Arch. Dis. Childh., 1967, 42, 40. Thymic Alymphoplasia J. C. HAWORTH*, J. HOOGSTRATEN, and H. TAYLOR From the Departments of Pathology and Paediatrics, the Children's Hospital, Winnipeg, and the University of Manitoba, Canada In 1950 Glanzmann and Riniker described two infants who died at 5 and 6 months of age following severe infection. These infants during life exhibit- ed profound lymphopenia, and at necropsy were found to have generalized hypoplasia of lymphoid tissues including the thymus. The authors named the condition 'essential lymphocytophthisis'. Dur- ing the next decade additional cases were described from Europe and it was soon recognized that hypo- y-globulinaemia was an essential feature of the condition (Kosenow and Schiimmelfeder, 1953; Tobler and Cottier, 1958; Hitzig, Biro, Bosch, and Huser, 1958; Hitzig and Willi, 1961; Jeune, Larbre, Germain, and Freycon, 1959). The disorder has also been called 'thymic alymphoplasia' or the 'Swiss type' of congenital hypo-y-globulinaemia. It has attracted much interest recently because it may represent an 'experiment of nature' which is analo- gous to the immunological defects observed in some animal species which have been thymectomized in the neonatal period. The relation of the experi- mental data to human immunological deficiency disease has recently been extensively reviewed by Peterson, Cooper, and Good (1965). Twelve cases of thymic alymphoplasia have been recognized in Winnipeg during the past 15 years. Another case was seen at the University Hospital, Saskatoon, and we are indebted to Professor J. W. Gerrard for details of this patient. Case Reports The clinical, laboratory, and pathological findings in the 13 cases are summarized in Tables I and II. The more recent cases were diagnosed during life from the clinical and laboratory features, with ultimate verification at necropsy. The earlier cases were recovered from the necropsy records by reviewing those necropsies which had exhibited marked thymic 'involu- tion', lymphoid hypoplasia, and unusual pneumonitis. Below follows in greater detail a description of the 'F' Received June 7, 1966. * Address: The Children's Hospital, 685 Bannatyne Avenue, Winnipeg 3, Manitoba, Canada. family (Cases 3 and 4) and also Case 11, which was our most recent case and the most fully investigated. The 'F' family. Both parents are Mennonite and, as far as is known, unrelated. The father is one of 10 children, all but one of whom are alive and well (Fig. 1). A sister died of burns at 2 years of age. Two male children of the father's paternal uncle are reported to have died in infancy but no details are known. The mother also comes of a large family, having 11 sibs. Her father's brother had a daughter who died from unknown causes when less than 1 year of age. In September 1959, the first child, a boy, was born and died at 15 weeks (Case 3). Two years later another boy was born and is alive and well. In 1963 the third son was born and he died at 61 months (Case 4). A fourth child, another boy, was born in 1965 and when seen at 2 weeks of age was healthy. Serum protein electrophoresis was recently performed on both parents and on the 2 surviv- ing children, and was normal. Assay of the immuno- globulins by an immunodiffusion technique (Haworth, Norris, and Dilling, 1965) gave the results shown in Table III. These values are within the normal range for the age of the subjects. The peripheral blood smear of the 2-week- old infant appeared normal, though at that age it was not possible to assess full immunological competence. Case 3. This infant appeared normal at birth (weight 3-91 kg.) but was reported as being unusually irritable. At 2 months he was admitted to a local hospital because of a sore mouth and difficulty in swallowing. There he did not improve, failed to gain weight, and developed diarrhoea, vomiting, and a cough, whereupon he was transferred to St. Boniface Hospital in Winnipeg at 3 months. Examination revealed pallor, generalized wasting, oral thrush, and scattered rales in the chest. He weighed 4 9 kg. (3rd centile) and his length was 62 cm. (50th centile). Radiographs of the chest showed increased hilar markings but were otherwise normal. Candida albicans was cultured from the mouth and Proteus vulgaris from the throat, stool, and urine. White blood cell counts over the 6-week period before death were 5900, 8100, and 5900/mm.3 with total lymphocyte counts of 2890, 2430, and 770/mm.', respectively. The