876 Short reports Common variable with CD4+

T and overproduction of soluble J Clin Pathol: first published as 10.1136/jcp.50.10.876 on 1 October 1997. Downloaded from IL-2 receptor associated with Turner's syndrome and dorsal kyphoscoliosis

Rabab A Al-Attas, Amjad H S Rahi, El-Fatih E M Ahmed

Abstract XO karyotype, short stature, and sexual infan- An unusual combination of common vari- tilism) and autoimmune endocrinopathy is well able immunodeficiency (CVID) and Turn- recognised5; however, CVID has been reported er's syndrome in a Saudi woman aged 20 only once in association with this syndrome.6 years is presented. In addition to pan- We report an unusual association of CVID hypogammaglobulinaemia, the patient with CD4+ T lymphocytopenia, overproduc- had CD4+ T lymphocytopenia; however, tion of soluble IL-2 receptor (sIL-2R), and there was evidence of in vivo activation of skeletal malformation in a patient with Turn- T celis and overproduction of soluble er's syndrome. To the best of our knowledge, interleukin 2 receptor in culture super- this is the first documentation of such an un- nate. Mantoux test was positive, but usual presentation, at least from the Middle lymphoblastic response to non-specific East. mitogen was impaired. Immunogeneti- cally the patient was HLA-DR3 positive and karyotypically she was a mosaic Case report (45XO/46XX) with ring X chromosome A Saudi woman aged 20 years presented with a (46Xr(X)). The presence of severe kypho- history ofrecurrent chest and ear infection, and scoliosis was possibly related to ring X chronic diarrhoea since early childhood, she chromosome. This case highlights the also had sickle cell and a thalassaemia traits, grave consequences ofthe delayed diagno- and primary amenorrhoea. On clinical examin- sis of immunodeficiency and emphasises ation, the patient was found to be of short stat- the nature of CVID. ure with prepubertal appearance (height heterogeneous 1 8 cm, weight 20 kg). There was digital club-

(7 Clin Pathol 1997;50:876-879) http://jcp.bmj.com/ bing but no cyanosis. Eyes showed mild Keywords: common variable immunodeficiency; Turn- inflammation; there was no lymphadenopathy. er's syndrome; CD4+ T lymphocytopenia; soluble The patient had marked dorsal kyphoscoliosis interleukin 2 receptor with convexity towards the left side. Chest examination showed partial breast develop- Common variable immunodeficiency (CVID) ment and auscultation revealed crepitation.

is a rare disorder with an estimated prevalence on September 30, 2021 by guest. Protected copyright. of 1 per 100 000 population. The hallmark of the disease is hypogammaglobulinaemia affect- ing at least two of the three major serum immunoglobulin isotypes.' Typically patients Department of present with recurrent sinopulmonary infec- , Regional tions as well as a wide variety of autoimmune Laboratory and Blood and neoplastic disorders. Precise aetiopatho- A Bank, Dammam genesis is unknown, but retroviral infection, B Central Hospital, Ministry of Health, cell anergy, deficiency of several enzymes (such Eastern Province, as 5'-nucleotidase, glutathione, and dipeptidyl Dammam, Saudi peptidase IV), abnormality of subsets, T Arabia cell dysfunction, deficient antigen-TcR cou- RA Al-Attas pling, and abnormal cytokine production (such A H S Rahi as decreased synthesis of interleukin (IL)-2, Department of interferon t, IL-4, IL-5, IL-9, or increased pro- Internal Medicine duction of IL-4, IL-6, and tumour necrosis E-F E M Ahmed factor a) have been implicated.` Recently a subset of CVID with decreased CD4:CD8 Correspondence to: ratio and raised CD8+ suppressor T cells has Dr Al-Attas, Consultant Immunopathologist, been identified'; within this subset there is a Department of Immunology, rare occurrence of CD4+ T lymphocytopenia PO Box 6571, Dammam (< 20% of total lymphocytes) affecting mainly d 31452, Saudi Arabia. the virgin (CD4+, CD45RA+) helper T cells.4

Accepted for publication The association of Turner's syndrome (a sex Figure 1 Lateral view of the cervical spines showing 28 July 1997 chromosomal disorder with female phenotype, kyphosis in the lower region. Short reports 877

Laboratory investigation Routine biochemical profile was normal; sex

hormone analysis was not available. Routine J Clin Pathol: first published as 10.1136/jcp.50.10.876 on 1 October 1997. Downloaded from haematological indices were within normal range except for microcytosis and hypochromia because of thalassaemic trait. Haemoglobin electrophoresis showed 66.7% HbAl, 31.9% HbS, and 1.4% HbA2.

