American Journal of Medical Genetics 40482-484 (1991)
Autosomal Dominant Transmission of Congenital Erythroid Hypoplastic Anemia With Radial Abnormalities J.A. Hurst, M. Baraitser, and B. Wonke Department of Clinical Genetics, Hospital for Sick Children ( J A.H., M.B.) and Department of Haematology, Whittington Hospital (B.W.), London, England
We describe a mother and son with congenital hypoplastic anemia. The mother has apparently normal thumbs and forearms but her son has bilateral radial hypoplasia. They provide a further example of dominant inheritance of Diamond-Blackfan anemidAase syndrome and suggest that thumb and radial abnormalities are a component of this syndrome. KEY WORDS: congenital hypoplastic anemia, Diamond-Blackfan, radial hypoplasia, autosomal dominant inheritance, Aase syndrome INTRODUCTION The inheritance of congenital (erythroid)hypoplastic anemia or Diamond-Blackfan anemia is not well described in the literature. It is generally considered to be a sporadic condition but there are reports of autosomal dominant and of autosomal recessive inheritance. Additionally, the association of congenital hypoplastic anemia with a triphalangeal thumb is known as the Aase syndrome lAase and Smith, 19691, which is thought to be recessively inherited. We report here a mother with congenital hypoplastic anemia and her son with the same anemia and bilaterally hypoplastic radii. This gives further evidence for dominant inheritance of Diamond-Blackfan anemia. We consider that patients with Aase syndrome should not be separated from the larger group of patients with congenital hypoplastic anemia. CLINICAL REPORTS Patient 1: dob 20:08:88 LM was born a t term with a weight of 2,680 g. His mother, Patient 2 in this report has Diamond-Blackfan Received for publication September 4, 1990; revision received ,January 14, 1991. Address reprint requests to Dr. J . A. Hurst, Department of Clinical Genetics, Hospital for Sick Children, Great Ormond Street, London, England WC1.
63 1991 Wiley-Liss, Inc.
anemia. The abnormalities of his hands were noted a t birth but there were no other neonatal problems. He was reviewed a t age 4 months. The forearm abnormalities are shown in Figure 1. The left thumb was small and useless and attached to the radial aspect of the index finger. Wrist movements were normal on the left. He had a right radial club hand with an absent thumb. Radiologically the left radius and ulna were normal but the first metacarpal was hypoplastic and applied to the index metacarpal. There was a conjoined radius and ulna on the right. Shoulders, elbows, hips, and feet showed no abnormalities. Hematological investigations on day two were normal but a t age 4 months he had a Hb of 7.7 g/dl, MCV 110 fl, and WBC 10.1 x 10y/l,platelets 765 x lo9 1. There was an absolute reticulocytopenia. Bone marrow examination showed a cellular marrow with erythroid hypoplasia and high myeloid/erythroid ratio. The morphology of the myeloid and megakoryocytic cells was normal, as were the plasma cells and lymphocytes. Cytogenetic studies showed normal male chromosomes and the phytohemoglutinin stimulated marrow cultures showed no chromosome damage. His general development has been normal but a t 1 year his height is 3 cm below the third centile. The vestigal thumb has been removed and pollicisation of the index fingers was performed. One month after surgery he was admitted with a red swollen eye and required intravenous antibiotics for left preseptal cellulitis. Blood cultures and swabs grew no organisms. He has had five blood transfusions, a total of 700 ml of packed filtered red cells.
