Familial MPD

Familial MPD

MPD is an uncommon hematologic malignancy, with an annual incidence of 0.5 to 1 per 1,000.000 for each of the syndromes. Numerous reports of familial polycythemia have appeared, but most cases do not fulfill the diagnostic criteria for primary PV and are better classified as secondary polycythemia. Documented cases of familial MPD's other than PV are rare and insufficient to implicate a common genetic defect or basis of inheritance. However, some compelling evidence of familial occurrence of PV was provided by a systematic study of patients enrolled in the Polycythemia Vera Study Group (PVSG) in which an increased prevalence of PV in parents of these patients was demonstrated. In a subsequent report, PV in four members of one family was described³ and the literature was reviewed. Thirteen kindreds with familial PV in 31 members were felt to have adequate documentation. In view of these findings, it appears that familial PV is not a rare occurrence.

Reports and reviews of familial involvement with other phenotypes of MPD are sparse.^4-6 They include rare instance of familial ET, myelofibrosis, and osteosclerosis. The paucity of cases may be due to the lack of a collective patient population, such as that made available by the PVSG. Appreciation of a familial occurrence of MPD is facilitated by prolonged contact with a sufficiently large patient population in whom family history data are obtained initially and monitored prospectively. During such an experience, I have encountered 12 kindreds in whom 2 or more members developed MPD. One striking feature of this series is the phenotypic variation of the MPD that occurred in some of the kindreds. This experience is presented and compared with the existing body of literature on familial MPD in which phenotypic homogeneity of the MPD has been observed.

Twelve kindreds with 26 patients exhibiting an MPD have been observed by me. The diagnosis was confirmed personally in the 12 index cases from each family and in 1 additional involved family member of 5 families, all of whom were under my care. The presence of MPD in the remaining 9 family members was documented by records obtained from attending physicians and/or hospitals. Instances in which other family members were alleged to have MPD but for which documentation was lacking were not included. The classification of the MPD phenotype was based published criteria.¹

Table 17-1 summarizes the findings in 12 families with familial MPD involving 26 patients. Ten families with familial MPD had 2 involved members, and 2 families had 3 involved members. In 4 of the families, MPD developed in a family member subsequent to its diagnosis in the propisitus and was reported to me after the initial family history of the propisitus was obtained. The MPD involved siblings in 7 families and parent-child combinations in 7 families.

There were 8 families in this series in which 1 or more family members had PV. Eight of the 12 patients with PV (67 percent) in 7 families developed MM, and this transformed to acute leukemia in 2 patients (16 percent). In the eight family, the patient with PV did not develop MM or leukemia, but the other involved family member had MM. The high incidence of MM and leukemic transformation in the patients with PV in the present series is further confirmation that the diagnosis of familial PV was correct and that the series does not include families with secondary polycythemia. There was no known exposure to toxic agents that have been implicated in the etiology of MPD⁷ and have been suggested as the etiology of "familial PV" reported in 2 families.⁸

The phenotype of the MPD was the same in 5 families: 3 with PV, 1 with ET, and 1 with agnogenic MM. In 7 families, the MPD phenotype of the involved family members differed. Combinations of PV and MM occurred in 4 families, ET and MM in 2 families, ET and MM in 2 families, and ET and PV in 1 family. In the family of case 2, family members with PV were reported in the two generations. In addition to PV in her father, there were 3 additional members with PV in the two generations preceding her father's. Two great aunts died in their eighth decade with PV documented by hospital records, and a great grandfather is reputed to have had PV. Since the details of these cases are not available, they have not been tabulated but are listed under Comments. Also noted under Comments is the occurrence of de novo acute leukemia in family members of 3 other kindreds with MPD.

The presentation of mixed phenotypes of MPD in families has not been reported previously. The PVSG searched the records of 652 cases for a family history of polycythemia but made no mention of other forms of MPD in family members.² In all the case reports of familial PV or familial MPD, only one MPD phenotype was observed at presentation, although transformation to another MPD phenotype was or acute nonlymphocytic leukemia occurred during the course of some patients.

