What congenital syndromes are associated with hypospadias, renal (kidney) agenesis, and possible cardiac anomalies?

Syndromes Associated with Hypospadias, Renal Agenesis, and Cardiac Anomalies

The triad of hypospadias, renal agenesis, and cardiac anomalies most strongly suggests 22q11.2 deletion syndrome (DiGeorge syndrome), CHARGE syndrome, or diabetic embryopathy, with 22q11.2DS being the most common genetic cause requiring immediate evaluation.

Primary Syndromes to Consider

22q11.2 Deletion Syndrome (DiGeorge Syndrome)

This is the most common genetic syndrome presenting with this constellation of features. 1

• Genitourinary manifestations affect approximately 15% of patients and include:

  • Hypospadias and cryptorchidism (more prevalent in males) 1
  • Unilateral renal agenesis 1
  • Multicystic dysplastic or hypoplastic kidney 1
  • Bilateral renal agenesis has been reported 1

• Cardiac anomalies occur in approximately 40% of cases and include: 1

  • Conotruncal defects, especially tetralogy of Fallot 1
  • Ventricular septal defect 1
  • Interrupted aortic arch 1
  • Vascular rings and other aortic arch abnormalities 1

• Inheritance pattern: De novo in 90-95% of cases; autosomal dominant in 5-10% 1

CHARGE Syndrome

CHARGE syndrome (CHD7 haploinsufficiency) presents with overlapping features and should be strongly considered. 1

• Genitourinary abnormalities are a cardinal feature of the acronym itself 1

• Cardiac defects are part of the variable features of DiGeorge-like presentation 1

• Additional distinguishing features include:

  • Coloboma 1
  • Choanal atresia 1
  • Growth retardation 1
  • Ear anomalies and cranial nerve dysfunction 1

• Inheritance: De novo in the majority of cases 1

Diabetic Embryopathy

Environmental exposure to maternal diabetes during embryogenesis produces this specific pattern. 1

• Classic triad includes:

  • Renal agenesis 1
  • Variable features of DiGeorge syndrome 1
  • Vertebral anomalies 1

• This is not inherited but represents an environmental teratogenic effect 1

Additional Syndromes with Partial Overlap

VACTERL Association

While VACTERL includes renal and cardiac anomalies, hypospadias is not a cardinal feature, making it less likely when all three findings are present together. 2

• Cardiovascular anomalies occur in 60-77.8% of cases, including VSD, ASD, PDA, tetralogy of Fallot, and TGA 2
• Renal anomalies are part of the diagnostic criteria 2
• Requires at least 3 of the cardinal features for diagnosis 2

Other Genetic Syndromes

Several other conditions show partial overlap but are less common:

• TBX1 and TBX2 deficiency: Present with variable features of DiGeorge syndrome including genitourinary and cardiac defects 1
• FOXI3 haploinsufficiency: Autosomal dominant with variable DiGeorge features 1
• Partial monosomy 10p: De novo with craniofacial malformation and variable DiGeorge features 1

Clinical Approach and Pitfalls

Immediate Evaluation Required

All patients presenting with this triad require:

• Complete physical examination including genital exam 1
• Screening renal and bladder ultrasound 1
• Echocardiography to evaluate for cardiac defects 1
• Genetic testing for 22q11.2 deletion and CHARGE syndrome 1

Common Pitfalls to Avoid

• Do not assume isolated findings: The presence of hypospadias alone warrants evaluation for renal anomalies, as congenital heart diseases are the most common malformations associated with urinary tract abnormalities 3
• Bilateral vs. unilateral renal agenesis: Bilateral renal agenesis with cardiac malformations may indicate abnormal WT1 expression and carries a different prognosis 4
• Maternal history is critical: Always obtain detailed maternal history regarding diabetes control during pregnancy, as diabetic embryopathy is preventable in future pregnancies 1

Associated Findings That Support Specific Diagnoses

• Facial dysmorphism, palatal defects, and hypocalcemia: Strongly suggest 22q11.2DS 1
• Coloboma and choanal atresia: Pathognomonic for CHARGE syndrome 1
• Multiple vertebral anomalies: Consider VACTERL association or diabetic embryopathy 1, 2

Prognosis and Surveillance

• 22q11.2DS patients require lifelong multidisciplinary follow-up including endocrinology (hypocalcemia, thyroid), immunology (variable immunodeficiency), and cardiology 1
• Isolated unilateral renal agenesis generally has good prognosis but requires lifetime monitoring for hypertension and renal insufficiency 3
• Vesicoureteral reflux is the most common contralateral kidney abnormality in unilateral renal agenesis and requires surveillance 3