Annals of Case Reports

Introduction

Autosomal Recessive Polycystic Kidney Disease (ARPKD) is a prevalent kidney disorder marked by the development of large cystic kidneys and hepatic fibrosis [1]. ARPKD carries significant kidney and liver-related morbidity and mortality in children. The severity of the disease varies widely; some individuals succumb to the disease in the neonatal period, while others survive into adulthood [2]. The estimated occurrence of the condition ranges from 1 in 10,000 to 1 in 40,000 live births. However, the actual incidence may be higher, as the most severely affected newborns may not survive beyond the first few days of life and may never receive a confirmed diagnosis [3]. ARPKD is caused by mutations in the PKHD1 gene, which is located on chromosome 6p12. This gene is notably large, containing at least 86 exons that can undergo alternative splicing. Individuals with ARPKD who have two truncating mutations in the PKHD1 gene generally exhibit a severe phenotype leading to death during the perinatal or neonatal period. In contrast, those who survive the neonatal period typically have at least one missense mutation [2].

22q11.2 DS is the most common microdeletion syndrome with an estimated prevalence of 1 in 2148 live births and a very heterogeneous presentation [4]. The hallmarks of this multisystem disorder are defined by immunodeficiency secondary to thymic hypoplasia or aplasia, hypoparathyroidism, and cardiac abnormalities [5]. While 22q11.2 DS can also present with renal complications, no cases of its co-occurrence with ARPKD have been documented in the literature.

Here, we present the case of a 10-year-old male diagnosed with both 22q11.2 DS and ARPKD. Genetic testing revealed one pathogenic variant in the PKHD1 gene and two other variants in the same gene, which were classified as VUS. This report aims to highlight the clinical features, diagnostic workup, and management considerations of this unique dual-diagnosis case while exploring potential genetic interactions and their implications.

Case Presentation

A 10-year-old Hispanic male presented with a longstanding history of 22q11.2 DS 2.5MB deletion involving the TBX1 gene. His medical history was significant for autism spectrum, asthma, speech delay, developmental delay, repaired tetralogy of Fallot, GERD, recurrent respiratory tract infections, allergic rhinitis, and renal cysts. His family history was otherwise unremarkable.

When the patient first came for evaluation to our 22q Multidisciplinary Clinic at Joe DiMaggio Children’s Hospital in 2020, the primary goal was to seek genetic counseling and management for 22q11.2 DS following a recent relocation. During the visit, the mother provided a comprehensive history of the patient’s renal disease, which was first identified shortly after birth through a kidney ultrasound revealing renal fluid accumulation and cyst formation. The patient reported chronic intermittent abdominal pain; therefore, an abdominal ultrasound and kidney function tests were ordered for further evaluation. Notably, he had no history of hypertension, hematuria, urinary tract infections, or kidney stones. The abdominal ultrasound revealed abnormally echogenic kidneys with multiple tiny bilateral cysts. The largest cyst in the right kidney measured 3 mm. Cystic structures were also found in the right hepatic dome. The patient’s BUN was elevated at 28, with a BUN/Creatinine ratio of 62. Additionally, the albumin/globulin ratio was low at 1.4. Because these findings were atypical for 22q11.2 DS, a referral to a nephrologist was recommended. However, the patient was lost to follow-up during the COVID-19 pandemic and did not receive care until 2022.

Follow-ups included discussions of his high risk of renal and genitourinary anomalies due to 22q11.2 DS and subsequent testing. A 2023 renal ultrasound showed normal kidney size and echogenicity, with a 4 mm cyst in the right kidney and a 6 mm cyst in the left kidney. Additionally, the 2023 ultrasound of the abdomen revealed multiple hepatic cysts, the largest measuring up to 1 cm. Bloodwork from 2023 to 2024 indicated elevated BUN, BUN/Creatinine ratio, and AST levels, suggestive of impaired renal and liver function. An abdominal MRI was ordered for further evaluation of renal and hepatic cysts which is pending insurance approval. Further genetic testing was also ordered. The patient's expanded genetic testing revealed three heterozygous variants in the PKHD1 gene. 

In terms of his immune system, he has a history of recurrent sinopulmonary infections. Immune labs have revealed normal serum immunoglobulins, but persistent T cell lymphopenia and low titers to Streptococcus pneumoniae. He received a PPSV23 booster vaccine in March 2022 and mounted an excellent response initially. However, his most recent labs revealed he has lost over 50% of the protective pneumococcal titers he had after booster vaccination. Given that he has not been experiencing recurrent bacterial infections, a second Pneumovax has been deferred at this time. However, his CD4 T-cell count, and pneumococcal titers continue to be closely monitored.

