absent thumb, immune disorder, and congenital anemia presenting with hydrops fetalis

5
American Journal of Medical Genetics 42736-740 (1992) New Syndrome? Absent Thumb, Immune Disorder, and Congenital Anemia Presenting With Hydrops Fetalis Ben A. Semmekrot, Asgeir Haraldsson, Corry M.R. Weemaes, Dominique F.C.M. Smeets, Wil B. Geven, and Han G. Brunner Department of Pediatrics and Department of Human Genetics (D.F.C.M.S., H.G.B.); University Hospital, Nijmegen, The Netherlands. A patient is described who presented with se- vere congenital anemia, hydrops fetalis, im- mune disorder, and absent thumbs. No toxic, infectious, or metabolic cause was found to explain these symptoms. Immunologic and cytogenetic studies excluded several syn- dromes that combine radial ray anomalies with hematological involvement. After care- ful study of the literature, it is concluded that the disorder described here represents a new syndrome that can be added to a growing list of hematological-radial syndromes. KEY WORDS: radial ray anomalies, neu- tropenia, dysgammaglobuli- nemia, Diamond-Blackfan syndrome INTRODUCTION Amongst the causes of nonimmunologic hydrops fetalis are cardiac anomalies, chromosomal disorders, congenital malformations, infections, hematological disorders, and twin-twin transfusion [Machin, 1981; Holzgreve et al., 1984;Im et al., 19841. Nonimmunologic hydrops fetalis has an incidence varying from 1 in 2,500 to 1 in 3,500 neonates and carries a poor prognosis [Holz- greve et al., 1984; Im et al., 19841. Radial ray abnormalities have been described in com- bination with various hematological and immunologic disorders [Fanconi, 1927; Aase and Smith, 1969; Dia- mond et al., 1976; Gonzalez et al., 1977; Shokeir, 1978; Alter and Nathan, 1979;Arias et al., 1980;Cherstvoy et al., 1980; Schlegelberger et al., 1986; Hall, 1987; Van Haeringen et al., 19871. Received for publication March 8, 1991; July 9, 1991. Address reprint requests to Ben A. Semmekrot, M.D., Ph.D., University Hospital Nijmegen, P.O. Box 9101,6500 HB Nijmegen, The Netherlands. We report on a patient with absent thumbs, immune disorder, and congenital anemia who presented with hydrops fetalis. Since this patient does not appear to have one of the above mentioned disorders, her condition probably represents a new syndrome. CLINICAL REPORT The subject of this report, a Caucasian girl, the second child of healthy unrelated Dutch parents, was admitted to the neonatal intensive care unit. The family history was negative. At 34 weeks of gestation, premature con- tractions occurred, requiring tocolytic treatment. One week later contractions recurred. Tocography suggested fetal distress necessitating immediate cesarean section. An extremely hydropic child was born who required mechanical ventilation. Instant laboratory investiga- tion showed severe anemia: Hb 1.2 mmolll; Ht 0.06 1/1.A transfusion with packed red cells was given and she was subsequently referred. Physical examination on admission showed a prema- ture, extremely hydropic, and anemic child (Fig. 1) with weight at the 70th centile (3,090 g), length at the 50th centile, and OFC at the 2nd centile. Aplasia of both thumbs (Fig. 2) was noted without other anomalies. No abnormal skin pigmentation could be detected. Aus- cultation of the lungs and the heart revealed no abnor- malities, except for a relative bradycardia (90-1 10/ min). The abdomen was distended. The liver could be palpated 2 cm below the costal margin. The spleen was not palpable. Peripheral arterial pulsations were nor- mal. Blood gas analysis showed slight metabolic acidosis and low serum albumin (20 gll). Serum electrolytes, urea, and liver function tests were normal. The blood parameters after transfusion were Hb 4.9 mmol/l; Ht 0.25 111; thrombocytes 84,000/mm3;leuco- cytes 2,500/mm3. No reticulocytes were seen. Serum ti- ters to specific congenital infections in the mother and child were negative, and the results of metabolic and endocrine studies were normal. Cardiac examination on admission showed severe congestive heart failure but normal cardiac anatomy. Cerebral ultrasound and CT scanning showed extensive intracranial hemorrhage 0 1992 Wiley-Liss, Inc.