results of serum protein electrophoresis are shown in Table IV. Therapy included nystatin, amphotericin, and y- 40 co p yrig h t. o n A p ril 5 , 2 0 2 1 b y g u e st. P ro te cte d b y h ttp ://a d c.b m j.co m / A rch D is C h ild : first p u b lish e d a s 1 0 .1 1 3 6 /a d c.4 2 .2 2 1 .4 0 o n 1 F e b ru a ry 1 9 6 7 . D o w n lo a d e d fro m http://adc.bmj.com/ Thymic Alymphoplasia TABLE I Clinical Details of 13 Cases of Thymic Alymphoplasia 41 Age at Onset Age at Lymphopenia* Racial Origin and Case No. Sex of Death (1 or more counts Hypo-y-globulinaemia* Family History Symptoms (mth.) < 2000/mm.3) Half-breed N. I F 4 mth. 6k 0 Not done Sib American Indian 2 F 2kmth. 5 0 + is and Swiss: 2 normal sibs 3 M 2 mth. 41 + + Sib Mennonite: 4 M Birth 6k + + is 5 2 normal sibs 5 F Birth 3 + + Sb ennt 6 M Birth 5 + Not done Sibs Mennonite 7 M Birth 6 Not done Not done Mennonite: 3 sibs died in infancy; 2 normal sibs 8 M 4 dy. 2 + Not done 3 normal sibs 9 F 10 dy. 2 + + Mennonite: 1 normal sib 10 M Birth 2 + Not done Mennonite: 2 normal sibs 11 M 1kmth. 5 + + 3 normal sibs 12 F 5 wk. 2 + Not done 1 sib died at 3 years 13 F 3 mth. 6 + 0 2 sibs died in infancy; l________ _____________________ 2 normal sibs * + indicates patient exhibited this feature; 0 indicates patient did not exhibit this feature. TABLE II Necropsy Findings of 13 Cases of Thymic Alymphoplasia Thymus Nodes and Spleen Case No. Absent Lymphoid Showing Lung Other Findings Weight (g.) Hassall's Hypoplasia* Lymphoid Bodies* Hypoplasia* 1 'Quite + + + Pneumocystis carinii; Moniliasis vocal cord; small' adenovirus pneumonia; fatty metamorphosis alveolar proteinosis liver, patent ductus 2 1 + + + Cytomegalic inclusion Cytomegalic inclusion disease; pyogenic disease of kidneys, pneumonia gut, adrenals, ovary; colonic haemorrbage 3 5 + + + Giant cell pneumonia; alveolar proteinosis 4 < 1 + + + Alveolar proteinosis; Enlarged spleen lung abscesses 5 5 No histology + Pyogenic pneumonia; alveolar proteinosis 6 Not examined + Pyogenic pneumonia; alveolar proteinosis 7 - + + + Alveolar proteinosis 8 3 + + + Giant cell pneumonia Mitral atresia, single ventricle, anomalous pulmonary drainage 9 < 2 + + + Tracheobronchitis Pyelonephritis, staphylococcal 10 1 No histology + Pseudomonas pneumonia meningitis 11 < 1 + + + Pneumocystis carinii Moniliasis 12 'Barely No histology + Pseudomonas pneumonia identifiable' 13 2 + + + Pneumocystis carinii * + indicates patient exhibited this feature. TABLE III Results of Assay of Immunoglobulins in Surviving Members of 'F' Family (mg./100 ml.) yA yM yG Father .. 404 163 990 Mother ... 261 324 1056 Brother (5 years old) 375 216 1452 Brother (2 weeks old) .. < 1-5 11 957 co p yrig h t. o n A p ril 5 , 2 0 2 1 b y g u e st. P ro te cte d b y h ttp ://a d c.b m j.co m / A rch D is C h ild : first p u b lish e d a s 1 0 .1 1 3 6 /a d c.4 2 .2 2 1 .4 0 o n 1 F e b ru a ry 1 9 6 7 . D o w n lo a d e d fro m http://adc.bmj.com/ Haworth, Hoogstraten, and Taylor TABLE IV Serum Protein Concentrations (g./100 ml.) in 8 Cases of Thymic Alymphoplasia Paper Electrophoresis Immunoassay Case ______________________ ________ _ No. Total oc 2y y MyProtein Albumin Globulin Globulin Globulin Globulin yA yM yG 2 4.9 3-19 0-18 0-69 0-63 0-13 3 5-5 3 94 0-22 0 54 0 61 0.19 4 4 5 3*14 0 20 0*69 0*34 0 14 ND* 0*06 ND y-globulin 5 ml. I.M. 4-8 3 00 0-23 0-96 0-51 0 12 y-globulin 6 ml. I.M. 5 5-0 3 32 0-30 0 49 0 47 0-15 ND ND 0 15 y-globulin 4 ml. I.M. 5-3 3-60 0-43 0-61 0-39 0 30 3-7 2-35 0 37 0 49 0 30 0 18 y-globulin 4 ml. I.M. 9 4-5 32 030 050 040 010 10 4 9 4-0 0 90 5-4 3-85 0-25 0 70 0 50 0 11 ND 0-02 0 05 y-globulin 6 ml. I.M. 6-2 3-88 0-42 0-86 0-64 0 39 5-7 3-85 0-23 0 90 0 50 0-21 y-globulin 6 ml. I.M. 6 6 4-61 0-28 0 90 0-64 0-25 ND 0 01 0 21 5-5 3-45 0 26 0-69 0-67 0-42 y-globulin 18 ml. I.M. 5-8 3-31 0 35 0-82 0 77 0-58 * ND = not detectable. The immunodiffusion method used (Haworth et al., 1965) was capable of detecting yA-globulin in excess of 1 -5 mg./100 ml., yM-globulin in excess of 2-5 mg./100 ml., and yG-globulin in excess of 5 0 mg./100 ml. globulin, intramuscularly. His general condition re- mained poor, and the signs in the chest increased in severity. A further chest radiograph shortly before death showed diffuse infiltration in both hilar areas and in the left lower lobe. Death occurred at the age of 15 weeks. The necropsy findings are presented in Table II. Case 4. The third child was born after a normal