The patient’s growth parameters indicated he was at the 5th percentile for height (Z = -1.65) and the 10th percentile for weight (Z = -1.31) based on CDC Stature-for-Age and Weight-for-Age data for boys aged 2-20 years, using vitals recorded on 4/17/2024. The patient will continue to undergo frequent renal function monitoring, close GI follow-up, and regular imaging to monitor his polycystic disease, as well as multidisciplinary care for his 22q11.2 DS.

Discussion

The purpose of this case report is to highlight a rare and unique presentation of 22q11.2 deletion syndrome occurring in conjunction with ARPKD in a 10-year-old male, along with its clinical implications. While various renal abnormalities have been documented in the literature, there have been no prior reports of ARPKD associated with 22q11.2 DS, making this case an unprecedented finding.

The patient's expanded genetic testing revealed a complex picture, identifying three heterozygous variants in the PKD1 gene. One of these variants was classified as likely pathogenic, while the other two were classified as VUS by the genetic lab [6].The pathogenic variant, described as p. (Cos660Arg) (TGC>CGC): c.1978 T>C is found in exon 21 of the PKHD1 gene. This variant was reported with a second variant in a patient with ARPKD in published literature [7]. The same variant was observed in homozygous state in a patient with ARPKD referred for genetic testing in GeneDx [6]. In silicon analysis supports that this missense variant has deleterious effect on protein structure and function. The variant is not observed at significant frequency in large population cohorts [6]. The first VUS is described as p. AAla1030Val) (GCG>GTG): c. 3069 C>T. It is found in exon 27 of the PKHD1 gene. This variant was identified in a patient with ARPKD who did not harbor a second variant in the PKHD1 gene in published literature [8]. In silicon analysis supports that this missense variant has deleterious effect on protein structure/ function. The variant was also not observed at significant frequency in large population cohorts. The second VUS is described as p. (Arg2714Gln) (CGG>CAG): c8141 G>A. It is found in exon 51 on the PKHD1 gene. According to the genetic report of GeneDx, in silicon analysis supports that this missense variant does not alter protein structure and function. It was observed in large population cohorts and has not been published as pathogenic or benign.

As only one likely pathogenic variant was identified in PKHD1, this result is consistent with this patient being at least a carrier for ARPKD but does not establish a molecular diagnosis. This analysis cannot determine whether the identified variants are on the same allele (cis) or on opposite alleles (trans). Nonetheless, the presence of three variants, particularly one that is likely pathogenic and a VUS that has been seen in another patient with ARPKD, suggests a potential cumulative effect contributing to the patient's phenotype.

Due to the complexity of the genetic findings, additional investigations are recommended. Next-generation sequencing should be considered to identify any copy number variants, which may further clarify the genetic underpinnings of the patient's condition. The parents should also be tested to determine if they carry any of the same PKHD1 variants.

Given the combined findings of the identified PKHD1 variants and the patient's clinical presentation, which includes confirmed kidney and liver cysts, we recommend the following reclassifications: The variant currently classified as 'likely pathogenic' should be promoted to 'pathogenic'. This reclassification is supported by the patient's clinical findings, which are consistent with the known effects of PKHD1 mutations in ARPKD. The variant currently classified as a 'VUS', that was proven to have a deleterious effect on protein structure/function, and observed in another patient with ARPKD, should be promoted to 'likely pathogenic'. The fact that it has been seen in another ARPKD patient, coupled with the functional data, strongly suggests its contribution to the disease phenotype.

The clinical presentation of this patient, which includes renal and hepatic cysts, aligns with the known manifestations of ARPKD. The patient's initial presentation with renal fluid accumulation and cyst formation shortly after birth, along with the presence of multiple tiny bilateral renal cysts and hepatic cysts, are characteristic of ARPKD. The subsequent findings of elevated BUN, BUN/Creatinine ratio, and AST levels further support the diagnosis and underscore the impact on renal and liver function. The fact that the patient is a carrier for the autosomal recessive gene variant of PKHD1, is consistent with the genetic basis of ARPKD.

While individuals who are heterozygous for a PKHD1 pathogenic variant are typically not at risk of developing ARPKD, they can, in rare instances, manifest very mild cystic kidney manifestations or liver cysts. However, given that this patient has multiple variants, particularly one that is now recommended to be classified as 'pathogenic' and one that we also recommend being reclassified as 'likely pathogenic, we believe this suggests the combined effect of these two genetic defects in the PKHD1 as the most likey cause of the patient’s clinical presentation.