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Page 1: Absent thumb, immune disorder, and congenital anemia presenting with hydrops fetalis

American Journal of Medical Genetics 42736-740 (1992)

New Syndrome?

Absent Thumb, Immune Disorder, and Congenital Anemia Presenting With Hydrops Fetalis Ben A. Semmekrot, Asgeir Haraldsson, Corry M.R. Weemaes, Dominique F.C.M. Smeets, Wil B. Geven, and Han G. Brunner Department of Pediatrics and Department of Human Genetics (D.F.C.M.S., H.G.B.); University Hospital, Nijmegen, The Netherlands.

A patient is described who presented with se- vere congenital anemia, hydrops fetalis, im- mune disorder, and absent thumbs. No toxic, infectious, or metabolic cause was found to explain these symptoms. Immunologic and cytogenetic studies excluded several syn- dromes that combine radial ray anomalies with hematological involvement. After care- ful study of the literature, it is concluded that the disorder described here represents a new syndrome that can be added to a growing list of hematological-radial syndromes.

KEY WORDS: radial ray anomalies, neu- tropenia, dysgammaglobuli- nemia, Diamond-Blackfan syndrome

INTRODUCTION Amongst the causes of nonimmunologic hydrops

fetalis are cardiac anomalies, chromosomal disorders, congenital malformations, infections, hematological disorders, and twin-twin transfusion [Machin, 1981; Holzgreve et al., 1984; Im et al., 19841. Nonimmunologic hydrops fetalis has an incidence varying from 1 in 2,500 to 1 in 3,500 neonates and carries a poor prognosis [Holz- greve et al., 1984; Im et al., 19841.

Radial ray abnormalities have been described in com- bination with various hematological and immunologic disorders [Fanconi, 1927; Aase and Smith, 1969; Dia- mond et al., 1976; Gonzalez et al., 1977; Shokeir, 1978; Alter and Nathan, 1979; Arias et al., 1980; Cherstvoy et al., 1980; Schlegelberger et al., 1986; Hall, 1987; Van Haeringen et al., 19871.

Received for publication March 8, 1991; July 9, 1991. Address reprint requests to Ben A. Semmekrot, M.D., Ph.D.,

University Hospital Nijmegen, P.O. Box 9101,6500 HB Nijmegen, The Netherlands.

We report on a patient with absent thumbs, immune disorder, and congenital anemia who presented with hydrops fetalis. Since this patient does not appear to have one of the above mentioned disorders, her condition probably represents a new syndrome.

CLINICAL REPORT The subject of this report, a Caucasian girl, the second

child of healthy unrelated Dutch parents, was admitted to the neonatal intensive care unit. The family history was negative. At 34 weeks of gestation, premature con- tractions occurred, requiring tocolytic treatment. One week later contractions recurred. Tocography suggested fetal distress necessitating immediate cesarean section. An extremely hydropic child was born who required mechanical ventilation. Instant laboratory investiga- tion showed severe anemia: Hb 1.2 mmolll; Ht 0.06 1/1. A transfusion with packed red cells was given and she was subsequently referred.

Physical examination on admission showed a prema- ture, extremely hydropic, and anemic child (Fig. 1) with weight at the 70th centile (3,090 g), length at the 50th centile, and OFC at the 2nd centile. Aplasia of both thumbs (Fig. 2) was noted without other anomalies. No abnormal skin pigmentation could be detected. Aus- cultation of the lungs and the heart revealed no abnor- malities, except for a relative bradycardia (90-1 10/ min). The abdomen was distended. The liver could be palpated 2 cm below the costal margin. The spleen was not palpable. Peripheral arterial pulsations were nor- mal. Blood gas analysis showed slight metabolic acidosis and low serum albumin (20 gll). Serum electrolytes, urea, and liver function tests were normal.

The blood parameters after transfusion were Hb 4.9 mmol/l; Ht 0.25 111; thrombocytes 84,000/mm3; leuco- cytes 2,500/mm3. No reticulocytes were seen. Serum ti- ters to specific congenital infections in the mother and child were negative, and the results of metabolic and endocrine studies were normal. Cardiac examination on admission showed severe congestive heart failure but normal cardiac anatomy. Cerebral ultrasound and CT scanning showed extensive intracranial hemorrhage

0 1992 Wiley-Liss, Inc.