Tuberculin test Mantoux was positive in 2IU of PPD, the size of induration after 72 hours being 14 mm.

Cytogenetic study Buccal smear was negative for sex chromatin and chromosomal analysis showed mixoploidy of 45XO/46XX compatible with mosaic mono- somy X. In addition, chromosomal structural abnormality (ring X chromosome) was noted.

Microbiological study Sputum culture revealed growth of Haemo- philus influenzae, and stool examination showed Giardia lamblia and Trichomonas hom- Figure 2 Lateral view of dorsal spines showing kyphosis. inis. ELISA test was negative for human immu- nodeficiency (HIV) infection.

Immunological study Rate nephelometry showed marked reduction of all three major immunoglobulin classes (IgG 1 12 g/l, IgA 13 g/l, IgM 16 g/l). Serum isohaem- agglutin was severely reduced; as the patient |i was B+, anti-A was detectable only in undiluted serum (normal for age > 1:16). Immunofluo- i: rescence and haemagglutination tests for organ and non-organ specific autoantibodies were

negative. http://jcp.bmj.com/ d subsets-Flow cytometry for B and T and their subsets showed CD3+ T lymphocytes 82% (3040/gl), CD3` CD4+ helper T cells 13% (480/gl), CD3+, CD8+ suppressor/cytotoxic T cells 71% (2630/jl), A.. CD4+:CD8+ ratio 0.2, natural killer cells

(CD3-, CD16+, CD56+) 7% (260/jld), CD19+ B on September 30, 2021 by guest. Protected copyright. cell 3% (1 10/pl), and activated T (CD3+, DR+) 21%.

Figure 3 Anterioposterior chest radiogram showing In vitro lymphocyte stimulation study distortion of thoracic cage and hilar calcification. Peripheral mononuclear cells were separated on a discontinuous density gradient and Cardiovascular and abdominal examination cultured in microtitre plate suspended in was normal. The patient was partially deaf, RPMI 1640 (106 lymphocytes/ml). Standard mentally slow, and had been able to achieve not techniques were used for blastic transforma- more than primary education. tion using phytohaemagglutin (at three differ- 20 cell INVESTIGATIONS ent concentrations 10, 15, and pl/100 gl Radiology suspension). The transformation index in the Radiography of the spine showed kyphoscolio- patient's sample was 50% of the control at the same Soluble sis involving the lower cervical and upper dor- lymphocytes (tested time). sal leading to distortion of the thoracic IL-2 receptor (sIL-2R) was measured by spine in the cage and crowding of the ribs on the left side. ELISA (Genzyme, California, USA) it was 5900 There were bilateral bronchiectatic changes culture supernate; pg/ml (control < were used). with calcified areas in both hilar regions 100 pg/ml; 106 lymphocytes/ml suggestive of healed tubercular lesions (figs 1-3). HLA study Ultrasonography of the abdomen showed a Class I and class II histocompatibility antigens bulky spleen for stature; the left ovary was nor- were tested by NIH complement dependent mal but the right ovary was not visible, and the microlymphocytotoxicity technique. The pa- uterus was reduced in size. tient was HLA-DR3+ve.' 878 Short reports