Patient 2: dob 25:0669 DM is the mother of LM. She was noted to be anemic (Hb 4 gidl) a t age 13 months. A diagnosis of DiamondBlackfan anemia was made and she was initially treated with blood transfusions followed by corticosteroid treatment from age 14 months. She had 2 mgkgi day prednisolone and after a satisfactory reticulocyte response this large dose was reduced to a maintenance dose of 5-2.5 mg and 2.5 mg on alternate days until her pregnancy. During pregnancy in addition to her prednisolone she required transfusions aiming for a pre-
Congenital Erythroid Hypoplastic Anemia
483
Fig. 1. (A)Left hand. Vestigal thumb attached to the radial aspect of the index fingers. (B)Right hand. Absent thumb. Radial club hand.
transfusion Hb of not less than 10.5 g/dl. Since her pregnancy she has needed 10 mg prednisolone every day to maintain her Hb a t satisfactory levels. Her height is 145 cm (6 cm less than the 3rd centile.). She has no apparent abnormalities of the thumbs or forearms and her thenar eminences are normal. Radiographs of the hands and forearms confirmed normal structure. She has no brothers or sisters. Her parents have no history of anemia in childhood and they show no hematological abnormalities. Her father is 170 cm and her mother is 164 cm tall.
DISCUSSION In 1938 Diamond and Blackfan [Diamond and Blackfan, 19381described four children with congenital anemia affecting the red blood cells. They called this condition congenital (erythroid) hypoplastic anaemia and in 1961 Diamond et al. reported a 25-year study of 30 patients. There were two sets of affected sibs in the group of 30 patients and additionally three families in whom a child had died previously of a congenital anemia. These 33 affected children had a total of 39 normal sibs, which mitigates against simple autosomal recessive inheritance. One child had a unilateral triphalangeal thumb and another bilateral duplication of the thumbs. The known association of congenital hypoplastic anaemia and triphalangeal thumbs was described in two brothers by Aase and Smith [19691 and this has subsequently been called the Aase syndrome. Both the boys had triphalangeal thumbs with hypoplastic thenar eminences and radiographs showed mild distal radial hypoplasia. One of the boys had a midline cleft lip and the other a presumed ventricular septa1 defect. They thought that this syndrome was likely to be autosomal recessive trait as both parents were clinically normal but could not exclude X-linked inheritance. Since then reports of females with thumb abnormalities and congenital hypoplastic anemia have led other authors to
conclude that the Aase syndrome is a recessive trait, but in no patients has there been parental consanguinity or other reports of affected sibs (Table I). This distinction is of great importance in the counselling of patients with congenital hypoplastic anemia because since the review by Diamond et al. [19611 the anemia alone has been thought to be a sporadic occurrence in most instances. However, dominant transmission of congenital hypoplastic anaemia has been reported [Forare 1963; Mott, 1969;Hunter and Hakami, 1972;Viskochil et al., 19901. Viskochil et al. [19901were able to demonstrate in their large pedigree that obligate affected members were clinically asymptomatic but showed mild haematological abnormalities suggestive of congenital hypoplastic anemia. Spontaneous remission of the anemia is well documented. In the four patients originally reported by Diamond and Blackfan, two remitted at age 2 years. Short stature is a recognised manifestation of Diamond-Blackfan anemia and the Aase syndrome. This has sometimes been attributed to steroid therapy but some patients with the anemia who have not had steroids, or have had only small doses, have final heights below the 3rd centile. Alter [19781considered that patients with thumb abnormalities should not be separated from those with the anemia alone as the natural history of the congenital anemia was the same in the two groups. Indeed, in the recent edition of “Symptoms of the Head and Neck,” Gorlin et al. [19901 state that the patients described by Aase and Smith have the Blackfan-Diamond syndrome. We support this and suggest that the inheritance in the two groups may be the same. Our case reports show dominant inheritance of the congenital hypoplastic anemia but discordance for the thumb abnormalities. A similar family was reported by Murphy and Lubin [1972]. The proband had congenital erythroid hypoplasia and had triphalangeal thumbs, whereas his mother (and possibly her sister) had the thumb abnormality alone. We know that the anemia can vary in
484
Hurst et al. _
_
_
_
_
_
~
~
~
TABLE I. Previous ReDorts of the Aase Syndrome ~ ~ ~
Case report
Number of Patients
Consanguinity
Diamond et al., 1961
1F
No
Unilateral triphalangeal thumb
1 1F 2M sibs
No
Terheggen, 1974 van Wel-Sipman, 1977 Higginbottom et 1978 Pfeiffer and Ambs, 1983 Muis et al., 1986
1M 1F
No
Bilateral duplicated thumb Triphalangeal thumbs. BW 2,300 g Triphalangeal thumbs. Cleft lip and palate in one boy. BW 2,600 g “small” Triphalangeal thumbs. BW 2,200 g Triphalangeal thumbs. BW 3,500 g
1F
No
1F
No
1M
No
Jones and Thompson, 1973
1M
No
Harvey, 1966 Aase and Smith, 1969
a:,
No No
No
severity and can remit spontaneously and therefore propose that there is increasing evidence for dominant inheritance of congenital hypoplastic anemia. Thus the explanation of two affected children born to normal parents could be either that one parent has mild disease or alternatively by germ line mosaicism. Many adults with Diamond-Blackfananemia will now have children and a review of these would help to delineate the clinical manifestations and establish the inheritance with greater certainty.
