What syndromes are associated with congenital renal dysplasia?

Syndromes Associated with Congenital Renal Dysplasia

Congenital renal dysplasia is associated with multiple genetic syndromes that require specific surveillance and management due to their high risk of morbidity and mortality.

Common Syndromic Associations

Mulibrey Nanism

• Autosomal recessive growth disorder caused by biallelic mutations in TRIM37
• Features:
  • Severe growth retardation
  • Distinct dysmorphic features
  • Constrictive pericarditis
  • Hepatomegaly
  • Male infertility
  • Insulin resistance
• High tumor risk (74% of patients develop tumors):
  • Wilms tumor (median age 2.5 years)
  • Renal papillary carcinoma
  • Various thyroid carcinomas
  • Requires renal ultrasound surveillance 1

Perlman Syndrome

• Autosomal recessive overgrowth syndrome (mutations in DIS3L2)
• Features:
  • Polyhydramnios
  • Macrosomia
  • Characteristic facial dysmorphology
  • Renal dysplasia and nephroblastomatosis
• High mortality (53% die in neonatal period)
• Very high Wilms tumor risk in survivors:
  • Earlier onset (<2 years vs 3-4 years in sporadic cases)
  • High rate of bilateral tumors (55%)
  • Requires intensive surveillance 1

Simpson-Golabi-Behmel Syndrome (SGBS)

• X-linked disorder (mutations in GPC3 or GPC4)
• Features:
  • Pre- and postnatal macrosomia
  • Distinctive craniofacies (macrocephaly, coarse features)
  • Macroglossia
  • Intellectual disability
  • Skeletal anomalies
• Associated tumors:
  • Wilms tumor and nephroblastomatosis
  • Liver tumors in children 1

Prune Belly Syndrome

• Characterized by:
  • Marked deficiency of abdominal muscles
  • Bilateral cryptorchidism
  • Urinary tract abnormalities
• Histologically shows renal dysplasia
• Urinary tract features:
  • Partial/total absence of muscle fibers in ureter
  • Hypertrophy of the bladder
  • Dilated prostatic urethra
• Prognosis depends on functional renal parenchyma and degree of dysplasia 2

Pathophysiology and Classification

Renal dysplasia represents aberrant kidney development with an estimated prevalence of 0.1% in infants via ultrasound screening and up to 4% in autopsy studies 3. The pathogenesis involves:

1. Nephron induction deficit due to:

   • Ampullary inactivity
   • Abnormal budding of the ureteric bud
   • PAX2 mutations or interaction with p53 pathway 3

2. Obstruction-related mechanisms:

   • Urinary retention causing abnormal kidney development
   • Two phenotypes: Multicystic dysplastic kidney (MCDK) and obstructive renal dysplasia (ORD)
   • Cyst formation in once-induced nephrons due to fluid retention 4

Histopathological Features

• Primitive tubules surrounded by fibromuscular collar
• Increased immunohistochemical expression of PAX2/8 and WT1 in primitive ducts and fibromuscular collar 3
• Differential diagnosis includes renal hypoplasia and renal atrophy

Clinical Implications and Management

1. Surveillance for malignancy:

   • Regular renal ultrasound for Wilms tumor detection in high-risk syndromes
   • Additional screening for other associated tumors based on syndrome

2. Renal function monitoring:

   • CAKUT (including renal dysplasia) represents approximately 30% of all prenatally diagnosed malformations
   • Leading cause of kidney failure in young children
   • Can lead to significant renal problems in adulthood (hypertension/proteinuria) 5

3. Genetic counseling:

   • Evaluation for syndromic vs. non-syndromic forms
   • Consideration of familial patterns

Management Considerations

• Nephrectomy may be indicated for symptomatic renal dysplasia 3
• For syndromic forms, management should address both renal and extra-renal manifestations
• Prophylaxis and control of infections are crucial in cases with urinary tract abnormalities
• Careful monitoring of renal function and early intervention for complications

Pitfalls to Avoid

1. Failing to recognize syndromic associations that require specific surveillance
2. Overlooking the need for multisystem evaluation in suspected syndromic cases
3. Inadequate follow-up for potential development of Wilms tumor or other malignancies
4. Missing opportunities for early intervention to preserve renal function

Congenital renal dysplasia should prompt evaluation for associated syndromes, as early identification can significantly impact morbidity and mortality through appropriate surveillance and management strategies.