Page 2: Absent thumb, immune disorder, and congenital anemia presenting with hydrops fetalis

Fetal Hydrops with Absent Thumbs, Immunodeficiency, Anemia 737

Fig. 1. The patient at 2 days of age. Note severe hydrops.

Fig. 2. Radiograph of the patient's right hand showing absent thumb.

without evidence of structural malformations. Abdomi- nal sonography displayed ascites and an enlarged con- gested liver. The kidneys appeared normal.

Following abdominal paracentesis, the child received partial exchanges of filtered and irradiated erythro- cytes, diuretics, and cardiotonics. Because of hypoten- sion and hypalbuminemia, a single dose of fresh-frozen plasma was given. Her general condition improved rap- idly and she could be extubated on the 3rd day of life. During the first 6 days of life, the child's weight fell from 3,090 to 1,740 g (5th percentile). The initial thrombocy- topenia normalized completely within 10 days. She was discharged at age 5 weeks.

One week later she was readmitted with fulminant varicella, contracted from an older sib in spite of pro- phylactic administration of hyperimmune zoster glo- bulin. Because of respiratory insufficiency due to bilat- eral pneumonia, mechanical ventilation was needed. After a satisfactory recovery, the child again developed

varicella 3 weeks later. At that time low levels of immu- noglobulins were found and treatment with intravenous immunoglobulins, hyperimmune varicella-zoster im- munoglobulin, and acyclovir was started. This second infection was limited to the skin and mucous mem- branes. At age 16 weeks she again presented a few varicella lesions without further complications.

This patient has always been blood transfusion-de- pendent. Reticulocytes were never found. She has re- quired gammaglobulin transfusions. At age 12 months she is doing well and is gaining weight adequately.

Mother and child both had blood group A, Rhesus negative. Coomb's reaction was negative and fetomater- nal transfusion was excluded by a negative Kleihauer- Betke test. At age 2 weeks a bone marrow aspirate was extremely hypocellular: Abundant peripheral blood cells were seen with virtual absence of bone marrow precursor cells. At age 4 weeks a bone marrow aspirate was still hypocellular, with minimal erythropoiesis and myelopoiesis, and no megakaryocytes, but lymphocytes and platelets were both present. Since at both occasions hardly any bone marrow could be obtained, i t is possible that both aspirates represent peripheral blood only. A bone biopsy has not been performed.

Leucocyte counts varied between 1,500 and 4,5001 mm3, with severe granulopenia and mild lymphopenia (Table I). Bone marrow stem cells from the patient ap- peared to be unresponsive to stimulation in vitro with recombinant granulocyte macrophage-stimulating fac- tor (GM-CSF), interleukin-3 (IL-31, and the combination of both. Serum immunoglobulins a t age 9 weeks showed IgG deficiency, whereas IgA and IgM were normal for age. Total B cells in peripheral blood were normal. Se- rum titers to varicella after infection remained nega- tive. At age 7 months, several weeks after temporarily discontinuing replacement therapy, IgG was still defi- cient (Table I). Cellular immunity studies showed a nor- mal percentage of T cells and normal T-cell subpopula- tions. The response of peripheral blood lymphocytes to PHA and PWM was approximately 40 percent of nor- mal. Normal concentrations of purines and pyrimidines were found.

To rule out Fanconi anemia, the following cytogenetic studies were performed. Standard peripheral blood cul- ture (10 cells analyzed), as well as cultured fibroblasts (10 cells) showed a normal 46,XX female karyotype. Analysis of 100 mitoses from peripheral lymphocytes cultured in medium with mitomycin C showed 7% ab- normalities: 3 gaps, 3 breaks, and 1 extra fragment. No triradials or quadriradials were seen. The results were virtually identical to those of a normal control (5/1w cells abnormal). Analysis of a fibroblast culture in the presence of mitomycin C (50 mitoses) again showed no triradials, quadriradials, or cells with multiple abnor- malities. The percentage of cells with a chromosome abnormality (38%) was slightly higher than that from a normal control (26%), but clearly below that from one of our Fanconi patients (60%), in whom numerous triradial figures and fragments were also seen.