pregnancy and delivery (birthweight 3-63 kg.). At 1 week of age he developed an infected napkin rash for which he was given local medication and penicillin. He was first admitted to hospital at 41 months, because the rash had spread to involve the whole body. He was an emaciated, irritable, and pale infant, weighing 5 kg., who had a generalized rash, considered to be seborrhoea, with secondary bacterial infection. The chest was clinically and radiologically clear. There was no lymphadeno- pathy. Local treatment of the skin resulted in improve- ment, but a few days after admission he developed a purulent rhinorrhoea and an abscess of the scalp from both of which sites Staphylococcus aureus was cultured. Following treatment, his condition improved and he was discharged home. At 5i months he developed diarrhoea, vomiting, and anorexia, and was readmitted to hospital. Examination showed a toxic, malnourished, and dehydrated infant. His weight was 4 - 8 kg. and his length 62 cm. (both less than the 3rd centile). He had seborrhoeic dermatitis of the scalp and trunk and an otorrhoea. There was cervical, axillary, and inguinal lymphadenopathy, but the liver and spleen were not enlarged. The chest was clinically clear with the exception of a few riles at the base of the right lung. Laboratory findings. Hb on the first admission was 12 * 6 g./100 ml. and the white blood count 14,600/mm.3, with lymphocytes 5840/mm.3. Hb on the second admission was 8-7 g./100 ml. and white blood cell counts ranged from 3000-6400/mm.3, with lymphocyte counts of 720-2180/mm.3. Throat culture yielded pneumococci and a staphylococcus was recovered from the blood. The bone-marrow showed a granulo- poietic hyperplasia. Radiographs of the chest showed infiltration in both lower and both upper lobes. The results of serum protein electrophoresis and assay of the immunoglobulins are shown in Table IV. The blood group was 0 and no anti-A or anti-B isohaemoagglutinins could be detected in the serum. A drop of 500 2,4- dinitrofluorobenzene (DNFB) was placed on his skin, and challenge 14 days later with 0 1M DNFB produced an area of erythema (3 x 5 mm.) on two occasions. The Schick test was positive and he did not form antibodies following diphtheria toxoid immunization. The baby was treated with oxacillin, intravenous fluids, and blood. Following the diagnosis of hypo-y- globulinaemia, a total of 11 ml. y-globulin was given intramuscularly. He seemed to improve at first but 42 co p yrig h t. o n A p ril 5 , 2 0 2 1 b y g u e st. P ro te cte d b y h ttp ://a d c.b m j.co m / A rch D is C h ild : first p u b lish e d a s 1 0 .1 1 3 6 /a d c.4 2 .2 2 1 .4 0 o n 1 F e b ru a ry 1 9 6 7 . D o w n lo a d e d fro m http://adc.bmj.com/ Thymic Alymphoplasia soon there was a return of anorexia, abdominal disten- sion, diarrhoea, and vomiting, necessitating further intravenous fluid therapy. The chest deteriorated clinically and radiologically. The feet became red and puffy, and there was an erythematous mottled rash on the face and trunk. Death occurred at 61 months. The necropsy findings are summarized in Table II. Case 11. This baby boy was the fourth child of healthy parents who have three other healthy children, aged 3 to 8 years. He was born after a normal pregnancy and delivery (weight 3 * 71 kg.), and was well until 8 weeks when he developed diarrhoea. He continued to gain weight in spite of this, but at 131 weeks he became more ill and was admitted to the Children's Hospital, Winni- peg. Examination revealed a pale, wasted, and dehydrated baby, weighing 4 - 85 kg. (less than the 3rd centile). The chest was clear. The tip of the spleen could just be felt. There were no palpable lymph nodes. Pertinent laboratoryfindings. Hb was 12-6 g./100 ml. White blood counts ranged from 7200-16,800/mm.3, with lymphocyte counts of 1680-3820/mm.3 Radiographs of the chest showed infiltration in the upper lobe of the right lung. Pneumococci and haemolytic streptococci were isolated from the throat and Pseudomonas aeruginosa was grown from the nasopharynx. Serum protein estimations are shown in Table IV. A fat balance showed that 78% of ingested fat was excreted in the stool. Sensitization with 5% DNFB and challenge with 0 1M DNFB 14 days later resulted in an area of indura- tion 3 x 6 mm. The Schick test was positive and he did not form antitoxin following diphtheria toxoid immuni- zation. Two attempts to culture the peripheral lympho- cytes were