EDITORIAL Unstable Chromosomes in Heritable Tumor Syndromes Multiple Endocrine Neoplasia Type 1 (MEN1)
Life seems simple and straightforward. Penetrate the surface and life does not seem so simple or straightforward. The original syndromes with cl~romosonle instability shared three features. They were autosonml recessive disorders. They predisposed to malignan(:y. And the main malignancies were hematological. The classic prototype disorders were Bloom syndrome [11, Fan(:oni anemia 12l, and ataxia telangiectasia [31. Chromosome instability was discovered first in Bloom syndrome, next in Fanconi anemia, and then in ataxia-telangiectasia [4]. Bloom syndrome is a rare autosomal recessive trait 151. It predisposes to malignancy [61. The main malignancies are acute leukemias, nonlymphoc;'tic in type. Fanconi anemia is also a rare autosomal recessive trait 171. It. too, predisposes to malignancy [81, The main malignancies are acute leukemias, especially mvelomonocvtic:. Ataxia-telangiectasia is a rare autosomal recessive trait [91.1[ predisposes to malignam:v. The nlai[l malignancies are lymphomas I11)] and lymphocytic leukemias [31. The addition of xeroderma pigmentosunl to the group increased tile complexity of tile chromosome instability syndromes. A rare autosomal recessive trait [111, it predisposes to malignancies of the skin. This is consistent with the discovery of a defect in DNA repair after ultraviolet irradiation [121. Had research halted then, life as regards chromosome instability syndromes would have still remained straightforward and simple. The genes responsible for these diseases had to be located and their mode of action explored, but the general layout was believed to be comph~,te. Now the blueprint is no longer adequate, simple, or straightforward. Consi(ter, for example, the situation with nmltiple endo(:rine neoplasia (MEN) an(t spe(:ifi(:ally with type 1 (MEN1), MEN1 is reported in this issue t)3' Scappaticci and her (:olleagues of Pavia, Italy, to show consistent cl~romosome instability [131. These investigators studied lymphocytes and fibroblasts in skin cultures from three unrelated patie, nts. Not only did the team from Pavia find increased chromosome breakage in both cell types, but they also observed a spectacular sequence of chrornosome rearrangements and clones of trisomic cells sprouting in tile cultures. Tile rearrangements were most evident in short-term lymphocyte cultures. The clones of trisomic cells were observed in cultures of skin fibroblasts at the first transfer. Doubt dwells eternal within good scientists. "Show me." says the good scientist, not an unreasonable request, particularly in cytogenetics, a very visual area of study. Figures 1 and 2 provided by tile team from Pavia 1131 show us tricentri(: (:hromosomes, di(:entric and ring chromosomes, double minutes, single minutes, and acentri(: fragments in MEN1 cells. You need not be a cytogeneticist to recognize that these are the products of chromosome hreakage and rearrangement. Science is similar to the field of law in that precedent is prized. Precedents are at hand here. One precedent dates hack to 1983 when (;ustavsen et al. 1141 first foun(t
131 19!11 E l s e v i e r Sc:imu:e I h l b l i s h i l l g Co., In(:. (i,cl5 A\:q~lltl~! ii1 lilt! :\l/iq![il ~lS. Nt?t\' Yi)rk, N Y HIll I I)
(~l[/(:el" (;l!llet (]ylogl!l]t!i 5 2 : 1 3 1 01 li5-.tfii)ll !l 1/,.%O3.50
13-1 ( l ! ) ! ) l )
132
1". ttecht and B. K. th~'t:ht
Table 1
Main tumor targets ill MEN1 with approximate frequency of involvement
Kndo~:rine gland
(]ast~s (%)
Parathyroid Endo~:rine p a n c r e a s
90 80
Pituitary Adrenal cortt!x Thyroid (~qfithelial ~:~111
~5 35
"0
chromosome breakage in MEN1. In 1988 Benson et al. ]15} reported increased chronmsome breakage in lympbo(:ytes fronl several individuals from MEN1 families as compared with those from controls. MEN1 is a bizarre and confusing disease. The, confusion extends to its names, for it has also gone by eponyms such as Wermer syndrome 1161 and by unlovely long names such as multiple endocrine adenomatosis [171. The typical tumors are ademmlas 1181. They are not malignant but benign, out of the cancerous context typical for a chromosome instability syndrome. The adenomas in MEN1 are not confined to one location. They can occur in the he,ad, neck, chest. abdomen, and elsewhere. They tend most often to occur in the parathyroid, pancreas, and pituitary and, less frequently, in the adrenal and thyroid (Table 1 }. Table 1 needs comments. A crucial point in that the thyroid tumor in MEN1 is never a medullary carcinoma. It is of epithelial cell origin and. although ()f variabh; histology, is invariably benign. Table 1. furthermore, shows only the sites involving major endocrine targets in MEN1. There are also carcinoid tumors in diverse locations, including the thymus, bronchus, pancreas, and intestine and they, like other tumors in MEN1, can elaborate ectopic hormones. Furthermore, there may be epithelial tbymomas, benign tumors of epithelial derivation in the thymus; lit)omas, single or multiple benign tumors of fat cells: and sclm'annomas, benign tumors of Schwann cells [named for the German scientist, Theodor Schwann (1844 1511711 of tim myelin sheath of llel.lrOllS.