To exclude syndromes with increased X-ray sensi- tivity [van Haeringen et al., 1987; Natarajan et al., 19891, the relative DNA synthesis after X-irradiation in

Page 3: Absent thumb, immune disorder, and congenital anemia presenting with hydrops fetalis

738 Semmekrot et al.

TABLE I. Immunologic Data of the Patient Age 1 day 9 weeks 14 weeks 18 weeks 30 weeks Leucocytes/mm3 2500 4000 1700 2900 1200 Granulocyteslmm' 5 600 350 5 Lymphocytes/mm3 2400 3160 2500 1050 Serum immunoglobulins

1.2 1.4 2.4 1.1 0.1 0.2 0.3 0.3

I& g/l IgA gll IgM gll 0.7 0.5 0.6 0.3 IgD IU/ml 3 1 IgE IU/ml <2 <2

Markers in peripheral blood % B cells 18 % CD3 + cells 58 % CD4+ cells 46 % CD8+ cells 10

With PHA stimulation With PWM stimulation

In vitro proliferation of lymphocytes 40% of control 40% of control

fibroblasts was compared to a normal control and to a patient with the Nijmegen breakage syndrome, a condi- tion with known X-ray induced chromosome instability [Weemaes et al., 19871. The relative DNA synthesis for our patient was intermediate between the positive and the negative controls, but appeared within the normal range for our laboratory.

DISCUSSION Hydrops fetalis has been associated with multiple

conditions, most of which, before the use of anti-Rhesus immunoglobulin, were immunologic. Since the success- ful prevention of Rhesus hemolytic disease, the majority of cases of hydrops fetalis are now due to nonimmuno- logic causes [Machin, 1981; Holzgreve et al., 19841. Hy- drops fetalis as the presenting sign of congenital hypo- plastic anemia has been described once in a child with Diamond-Blackfan syndrome [Scimeca et al., 19881.

Diamond-Blackfan syndrome (DBS), also known as congenital hypoplastic anemia, is a congenital disorder of erythropoiesis usually presenting with anemia in the first year of life [Alter and Nathan, 1979; Alter et al., 19811. Some 30% of patients with DBS show radial ray abnormalities, especially bifid or triphalangeal thumbs, but thumb aplasia has not been reported [Alter and Nathan, 19791. Approximately 10% of patients are noted to have mildly decreased total leucocyte counts [Alter and Nathan, 1979; Alter et al., 19811. Nonethe- less, severe neutropenia as seen in our patient excludes a diagnosis of DBS [Alter and Nathan, 1979; Alter et al., 19811.

The combination of the hematological and the lym- phoid tissue abnormalities in our patient suggests a defect at the level of the pluripotent stem cell. In hu- mans, the in vivo correlation of decreased basal erythropoiesis with decreased T-cell function has been observed in patients with DBS [Finlay et al., 19821. As in these patients, the condition in our patient indicates some intrinsic cellular defect not restricted to the erythroid series, but extending to involve the immune system.

The patient presented here showed extreme anemia at birth, in combination with neutropenia. The quick re-

covery of the blood platelets excludes pancytopenia as found in congenital aplastic anemia [Alter et al., 19811.

Several syndromes combine radial ray abnormalities with a disturbance of the hematopoetic system. These are summarized in Table 11. Most of these conditions, however, do not cause birth anemia and granulocyto- penia. A continuous granulocytopenia was demon- strated in our patient, with granulocyte counts below

Preterm infants have been found to have lower neu- trophil counts [Lloyd and Oto, 19821, and perinatal com- plications, such as periventricular haemorrhage, peri- natal asphyxia, and blood exchange transfusion, have been encountered in perinatal temporary neutropenia [Manroe et al., 1979; Baley et al., 19881. However, in these conditions granulocyte counts invariably re- turned to normal.

