Case Report

Case Report: Activating PIK3CD Mutation in a Patient with Refractory Ascites

by Emadia Elaki1, Abdulwahab Al-Ayoubi1*, Ghannam Al-Ghannam1, Abdulaziz Alsayegh1, Amani Siddig1, Ahmed Alawfi2, Arwa Safar Al Shaibani2, Yasser Al Barrak2, Eid Alrasheedi3, Adel Homoud Almudaibigh4

1Pediatric Allergy &Immunology Department, King Saud Medical City, Riyadh, Saudi Arabia

2Pediatric Gastroenterology King Saud Medical City, Riyadh, Saudi Arabia

3General Pediatric King Saud Medical City, Riyadh, Saudi Arabia

4Pediatric Hematomcology King Saud Medical City, Riyadh, Saudi Arabia

*Corresponding author: Abdulwahab Al-Ayoubi, Pediatric Allergy &Immunology Department, King Saud Medical City, Riyadh, Saudi Arabia.

Received Date: 02 February 2024

Accepted Date: 06 February 2024

Published Date: 08 February 2024

Citation: Elaki E, Al-Ayoubi A, Al-GhannamG, Alsayegh A, et al. (2024) Case Report: Activating PIK3CD Mutation in a Patient with Refractory Ascites. Ann Case Report 9: 1630. https://doi.org/10.29011/2574-7754.101630

Abstract

Background: Activated phosphoinositide 3-kinase delta syndrome (APDS) is a recently described combined immunodeficiency condition resulting from gain-of-function mutations in PIK3CD, which encodes the catalytic subunit of phosphoinositide 3-kinase D (PI3Kd). Mutations in PIK3CD cause primary immunodeficiency with a spectrum of clinical manifestations characterized by recurrent respiratory tract infections, susceptibility to uncontrolled viral infections, impaired vaccine response, autoimmunity, hepatosplenomegaly, and an increased incidence of B-cell lymphoproliferation and lymphoma. Diagnosis of these deficiencies is crucial for their management. In recent years, targeted treatment with selective PI3Kd inhibitors has had a substantial effect on controlling the symptoms of these diseases. Case Presentation: Herein, we report a case of a patient with genetically confirmed PIK3CD mutation who initially presented with generalized lymphadenopathy. Hepatosplenomegaly complicated by immune-mediated anemia and thrombocytopenia resolved after a splenectomy. Over the next few months, the patient developed idiopathic, severe, and refractory chronic ascites requiring repeated diagnostic and therapeutic paracentesis. We hypothesized that autoimmune ascites, after exclusion of common and rare causes of ascites, especially the PIK3CD mutation, is a risk factor for autoimmune complications. The patient responded well to the corticosteroid therapy. Conclusion: PIK3CD mutation is a rare primary immune disease associated with immune dysregulation, immunodeficiency, and malignancy. Autoimmune ascites is an extremely rarely reported complication that needs to be considered after ruling out other known causes.

Keywords: Activated PI3Kδ Syndrome; PIK3CD; Genetic variant; Sirolimus

Introduction

Primary immunodeficiencies are inherited disorders of the immune system that include approximately 500 single-gene inborn errors of immunity [1,2]. Genetic defects in the immune system lead to an increased susceptibility to recurrent, severe, or unusual infections. Recently, germline heterozygous gain-of-function (GOF) mutations in PIK3CD, encoding catalytic p110δ, have been shown to cause a primary immunodeficiency. Mutations in this gene can result in lymphadenopathy and combined immunodeficiency and have been reported to induce immunodeficiency in different ways [3]. Activated phosphoinositide 3-kinase δ syndrome (APDS) is a rare, autosomal dominant primary immunodeficiency caused by GOF mutation in PIK3CD or PIK3R1 genes. Overactivation of this kinase leads to the activation of mTOR, promotion of cell growth and protein synthesis, and inhibition of apoptosis, leading to autoimmunity, lymphoproliferation, and recurrent infections. Paradoxically, both loss-of-function and gain-of-function mutations of these genes lead to immunosuppression through different mechanisms [4,5]. The biochemical and clinical symptoms of patients with APDS1 (PIK3CD mutations) and APDS2 (PIK3R1 mutations) are similar [6,7]. (Tables 1)

Laboratory investigations

During admission and follow-up (before splenectomy)

After splenectomy

Recent Lab Values

Reference

White blood cell

14.34

1.84

3.74

27.78

23.9

4–12

Hemoglobin (g/dL)

7.5 g/L

7.4

9.1

11

9.98

12.9–15.5

Neutrophils

5.3

0.5

3

21.2

16.6

 

Platelets

98

29

64

848

596

150–350

Retic count

7.76

5.75

7.69

     

PT second

2.3

11.6

13.3

5.54

14.2

12.3–14.7

INR

1

1.1

1

 

1.1

0.8–1.2

PTT second

38

30

40

 

34.1

26–40

ESR

120

120

120

120

130

0–30 mm/h

CRP (mg/L)

221

78

9.37

75.36

10

<10

ALT

12

14

4.6

2.3

43

0–41

AST

20

54

13.1

18.1

42

0–40

ALP

130

107

92

129

170

<115

LDH

404

315

100

 

273

<248

Amylase

20

     

11

 

Total protein

(77.3 g/dl)

         

Bilirubin total

(6 µmol\L)

         

Immunological work up

IgA (g/L)

<0.3 g/dl

0.21

0.34

 

<0.5

0.76–3.9

IgG (g/L)

1.1 g/dl

2.5 g/dl

5.3 g/dl

 

6.78 g/dl

7.0–16.0

IgM (g/L)

41.6 g/dl

18.81 g /dl

10 g/dl

 

7.34 g/dl

0.45–2.30

IgE

6.3

         

CD3 Absolute count

3517

       

2000–6900

CD19 Absolute count

86

       

700–2500

CD16+CD56 Absolute count

619

       

100–1000

CD3+CD4 Absolute count

581

       

14005100

CD3+CD8 Absolute count

2635

       

600–2100

Sodium

141

139

138

     

Potassium

4.6

4.8

4.87

     

Phosphorus

1.58

1.04

1.45

     

Magnesium

0.94

0.78

1.02

     

Urea

1.03

3.6

1.8

     

Creatinine

18.7

18.8

24

     

Albumin

29.87

31.3

32

     

Ferritin

130.2

         

Ammonia

63.1

         

Anti SSA(RO)

Normal

         

Antibody 1.7 units

Table 1: Laboratory Investigation.