REFERENCES Aase JM, Smith DW (1969): Congenital anemia and triphalangeal thumbs: A new syndrome. J Pediatr 74:471-474. Alter BP (1978): Thumbs and anemia. Pediatrics 62:613-614. Diamond LK, Blackfan KD (1938): Hypoplastic anemia. Am J Dis Child 56:464-467. Diamond LK, Aller DM, Magill FB (1961): Congenital (erythroid) hypoplastic anemia. Am J Dis Child 102:403-415. Forare SA (1963): Pure red cell anemia in step siblings. Acta Paediat Scand 52:159-160. Gorlin JR, Cohen MM, Jr., Levin LS (1990): “Syndromes of the Head and Neck,” 3rd Ed. New York: Oxford University Press.
Manifestations
Triphalangeal thumb, L hypoplastic thumb. BW 2,900 g Triphalangeal thumb, hypoplastic thumb Bilateral triphalangeal thumbs. L Cleft liD and Dalate (Father cleft lip). BW 2,646 g Bilateral triphalangeal thumbs, radial hypoplasia, radio-ulnar synostosis
Harvey DR (1966): Congenital hypoplastic anaemia. Proc R SOCMed 59:490-491. Higginbottom MC, Jones KL, Kung FH, Koch TK, Boyer JL(1978): The Aase syndrome in a female infant. J Med Genet 15484-486. Hunter RE, Hakami N (1972):The occurrence of congenital hypoplastic anemia in half brothers. J Paediatr 81:346-348. Jones B, Thompson H (1973): Triphalangeal thumbs associated with hypoplastic anaemia. Paediatrics 52:609-612. Mott MG, Apley J , Raper AB (1969):Congenital (erythroid) hypoplastic anaemia: Modified expression in males. Arch Dis Child 44: 757-760. Muis N, Beemer FA, van Dijken P, Klep-de Pater JM (1986): The Aase syndrome: Case report and review of the literature. Eur J Pediatr 145:153-157. Murphy S, Lubin B (1972): Triphalangeal thumbs and congenital erythroid hypoplasia: Report of a case with unusual features. J Pediatr 81(5):987-989. Pfeiffer RA, Ambs E (1983): Das Aase-Syndrom: Autosomal-rezessiv vererbte, konnatal insuffiziente Erythropiese and Triphalangie der Daumen. Monatsschr Kinderheilkd 131:235-237. Terheggen HG (1974): Hypoplastische Anamie mit dreigliedrigem Daumen. Z. Kinderheilk 1185‘1-80. van Weel-Sipman MA, van de Kamp JJP, de Konig J (1977):A female patient with Aase syndrome. J Pediatr 91:753-755. Viskochil DH, Carey JC, Glader JC, Rothstein G, Christensen RD (1990): Congenital hypoplastic (Diamond-Blackfan) anemia in seven members of one kindred. Am J Med Genet 35251-256.
