Case report

A Japanese boy aged 3 years 6 months was referred to our hospital for investigation into the cause of recurrent infections. His parents were cousins, and a 2 year old male sibling was healthy. There was no immunological disease or chromosomal abnormality among relatives. He had been born to a healthy mother with no history of medication or infection during the pregnancy at 42 weeks’ gestation and weighed 2098 g at birth. IUGR was diagnosed antenatally. At 47 days, patent ductus arteriosus and mild aortic stenosis were found. Cytogenetic study of peripheral lymphocytes revealed a karyotype of 46,XY,r(21)(p11 q22) in all 20 cells examined. High resolution analysis showed the fusion site of a ring chromosome 21 (fig 1). Heart failure resolved after ligation of the patent ductus arteriosus at 12 months of age. Convulsions emerged at 19 months of age and he suffered from acute hepatitis of an unknown cause at 24 months of age. Thereafter, he was hospitalised seven times during a period of 18 months because of pneumonia, otitis media, and convulsions.

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Figure 1

G banding karyotype and high resolution analysis of peripheral blood obtained from the patient showed 46,XY,r(21)(p11 q22).

On admission, physical examination revealed an alert short, skinny boy of 89 cm in height (−6.1 SD) weighing 8629 g (−3.9 SD) with high fever (39°C), tachycardia, and tachypnoea due to pneumonia. Antimongoloid slant, prominent and broad nasal bridge, large saccular low set ears, high arched palate, micrognathia, and cryptorchidism were noted, but there was no anaemia, jaundice, skin eruption, purpura, lymphadenopathy, or hepatosplenomegaly. Auscultation revealed respiratory moist rales and an ejection systolic heart murmur (Levine 3/6) at the left sternal border. Neurological examination demonstrated general hypertonicity, hyperactive reflexes, and psychomotor retardation. He was able to roll over, but could not crawl or sit up by himself. Peripheral blood counts showed a white cell count 15.4 × 10⁹/l with 3% metamyelocytes, 12% bands and 38% segmented neutrophils, 26% lymphocytes, 20% monocytes, and 1% eosinophils, red cell count 4140 × 10⁹/l, haemoglobin 123 g/l, and a platelet count of 45 × 10⁹/l. Blood chemistry indicated normal liver and kidney function. Analysis of the serum protein fraction before the first administration of gammaglobulin showed a total protein level of 41 g/l (normal range 67–83), with 63.7% albumin (59.7–70.8), 7.0% alpha₁- (1.6–2.9), 17.3% alpha₂- (5.8–9.1), 9.5% beta- (7.1–10.8), and 2.5% gammaglobulin (11.6–20.9) (1.0 g/l). The low albumin concentration was found only at that time. There was no protein loss in urine and stool. Serum immunoglobulin concentrations and specific antibody responses to measles immunisation were not examined before the first administration of gammaglobulin (10 g). Serum immunoglobulin concentrations two months after the first gammaglobulin replacement were documented as IgG 3.9 g/l (normal range 5.3–13.4), IgA <0.2 g/l (0.3–1.7), IgM 0.3 g/l (0.6–2.8), and IgE <24 μg/l (24–4320). Neutrophil function was normal with regard to superoxide anion release and chemoattractance. The expression of CD18 on lymphocytes and total haemolytic activity of complement were normal. Surface marker analysis of peripheral mononuclear cells revealed 70% T cells, 15% B cells, with a CD4/CD8 ratio of 0.78, and no skewing B cell subpopulation expressing any specific immunoglobulin class. Mitogen response of lymphocytes to phytohaemagglutinin and concanavalin A was normal. Superoxide dismutase activity (SOD) was normal (10.4%; normal range 6.4–12.8%). The findings of analyses of Bruton’s tyrosine kinase (Btk) activity and the Btk gene were normal as assessed by a previous method.8 Bone marrow aspiration yielded normocellular marrow with no abnormal cells. Platelet associated antibody was not detected.

The patient was hospitalised 11 times before his referral at 3 years 6 months of age, the first three admissions were for cardiac management, and the remaining eight were for the treatment of infections. However, during the next four years while receiving gammaglobulin replacement (2.5–5 g/month), he was hospitalised only once for the control of seizures, while maintaining serum IgG concentrations in excess of 4.0 g/l.

Discussion

This is the first reported case of a patient with ring chromosome 21 demonstrating the clinical association of hypogammaglobulinaemia and recurrent infections. Monosomy 21 syndrome was originally defined as group G monosomy; the first description was of an infant with multiple anomalies whose karyotype was 45,XY,-G/46,XY,r(G), characterised as antimongolism in contrast to trisomy 21 (Down’s syndrome).1 Advanced chromosome banding techniques have classified the group G monosomy into 21-deletion and 22-deletion syndromes based on their distinct clinical features. The patient described here showed the common phenotypic pictures described as monosomy 21 syndrome, such as growth retardation, psychomotor retardation, large saccular ears, prominent nose, high arched palate, and hypertonicity, along with unfamiliar features including cardiac anomaly, cryptorchidism, and thrombocytopenia, but with no skeletal malformation or eosinophilia. Although several reports have been published on monosomy 21 syndrome,1-6 including ring chromosome 21,9-12 hypogammaglobulinaemia was not described in detail. There was no report on the high resolution analysis of ring chromosome 21 associated with hypogammaglobulinaemia. In the review of Warren and Rimoin hypogammaglobulinaemia was reported in two out of three patients with G deletion (21-deletion) syndrome, but they provided no information about deficient IgG concentrations, cellular immunological functions or the clinical severity of infections.1 The patient studied by Gripenberg et al showed decreased gammaglobulin concentrations, although no IgG levels were described.4 Kaneko et alreported a male infant with ring chromosome 21 who suffered from occasional dyspnoeic pneumonias with low serum IgG concentrations (4.1 g/l).6

Some subjects with ring chromosome 18 have an IgG deficient state and this can partly lead to recurrent infections.13-15 The ring chromosome formation follows terminal deletions and the amount deleted may result in the clinical variety of presentation. The patient described here showed normal SOD activity and normal CD18 expression. Patients with an interstitial deletion of the chromosome segment 21q11 to 21q21.3 have minor anomalies and mental retardation, but not hypogammaglobulinaemia.16 In this context, the high resolution analysis of ring chromosome 21 (fig 1) suggests that hypogammaglobulinaemia associated genes may be located on the terminal deleted sites distal from q22.2 (SOD1) or q22.3 (CD18).17On the other hand, Theodoropoulos et al suggest that the critical region for a severe phenotype of 21q⁻ lies within 21q22.1-22.2.18 Most cases described as monosomy 21 represent unbalanced translocations or other structural aberrations resulting in only partial monosomy 21.19 Further DNA studies are required to explore the possibility that the hypogammaglobulinaemia is due to 21q⁻ deletion or other accompanied defects.20 The examination of Btk genes to exclude the chance association of X linked agammaglobulinaemia with this syndrome showed no abnormality. No excessive protein loss was evident. These indicate a congenital defect in immunoglobulin production in this syndrome, but do not confirm a specific intrinsic abnormality within the B cells. Our observation may provide helpful information in elucidating the basic mechanism of B cell maturation, as well as in the further mapping of chromosome 21.