What syndromes are associated with congenital renal dysplasia?

Syndromes Associated with Congenital Renal Dysplasia

Congenital renal dysplasia is associated with several well-defined syndromes, including Mulibrey nanism, Perlman syndrome, Simpson-Golabi-Behmel syndrome, and Prune Belly syndrome, each with distinct clinical features and management requirements.

Major Syndromic Associations

1. Mulibrey Nanism

• Autosomal recessive growth disorder caused by biallelic mutations in TRIM37
• Clinical features:
  • Severe growth retardation
  • Distinctive dysmorphic features
  • Constrictive pericarditis
  • Hepatomegaly
  • Male infertility
  • Insulin resistance
  • High risk of Wilms tumor (median age 2.5 years) 1
  • Risk of renal papillary carcinoma in adulthood

2. Perlman Syndrome

• Autosomal recessive overgrowth syndrome caused by DIS3L2 mutations
• Clinical features:
  • Polyhydramnios
  • Macrosomia
  • Characteristic facial dysmorphology (broad depressed nasal bridge, everted V-shape upper lip)
  • Renal dysplasia and nephroblastomatosis (75% of cases)
  • High risk of early-onset Wilms tumor (<2 years)
  • Bilateral Wilms tumors common (55%)
  • High neonatal mortality (53%) 1

3. Simpson-Golabi-Behmel Syndrome (SGBS)

• X-linked disorder caused by mutations in GPC3 or GPC4
• Clinical features:
  • Pre- and postnatal macrosomia
  • Distinctive craniofacies (macrocephaly, coarse facial features)
  • Macrostomia and macroglossia
  • Intellectual disability
  • Supernumerary nipples
  • Diastasis recti/umbilical hernia
  • Increased risk of Wilms tumor and nephroblastomatosis
  • Risk of liver tumors in children 1

4. Prune Belly Syndrome

• Characterized by:
  • Marked deficiency of abdominal muscles
  • Bilateral cryptorchidism
  • Urinary tract abnormalities including renal dysplasia
  • Histologically shows renal dysplasia with partial or total absence of muscle fibers in the ureter
  • Hypertrophy of the bladder with normal ganglionar cells
  • Dilated prostatic urethra 2

Evaluation Approach for Suspected Syndromic Renal Dysplasia

First-line Evaluation

• Family history: consanguinity, ethnicity, history of early infantile death
• Prenatal and perinatal history: enlarged nuchal translucency, increased amniotic fluid alpha-fetoprotein, fetal edema, oligohydramnios
• Growth parameters: height, weight, head circumference
• Physical examination:
  • Dysmorphic features and skeletal abnormalities
  • Genital examination
  • Abdominal wall defects
  • Hepatomegaly 1

Imaging Studies

• Renal ultrasound to assess:
  • Kidney echogenicity and size
  • Evidence of dysplasia
  • Presence of cysts
• Cardiac ultrasound (for effusions and structural abnormalities) 1

Extended Evaluation

• Ophthalmological examination
• Hearing test
• Neurological examination
• Genetic testing based on clinical presentation 1

Surveillance Recommendations for Associated Malignancies

Wilms Tumor Surveillance

• For children with Mulibrey nanism, Perlman syndrome, and SGBS:
  • Regular renal ultrasound screening
  • Begin in infancy
  • Continue until at least age 7 years for WT1-related syndromes 1

Additional Surveillance

• For Mulibrey nanism in adulthood:
  • Consider screening for renal papillary carcinoma
  • Thyroid cancer screening
  • Ovarian and endometrial cancer screening in females 1

Pathogenesis and Pathology

Renal dysplasia represents aberrant kidney development with:

• Primitive tubules surrounded by fibromuscular collar
• Increased immunohistochemical expression of PAX2/8 and WT1 in primitive ducts and fibromuscular collar
• Potential pathogenic mechanisms include:
  • Nephron-inductive deficit due to ampullary inactivity
  • Abnormal budding of the ureteric bud
  • PAX2 mutation or interaction with p53 pathway 3

Management Considerations

• Early referral to specialized pediatric nephrology unit
• Genetic counseling for affected families
• Monitoring for development of renal failure
• Surveillance for associated malignancies based on specific syndrome
• For symptomatic renal dysplasia, nephrectomy may be considered 3

Pitfalls and Caveats

1. Congenital renal dysplasia can be sporadic or familial, syndromic or nonsyndromic - genetic testing should be guided by clinical features 4

2. Prenatal diagnosis is challenging due to:

   • Extensive variability in presentation
   • Genetic and phenotypic heterogeneity
   • Difficulty in assessing postnatal renal function on prenatal imaging 5

3. Early in-utero decompression may prevent or ameliorate renal dysplasia in cases of urinary tract obstruction, but some post-obstructive changes may persist 6

4. Differential diagnosis includes renal hypoplasia and renal atrophy, which require different management approaches 3