Case Report - (2022) Volume 7, Issue 8
Retroperitoneal fibrosis is a rare disease that is often discovered late, and its most frequent complication is a non-functional kidney. Intravenous urography and ultrasound are essential for the diagnosis of complications. CT and MRI are the key examinations for a positive diagnosis. The objectives of our study are knowing the radiological aspects of idiopathic retroperitoneal fibrosis, Learning how to identify the principal signs of retroperitoneal fibrosis, Search for the main associated signs that can indicate a multi-systemic pathology.
Traumatic optic neuropathy • Visual evoked potential • Traumatic brain injury • Concussion • Disability
Primary immunodeficiencies (PID) are rare diseases caused by a deficiency or absence of immune system elements, including lymphocytes, phagocytes, and the complement system. Adenosine Deaminase (ADA) enzyme deficiency is an autosomal recessive inherited primary immunodeficiency and is classified as a subtype of Severe Combined Immunodeficiency (SCID) disease [1,2]. Adenosine deaminase is an enzyme involved in many cellular processes and is expressed on many cell surfaces. Deficient and impaired ADA activity results in the accumulation of metabolic substrates, especially dATP. Since lymphocyte maturation and functions are affected, ADA deficiency leads to Severe Combined Immunodeficiency (SCID) [3,4].
The incidence of ADA enzyme deficiency is estimated to be between 1:200,000 to 1: 1,000,000 live births [5]. SCID, which occurs due to ADA enzyme deficiency, is a rare disease [6]. Patients with severe combined immunodeficiency are hospitalized for severe infection in the first years of life, and these patients may experience growth retardation, persistent oral moniliasis, and chronic diarrhea. Early diagnosis of immunodeficiency based on the patient's symptoms is of great importance in improving the patient's life expectancy and quality of life. The rate of consanguineous marriage is quite high in our region, and in this study, we present a case of two sisters with ADA enzyme deficiency, an extremely rare subtype of PID. In addition, it is aimed to contribute to the literature on this disease, in which the life expectancy of patients can be extended with early diagnosis and treatment, and to emphasize the importance of early diagnosis in PID.
The patient was admitted to our hospital in February 2012, when she was three months old, with complaints of respiratory distress and vomiting. According to the anamnesis, the patient's parents were cousins (Figure 1), the respiratory distress that started when she was 15 days old was accompanied by vomiting, and the patient was hospitalized in the neonatal intensive care unit of an external center due to pneumonia. The patient was sent to our center for further examination, diagnosis, and treatment. According to the patient's family history, she has a two-yearold and completely healthy brother. The patient had the routine vaccines (BCG, Hib, DTaP), and no reaction occurred after the vaccinations. On physical examination at presentation, her height and weight were below the 3rd percentile, and there was extensive moniliasis of the mouth, tongue, buccal mucosa, and hard and soft palate. Eczematous rashes were observed all over the body and especially on the face. On auscultation, prominent rales and rhonchi were detected in the bases of both lungs.
Figure 1: Case 1, 6th month of treatment, scapular spurring.
The results obtained in laboratory tests were as follows:
WBC: 4100; Absolute Neutrophil Count (ANS): 2600; Absolute Lymphocyte Count (ALS): 100; IgG: 534 mg/dl; IgA:<6 mg/dl; IgM:<22 mg/dl; IgE:5 IU/ml; CD3:0%; CD4:0%; CD8: 22%; CD19: 2%; CD16-56:27%; CMV PCR:240 positive.
On radiological imaging, there were opacities consistent with peribronchovascular infiltration in all zones of the right lung and upper zones of the left lung. In addition, scapular spurring was observed in both scapulae (Figure 2). Immunodeficiency was considered due to lymphopenia, low immunoglobulin levels, and the absence of CD3 and CD4. IVIG treatment was started at a dose of 1 g/kg, and ganciclovir was administered at a dose of 10 mg/kg/day.
Figure 2: Chest X-ray at the time of admission.