Autosomal Dominant Transmission of Congenital Erythroid Hypoplastic Anemia With Radial Abnormalities J.A. Hurst, M. Baraitser, and B. Wonke Department of Clinical Genetics, Hospital for Sick Children ( J A.H., M.B.) and Department of Haematology, Whittington Hospital (B.W.), London, England
We describe a mother and son with congenital hypoplastic anemia. The mother has apparently normal thumbs and forearms but her son has bilateral radial hypoplasia. They provide a further example of dominant inheritance of Diamond-Blackfan anemidAase syndrome and suggest that thumb and radial abnormalities are a component of this syndrome. KEY WORDS: congenital hypoplastic anemia, Diamond-Blackfan, radial hypoplasia, autosomal dominant inheritance, Aase syndrome INTRODUCTION The inheritance of congenital (erythroid)hypoplastic anemia or Diamond-Blackfan anemia is not well described in the literature. It is generally considered to be a sporadic condition but there are reports of autosomal dominant and of autosomal recessive inheritance. Additionally, the association of congenital hypoplastic anemia with a triphalangeal thumb is known as the Aase syndrome lAase and Smith, 19691, which is thought to be recessively inherited. We report here a mother with congenital hypoplastic anemia and her son with the same anemia and bilaterally hypoplastic radii. This gives further evidence for dominant inheritance of Diamond-Blackfan anemia. We consider that patients with Aase syndrome should not be separated from the larger group of patients with congenital hypoplastic anemia. CLINICAL REPORTS Patient 1: dob 20:08:88 LM was born a t term with a weight of 2,680 g. His mother, Patient 2 in this report has Diamond-Blackfan Received for publication September 4, 1990; revision received ,January 14, 1991. Address reprint requests to Dr. J . A. Hurst, Department of Clinical Genetics, Hospital for Sick Children, Great Ormond Street, London, England WC1.
63 1991 Wiley-Liss, Inc.
anemia. The abnormalities of his hands were noted a t birth but there were no other neonatal problems. He was reviewed a t age 4 months. The forearm abnormalities are shown in Figure 1. The left thumb was small and useless and attached to the radial aspect of the index finger. Wrist movements were normal on the left. He had a right radial club hand with an absent thumb. Radiologically the left radius and ulna were normal but the first metacarpal was hypoplastic and applied to the index metacarpal. There was a conjoined radius and ulna on the right. Shoulders, elbows, hips, and feet showed no abnormalities. Hematological investigations on day two were normal but a t age 4 months he had a Hb of 7.7 g/dl, MCV 110 fl, and WBC 10.1 x 10y/l,platelets 765 x lo9 1. There was an absolute reticulocytopenia. Bone marrow examination showed a cellular marrow with erythroid hypoplasia and high myeloid/erythroid ratio. The morphology of the myeloid and megakoryocytic cells was normal, as were the plasma cells and lymphocytes. Cytogenetic studies showed normal male chromosomes and the phytohemoglutinin stimulated marrow cultures showed no chromosome damage. His general development has been normal but a t 1 year his height is 3 cm below the third centile. The vestigal thumb has been removed and pollicisation of the index fingers was performed. One month after surgery he was admitted with a red swollen eye and required intravenous antibiotics for left preseptal cellulitis. Blood cultures and swabs grew no organisms. He has had five blood transfusions, a total of 700 ml of packed filtered red cells.