The potential confusion increases if we consider two more disorders currently clumped u n d e r the rubric of MEN: MEN2A and MEN2B. MEN2A overlaps MEN1 in phenotype but has two distinguishing features: medullary carcinoma of the thyroid, which is not a part of MEN1, and I~heochromocytoma [19[. MEN2B might better be called the mucosal neuroma syndrome since mucosal neuromas are its halhnark [2(11. The physical pbenotype in MEN2B is also a distinguishing component: the patients look as thotlgh they have Marfan syndrome and also have soft blubbery lips and a soft jutting jaw [21]. MEN1 shatters the prototype of the classic chromosome instability syndrome in another respet:t: It is autosomal. The gene locus [22, 231 is on chromosome 11, specifically in band 1 1(t 13. However, it is not a recessive disorder. MEN1 is a d o m i n a n t trait with a high degree of penetrance 118]. The chromosomes are clearly unstable in MEN1 113 151. MEN1 breaks chromoseines, and it breaks the moht of the classic chromosolne instability syndromes. It is not alone in being iconoclastic. Other genetic disorders are coming under study that are equally revolutionary with regard to chromosome instability. Seine, like MENI, are autosomal d o m i n a n t diseases. An X-linked trait would not be much of a surprise among the chromosome i n s t a b i l i t y states. C h r o m o s o m e i n s t a b i l i t y s y n d r o m e s can lead to benign neoplasms. M E N 1 is a case
in point, indeed, we will probably learn that disorders believed not to be neoplastic are
Ih~stable C h r o m o s o m e s in H e r i t a b l e T u m o r S y n d r o m e s : MEN 1
neoplastic
1 3~
t h a n k s to c h r o m o s o m e i n s t a b i l i t y p e r m i t t i n g and p r o m o t i n g the (:lonal
growth of selected cells. T h e first c h r o m o s o m e i n s t a b i l i t y s y n d r o m e s ( a t a x i a - t e l a n g i e c t a s i a . Bh)om synd r o m e , and Fam:(mi allell/ia I at)l)eare(t s i m i l a r . T h e y all s h o w e d sp(mhu]e, ous (:hromos o m e i n s t a b i l i t y on the c y t o l o g i c level. All the s y n d r o m e s we, re i n h e r i t e d as rare autos()mal r e c e s s i v e (:onditions. A n d all ot the s w u h ' o m e s p r e d i s p o s e d t() h e m a h d o g i ( : lnalignan(:ies. S i n c e that t i m e , e v i ( t e n c e in(li(:ates a (lili:erenl I)i(:lure.
ESSENTIAL PROPERTIES OF CHROMOSOME INSTABILITY SYNDROMES T h e (:}u'tmmsome i n s t a b i l i t y s \ ' n d r o m e s are wlriable but they t)ussess (:e,rtain e s s e n t i a l properties. 1) Chrom()som(~ lnst(H~ilitv: lh~stal)le (:hrom(>somes m u s t be e v i d e n l si)(mlalw(msly or by indu(:ti()n on the (:yt(dogic or m o l e c u l a r lexel. 2) (;eneti(:s: T h e s y n d r o m e s are inherite(I but the t)altern can I)e a u t o s o m a l , (h)minaiH, or r e c e s s i v e , probalfly X - l i n k e d a n d p o s s i b l y p o l y g e n i c . 3) l:requencv: T h e s w ] ( h ' o m e s ( a n rmige in f r e q u e n c y frnIII rare t() (:()lllnl()ll. 4) Neophzsia: T h e (:]]romosome i n s t a b i l i t y s v m h ' o m e s pre(lispose to neol)lasia, but not a l w a y s t¢)malignan(:y. 5) Types of Ncoph~sms: The lleul)lasms are varied in t~,pe and target tissue.