unsuccessful. Initially the baby was treated for gastro-enteritis. However, diarrhoea, anorexia, and weight loss continued. He also developed signs of respiratory infection and oral moniliasis. Because of the hypoproteinaemia and hypo-y- globulinaemia, he was given 3 g. albumin intravenously and 6 ml. y-globulin intramuscularly. The immuno- logical defect, the deteriorating general condition, and the increasing respiratory difficulty suggested the possibility ofPneumocystis carinii infection, and efforts were made to obtain a supply ofpentamidine. Since this was not at first possible, stilbamidine was given in a daily dose of 20 mg. intramuscularly. Attempts were also made to obtain foetal thymus tissue to implant into the patient, but he died before this could be done. At the time of death he was 25- weeks old. The necropsy findings are summar- ized in Table II. Discussion It was possible to find detailed reports of 27 cases of thymic alymphoplasia or the Swiss type of hypo- y-globulinaemia (Kosenow and Schummelfeder, 1953; Tobler and Cottier, 1958; Hitzig et al., 1958; Jeune et al., 1959; Hitzig and Willi, 1961; Rosen, Gitlin, and Janeway, 1962; Gitlin and Craig, 1963; Sacrez, Willard, Beauvais, and Korn, 1963; Gitlin, Rosen, and Janeway, 1964; Bonnevier, Killander, Olding, and Vahlquist, 1964; Nezelof, Jammet, Lortholary, Labrune, and Lamy, 1964; Beltaos and McCreadie, 1965; Hitzig, Kay, and Cottier, 1965; Kadowaki, Thompson, Zuelzer, Woolley, Brough, and Gruber, 1965; Rosen, Gotoff, Craig, Ritchie, and Janeway, 1966; Fireman, Johnson, and Gitlin, 1966). In addition to these cases there were 9 reported cases of vaccinia gangrenosa or progressive vaccinia (Keidan, McCarthy, and Haworth, 1953; Kozinn, Sigel, and Gorrie, 1955; Somers, 1957; Jarkowski, Mohagheghi, and Nolting, 1963; White, 1963; Flewett and Ker, 1963; Allibone, Goldie, and Marmion, 1964; Hathaway, Githens, Blackburn, Fulginiti, and Kempe, 1965) and 3 cases dying of generalized BCG infection (Bonnevier et al., 1964; Falkmer, Lind, and Ploman, 1955; Ariztia, Moreno, Garces, and Montero, 1960; Bouton, Main- waring, and Smithells, 1963) which almost certainly had the same disorder. A number of other cases were mentioned, notably by Hitzig and Willi (1961), Barandun, Stampfli, Spengler, and Riva (1959), and Peterson et al. (1965), but insufficient detail was available to make an adequate review of these cases. The case of 'alymphocytosis' described by Donohue (1953) has been included in most previous reviews of thymic alymphoplasia, but in our opinion does not fall into this group. The symptoms appeared much later than is usual in this disorder and the patient survived until 29 months of age: at necropsy Hassall's corpuscles were present in the thymus, and the liver and spleen were much enlarged for which there was no adequate histological explanation. Hypoplasia of the thymus has been found in association with other disease syndromes: (1) 'reticular dysgenesis' or 'aleucocytosis' in which, as well as hypoplasia of all lymphoid tissues, there is complete myeloid aplasia with absent or very few circulating leucocytes (De Vaal and Seynhaeve, 1959; Gitlin, Vawter, and Craig, 1964); the 3 children with this disorder, who were described, died within a few days of birth of overwhelming infection; (2) ataxia-telangiectasia (Peterson et al., 1965); (3) the leprechaun syndrome (Salmon and Webb, 1963). The case described by Robbins, Miller, Arean, and Pearson (1965) may represent another variant and possibly an incomplete form of the disorder. This was a girl who had suffered from respiratory infection all her life. At 8 years of age she was small and underweight and had signs of pulmonary infection. She had lymphopenia and hypo-y- globulinaemia, and a lung biopsy showed Pneumo- cystis carinii pneumonia. She was treated with 43 co p yrig h t. o n A p ril 5 , 2 0 2 1 b y g u e st. P ro te cte d b y h ttp ://a d c.b m j.co m / A rch D is C h ild : first p u b lish e d a s 1 0 .1 1 3 6 /a d c.4 2 .2 2 1 .4 0 o n 1 F e b ru a ry 1 9 6 7 . D o w n lo a d e d fro m http://adc.bmj.com/ Haworth, Hoogstraten, and Taylor TABLE V Principal Presenting Symptoms in 22 Previously Reported Cases of Thymic Alymphoplasia (cases of progressive vaccinia and generalized BCG infection not included) and in 13 Cases in Present Series Reported Cases (22) Present Series (13) Presenting Symptoms. No. of Cases % Cases No. of Cases % Cases Cough .. .11 50 6 46 Diarrhoea 7 33 5 38 Anorexia and feeding difficulty 2 9 6 46 Rash (seborrhoea, impetigo, pustules) 6 27 2 15 Vomiting . . . 