Patient 2: dob 25:0669 DM is the mother of LM. She was noted to be anemic (Hb 4 gidl) a t age 13 months. A diagnosis of DiamondBlackfan anemia was made and she was initially treated with blood transfusions followed by corticosteroid treatment from age 14 months. She had 2 mgkgi day prednisolone and after a satisfactory reticulocyte response this large dose was reduced to a maintenance dose of 5-2.5 mg and 2.5 mg on alternate days until her pregnancy. During pregnancy in addition to her prednisolone she required transfusions aiming for a pre-
Congenital Erythroid Hypoplastic Anemia
483
Fig. 1. (A)Left hand. Vestigal thumb attached to the radial aspect of the index fingers. (B)Right hand. Absent thumb. Radial club hand.
transfusion Hb of not less than 10.5 g/dl. Since her pregnancy she has needed 10 mg prednisolone every day to maintain her Hb a t satisfactory levels. Her height is 145 cm (6 cm less than the 3rd centile.). She has no apparent abnormalities of the thumbs or forearms and her thenar eminences are normal. Radiographs of the hands and forearms confirmed normal structure. She has no brothers or sisters. Her parents have no history of anemia in childhood and they show no hematological abnormalities. Her father is 170 cm and her mother is 164 cm tall.
DISCUSSION In 1938 Diamond and Blackfan [Diamond and Blackfan, 19381described four children with congenital anemia affecting the red blood cells. They called this condition congenital (erythroid) hypoplastic anaemia and in 1961 Diamond et al. reported a 25-year study of 30 patients. There were two sets of affected sibs in the group of 30 patients and additionally three families in whom a child had died previously of a congenital anemia. These 33 affected children had a total of 39 normal sibs, which mitigates against simple autosomal recessive inheritance. One child had a unilateral triphalangeal thumb and another bilateral duplication of the thumbs. The known association of congenital hypoplastic anaemia and triphalangeal thumbs was described in two brothers by Aase and Smith [19691 and this has subsequently been called the Aase syndrome. Both the boys had triphalangeal thumbs with hypoplastic thenar eminences and radiographs showed mild distal radial hypoplasia. One of the boys had a midline cleft lip and the other a presumed ventricular septa1 defect. They thought that this syndrome was likely to be autosomal recessive trait as both parents were clinically normal but could not exclude X-linked inheritance. Since then reports of females with thumb abnormalities and congenital hypoplastic anemia have led other authors to
conclude that the Aase syndrome is a recessive trait, but in no patients has there been parental consanguinity or other reports of affected sibs (Table I). This distinction is of great importance in the counselling of patients with congenital hypoplastic anemia because since the review by Diamond et al. [19611 the anemia alone has been thought to be a sporadic occurrence in most instances. However, dominant transmission of congenital hypoplastic anaemia has been reported [Forare 1963; Mott, 1969;Hunter and Hakami, 1972;Viskochil et al., 19901. Viskochil et al. [19901were able to demonstrate in their large pedigree that obligate affected members were clinically asymptomatic but showed mild haematological abnormalities suggestive of congenital hypoplastic anemia. Spontaneous remission of the anemia is well documented. In the four patients originally reported by Diamond and Blackfan, two remitted at age 2 years. Short stature is a recognised manifestation of Diamond-Blackfan anemia and the Aase syndrome. This has sometimes been attributed to steroid therapy but some patients with the anemia who have not had steroids, or have had only small doses, have final heights below the 3rd centile. Alter [19781considered that patients with thumb abnormalities should not be separated from those with the anemia alone as the natural history of the congenital anemia was the same in the two groups. Indeed, in the recent edition of “Symptoms of the Head and Neck,” Gorlin et al. [19901 state that the patients described by Aase and Smith have the Blackfan-Diamond syndrome. We support this and suggest that the inheritance in the two groups may be the same. Our case reports show dominant inheritance of the congenital hypoplastic anemia but discordance for the thumb abnormalities. A similar family was reported by Murphy and Lubin [1972]. The proband had congenital erythroid hypoplasia and had triphalangeal thumbs, whereas his mother (and possibly her sister) had the thumb abnormality alone. We know that the anemia can vary in
484
Hurst et al. _
_
_
_
_
_
~
~
~
TABLE I. Previous ReDorts of the Aase Syndrome ~ ~ ~
Case report
Number of Patients
Consanguinity
Diamond et al., 1961
1F
No
Unilateral triphalangeal thumb
1 1F 2M sibs
No
Terheggen, 1974 van Wel-Sipman, 1977 Higginbottom et 1978 Pfeiffer and Ambs, 1983 Muis et al., 1986
1M 1F
No
Bilateral duplicated thumb Triphalangeal thumbs. BW 2,300 g Triphalangeal thumbs. Cleft lip and palate in one boy. BW 2,600 g “small” Triphalangeal thumbs. BW 2,200 g Triphalangeal thumbs. BW 3,500 g
1F
No
1F
No
1M
No
Jones and Thompson, 1973
1M
No
Harvey, 1966 Aase and Smith, 1969
a:,
No No
No
severity and can remit spontaneously and therefore propose that there is increasing evidence for dominant inheritance of congenital hypoplastic anemia. Thus the explanation of two affected children born to normal parents could be either that one parent has mild disease or alternatively by germ line mosaicism. Many adults with Diamond-Blackfananemia will now have children and a review of these would help to delineate the clinical manifestations and establish the inheritance with greater certainty.