FREDERICK HECHT BARBARA K. HECHT
Molecular Medicine and Genetics Children's Mercy Hospital Kansas City, Missouri
REFERENCES 1. German J, Archibald R, Bloom I) (1965/: (]hromosomal breakage in a rare and probably gKIreti(:aHy deterinined syndrome of man. Sciem:e 148: 506-507. 2. Bloom GE, Warner S, Gerald PS, Diamond LK (1966): (Swomosome abnormalities in constitu tional aplastic anemia. N Engl I Med 274:8-14. 3. Hecht F, Kole,r RD, Rigas DA, Dahnke GS, (]aSK MP, Tisdale V, Miller RW {1966]: l,eukemia and lylnphocytes in ataxia-telangiectasia. Lance,t 2:1193. 4. Hecht F. Kaiser McCaw B (1977}: (]hromosome instability syndromes. In: Genetics of Human Cam:er. II Mulvihill. RW MillKr, IF' Fraumeni Ir, eds. Raven Press, New York, pll. 105-123. 5. (;(H'lllall l, An:hibaht R, Bloom I) (19(15): (]hrolll(IStllll(! hr(!aka~4l~ ill a rill'l! dllll prol)ald\ gelwlit:ally d e t e r m i n e d SVll(h'olllC, of lllall. ~ciell(:c [4}1:5()(i 507.
6. Sawitsky A, Bloom D. German I {1966): (]hromosolnal breakage and actlle h!ukelnia in congenital telangiectatic ervlhel]la alia Munted growth. Ann Intern Med 65:487 495. 7, Fam:oni G (1966): Familial (:onstitutional panmyelocytopathy, Falr{ol]i's anemia (FLA.). I. Clinical aspects. Semin Heinato] 4:233 240, 8. Garriga S,(]rosby WH (1959): The incidence of leukemia in familiKs of patients with hypoplasia of tim inarrow. Bh)od 14:1008-1014. 9. Tadjoedin MK, Fraser FC (1965): Heredity of ataxia telangiectasia (Louis-Bar s~ndi'ome]. At]] ] Dis (]hild 110:64-68, 10. Peterson RI)A, Kcqly WD, Good RA (1964): Ataxia-lelangiectasia: its association with a defe(:tive thymus, iInmunological-defi(:iency disease and lllalignancv, l,almel 1:1189 1193.
1 1. Macklin MT (19441: Xeroderma pigmKntosum: Report of a (:aSKand consideration of in(:oinplete sex linkage iir inheritance of the disKase. Ar(:h I)KrmatoI Syph 49:157-171. 12. Cleaver JE (1968): DKfective rel)air replication of DNA in xeroderma pigl'nentosun]. Naturl! 218:652 656. 13. Scappaticci S, Maraschio P, del (]lotto N, Fossati GS. Zonta A, Fraccaro M (1990): (]hromosome abm)rmaIitics in lyinpho(:ytes ~.tll(t fibroblasts o[ subjKcts with llltlltipIe Klldot:rillt! lmtqflasia t}.'pe I. (2ant:er (;crier (]ylogenel 5Z:fi5 92.