3 14 2 15 Loss of weight and 'failure to thrive' . . . 3 141 8 Fever .. .4 18 0 0 Mouth 'sores' . . .3 14 1 8 pentamidine and recovered. Another patient, a boy, is also difficult to classify (Breton, Walbaum, Boniface, Goudemand, and Dupont, 1963): he had recurrent infections from the age of 3 months, and showed lymphopenia, low levels of yG and yA- globulins, but raised levels of yM-globulin in the serum. He also had a haemolytic anaemia and the direct Coombs' test was positive. He was treated with corticosteroids and thymic extracts and was alive and apparently improving at 20 months. It was thought that it might be of value to com- pare the clinical and pathological features of our patients with the published reports of those with the Swiss type of hypo-y-globulinaemia. Sex. Of our patients, 7 were boys and 6 were girls. This approximately equal sex distribution is similar to that reported by European writers and could be explained by the defect being inherited as an autosomal recessive. The 6 reported by Gitlin and Craig (1963) in the United States were male as were 13 close relatives who died in infancy and who it seems probably had the same defect. These authors suggested that the condition was probably inherited as a sex-linked recessive trait. It appears possible that the disorder in the patient reported by White (1963) from Britain, a case of progressive vaccinia, was also inherited in the same manner, since 3 other boys on the mother's side of the family had died in infancy. Of the remaining 32 fully reported cases of thymic alymphoplasia, 21 were male and 11 were female. Thus, thymic alympho- plasia may possibly be inherited in two different ways: as a sex-linked recessive and as an autosomal recessive. Birth history and age of onset of symptoms. All 13 of our patients were born at term and birth- weights ranged from 2 78 to 3'91 kg. The birth- weight was recorded in 20 of the published reports and ranged from 2 * 82 to 4 *45 kg. In 6 of the 13 patients in the present series the symptoms began during the first week of life; in 1 other between 1 week and 1 month of age; in 3 between 1 and 2 months of age; and in the 3 remain- ing patients at 21, 3, and 4 months of age. In 2 of 27 reported cases of thymic alymphoplasia the symptoms dated from the first week of life; in 7 between 1 week and 1 month; in 5 between 1 and 2 months; in 6 between 2 and 3 months; and in 6 between 3 and 6 months. In one case the symp- toms dated from 21 months of age (Gitlin and Craig, 1963). Thus, the onset of symptoms began before 3 months of age in 77% of all cases. Of the 9 patients with vaccinia, 8 were apparently well until vaccinated between 1 and 4 months of age; the other, who was vaccinated at 6 months of age, had had oral moniliasis at 4 months (White, 1963). The 3 patients who died of generalized BCG infection were vaccinated between 2 and 4 days of age, and symptoms of generalized infection began at 21 months in 1 and at 6 months in the other 2. Clinical symptoms and signs. Table V shows the principal presenting symptoms in the previously reported cases and in the present series. Cough, often of a spasmodic nature, was one of the earliest symptoms in all cases. Anorexia, feeding difficulty, and gastro-intestinal symptoms were also common in our cases. On physical examination, respiratory system signs predominated in our series. Evidence of malnutri- tion was also a common feature. In 11 infants the weight on admission to hospital was at or below the 3rd centile, and the other 2 were at the 50th centile. The length of 4 of the children approximated to the 3rd centile. Table VI summarizes the clinical features of the 39 reported cases as well as of our own series. Signs of lung infection, diarrhoea, vomiting, oral moniliasis, and wasting predominated. The patients with progressive vaccinia and generalized BCG 44 co p yrig h t. o n A p ril 5 , 2 0 2 1 b y g u e st. P ro te cte d b y h ttp ://a d c.b m j.co m / A rch D is C h ild : first p u b lish e d a s 1 0 .1 1 3 6 /a d c.4 2 .2 2 1 .4 0 o n 1 F e b ru a ry 1 9 6 7 . D o w n lo a d e d fro m http://adc.bmj.com/ Thymic Alymphoplasia TABLE VI Principal Signs and Symptoms Exhibited During Course of Illness in Previously Reported Cases of Thymic Alymphoplasia and in Present Series Reported Cases* (39) Present Series (13) Signs and Symptoms No. Cases % Cases No. Cases % Cases Signs of respiratory infection .33 85 13 100 Diarrhoea 28 72 10 77 Thrush .21 54 5 38 Morbilliform rash 19 49 1 8 Wasting. 