Clinical exome analysis was planned for diagnostic purposes. In a short time, bone marrow transplantation was planned. Since the HLA samples taken from the patient's mother, father and sibling were not compatible, a donor search was initiated for unrelated transplantation. The patient, who was receiving IVIG treatment, was hospitalized for the second time at the age of 4 months with complaints of cough, generalized dermatitis and diarrhea. In laboratory examinations, severe lymphopenia was also noted (WBC: 6000/mm3; ANS: 2600; ALS: 50) (The results of laboratory tests performed during hospitalization are given in Table 1). During the hospitalization, the patient's blood pressure values remained around 140/80 mmHg (high for her age). Amlodipine was started at a dose of 0.2 mg/kg and enalapril at a dose of 0.2 mg/kg/day. Blood pressure returned to normal after antihypertensive treatment. Renal Doppler USG was performed due to hypertension, and no pathology was detected. Echocardiography revealed minimal pericardial effusion and left ventricular hypertrophy.
When the patient was 8.5 months old, she was hospitalized for the third time with the complaints of persistent vomiting occurring 7 times-8 times a day and respiratory distress. With the preliminary diagnosis of sepsis, 300 mg/kg/day of piperacillin-tazobactam was started. There was no growth in blood and urine cultures. Blood pressure increases up to 160/80 mmHg were recorded during the follow-up. 0.3 mg/kg/day amlodipine and 0.3 mg/kg/day enalapril treatment were administered. Brain CT, transcranial USG and Renal Doppler USG were performed to investigate the etiology of vomiting and the cause of hypertension. No pathology was detected in radiological imaging. On the 7th day of hospitalization, low saturation was noted in the patient, respiratory arrest developed, and intubation was performed. On chest X-ray, lung aeration in the right lower zone of the right lung was minimal, heart borders could not be outlined, there were signs of infiltration in the upper zone of the left lung, and the costovertebral angle was open in the lower zone of the left lung (Figure 3).
Figure 3: Chest x-ray with bilateral infiltrates compatible with ARDS.
Clinical exome analysis could not be performed due to sample incompatibility (insufficient number of I cells). Therefore, to confirm the diagnosis, a whole gene sequence analysis was applied to the samples taken from the parents. The results were as follows:
Maternal ADA gene: NM_000022.4 c.956_960delAAGAG (p.e319Gfs*3) (p.Glu319GlyfsTer3) (Heterozygous),
Paternal ADA gene: NM_000022.4 c.956_960delAAGAG (p.e319Gfs*3) (p.Glu319GlyfsTer3) (Heterozygous).
Genetic counseling was provided to the family. The mother applied to our center for genetic analysis due to unplanned pregnancy in 2016. ADA gene analysis was performed from the amniotic fluid obtained by amniocentesis. The result was as follows: NM_000022.4 c.956_960delAAGAG (p.e319Gfs*3) (p.Glu319GlyfsTer3) (Heterozygous).
The patient presented for the first time in June 2019, when she was 40 days old. From the patient's history, it was learned that one of her siblings had died, and her parents were relatives and carriers. Complaints of respiratory distress and wheezing started at 7 days of age, and she was admitted to a neonatal intensive care unit at 25 days of age. The patient has a healthy 9-year-old brother, a 3-year-old brother with amblyopia, and a sister who died at the age of 8.5 months due to ADA enzyme deficiency (Figure 4). According to physical examination, her height and weight were below the 3rd percentile, diffuse oral moniliasis was observed, and widespread rales in both lungs were present. Chest radiograph showed an absence of thymus shadow and infiltration in the lateral right lower lobe. PFO was detected on echocardiography, and there were no other findings. Immunodeficiency was considered due to growth retardation, hospitalization in the intensive care unit due to lung infection, a history of sibling death, and consanguineous marriage (Figure 5).
Figure 4: Family pedigree chart.
Figure 5: Case 2: No thymic shadow on chest X-ray.