134
V. t le(:hl a n d B. K. t l e c h l
14. G u s t a v s o n KH, Jansson R. ()berg K (1,q83): (]hi'omosomal breakage in m u l t i p l e en(lo(:rint~ a(lenonlatosis (tyl:)es I and 11). (]Iin (;e, net 23:143 I49. 1~. [~t~I]SOl] I. (',I.IStaVSOI] K-H, Rastad ], A k e r s t r o m (;, ()[)(!I'g K, l~junghall S { 1 .'.),~al): (]},togenetic:al inxt;stigations in t)atients with primary hyt)erl)aralhyroi(lism and mullit)le t,Mo(:rim~ nr, oI)]asia t?,'l)e 1, H e r e d i t a s 1()~:227 22!). l(k W e r m e r P {19541: (.]eneih: aspec:ts of a d ( m o m a t o s i s ()f (,Moc:rine ~lands. A m I Nled 16:3t$3-371. 17. Lamers (H3HW. Fr(.',lit~ P(L\M (197,q): (Hinital si~iHN(:an(:l~ ()t h?,'perparaHlyroidisin in familial m u l t i p l e e i M o ( : r i n e a d e i l o m a t o s i s . Am ] Med 6~i:422 424. lg. S(:himke RN (197,q): (;(ultHi~:s
Life seems simple and straightforward. Penetrate the surface and life does not seem so simple or straightforward. The original syndromes with cl~romosonle instability shared three features. They were autosonml recessive disorders. They predisposed to malignan(:y. And the main malignancies were hematological. The classic prototype disorders were Bloom syndrome [11, Fan(:oni anemia 12l, and ataxia telangiectasia [31. Chromosome instability was discovered first in Bloom syndrome, next in Fanconi anemia, and then in ataxia-telangiectasia [4]. Bloom syndrome is a rare autosomal recessive trait 151. It predisposes to malignancy [61. The main malignancies are acute leukemias, nonlymphoc;'tic in type. Fanconi anemia is also a rare autosomal recessive trait 171. It. too, predisposes to malignancy [81, The main malignancies are acute leukemias, especially mvelomonocvtic:. Ataxia-telangiectasia is a rare autosomal recessive trait [91.1[ predisposes to malignam:v. The nlai[l malignancies are lymphomas I11)] and lymphocytic leukemias [31. The addition of xeroderma pigmentosunl to the group increased tile complexity of tile chromosome instability syndromes. A rare autosomal recessive trait [111, it predisposes to malignancies of the skin. This is consistent with the discovery of a defect in DNA repair after ultraviolet irradiation [121. Had research halted then, life as regards chromosome instability syndromes would have still remained straightforward and simple. The genes responsible for these diseases had to be located and their mode of action explored, but the general layout was believed to be comph~,te. Now the blueprint is no longer adequate, simple, or straightforward. Consi(ter, for example, the situation with nmltiple endo(:rine neoplasia (MEN) an(t spe(:ifi(:ally with type 1 (MEN1), MEN1 is reported in this issue t)3' Scappaticci and her (:olleagues of Pavia, Italy, to show consistent cl~romosome instability [131. These investigators studied lymphocytes and fibroblasts in skin cultures from three unrelated patie, nts. Not only did the team from Pavia find increased chromosome breakage in both cell types, but they also observed a spectacular sequence of chrornosome rearrangements and clones of trisomic cells sprouting in tile cultures. Tile rearrangements were most evident in short-term lymphocyte cultures. The clones of trisomic cells were observed in cultures of skin fibroblasts at the first transfer. Doubt dwells eternal within good scientists. "Show me." says the good scientist, not an unreasonable request, particularly in cytogenetics, a very visual area of study. Figures 1 and 2 provided by tile team from Pavia 1131 show us tricentri(: (:hromosomes, di(:entric and ring chromosomes, double minutes, single minutes, and acentri(: fragments in MEN1 cells. You need not be a cytogeneticist to recognize that these are the products of chromosome hreakage and rearrangement. Science is similar to the field of law in that precedent is prized. Precedents are at hand here. One precedent dates hack to 1983 when (;ustavsen et al. 1141 first foun(t
131 19!11 E l s e v i e r Sc:imu:e I h l b l i s h i l l g Co., In(:. (i,cl5 A\:q~lltl~! ii1 lilt! :\l/iq![il ~lS. Nt?t\' Yi)rk, N Y HIll I I)
(~l[/(:el" (;l!llet (]ylogl!l]t!i 5 2 : 1 3 1 01 li5-.tfii)ll !l 1/,.%O3.50
13-1 ( l ! ) ! ) l )
132
1". ttecht and B. K. th~'t:ht
Table 1
Main tumor targets ill MEN1 with approximate frequency of involvement
Kndo~:rine gland
(]ast~s (%)
Parathyroid Endo~:rine p a n c r e a s
90 80
Pituitary Adrenal cortt!x Thyroid (~qfithelial ~:~111
~5 35
"0
chromosome breakage in MEN1. In 1988 Benson et al. ]15} reported increased chronmsome breakage in lympbo(:ytes fronl several individuals from MEN1 families as compared with those from controls. MEN1 is a bizarre and confusing disease. The, confusion extends to its names, for it has also gone by eponyms such as Wermer syndrome 1161 and by unlovely long names such as multiple endocrine adenomatosis [171. The typical tumors are ademmlas 1181. They are not malignant but benign, out of the cancerous context typical for a chromosome instability syndrome. The adenomas in MEN1 are not confined to one location. They can occur in the he,ad, neck, chest. abdomen, and elsewhere. They tend most often to occur in the parathyroid, pancreas, and pituitary and, less frequently, in the adrenal and thyroid (Table 1 }. Table 1 needs comments. A crucial point in that the thyroid tumor in MEN1 is never a medullary carcinoma. It is of epithelial cell origin and. although ()f variabh; histology, is invariably benign. Table 1. furthermore, shows only the sites involving major endocrine targets in MEN1. There are also carcinoid tumors in diverse locations, including the thymus, bronchus, pancreas, and intestine and they, like other tumors in MEN1, can elaborate ectopic hormones. Furthermore, there may be epithelial tbymomas, benign tumors of epithelial derivation in the thymus; lit)omas, single or multiple benign tumors of fat cells: and sclm'annomas, benign tumors of Schwann cells [named for the German scientist, Theodor Schwann (1844 1511711 of tim myelin sheath of llel.lrOllS.