The pathogenesis of congenital neutropenia remains obscure. Various mechanisms have been proposed, in- volving intrinsic neutrophil defects [Zucker-Franklin et al., 1977; Parmley et al., 19801, abnormalities of the bone marrow microenvironment [Parmley et al., 19801, and/or disturbed cell-cell interaction [Kostmann, 1975; Amato et al., 1976; Baley et al., 19881. Although erythropoiesis is generally regarded as normal in pa- tients with congenital neutropenia, a slight maturation arrest has been noted [Kostmann, 19751. Neutropenia is frequently observed in Fanconi anemia, WT syndrome, and Shokeir syndrome, but not in the other conditions listed in Table 11. However, several points argue against these diagnoses. Fanconi anemia is characterized by pancytopenia and radial ray abnormalities, in combina- tion with increased chromosome breakage, especially after induction with clastogenic agents, such as diepoxy- butane (DEB) or mitomycin C (MMC). Although in- creased chromosome breakage is typical of Fanconi ane- mia, this has been difficult to prove in a number of patients. Some patients with otherwise typical Fanconi anemia [Auerbach et al., 19891 showed increased chro- mosome breakage in only a portion of their peripheral lymphocytes, ranging from 19 to 40% (mean 29.7%), whereas others had an increased chromosome breakage rate only in fibroblasts [Arwert and Kwee, 19891. In our

1 ,000/mm3.

Page 4: Absent thumb, immune disorder, and congenital anemia presenting with hydrops fetalis

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Page 5: Absent thumb, immune disorder, and congenital anemia presenting with hydrops fetalis

740 Semmekrot et al.

patient both tissues showed normal breakage rates in all cells. Also, hematological manifestations of Fanconi anemia are reported only rarely in infants [Alter et al., 19811 and, to our knowledge, no case of Fanconi anemia presenting with fetal hydrops has been reported in the literature. In addition, other clinical symptoms fre- quently described in Fanconi anemia, such as skin pig- mentations and renal abnormalities, were not present. Based on these considerations, we can rule out Fanconi anemia in our patient.

The WT syndrome is an autosomal dominant condi- tion characterized by pancytopenia, leukemia, hypo- plastic thumbs, and clinodactyly of the 5th fingers [Gonzalez et al., 19771. No patient had total thumb aplasia, as seen in our patient. Also, our patient did not show clinodactyly of the 5th fingers, which is character- istic of the WT syndrome. The age at onset of hema- tological abnormalities in the WT syndrome ranged from 15 months to 67 years, while onset was prenatal in our patient. In view of these differences, a diagnosis of WT syndrome is unlikely in our patient.

Our patient bears some resemblance to the syndrome of thumb aplasia and combined immune deficiency, de- scribed by Shokeir [1978]. These patients presented at age 3-14 years with a characteristic pattern of hema- tological abnormalities, consisting of mild leukopenia with absent IgA and a reduced IgG and IgM. PHA re- sponses were also reduced. Anemia was not reported. In contrast, our patient has neonatal onset of severe ane- mia and neutropenia, with normal IgA and IgM, but reduced IgG. Thus, we can rule out Skokeir syndrome in our patient.

We conclude that our patient represents a new syn- drome consisting of fetal hydrops, congenital anemia, absent thumbs, neutropenia, and immune deficiency. This observation is in keeping with the concept of a developmental field comprising the radial ray, the he- matopoetic system, and the immunologic system.

ACKNOWLEDGMENTS We are indebted to H.M.J. Klinkers, MD, pediatri-

cian, and P.J.J. van Vught, MD, PhD, gynecologist, at the Maria Hospital, Tilburg, the Netherlands, for refer- ral of the patient and close cooperation in the patient’s treatment, and to E.J.A. Gerritsen, MD, and H. van den Berg, MD, for assessing bone marrow stimulation with GM-CSF and IL-3.

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Arias S, Penchaszadeh VB, Pinto-Cisternas J , Larrauri S (1980): The IVIC syndrome: A new autosomal dominant complex pleiotropic syndrome with radial ray hypoplasia, hearing impairment, exter- nal ophthalmoplegia, and thrombocytopenia. Am J Med Genet 6:25-59.

Arwert F, Kwee ML (1989): Chromosomal breakage in response to cross-linking agents in the diagnosis of Fanconi-anemia. In Schro- eder-Kurth TM, Auerbach AD, Obe G (4s ) : “Fanconi Anemia.” Berlin: Springer Verlag, pp 83-93.

Auerbach AD, Rogatko A, Schroeder-Kurth TM (1989): International Fanconi Anemia Registry: First report. In Schroeder-Kurth TM, Auerbach AD, Obe G (eds): “Fanconi Anemia.” Berlin: Springer Verlag, pp 3-18.

Baley JE, Stork EK, Warkentin PI, Shurin SB (1988): Neonatal neu- tropenia, clinical manifestations, cause and outcome. Am J Dis Child 142:1161-1166.

