Neurology India, Vol. 59, No. 3, May-June, 2011, pp. 435-437
Recurrent pyogenic meningitis in a 17-year-old: A delayed presentation of X-linked agammaglobulinemia with growth hormone deficiency
Girish R Sabnis, Niteen D Karnik, Swati A Chavan, Deepa S Korivi
Department of General Medicine, Lokmanya Tilak Municipal Medical College and General Hospital, Sion, Mumbai, India
Correspondence Address: Girish R Sabnis 89/3, Society Bldg, Lane 3, Hindu Colony, Dadar (East), Mumbai- 400 014, Maharashtra India email@example.com
Date of Submission: 20-Feb-2011
Code Number: ni11125
AbstractWe report an adolescent male with X-linked agammaglobulinemia (XLA) and recurrent episodes of pyogenic meningitis. The workup for proportionate short stature revealed isolated growth hormone deficiency. This patient highlights the delayed presentation of the XLA variant and the need to consider primary immunodeficiency in patients with recurrent serious infections, irrespective of age.
Keywords: Isolated growth hormone deficiency, primary immunodeficiency, recurrent pyogenic meningitis, X-linked agammaglobulinemia
Recurrent meningitis is a challenging clinical problem needing early diagnosis of risk factors such as immunodeficiency or craniospinal defect to prevent recurrences.  We report an adolescent with X-linked agammaglobulinemia (XLA), isolated growth hormone deficiency (GHD), and three episodes of pyogenic meningitis.
A 17-year-old male presented with fever, headache, projectile vomiting, and drowsiness of 7-day duration and had single generalized convulsion on the day of admission. He had experienced two such similar episodes in the last three years, which were treated successfully. The patient was born of non-consanguineous marriage, full term, and completely immunized. There was no history of frequent or serious childhood infections, head trauma, cerebrospinal fluid (CSF) rhinorrhea, or ear discharge. There was no family history of similar illness.
On examination, he was febrile (39 o C) and blood pressure (BP) was 90/54 mm Hg. No rash or oral thrush were observed. The skull; spine; and ear, nose, throat (ENT) examinations were normal. Proportionate short stature (153 cm) and underdeveloped secondary sexual characteristics were noted. On neurological examination, he was conscious, oriented but drowsy, plantar response was extensor bilaterally, and meningeal signs were positive. Results of other system examinations were normal.
Investigations: Hemoglobin: 7.1 g/dL; peripheral smear: Microcytic, hypochromic RBCs, and no sickling; leucocyte count: 26,500/mm 3 , with neutrophilic pleocytosis; platelets: 490,000/mm 3 ; and sedimentation rate: 104 mm/hr. CSF findings [Table - 1] were consistent with pyogenic meningitis. Random blood glucose was 108 mg/dL, and retroviral serology was negative. Results of blood cultures were negative. Computed tomography (CT) of the brain [Figure - 1] revealed early gliotic changes in the right frontal lobe and mild ventricular enlargement. There was no structural defect at the skull base. Audiometry showed bilateral moderate sensorineural hearing loss. Echocardiography and abdominal ultrasound were grossly unremarkable.
An immunological screen revealed normal complement (C3, C4) levels and normal CD4 T-cell counts and CD4:CD8 ratio. Serum protein electrophoresis showed complete absence of the gamma globulin fraction [Table - 2] and component analysis by nephelometry showed extremely low levels [Se IgG <33.3 mg/dL (normal, 736-1195 mg/ dL) and Se IgA <6.67 mg/dL (normal, 81-369 mg/dL)]. CD-19 by fluorocytometry was absent, implying total absence of B-lymphocytes and corroborating XLA in this patient. Investigations for short stature: Radiological bone age was 10-12 years; human growth hormone level obtained 2 hr post-clonidine stimulation was very low (0.18 ng/mL; expected >3 ng/mL), with failure to normalize after testosterone priming; concomitant gonadotropin, prolactin, Thyroid Stimulating Hormone (TSH), and adrenocorticotropic hormone (ACTH) reserve levels were normal and pituitary magnetic resonance imaging was also normal.
He improved rapidly with intravenous ceftriaxone and initial dexamethasone therapy. He was thus discharged after 2 weeks with an advice for monthly intramuscular injection of benzathine penicillin 1.2 MU prophylaxis, as he has financial constraints for intravenous immunoglobulin (IVIG) therapy. However, he was re-admitted 6 months later with pneumonia, after two months of non-compliance of penicillin prophylaxis. He responded well to antibiotics. Further course over a year after resumption of penicillin prophylaxis has been unremarkable.
Recurrent meningitis is defined as a second or subsequent episode of meningitis caused by an organism other than the one that caused the first episode or by the same organism >3 weeks after completion of the therapy for the first episode.  Often, recurrent meningitis occurs in the presence of predisposing risk factors; in the review by Kline,  the reported risk factors included craniospinal defects in 72% of cases and immunodeficiency in 21%. The most common associated immunodeficiencies were immunoglobulin deficiency, complement deficiency, and hyposplenia.
X-linked agammaglobulinemia was the first primary immunodeficiency disease to be described in 1952 by Bruton.  It is usually diagnosed in the first decade, in males with recurrent bacterial infections. However, the diagnosis can be delayed into adulthood, with only 18 documented cases till 2008.  The molecular defect has been mapped to the Bruton tyrosine kinase (Btk) gene at band Xq21.3.  In the absence of functional Btk, mature B cells expressing the marker CD19 are few or absent. A variant disorder first reported in 1980, XLA with growth hormone deficiency,  has been associated with Btk mutations that result in a truncated message. A newly discovered mutation in myeloid elf-1-like factor may be responsible for the disease.  These patients may have delayed growth and puberty  and must be distinguished from patients with XLA who have poor growth secondary to malnutrition. Although chronic enteroviral meningoencephalitis is common in these patients,  recurrent bacterial meningitis is only rarely reported.  Encapsulated bacteria, most commonly Streptococcus pneumoniae, followed by Haemophilus influenzae type b and Staphylococcus species, are the typical pathogens. 
Measurement of IgG using quantitative techniques supports the diagnosis of XLA when the IgG level is less than 200 mg/dL, though higher levels are seen in about 10% of patients. Confirmation requires low (<1%) or absent expression of CD19+ lymphocytes. Measurement of monocyte Btk activity firmly establishes the diagnosis, but is rarely necessary. 
Until a gene therapy is developed, the mainstay of therapy for agammaglobulinemia is IVIG administration at a dose of 400-600 mg/kg/month.  A recent consensus statement suggests that maintaining trough IgG levels greater than 800 mg/dl prevents serious bacterial illness and enteroviral meningoencephalitis. Chronic antibiotic prophylaxis is used in centers with resource limitations,  as was done in our patient. While live vaccines are absolutely contraindicated, others have extremely low efficacy as these patients have no ability to mount an antibody response to any vaccine.  Antibody unresponsiveness to type 2 thymus-independent antigens may be overcome by inducing T-cell help for responses to polysaccharide antigens (eg, with conjugate vaccines).  The role of growth hormone supplementation in the GHD variant is not well-defined but is probably indicated, with reported benefit in one of the patients in the original report of 1980. 
Copyright 2011 - Neurology India
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