Laboratory results at the time of presentation were as follows: WBC: 8300/mm3 (ANS: 6900, ALS: 100); IgG: 320 mg/dl; IgA: <0.10 mg/dl; IgM: 33 mg/dl; IgE: 5.15 IU/ml; CD4: 32%; CD8: 8%; CD19: 4%; CD3: 36%; CD45: 100%. (Table 2: Laboratory values before and after bone marrow transplantation in hospitalizations of the patient). The patient's ADA enzyme level was measured and genetic analysis was performed. ADA enzyme activity was determined as 0.0 nmol/h/mg (normal level=26.4 ± 10.0). Whole gene exome sequencing was performed and according to the analysis result, ADA gene: NM_000022.4 c.956_960delAAGAG (p.e319Gfs*3) (p.Glu319GlyfsTer3) (Homozygous).
The patient was started on IVIG treatment at a dose of 1 g/kg every 3 weeks. In July 2019, when the patient was 2 months old, ADA GEN ADA enzyme replacement therapy was started at a dose of 1*10 MIU/kg twice a week, and then the dose was gradually increased to 1*20 MIU/kg and 1*30 MIU/kg. There was no severe lung infection or hospitalization after enzyme replacement therapy and IVIG therapy. In March 2020, when the patient was 9 months old, unrelated allogeneic stem cell transplantation was performed (Figure 6). In May 2020, 2 months after bone marrow transplantation, the patient was hospitalized for vomiting and feeding problems. IV hydration therapy was given, and she was discharged on the 5th day of hospitalization due to the disappearance of symptoms.
Figure 6: Case 2: Scapular spurring on chest X-ray.
In June 2020, 3 months after bone marrow transplantation, the patient was hospitalized for the second time due to vomiting and diarrhea. Vital signs were stable, and IV fluid replacement was given. She was discharged on the 6th day of hospitalization due to the disappearance of symptoms (Figure 7). In July 2020, 4 months after the bone marrow transplantation, the patient was hospitalized again due to the detection of elevated creatinine (Cr = 3.27 mg/dl) in her routine outpatient visit. Laboratory results were as follows: WBC: 8200 (ANS: 4200, ALS: 1100); monocyte: 900; eosinophile: 800; Hgb: 8.2 g/dl; PLT: 293,000. IV fluid replacement was given, and the treatment dose was adjusted according to renal functions. The patient was discharged when the creatinine value decreased to 0.22 mg/dl (within normal limits for the age of the patient). The result of the chimerism test performed in November 2020 was 0%, and unrelated BMT was performed for the second time in January 2021. No metabolites were detected in the adenosine deaminase metabolite screening test performed after bone marrow transplantation. After the second bone marrow transplantation, the patient did not experience any symptoms and did not receive hospitalization. The patient's follow-up and treatment continue in our hospital's Pediatric Allergy and Immunology clinic (Figure 8).
Figure 7: Improved scapular spurring.
Figure 8: Case 2: Rashes
Severe Combined Immunodeficiencies (SCID) are a group of inherited disorders responsible for severe dysfunctions of the immune system. These diseases are life-threatening when the diagnosis is made too late; they are the most severe forms of primary immunodeficiency. SCID patients often die during the first two years of life if appropriate treatments to reconstitute their immune system are not undertaken.
In patients with Severe Combined Immunodeficiency, the findings usually appear between 4 months and 6 months after the disappearance of maternal antibodies. Findings include recurrent lung infections, chronic diarrhea, and growth retardation [7]. Adenosine Deaminase (ADA) enzyme deficiency is a subgroup of Severe Combined Immunodeficiencies. The clinical phenotypic spectrum associated with ADA deficiency includes early-onset SCID diagnosed in infancy, “delayed/late” onset Combined Immunodeficiency (CID), which has a milder course and is diagnosed in older children and adults, and benign “partial ADA deficiency” detected in population screenings or screenings of erythrocyte ADA activity deficiency in relatives of patients with SCID [8].
Early-onset SCID due to ADA deficiency is usually diagnosed between 4 months and 6 months of age. However, about 15% to 20% of children with ADA deficiency have a "delayed" onset of clinical symptoms. This type of enzyme deficiency is called the late-onset type and is usually diagnosed between the ages of one and ten [8]. Our patients had respiratory distress since the neonatal period.