Cherstvoy E, Lazjuk G, Lurie I, Ostrowskaya T, Shved I (1980): Syn- drome of multiple congenital malformations including phocomelia, thrombocytopenia, encephalocele and urogenital abnormalities. Lancet 2:485.

Diamond LK, Wang WC, Alter BP (1976): Congenital hypoplastic ane- mia. Adv Pediatr 22:349-378.

Fanconi G (1927): Familiare infantile perniziosaartige Anaemie (per- nizioses Blutbild und Konstitution). Jahrb Kinderheilkd 17:257- 280.

Finlay, JL, Shahidi, NT, Horowitz, S, Borcherding, W, Hong, R (1982): Lymphocyte dysfunction in congenital hypoplastic anemia. J Clin Invest 70:619-626.

Gonzalez CH, Durkin-Stamm MV, Geimer NF, Shahidi NT, Schilling RF, Rubira F, Opitz JM (1977): The WT syndromeA “new” auto- soma1 dominant pleiotropic trait of radiavulnar hypoplasia with high risk of bone marrow failure and/or leukemia. Birth Defects Orig Art Ser 13(3B):31-38.

Hall J G (1987): Thrombocytopenia and absent radius (TAR) syndrome. J Med Genet 34:79-83.

Holzgreve W, Curry CJR, Golbus MS, Callen PW, Filly RA, Smith JC (1984): Investigation of nonimmune hydrops fetalis. Am J Obstet Gynecol 150:805-812.

Im SS, Rizos N, Joutsi P, Shime J , Benzie RJ (1984): Nonimmunologic hydrops fetalis. Am J Obstet Gynecol 148:566-569.

Kostmann R (1975): Infantile genetic agranulocytosis. A review with presentation of ten new cases. Acta Paediatr Scand 64:362-368.

Lloyd BW, Oto A (1982): Normal values for mature and immature neutrophils in very preterm babies. Arch Dis Child 57:233-235.

Machin GA (1981): Differential diagnosis of hydrops fetalis. Am J Med Genet 9:341-350.

Manroe BL, Weinberg AG, Rosenfeld CR, Browne R (1979): The neona- tal blood count in health and disease. I. Reference values for neu- trophilic cells. J Pediatr 95:89-98.

Natarajan AT, Vossen JMJJ, van Weel-Sipman MH (1989): Aplastic anemia and Fanconi anemia. Response of lymphocytes to X-rays and Mitomycin C. In Schroeder-Kurth TM, Auerbach AD, Obe G (eds): “Fanconi Anemia.” Berlin: Springer-Verlag, pp 100-150.

Parmley RT, Crist WM, Ragab AH, Boxer, LA, Malluh A, Lui VK, Darby CP (1980): Congenital dysgranulopoietic neutropenia: Clini- cal, serologic, ultrastructural and in vitro proliferative characteris- tics. Blood 56:465-475.

Schlegelberger B, Grote W, Wiedemann H-R (1986): Probable autoso- ma1 recessive syndrome with triphalangia of thumbs, throm- basthenia Glanzmann and deafness of internal ear. Klin Padiat 198:337-339.

Scimeca PG, Weinblatt ME, Slepowitz G, Harper RG, Kochen JA: Diamond-Blackfan syndrome (1988): An unusual cause of hydrops fetalis. Am J Ped Hem Onc 10:241-243.

Shokeir MHK. Short stature, absent thumbs, flat facies, anosmia and combined immune deficiency (CID) (1978): Birth Defects: Original Article Series, Volume XIV, Number 6A, pp 103-116.

Van Haeringen A, Veenstra F, Maaswinkel-Mooij PD, van de Kamp JJP (1987): Intermittent thrombocytopenia and absent radii. Re- port of a patient with additional unusual manifestations. Am J Med Genet 24:79-83.

Weemaes CMR, Hustinx TWJ, Scheres JMJC, van Munster PJJ, Bak- keren, JAJM, Taalman RDFM (1981): A new chromosomal insta- bility disorder: The Nijmegen breakage syndrome. Acta Paediatr Scand 70557-564.

Zucker-Franklin D, L’Esperance P, Good, RA (1977): Congenital neu- tropenia: An intrinsic cell defect demonstrated by electron micro- scopy of soft agar colonies. Blood 49:425-436.