18 46 10 77 Vomiting 10 26 5 38 Hepatomegaly .10 26 3 23 Oedema.5 13 1 8 Convulsions .7 18 0 0 Skin sepsis 5* 13 4 31 Lymphadenopathy. 6 15 2 15 Splenomegaly .2 5 0 0 * The specific manifestations of progressive vaccinia and of BCG infection are not included in this analysis. infection originally presented with the characteristics of these conditions, but most of the cases later show- ed signs and symptoms similar to those of the other cases. A morbilliform rash was seen in only one of our patients. This rash was reported to be one of the characteristic features of the condition by Hitzig and Willi (1961). It commonly occurs following injec- tion of y-globulin, and it has been postulated that it may be due to histamine release provoked by the reaction of antibody in the y-globulin with some antigen in the patient. Case 6 in the series of Hitzig and Willi also developed urticaria following y-globulin administration. In 5 of our cases the possibility of fibrocystic disease was considered in the differential diagnosis, because of the chronic respiratory infection and diarrhoea. One case described by Hitzig and Willi (1961) exhibited the clinical manifestations of the coeliac syndrome. Laboratory investigations. White blood cell counts: 44 total white blood cell counts and 45 differential counts from 12 of our patients were available for analysis. In one (Case 7) no white cell count was performed, and another (Case 12) had only a differential count. The highest and lowest total white cell and abso- lute lymphocyte counts of our patients and those published are analysed in Tables VII and VIII. Total white cell counts were very variable. Leucocytosis (counts of more than 15,000/mm.3) was fairly common. Terminal leucopenia and neutropenia were also frequently observed, includ- ing Case 8 in the present series. The lymphocyte count in normal infants between 2 and 6 months of age is 5000 to 6000/mm.3 (Tobler and Cottier, 1958; Smith and Vaughan, 1964). Two of the published cases had isolated total lymphocyte counts greater than 5000/mm.3, one following a thymic transplant and the intravenous injection of foetal liver (Hitzig et al., 1958; Hitzig et al., 1965). In another case an isolated count of 4200/mm.3 was recorded (Gitlin and Craig, 1963). A male Negro infant with thymic alymphoplasia described by Kadowaki et al. (1965) had XX/XY chimerism in the peripheral lymphocytes. The authors postulated an early intrauterine graft of TABLE VII Highest and Lowest Total WBC Counts in Previously Reported Cases of Thymic Alymphoplasia and in Present Series Reported Cases (39) Present Series (11) Count/mm.3 1 Lowest Highest Lowest Highest < 1000. 3 (8) - 1 (9) 1000-2999 9 (23) 4 (10) 1 (9) - 3000-4999 13 (33) 4 (10) 2 (18) - 5000-6999 5 (13) 5 (13) 2 (18) 2 (18) 7000-9999 4 (10) 7 (18) 2 (18) 2 (18) 10,000-15,000 .3 (8) 10 (26) 1 (9) 1 (9) > 15,000 2 (5) 9 (23) 2 (18) 6 (55) The figures show the number of cases with total WBC counts in the group indicated and figures in parentheses are percentages of the total cases. 45 co p yrig h t. o n A p ril 5 , 2 0 2 1 b y g u e st. P ro te cte d b y h ttp ://a d c.b m j.co m / A rch D is C h ild : first p u b lish e d a s 1 0 .1 1 3 6 /a d c.4 2 .2 2 1 .4 0 o n 1 F e b ru a ry 1 9 6 7 . D o w n lo a d e d fro m http://adc.bmj.com/ Haworth, Hoogstraten, and Taylor TABLE VIII Highest and Lowest Absolute Lymphocyte Counts in Previously Published Cases of Thymic Alymphoplasia and in Present Series Reported Cases (39) Present Series (12) Counts/mm.3 Lowest Highest Lowest Highest 0-99 8 (21) - 2 (17) 2 (17) 100-499 .12 (31) 5 (13) 3 (25) 500-999 .12 (31) 11 (28) 2 (17) 1 (8) 1000-1999 6 (15) 14 (36) 3 (25) 3 (25) 2000-2999. 2 (5) 2 (17) 1 (8) > 3000 . 