Case Presentation

A patient was admitted with septic arthritis when he was 12 months old and received a full course of antibiotics. Two months later, he had a similar episode. At 25 months, he was admitted with severe pneumonia and pleural effusion to the PICU, where he remained for a few days, and then moved to the general ward. At 29 months of age, he was admitted for bronchopneumonia.

At the age of 3 years, he was referred to our hospital, King Saud Medical City, with progressive abdominal distension, hepatosplenomegaly, and cytopenia. He thoroughly examined and common infectious, oncological, and metabolic causes were excluded. The basic immune workup was abnormal and showed high IgM and low IgG and IgA levels. Gene testing confirmed a heterozygous variant of the PIK3CD mutation. Therefore, regular intravenous immunoglobulin, prophylactic trimethoprim-sulfamethoxazole, and a pre-stem cell transplantation workup was initiated. He continued to have recurrent severe anemia and thrombocytopenia that required irradiated PRBC and platelet transfusion and did not respond well to corticosteroid and immunosuppressive therapy. Therefore, the patient underwent a splenectomy, which resulted in a substantial improvement in his blood profile. Rapamycin (sirolimus) was initiated, and the dose was adjusted based on serum drug levels.

However, over the next few months, he developed recurrent severe intractable ascites of undetermined etiology, complicated by peritonitis that required diagnostic and therapeutic ultrasound-guided paracentesis and pigtail drain placement several times (five times a year with approximately 5 L drained each time). In the absence of peritonitis, ascites fluids were transudate, and the serum ascetic albumin gradient (SAAG) was more than 1.1. Extensive workup by different subspecialties was performed, and both common and rare causes of ascites were ruled out. He was evaluated in another tertiary center, and no cause was identified.

Therefore, autoimmunity-related ascites was considered, and oral prednisolone was initiated at 2 mg/kg/d for two weeks then tapered gradually over six months. During the therapy, the patient was ascites-free for six months. However, at the end of corticosteroid tapering (0.125 mg/kg/dose) every other day, the patient experienced ascites relapse. Therefore, the initial prednisolone dose was resumed, and azathioprine was started. The patient was referred to a higher center for stem cell bone marrow transplantation.

 

Figure 1: A, B. Part of the spleen; C. Wedge biopsy showing expanded red bulb by sinusoidal dilatation, old hemorrhage (hemosiderin laden macrophages identified), fibrosis (feature of hemolytic anemia), and no malignancy.D. Lymph node biopsy showing reactive lymphoid hyperplasia and no malignancy.

Discussion

We present an overview of the clinical course of a patient with a unique clinical presentation of refractory ascites. Here, we report a case of a heterozygous, pathogenic, variant of PIK3CD, known as Known Saudi Mutation, including deleterious variants of PIK3CD. The present case is worth reporting because of the novelty of one of the clinical presentations of refractory ascites with undetectable causes. To the best of our knowledge, no PIK3CD mutations have been reported in patients with refractory autoimmune ascites.

In 2018, Simone et al. reported a case of 67-year-old male patients with autoimmune ascites who responded well to mycophenolate mofetil. APDS is a heterogeneous inborn error of immunity (IEI), first reported in 2013 [4]. It is caused by autosomal dominant mutations in PIK3CD (resulting in APDS1) or PIK3R1 (resulting in APDS2), which increases the activity of phosphoinositide-3-kinase delta (PI3Kd) [6]. Unfortunately, activating somatic PIK3CD mutations have been associated with variable clinical features, ranging from asymptomatic to severe immunodeficiency, causing profound complications and early death.

The most common clinical manifestation of APDS is recurrent respiratory infection. A complication of frequent respiratory tract infections is bronchiectasis [8], in addition to lymphoproliferative and autoinflammatory disease. Autoimmune presentations are features of APDS1 in up to 42% of cases [9]. Among these, were the most frequent manifestations, followed by Evans syndrome, type 1 diabetes mellitus, enteropathy, arthritis, SLE, autoimmune thyroiditis, sclerosing cholangitis, Sjogren syndrome, and autoimmune hepatitis [10,11].

Lymphoproliferation leads to lymphadenopathy and organomegaly and increases the risk of malignant lymphoma [12,13]. Some patients also experience failure to thrive, neurocognitive development, and syndromic features unrelated to immunodeficiency, especially APDS2, hyperextensibility of short stature, hyperextensibility of joints, and PIK3R1 variants [14].

Whole-genome sequencing is likely to become routine in IEI in the future. The new molecules being approved as targeted therapies will gain importance for the treatment of APDS and IEI in general [15] Genetic testing is a promising approach, and diagnosis via genetic testing is given priority over the clinical and even laboratory phenotypes and has been used successfully in diagnosing rare diseases [16].

Although our patient underwent two lymph node biopsies and a bone marrow biopsy that revealed no malignancies, he still requires long-term follow-up and lymph node biopsies in the future. The risk of malignancy increases with age. His initial presentation was pancytopenia (autoimmune anemia and thrombocytopenia), which responded well to splenectomy.