REFERENCES Aase JM, Smith DW (1969): Congenital anemia and triphalangeal thumbs: A new syndrome. J Pediatr 74:471-474. Alter BP (1978): Thumbs and anemia. Pediatrics 62:613-614. Diamond LK, Blackfan KD (1938): Hypoplastic anemia. Am J Dis Child 56:464-467. Diamond LK, Aller DM, Magill FB (1961): Congenital (erythroid) hypoplastic anemia. Am J Dis Child 102:403-415. Forare SA (1963): Pure red cell anemia in step siblings. Acta Paediat Scand 52:159-160. Gorlin JR, Cohen MM, Jr., Levin LS (1990): “Syndromes of the Head and Neck,” 3rd Ed. New York: Oxford University Press.
Manifestations
Triphalangeal thumb, L hypoplastic thumb. BW 2,900 g Triphalangeal thumb, hypoplastic thumb Bilateral triphalangeal thumbs. L Cleft liD and Dalate (Father cleft lip). BW 2,646 g Bilateral triphalangeal thumbs, radial hypoplasia, radio-ulnar synostosis
Harvey DR (1966): Congenital hypoplastic anaemia. Proc R SOCMed 59:490-491. Higginbottom MC, Jones KL, Kung FH, Koch TK, Boyer JL(1978): The Aase syndrome in a female infant. J Med Genet 15484-486. Hunter RE, Hakami N (1972):The occurrence of congenital hypoplastic anemia in half brothers. J Paediatr 81:346-348. Jones B, Thompson H (1973): Triphalangeal thumbs associated with hypoplastic anaemia. Paediatrics 52:609-612. Mott MG, Apley J , Raper AB (1969):Congenital (erythroid) hypoplastic anaemia: Modified expression in males. Arch Dis Child 44: 757-760. Muis N, Beemer FA, van Dijken P, Klep-de Pater JM (1986): The Aase syndrome: Case report and review of the literature. Eur J Pediatr 145:153-157. Murphy S, Lubin B (1972): Triphalangeal thumbs and congenital erythroid hypoplasia: Report of a case with unusual features. J Pediatr 81(5):987-989. Pfeiffer RA, Ambs E (1983): Das Aase-Syndrom: Autosomal-rezessiv vererbte, konnatal insuffiziente Erythropiese and Triphalangie der Daumen. Monatsschr Kinderheilkd 131:235-237. Terheggen HG (1974): Hypoplastische Anamie mit dreigliedrigem Daumen. Z. Kinderheilk 1185‘1-80. van Weel-Sipman MA, van de Kamp JJP, de Konig J (1977):A female patient with Aase syndrome. J Pediatr 91:753-755. Viskochil DH, Carey JC, Glader JC, Rothstein G, Christensen RD (1990): Congenital hypoplastic (Diamond-Blackfan) anemia in seven members of one kindred. Am J Med Genet 35251-256.