1 (3) 7 (18) - 5 (42) The figures show the number of cases with lymphocyte counts in the range indicated and figures in parentheses are percentages of the total cases. maternal cells. This patient showed total lympho- cyte counts of 3000-5000/mm.3, but when a calcula- tion was made of the circulating lymphocytes formed by the patient's own system, lymphopenic values prevailed. Five of our patients showed lymphocyte counts greater than 3000/mm.3 on one or more occasions (Cases 1, 2, 4, 8, and 11). Case 2 had a peripheral lymphocyte count of 8000/mm.3 on 2 occasions, and Cases 4, 8, and 11 each had a single lymphocyte count of approximately 6000/mm.3 The latter 3, however, had other lymphocyte counts of less than 2000/mm.3 on one or more occasions. It has been suggested that in these patients the lymphocyte counts decrease towards the end of their lives. This was so in a number of the reported cases, but in our experience it was not an invariable finding. Of the 8 patients in whom two or more lymphocyte counts were recorded, 4 had lower counts terminally than on initial examination, and in the other 4 patients the final counts were higher. Thus, the lymphocyte count is obviously variable in this condition. Lymphopenia may be present at birth or may develop later in the course of the disease. Other haematological findings. Of the infants in the present series, 3 developed anaemia severe enough to require blood transfusion; in one (Case 2) the anaemia was preceded by gastro-intestinal haemorrhage and was associated with thromboctyo- penia. The other 2 had microcytic hypochromic anaemias and no source of blood loss was detected. 8 other infants in whom Hb values were recorded showed no anaemia. A terminal pancytopenia was recorded in 3 of the previously published cases (Hitzig et al., 1958; Hathaway et al., 1965) and 2 others had thrombo- cytopenia (Gitlin and Craig, 1963). Four in our series had bone-marrow examinations during life. In all of them plasma cells were absent. Three of them showed granulopoietic hyperplasia, and in the fourth (Case 8) with neutropenia, there was granulopoietic hypoplasia. Serum protein concentrations. Serum protein estimations were performed by paper electrophoresis in 7 patients in the present series, and in another, the albumin and globulin fractions were measured. In 3 of the patients the immunoglobulins were estimat- ed by immunoassay. The results are shown in Table IV. Hypo-y-globulinaemia was found in 6 patients; in the seventh (Case 13) the y-globulin levels were within the normal range for an infant of 4 to 6 months of age. Immunoassay showed no detectable yA-globulin and very low or undetectable amounts of yM-globulin. In Case 4, yG-globulin could not be detected by immunoassay despite a y-globulin concentration of 140 mg./100 ml., as estimated by paper electrophoresis. Absence or gross deficiency of the immuno- globulins was found in most of the cases of thymic alymphoplasia reported. However, in one the concentration of the immunoglobulins in the serum was normal (Nezelof et al., 1964), in another yG-globulin was decreased, but yA- and yM- globulins were normal (Kadowaki et al., 1965), and in a third yG and yA were deficient but the concen- tration of yM-globulin was increased (Fireman et al., 1966). In each of these three cases plasma cells were seen in various lymphoid tissues. It thus appears that in man, plasma cells, the immuno- globulin-producing cells, may develop independent- ly of the thymus and the small lymphocyte. In the chick the bursa of Fabricius is necessary for the development of the immunoglobulin-producing system, and Petersen et al. (1965) suggested that in man the palatine tonsil, and perhaps other lymphoid tissue in the gastro-intestinal tract, may be the homologue of the chick bursa. However, in the case described by Fireman et al. (1966) there was hypoplasia of the lymphoid tissue in the gastro- 46 co p yrig h t. o n A p ril 5 , 2 0 2 1 b y g u e st. P ro te cte d b y h ttp ://a d c.b m j.co m / A rch D is C h ild : first p u b lish e d a s 1 0 .1 1 3 6 /a d c.4 2 .2 2 1 .4 0 o n 1 F e b ru a ry 1 9 6 7 . D o w n lo a d e d fro m http://adc.bmj.com/ Thymic Alymphoplasia intestinal tract, including the tonsil, with absence of germinal centres and plasma cells, and so evidently the site of origin of plasma cells in man remains uncertain. Immunologicalfindings. As stated above, Cases 4 and 11 did not form antibodies following immuniza- tion with diphtheria toxoid, and the Schick test remained positive. Case 4 also had no isohaemag- glutinins in the serum. Both cases, however, show- ed delayed hypersensitivity when challenged with DNFB and this was a most unexpected finding. These were 2 of the cases which showed the greatest number of circulating lymphocytes, and it must be presumed that the lymphocytes in these infants were capable of producing a degree of cellular immunity. Gitlin et al. (1964) could demonstrate no delayed hypersensitivity in one patient following challenge with DNFB, dinitrochlorobenzene (DNCB), and