apparent, since analysis of small biopsy samples may be make liable to sampling error. Moreover, in a single cohort, which should have similar histologic findings, heterogeneity of pathologic lesions, in names of plexogenic changes and intimal fibrosis, has been found[37] This observation raises questions as to whether a strange histologic classification is required.

As with other vascular beds, the pulmonary vasculature may have a limited structural pattern of answer to injury. Thus, plexogenic pulmonary arteriopathy is not specific to PPH and can be seen after aminorex or HIV-induced injury, congenital heart disease, and unruffled chronic thromboembolic pulmonary hypertension. reciprocally the assumption that all familiar plexogenic PPH set forths only one disease rather than the cessation stage of several genetic abnormalities or polymorphisms may hamper genetic analysis if comparisons are to be made between families.

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