There is not clear mode of inheritance in the kindreds reported here. There was no history of consanguinity in the involved families. The previous analysis of 13 kindreds with familial PV in 31 members³ supported a genetic predisposition for PV but failed to reveal a clear-cut mode of inheritance. The studies of a kindred with familial MPD involving the megakaryocytic cell line and presenting as thrombocytosis⁴ suggested an autosomal dominant transmission with variable penetrance based on its presence in more than one generation and in both sexes. A similar mode of inheritance was reported in another family with ET in 5 members of both sexes from 2 to 62 years of age in three successive generations.⁵ In the 2 kindreds in my series in which 3 family members were affected, MPD occurred in a father and 2 children, one male and one female. None of the 7 pairs of involved siblings were twins. Five pairs were of different genders, one pair was female, and one was male.

The occurrence of mixed phenotypes in familial MPD is entirely consistent with the accepted theory of MPD as a disease of the pluripotential hematopoietic precursor cell that manifests phenotypic heterogeneity of the expanded clone. Transformations from one phenotypic variant to another during the course of MPD are common, and it would be surprising if only a single MPD variant were to appear in all involved members of a family with MPD. The absence of reports of mixed phenotypes from the literature is striking but unexplained. Clearly if I was able to observe a dozen families with familial MPD, 7 of which exhibited mixed phenotypes, this cannot be a rare occurrence. One deterrent to detection of such cases may be the patient's lack of understanding of the nature of MPD and the diagnostic terminology. Unless the patient is introduced to the concept of MPDs as a group of syndromes, the occurrence of a different but related syndrome in a relative might go unreported. Familiarization of the patient with the terminology of MPD has elicited a family history in more than one case in my series. Another deterrent to the detection of MPD kindreds is dismissal by the physician of a possible familial occurrence and failure to explore the family history with this in mind because of its perceived rarity.

Although almost every type of cancer has been reported to occur in a familial form, evidence of hereditary and familial influence exists in only a few percent of cases.⁹ An awareness of the importance of molecular genetic events in the development of familial cancer has evolved through the evaluation of clinical observations, genetic epidemiology, and molecular biology of the rare but important family cancer syndrome, the Li-Fraumeni syndrome (LFS). Alterations of the p53 tumor suppressor gene are the most frequently encountered genetic events in human malignancy.¹⁰ Analysis of the DNA of 5 LFS families identified base-pair mutations of the gene encoding p53 in the germ line of all affected members.¹¹ The demonstration has resulted in analysis of large populations of patients for constitutional abnormalities of the p53 gene and the finding that certain high-risk patients and their families carry germ line p53 mutations that presumably predispose them in some manner to the development of their respective malignancies.

Chromosomal abnormalities involving the pluripotential hematopoietic stem cell are present with regularity in chronic myelocytic leukemia and with some frequency in non-CML MPD. These are the result of somatic mutations arising in the hematopoietic precursor cell. The familial occurrence of MPD cannot be explained by mutations that arise spontaneously in somatic tissues over the organism's life span. Familial incidence would require the presence of a germ line mutation that is vertically transmitted and predisposes family members to the development of MPD. As molecular biologic techniques become more sophisticated and more genes involved in cancer promotion are identified, cases of familial MPD will become increasingly important as subjects for studies of somatic and germ-line DNA. An awareness of the familial occurrence of MPD will lead to identification of "MPD families" that will be added to existing cases and lead to better characterization of the generic aspects of the syndromes that comprise MPD.