Audiogram syndrome'2 immunoglobulin concentrations Audiogram showed bilateral conductive hear are usually normal. Our patient was HIV nega- loss, a grommet had been inserted three years tive at least at the time of and, presentation, J Clin Pathol: first published as 10.1136/jcp.50.10.876 on 1 October 1997. Downloaded from previously but was removed because of re- there was no evidence of other viral infection, peated ear infection. generalised sepsis, acute pyelonephritis, or dis- seminated fungal infection or history of immu- TREATMENT nosuppressive therapy. All of these are known On the basis ofcellular and humoral studies the to cause a severe reduction in the CD4+ popu- patient was diagnosed as having CVID; she lation. Increased production of sIL-2R has received intravenous y globulin (300 mg/kg), been previously reported in CVID.'" It is also a co-amoxiclav, and metronidazole. A course of feature of disease activity in rheumatic disor- chest physiotherapy was also given. The patient ders and several other inflammatory diseases, had gained 1.5 kg during her three week stay in and is believed to play an immunomodulatory hospital. role'4; whether this was responsible in part for the cellular immunodeficiency in our patient is Discussion a matter of conjecture. CVID is a heterogenous group of disorders The present patient represents a unique case having in common defective forma- of CVID; although clinical manifestations tion, particularly IgA and IgG subclasses. As a (sinopulmonary infection and diarrhoea) were consequence, many of the affected individuals typical, the combination of immunological are prone to recurrent bacterial infections. In abnormalities such as panhypogammaglobulin- addition, such individuals exhibit increased aemia, slight reduction of B cells (described in susceptibility to autoimmune diseases, malig- about 20% ofCVID cases)," selective CD4+ T nancy, and certain viral infections; these lymphocytopenia, increased CD8+ T suppres- features suggest a generalised immune dys- sor cells, and decreased CD4+:CD8+ ratio were regulation rather than simple humoral unusual. immunodeficiency.' Reduced CD4+:CD8+ ratio has been de- Low serum immunoglobulin in association scribed in a subset of CVID characterised by with Turner's syndrome does not show a splenomegaly and skin anergy. " We consider consistent pattern. Wood et al ' noted a the positive tuberculin test in this patient an decrease in IgM only, whereas Cacciari et al 5 important variation. This patient may belong found modest reductions in both IgG and IgM. to a new subgroup or a variant of the existing In addition they found slight reductions in T subgroup. The positive tuberculin test but and populations; there was concomitant depressed lymphoblastic transformation re- increase in null cells and decreased lymphocyte sponse to non-specific mitogen indicates that response to non-specific mitogens. On the con- the impairment of cell mediated immunity is trary, one report failed to document such selective and may explain absence of viral abnormalities.8 infection in our patient, despite reports of cer- The present case is unique in that IgA (not tain viral infections in some cases of CVID.' http://jcp.bmj.com/ previously documented in Turner's) as well as Moreover, response to recall antigens depends IgG and IgM were low, in addition to gross on memory T cells that are known to be raised qualitative and quantitative abnormalities of T in CVID.4 Patients with this immunopheno- cells. Furthermore, recurrent sinopulmonary typic alteration also show increased expression infection, probably resulting from IgG, defi- of adhesion molecules ICAM-1 (CD54) and ciency as part of general IgG deficiency had LFA-3 (CD58) on T cells indicating in vivo been a major problem in this patient, which has activation.4 Although we did not test for these on September 30, 2021 by guest. Protected copyright. not been highlighted in previous reports5-8 that markers, other evidence of activation, such as discuss immunodeficiency in Turner's syn- increased expression of HIA-DR and overpro- drome only in the context of autoimmunity. duction of sIL-2R were seen. Although we did Whether humoral or cellular immunodefi- not investigate the relative importance of T ciency in our patient was coincidental or caus- helper 1 and T helper 2 cytokine responses in ally associated with Turner's syndrome is not this patient, it would be relevant to include known, but there are now at least five well these in future studies on such cases. Further- established X linked immunodeficiency dis- more, it is now known that the y chain of the eases with known loci including Wiskott- IL-2 receptor coded by a gene located at Aldrich syndrome, X linked severe combined Xq(13.1) is found in multiple cytokine recep- immunodeficiency (X SCID), X linked agam- tor complex'0 and is shared by the receptors for maglobulinaemia, chronic granulomatous dis- IL-4, IL-7, IL-9, and IL-15. It would be inter- ease, and X linked hyper-IgM syndrome.9 The esting to examine expression of this common gene for the y chain of the IL-2 receptor gene product at cytoplasmic level either in located on Xq is mutated in X-SCID"; as this terms of the finished product or at the level of y chain is common to receptors of some other mRNA. interleukins such as IL-4, IL-7, IL-9, and Genetic susceptibility to CVID has been IL-15, the X chromosome plays a significant previously reported; many patients show in- role in immune regulation. creased prevalence of HLA-DR3, deletion of CD4+ T lymphocytopenia mimicking AIDS C4A gene, and presence of valine or alanine at has been documented in one case of CVID." position 57 in HLA-DQ ,B chain.' It is of inter- Reduction of CD4+ T lymphocytes to < 20% est that our patient was also DR3 positive. We of total T cells is also a feature of idiopathic did not test for deletion of C4A, but we will CD4+ T lymphocytopenia, but in this include this in our protocol for future study. As Short reports 879