The potential confusion increases if we consider two more disorders currently clumped u n d e r the rubric of MEN: MEN2A and MEN2B. MEN2A overlaps MEN1 in phenotype but has two distinguishing features: medullary carcinoma of the thyroid, which is not a part of MEN1, and I~heochromocytoma [19[. MEN2B might better be called the mucosal neuroma syndrome since mucosal neuromas are its halhnark [2(11. The physical pbenotype in MEN2B is also a distinguishing component: the patients look as thotlgh they have Marfan syndrome and also have soft blubbery lips and a soft jutting jaw [21]. MEN1 shatters the prototype of the classic chromosome instability syndrome in another respet:t: It is autosomal. The gene locus [22, 231 is on chromosome 11, specifically in band 1 1(t 13. However, it is not a recessive disorder. MEN1 is a d o m i n a n t trait with a high degree of penetrance 118]. The chromosomes are clearly unstable in MEN1 113 151. MEN1 breaks chromoseines, and it breaks the moht of the classic chromosolne instability syndromes. It is not alone in being iconoclastic. Other genetic disorders are coming under study that are equally revolutionary with regard to chromosome instability. Seine, like MENI, are autosomal d o m i n a n t diseases. An X-linked trait would not be much of a surprise among the chromosome i n s t a b i l i t y states. C h r o m o s o m e i n s t a b i l i t y s y n d r o m e s can lead to benign neoplasms. M E N 1 is a case
in point, indeed, we will probably learn that disorders believed not to be neoplastic are
Ih~stable C h r o m o s o m e s in H e r i t a b l e T u m o r S y n d r o m e s : MEN 1
neoplastic
1 3~
t h a n k s to c h r o m o s o m e i n s t a b i l i t y p e r m i t t i n g and p r o m o t i n g the (:lonal
growth of selected cells. T h e first c h r o m o s o m e i n s t a b i l i t y s y n d r o m e s ( a t a x i a - t e l a n g i e c t a s i a . Bh)om synd r o m e , and Fam:(mi allell/ia I at)l)eare(t s i m i l a r . T h e y all s h o w e d sp(mhu]e, ous (:hromos o m e i n s t a b i l i t y on the c y t o l o g i c level. All the s y n d r o m e s we, re i n h e r i t e d as rare autos()mal r e c e s s i v e (:onditions. A n d all ot the s w u h ' o m e s p r e d i s p o s e d t() h e m a h d o g i ( : lnalignan(:ies. S i n c e that t i m e , e v i ( t e n c e in(li(:ates a (lili:erenl I)i(:lure.
ESSENTIAL PROPERTIES OF CHROMOSOME INSTABILITY SYNDROMES T h e (:}u'tmmsome i n s t a b i l i t y s \ ' n d r o m e s are wlriable but they t)ussess (:e,rtain e s s e n t i a l properties. 1) Chrom()som(~ lnst(H~ilitv: lh~stal)le (:hrom(>somes m u s t be e v i d e n l si)(mlalw(msly or by indu(:ti()n on the (:yt(dogic or m o l e c u l a r lexel. 2) (;eneti(:s: T h e s y n d r o m e s are inherite(I but the t)altern can I)e a u t o s o m a l , (h)minaiH, or r e c e s s i v e , probalfly X - l i n k e d a n d p o s s i b l y p o l y g e n i c . 3) l:requencv: T h e s w ] ( h ' o m e s ( a n rmige in f r e q u e n c y frnIII rare t() (:()lllnl()ll. 4) Neophzsia: T h e (:]]romosome i n s t a b i l i t y s v m h ' o m e s pre(lispose to neol)lasia, but not a l w a y s t¢)malignan(:y. 5) Types of Ncoph~sms: The lleul)lasms are varied in t~,pe and target tissue.