ADA enzyme deficiency is characterized by severe lymphopenia (T cells, B cells, and NK cells are affected) and impaired cellular and humoral immunity [9]. Although the white blood cell count was normal in both cases, lymphopenia was prominent (Table 1 and 2). In Case 1, lymphopenia was remarkable at every hospital admission. In Case 2, while there was no improvement in lymphopenia after IVIG and ERT, improvement in lymphopenia was remarkable after the first BMT (Table 2). One of the non-immunological manifestations of ADA enzyme deficiency is bilateral sensorineural hearing loss [10].
According to Tanaka et al., two siblings with adenosine deaminase deficiency were successfully treated with allogeneic bone marrow transplantation. Although the patients were free from infections after immunologic reconstitution, both showed sensorineural deafness at 1 year of age. Because there were no structural abnormalities in the inner and middle ears, no evidence of prenatal infections of rubella, cytomegalovirus or toxoplasma, and no postnatal infection of mumps in the siblings, sensorineural deafness might be one of the neurologic problems associated with adenosine deaminase deficiency [11]. Another finding in ADA enzyme deficiency is pulmonary involvement. In a study by Grunebaum et al., Bronchoalveolar Lavage (BAL) fluid was examined in patients with SCID due to ADA enzyme deficiency. Most of the BAL materials obtained from these patients were compatible with pulmonary alveolar proteinosis [12]. Apart from these, non-immunological symptoms include neurological symptoms such as hypotonia or seizure [13]. There were no neurological symptoms in our cases, but unexplained high blood pressure, left ventricular hypertrophy, and cardiac involvement was noted in case 1 [14,15].
According to a study by Manson et al., approximately half of patients with ADA enzyme deficiency have characteristic anterior rib cupping, scapular spurring, and other skeletal abnormalities on radiological imaging at the time of diagnosis, and these abnormalities tend to resolve after a few months of treatment. When we look at the radiological findings in our cases, the absence of the thymus shadow in Case 2 and scapular spurring in both cases was remarkable . In Case 1, only IVIG treatment was applied, and bilateral scapular spurring, which was present at the time of diagnosis, was still present in the 6th-month chest X-ray (Figure 2). In Case 2, scapular spurring disappeared after ERT and IVIG. One of the brothers of the cases has not developed a health problem so far, but amblyopia is present in the other 3-year-old brother, who has the heterozygous ADA gene.
Treatment of ADA enzyme deficiency includes enzyme replacement therapy, allogeneic stem cell transplantation, and a new approach, autologous stem cell transplantation with gene therapy. Only intravenous immunoglobulin was used in Case 1, and intravenous immunoglobulin and enzyme replacement therapy was used in Case 2. Immunoglobulin levels increased after treatment, but lymphopenia continued (Tables 1 and 2). In Case 1, stem cell transplantation could not be performed because a donor could not be found, and the patient died due to respiratory failure. In Case 2, no symptoms developed after stem cell transplantation, laboratory findings were normal, and there was no hospitalization. This article, which includes two cases with this very rare disease, aims to draw attention to immune deficiencies and emphasize that non-immunological symptoms accompanying lymphopenia may be a warning for the rare ADA enzyme deficiency disease.
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Citation: Çay E. et al. A Rare Cause of Immunodeficiency: Two Sisters with the Diagnosis of Adenosine Deaminase (ADA) Enzyme Deficiency. Med Rep Case Stud. 2022, 07 (8),001-004.
Received: 04-Aug-2022, Manuscript No. MRCS-22-71281; Editor assigned: 06-Aug-2022, Pre QC No. MRCS- 22- 71281 (PQ); Reviewed: 16-Aug-2022, QC No. MRCS-22-71281 (Q); Revised: 18-Aug-2022, Manuscript No. MRCS- 22-71281 (R); Published: 21-Aug-2022, DOI: 10.4172/2572 5130.22.7(8).1000211
Copyright: ©2022 Çay E, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