The literature reports several cases of 22q11.2 DS presenting alongside renal abnormalities such as congenital nephrotic syndrome, renal failure, multicystic kidneys, and renal agenesis. One notable case involved a Chinese newborn presenting with edema, dysmorphic facial features, and hypoproteinemia, who ultimately succumbed to cachexia. Chromosome microarray analysis identified two mutations in the NPHS1 gene, responsible for encoding nephrin and indicative of nephrotic syndrome, along with a 22q11.2 duplication [9]. Another case described a 9-year-old male with progressive cough and low-grade fever. Ultrasound revealed enlarged echogenic kidneys, and laboratory findings showed elevated blood urea nitrogen (84 mg/mL) and creatinine (5.3 mg/dL), indicative of renal failure [10].  In a separate instance, a 14-year-old female with developmental delay was found to have an absent left kidney, a characteristic association of 22q11.2 DS with renal agenesis [11]. Additionally, at least two other reports have documented unilateral renal agenesis co-occurring with 22q11.2 DS and Müllerian agenesis [12]. Another report described a 16-week-old fetus with a 22q11.2 DS exhibiting an absent right kidney and an enlarged, multicystic left kidney [13]. In fact, one study hypothesized that fetuses with multicystic dysplastic kidney and 22q11.2 DS may develop urinary system abnormalities due to alterations in the HNF1B, SNAP29, and CRKL genes [14]. These cases demonstrate the diverse and complex renal manifestations associated with 22q11.2 DS.

This case can therefore expand the spectrum of renal/liver abnormalities associated with 22q11.2 DS. To better understand the relationship between ARPKD and 22q11.2 DS, it is essential to investigate developmental pathways for potential overlap or shared mechanisms. For example, ARPKD is known to result from mutations in the PKHD1 gene, which is involved in renal and biliary duct development. It is possible that interactions between PKHD1 and genes implicated in 22q11.2 DS, such as CRKL or HNF1B, may underlie this presentation [14].

From a clinical perspective, this case illustrates the importance of comprehensive genetic testing and careful phenotypic evaluation in patients with unusual or overlapping features. Genetic counseling for 22q11.2 DS includes informing families that the mutation is typically de novo, with an affected individual having a 50% chance of passing the mutation to their offspring. Patients should be advised to undergo chromosome microarray analysis to identify the size of the deletion in order to account for all implicated genes. Additionally, a comprehensive family history should be obtained, focusing on recurrent infections, psychiatric disorders, congenital heart defects, and learning disabilities. For future reproductive counseling, options such as chorionic villus sampling in the first trimester and amniocentesis in the second trimester should be discussed [15]. Genetic counseling for ARPKD involves informing the patient that they carry virtually no risk of passing the mutation on to offspring. In addition, next-generation sequencing should be used to identify copy number variants [16].

The identification of both 22q11.2 DS and ARPKD in this patient has significant implications for prognosis and management. Regarding 22q11.2 DS, management is variable depending on the constellation of organ systems involved. Multidisciplinary care is becoming cornerstone. Treatments for ARPKD are limited but include respiratory, renal, growth, and liver support. Patients may utilize mechanical ventilation, gastrostomy, electrolyte therapy and portosystemic shunting as interventions. Close monitoring of hypertension and congenital hepatic fibrosis are also important [17].

Conclusion

This case highlights the rare coexistence of 22q11.2 DS ARPKD in a 10-year-old male. This unique case can contribute to the limited knowledge on dual diagnoses involving 22q11.2 DS and ARPKD and underscore the need for future research to investigate the potential genetic and mechanistic interactions, identify biomarkers, and explore targeted therapies.

The overlapping clinical features of these genetic disorders, including renal anomalies, and multisystem complications, emphasize the need for a comprehensive, multidisciplinary approach to diagnosis and management. Genetic testing plays a crucial role in the evaluation of atypical clinical presentations, as seen in this case, allowing for precise diagnoses that inform management strategies and long-term care. For patients with rare and complex conditions like these, integrated care involving nephrology, genetics, cardiology, and developmental specialists is essential to address their multifaceted needs. Additionally, the psychosocial impact and long-term outcomes of dual genetic diagnosis should be studied.

This report contributes to the limited literature on dual diagnoses involving 22q11.2 DS and ARPKD. Future research should explore potential genetic and mechanistic interactions between these two conditions, identify biomarkers for earlier diagnosis, and investigate targeted therapeutic strategies. Additionally, studies examining the psychosocial impact and long-term outcomes of such rare dual diagnoses could help improve the overall quality of care and patient support.

Conflict of Interest: On behalf of all authors, the corresponding author states that there is no conflict of interest.

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