FAMILY	AGE DX Yrs/SEX	MPD	TYPE OF TREATMENT	SURVIVAL FROM DX	OUTCOME	COMMENTS
Case 1 Brother	45/M 60/M	PV PV	Phleb, cyclosphosphamide Phleb	19 yrs --	Died, MM, acute Not known
Case 2 Father	37/F 52/M	PV PV	Phleb, interferon Phleb, 32 P, splenectomy	>15 8	Still active PV w. MM Died, MM of liver, hepatitis	PV in 2 great aunts & great grandfather
Case 3 Daughter	60/F 39/F	PV PV	Phleb, interferon Phleb	8 >10	Died, MM, acute leukemia Still active PV
Case 4 Father	50/M 67/M	PV MM,MF	Phleb, aspirin None	>0.5 3	Still active PV Died, diabetic complications
Case 5 Father	54/M 72/M	PV MM,MF	Phleb, aspirin None	>5 12	Transformed to MM, MF Died, congestive heart failure
Case 6 Brother Father	46/F 53/M 60/M	PV MM,MF PV	Phleb,hdroxyurea,interferon Splenectomy Phleb	>18 6 13	Still active PV with MM Died, acute leukemia Died, suicide
Case 7 Brother	66/F 65/M	ET ET	Aspirin Aspirin	>3 >1.5	Still active ET Still active ET
Case 8 Mother	63/F 35/F	ET PV	Anagrelide Phleb, hydroxyurea	>8 25	Still active ET Died, MM
Case 9 Brother Father	39/F 44/M 49/M	ET MM,MF MM,MF	Aspirin Hydroxurea Splenectomy	>2.5 3 3	Still active ET Died, acute leukemia Died, MM of liver	Acute leukemia 2 paternal Aunts and 2 cousins
Case 10 Sister	55/M 47/F	MM,MF PV	Interferon Phleb	>3 11	Still alive Died, MM, Acute leukemia	Son, acute leu- kemia, age 15
Case 11 Sister	53F/F 58/F	MM MM	Interferon Interferon	>3 1	Still Active Died, sepsis
Case 12 Sister	73/M 75/F	MM ET	Hydroxurea, procrit Hydroxurea	>2 >5	Still Active Still Active ET	Sister, acute leukemia, age 61

*MPD abbreviations: PV - polycythemia vera; ET - essential thrombocythemia; MM - myeloid metaplasia;

MF - myelofibrosis.

† Treatment abbreviations: Phleb - phlebotomy.

REFERENCES

1. Gilbert HS: Diagnosis and treatment of polycythemia vera, agnogenic myeloid metaplasia, and essential thrombocythemia. In Wuernik PH, Canellos GP, Kyle RA, Schiffer CA (eds): Neoplastic Diseases of the Blood. New York, Churchill Livingstone, 1991, pp 123-136
2. Brubaker LH, Wasserman LR, Goldberg JD, et al: Increased prevalence of polycythemia vera in parents of patients on Polycythemia Vera Study Group protocols. Am J Hematol 16:367-373, 1984
3. Miller RL, Purvis JD III, Weick JK: Familial polycythemia vera. Cleve Clin J Med 56(8):813-818, 1989
4. Slee PH, van Everdingen JJ, Geraedts JP, et al: Familial myeloproliferative disease: Hematological and cytogenic studies. Acta Med Scand 210(4):321-327, 1981
5. Eyster ME, Saletan SL, Rabellino EM, et al: Familial essential thrombocythemia. Am J Med 80(3):497-502, 1986
6. Randi ML, Fabris F, Visentin I, Girolami A: Low incidence of familial occurrence of thrombocythemia and/or thrombocytosis. Folia Haematol (Leipz) 115(5): 695-699, 1988
7. Modan B: Polycythemia: A review of epidemiological and clinical aspects. J. Chronic Dis 18:605-645 1965
8. Ratnoff WD, GressRE: The familial occurrence of polycythemia vera: Report of a father and son, with consideration of the possible etiologic role of exposure to organic solvents, including tetrachloroethylene. Blood56(2):233-236, 1980
9. Li FP: Genetic and familial cancer: Opportunities for prevention and early detection. Cancer Detect Prev 9:41, 1986
10. Levin AJ, Momand J. Finlay CA: The p53 tumor suppressor gene. Nature 351:453, 1991
11. MalkinD, Li FP, Strong LC, et al: Germ-linep53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250:1233, 1990