Candida albicans antigen (though the latter became positive following a thymic transplant, the donor being hypersensitive to the antigen). In addition, rejection of skin and thymic tissue grafts did not occur in this patient. Hitzig et al. (1965) reported absence of the delayed hypersensitivity reaction following challenge with DNCB on a number of occasions, and that a skin homograft was not rejected. Fireman et al. (1966) also found that the skin did not result in any demonstrable sensitivity to challenge with DNFB. In the 3 cases of generalized BCG infection, tuberculin skin tests were negative. No neutraliz- ing antibodies to vaccinia virus or antibodies in low titre were found in 5 of the cases of progressive vaccinia. Radiographic findings. One or more chest radiographs were obtained in all cases with one exception (Case 9). Case 13 was found to have pneumothorax on admission to hospital, and in the others diffuse densities were reported in one or more lobes of the lungs. The radiographs of 7 patients have recently been reviewed by Dr. A. E. Childe: in all of them the thymus looked small, giving rise to a narrow superior mediastinal shadow in the antero- posterior view and a translucent area behind the sternum in the lateral view. We are doubtful whether the failure to demonstrate thymus radio- graphically can be used as a diagnostic aid in thymic alymphoplasia, because in many chronic debilitating illnesses in patients of this age the thymus is very small. Radiographs of the pharynx in 4 patients revealed no adenoid tissue: this abnormality may be an important aid in diagnosis, as it is in the Bruton type of hypo-y-globulinaemia (Margulis, Feinberg, Lester, and Good, 1957). Age at death. In our series the average age at death was 4 months and all were dead by the age of 7 months. The average age of death in the pre- viously reported cases of thymic alymphoplasia was rather greater than in ours (mean 8 * 4 months, range 3-24 months) and girls died younger than boys (mean ages 6 6 and 9 4 months, respectively). Some of the cases which survived longest were in the series of Gitlin and Craig (1963), in which the disorder was possibly inherited as a sex-linked recessive trait. The immediate cause of death in all our cases appeared to be pneumonia, with a coexisting congenital heart lesion in one. Case 5 inhaled a milk feeding just before death. Two of the reported cases had terminal cor pulmonale (Gitlin and Craig, 1963), and another, who had oedema and ascites, also probably died in cardiac failure (Tobler and Cottier, 1958). Three infants had terminal convulsions, one associated with a haemorrhagic uraemic syndrome (Hitzig et al., 1958; Gitlin and Craig, 1963). Racial origin and family history. Seven of the patients reported here were from 5 Mennonite families. This ethnic group immigrated to central Canada from Russia and Eastern Europe during the latter decades of the last century and have generally married within their own order. It has not been possible to link the families together, though cousin marriages are common in the Mennonite group, and it seems likely that the families may be distantly related. As far as can be determined, these Mennonite families did not originate in Switzerland, and we can trace no connexion between them and the cases of thymic alymphoplasia reported from that country (W. H. Hitzig, 1966, personal com- munication). Cases 5 and 6 were brother and sister and came of a large family. There is consanguinity on the father's side, the grandparents being second cousins. As far as is known there have been no infant deaths on this side of the family but several of the maternal great grandmother's children by her first marriage are reported to have died in infancy. Case 7 was also a Mennonite. He died in 1950 and it has not been possible to trace the family recently. He was the sixth child of whom only 2, both girls age 7 and 3 years, were living. Three other children, 2 boys and a girl, had died at 1, 2, and 3 months of age, respectively, the first two from pneumonia and the third following an illness which had included skin pustules, diarrhoea, and pneu- monia. 47 co p yrig h t. o n A p ril 5 , 2 0 2 1 b y g u e st. P ro te cte d b y h ttp ://a d c.b m j.co m / A rch D is C h ild : first p u b lish e d a s 1 0 .1 1 3 6 /a d c.4 2 .2 2 1 .4 0 o n 1 F e b ru a ry 1 9 6 7 . D o w n lo a d e d fro m http://adc.bmj.com/ Haworth, Hoogstraten, and Taylor Part N. American Indian