FREDERICK HECHT BARBARA K. HECHT
Molecular Medicine and Genetics Children's Mercy Hospital Kansas City, Missouri
REFERENCES 1. German J, Archibald R, Bloom I) (1965/: (]hromosomal breakage in a rare and probably gKIreti(:aHy deterinined syndrome of man. Sciem:e 148: 506-507. 2. Bloom GE, Warner S, Gerald PS, Diamond LK (1966): (Swomosome abnormalities in constitu tional aplastic anemia. N Engl I Med 274:8-14. 3. Hecht F, Kole,r RD, Rigas DA, Dahnke GS, (]aSK MP, Tisdale V, Miller RW {1966]: l,eukemia and lylnphocytes in ataxia-telangiectasia. Lance,t 2:1193. 4. Hecht F. Kaiser McCaw B (1977}: (]hromosome instability syndromes. In: Genetics of Human Cam:er. II Mulvihill. RW MillKr, IF' Fraumeni Ir, eds. Raven Press, New York, pll. 105-123. 5. (;(H'lllall l, An:hibaht R, Bloom I) (19(15): (]hrolll(IStllll(! hr(!aka~4l~ ill a rill'l! dllll prol)ald\ gelwlit:ally d e t e r m i n e d SVll(h'olllC, of lllall. ~ciell(:c [4}1:5()(i 507.
6. Sawitsky A, Bloom D. German I {1966): (]hromosolnal breakage and actlle h!ukelnia in congenital telangiectatic ervlhel]la alia Munted growth. Ann Intern Med 65:487 495. 7, Fam:oni G (1966): Familial (:onstitutional panmyelocytopathy, Falr{ol]i's anemia (FLA.). I. Clinical aspects. Semin Heinato] 4:233 240, 8. Garriga S,(]rosby WH (1959): The incidence of leukemia in familiKs of patients with hypoplasia of tim inarrow. Bh)od 14:1008-1014. 9. Tadjoedin MK, Fraser FC (1965): Heredity of ataxia telangiectasia (Louis-Bar s~ndi'ome]. At]] ] Dis (]hild 110:64-68, 10. Peterson RI)A, Kcqly WD, Good RA (1964): Ataxia-lelangiectasia: its association with a defe(:tive thymus, iInmunological-defi(:iency disease and lllalignancv, l,almel 1:1189 1193.
1 1. Macklin MT (19441: Xeroderma pigmKntosum: Report of a (:aSKand consideration of in(:oinplete sex linkage iir inheritance of the disKase. Ar(:h I)KrmatoI Syph 49:157-171. 12. Cleaver JE (1968): DKfective rel)air replication of DNA in xeroderma pigl'nentosun]. Naturl! 218:652 656. 13. Scappaticci S, Maraschio P, del (]lotto N, Fossati GS. Zonta A, Fraccaro M (1990): (]hromosome abm)rmaIitics in lyinpho(:ytes ~.tll(t fibroblasts o[ subjKcts with llltlltipIe Klldot:rillt! lmtqflasia t}.'pe I. (2ant:er (;crier (]ylogenel 5Z:fi5 92.
134
V. t le(:hl a n d B. K. t l e c h l
14. G u s t a v s o n KH, Jansson R. ()berg K (1,q83): (]hi'omosomal breakage in m u l t i p l e en(lo(:rint~ a(lenonlatosis (tyl:)es I and 11). (]Iin (;e, net 23:143 I49. 1~. [~t~I]SOl] I. (',I.IStaVSOI] K-H, Rastad ], A k e r s t r o m (;, ()[)(!I'g K, l~junghall S { 1 .'.),~al): (]},togenetic:al inxt;stigations in t)atients with primary hyt)erl)aralhyroi(lism and mullit)le t,Mo(:rim~ nr, oI)]asia t?,'l)e 1, H e r e d i t a s 1()~:227 22!). l(k W e r m e r P {19541: (.]eneih: aspec:ts of a d ( m o m a t o s i s ()f (,Moc:rine ~lands. A m I Nled 16:3t$3-371. 17. Lamers (H3HW. Fr(.',lit~ P(L\M (197,q): (Hinital si~iHN(:an(:l~ ()t h?,'perparaHlyroidisin in familial m u l t i p l e e i M o ( : r i n e a d e i l o m a t o s i s . Am ] Med 6~i:422 424. lg. S(:himke RN (197,q): (;(ultHi~:s
