The functional loss of three of the four normally occurring alpha-globin genes [alphaalpha/alphaalpha to - -/-alpha or - -/alpha(T)alpha or - -/alphaalpha(T)] leads to a condition known as Hb H disease in which excess beta chains combine to form the unstable Hb H or beta4. Its fetal counterpart is Hb Bart's or gamma4 which is seen mainly in newborn babies with this disease; Hb Bart's is considerably more stable than Hb H but both Hb types have an extremely high affinity for oxygen and no Bohr effect, and are, therefore, useless for the transport of oxygen.
Higgs in his recent review (1) reports on the occurrence of the disorder quoting data from WHO reports. It appears that the number of subjects with Hb H disease in Southeast Asia alone approaches 700,000, with some 15,000 newborns with this disorder added each year. Other areas with a relatively high frequency are the Mediterranean countries.
The clinical spectrum varies from a benign disorder to a severe anemia which can be blood transfusion dependent. This heterogeneity at the clinical level can be explained by differences in the molecular defects that have been observed. Four different subclasses can be recognized:
Differences between males and females at the pediatric ages are small (Table XXIII), but somewhat more severe anemia is present in the girls. Phenotypical differences between adults and pediatric patients are most marked for the patients with the alpha(PA-1), as can be seen from the data given in the pedigree of Fig. 26.
FIG. 26. Pedigree of a family with several members with Hb H disease. The presence of Hb H was detected by electrophoresis and was confirmed by chromatography (from Ref. 8).
The clinical aspects of Hb H disease have been studied in great detail by Galanello et al (10) who compared data for 130 patients with Hb H of the deletional type [128 with - -/-alpha(3.7) and two with - -/-alpha(4.2)] with similar information for 22 Hb H patients with an alpha-thal-1 combined with nondeletional alpha-thal-2 [- -/alpha(T)alpha]. Of these, 66 were children and 86 adults. The clinical phenotypes were vastly different and are summarized in Fig. 27. Patients with the - -/alpha(T)alpha genotype have, more frequently, enlargements of the liver and spleen, jaundice, bone changes, hemolytic crises, and a greater transfusion requirement. The data show that children are often more severely affected than adult patients. Also interesting is the information that of the 58 pregnancies (in 24 women) seven ended in premature interruption, two in premature delivery, while often the anemia of the mother worsened considerably requiring blood transfusions.
FIG. 27. Clinical findings in Hb H disease patients according to the genotypes (modified from Ref. 10). A) Children. B) Adults.
|1.||Higgs, D.R.: in The Haemoglobinopathies, edited by D.R. Higgs and D.J. Weatherall, Bailliere's Clinical Haematology, Vol. 6, page 117, W.B. Saunders Company, London, 1993.|
|2.||Fei, Y-J., Öner, R., Bozkurt, G., Gu, L-H., Altay, Ç., Gürgey, A., Fattoum, S., Baysal, E., and Huisman, T.H.J.: Acta Haematol., 88:82, 1992.|
|3.||Liang, R., Liang, S., Jiang, N.H., Wen, X-J., Zhao, J-B., Nechtman, J.F., Stoming, T.A., and Huisman, T.H.J.: Br. J. Haematol., 86:351, 1994.|
|4.||Öner, C., Gürgey, A., Öner, R., Balkan, H., Gümrük, F., Baysal, E., and Altay, Ç.: Hemoglobin, 21:41, 1997.|
|5.||George, E., Li, H-J., Fei, Y-J., Reese, A.L., Baysal, E., Cepreganova, B., Wilson, J.B., Gu, L-H., Nechtman, J.F., Stoming, T.A., Liu, J-C., Codrington, J.F., and Huisman, T.H.J.: Hemoglobin, 16:51, 1992.|
|6.||Fei, Y-J., Liu, J-C., Jogessar, V.B., Westermeyer, K.R., Bridgemohan, R., and Huisman, T.H.J.: Acta Haematol., 87:11, 1992.|
|7.||Baysal, E., Kleanthous, M., Bozkurt, G., Kyrri, A., Kalogirou, E., Angastiniotis, M., Ioannou, P., and Huisman, T.H.J.: Br. J. Haematol., 89:496, 1995.|
|8.||Adekile, A.D., Gu, L-H., Baysal, E., Haider, M.Z., Al-Fuzae, L., Aboobacker, K.C., Al-Rashied, A., and Huisman, T.H.J.: Acta Haematol., 92:176, 1994.|
|9.||Çürük, M.A., Dimovski, A.J., Baysal, E., Gu, L-H., Kutlar, F., Molchanova, T.P., Webber, B.B., Altay, Ç., Gürgey, A., and Huisman, T.H.J.: Am. J. Hematol., 44:270, 1993.|
|10.||Galanello, R., Aru, B., Dessì, C., Addis, M., Paglietti, E., Melis, M.A., Cocco, S., Massa, P., Giagu, N., Barella, S., Turco, M.P., Maccioni, L., and Cao, A.: Acta Haematol., 88:1, 1992.|
|11.||Wasi, P.: Clin. Haematol., 10:707, 1981.|
|12.||Fucharoen, S. and Winichagoon, P.: Hemoglobin, in press, 1997.|
This new syndrome was first described some 15 years ago (1), while extensive clinical features and the first molecular analyses were detailed in 1990 (2,3). Presently, several families have been discovered where in members the hematological abnormality occurs together with severe mental handicap. Two specific conditions have been recognized:
A detailed description of these disorders is beyond the scope of this syllabus. The interested reader is invited to consult the quoted references.
|1.||Anneren, G. and Gustavson, K-H.: Acta Paediatr. Scand., 73:281, 1984.|
|2.||Wilkie, A.O.M., Buckle, V.J., Harris, P.C., Lamb, J., Barton, N.J., Reeders, S.T., Lindenbaum, R.H., Nicholls, R.D., Barrow, M., Bethlenfalvay, N.C., Hutz, M.H., Tolmie, J.L., Weatherall, D.J., and Higgs, D.R.: Am. J. Hum. Genet., 46:1116, 1990.|
|3.||Wilkie, A.O.M., Zeitlin, H.C., Lindenbaum, R.H., Buckle, V.J., Fischel-Ghodsian, N., Chui, D.H.K., Gardner-Medwin, D, MacGillivray, M.H., Weatherall, D.J., and Higgs, D.R.: Am. J. Hum. Genet., 46: 1127, 1990.|
|4.||Gibbons, R.J., Picketts, D.J., and Higgs, D.R.: Hum. Mol. Genet., 4:1705, 1995.|
|5.||Villard, L., Toutain, A., Lossi, A-M., Gecz, J., Houdayer, C., Moraine, C., and Fontès, M.: Am. J. Hum. Genet., 58:499, 1996.|
|6.||Gibbons, R.J. and Higgs, D.R.: Medicine, 75:45, 1996.|