DR3 is often associated with autoimmunity, 3 Aukrust P, Lein E, Kristofferson AK. Persistent activation of TNF system in a subgroup of patients with CVI: possible any patient with CVID with this HLA immunological and clinical consequences. Blood 1996;87:

haplotype requires close follow up. 676-86. J Clin Pathol: first published as 10.1136/jcp.50.10.876 on 1 October 1997. Downloaded from 4 Baumert E, Wolff-Vorbeck G, Schlesier P, Peter HH. On reviewing the literature, we found only Immunophenotypic alterations in subsets of patients with one case report of CVID in Turner's syndrome CVI. Clin Exp Immunol 1992;90:25-30. feature was recurrent 5 Cacciari E, Masi M, Fatini MP, Licastro F, Cicognani A, in which the presenting Pirazzoli P, et al. Serum immunoglobulin and lymphocyte sinopulmonary infection.6 To the best of our sub-populations derangments in Turner's syndrome. knowledge this is the second case report show- Immunogenet 1981;8:337-44. 6 Robson SC, Potter PC. Common variable immunodefi- ing this interesting combination; in addition, ciency in association with Turner's syndrome. _f Clin Lab we report a previously undocumented associ- Immunol 1990;32:143-6. 7 Wood CB, Martin W, Adinolfi M, Polani PE. Immu- ation of kyphoscoliosis. This malformation is noglobulins and X-chromosome [letter]. BMJ 1969;4: 110. probably related to ring X chromosome; this 8 Rongen-Westerlaken C, Rijkers GT, Scholtens EJ, Van Es A, Wit JM, van den Brande JL, et al. Immunologic studies in chromosomal structural abnormality is not a Turner's syndrome before and during treatment with common finding in Turner's syndrome,'5 but growth hormone. J Pediatr 1991; 119:268-72. with 9 Smith CIE, Vihinen M. Immunodeficiency databases-a when present, it is usually associated new research tool. Immunol Today 1196;17:495-6. severe phenotype.'6 If further cases come to 10 Puck JM. Molecular basis for three X-linked immune disor- light, this combination of immunodeficiency, ders. Hum Mol Genet 1994;3(suppl): 1457-61. 11 Kaczmarski RS, Webster ADB, Moxham T, Davison F, skeletal malformation, and structural chromo- Sutherland S, Mufti GJ. CD4+ lymphocytopenia due to somal aberration might constitute a novel syn- common variable immunodeficiency mimicking AIDS. _f Clin Pathol 1994;47:364-6. drome. 12 Spira TJ, Jones BM, Nicholson JKA, Lal RB, Rowe T, As diagnostic delay in this case had led to Mawle AC, et al. Idiopathic CD4+ T-lympho- cytopenia-an analysis of five patients with unexplained serious morbidity, we recommend that all cases . N Engl J Med 1993; 328:386-92. of Turner's syndrome should be carefully 13 Wright JJ, Wagner DK, Blaese RM, Hagengruber C, Wald- mann TA, Fleisher TA, et al. Characterization of CVID: examined, and at the earliest suggestion of identification of a subset of patients with distinctive immu- chronic or recurrent infection a full immuno- nophenotypic and clinical feature. Blood 1990;76:2046-51. logical assessment should be carried out. 14 Mahida YR, Gallagkar, Kurlak L, Hawkley CJ. Plasma and tissue IL-2 receptor level in inflammatory bowel disease. Clin Exp Immunol 1990;82:75-80. 1 Eisenstein EM, Sneller MC. Common variable immunode- 15 Dennis NR, Collins AL, Corolla JA. Three patients with ficiency: diagnosis and management. Ann Allerg ring X chromosome and severe phenotype. if Med Genet 1994;73:285-94. 1993;30:482-6. 2 Fischer MB, Hauber I, Eggenbauer H, Thon V, Vogel E, 16 Collins AL, Cockwell AE, Jacobs PA, Dennis NR. A Schaffer E, et al. A defect in early phase of T-cell receptor comparison of the clinical and cytogenetics findings in 9 mediated T-cell activation in patients with CVID. Blood patients with a ring (X) cell line and sixteen 45X patients. if 1994;84:4234-41. Med Genet 1994;31:528-33. http://jcp.bmj.com/ on September 30, 2021 by guest. Protected copyright.