Johanson-Blizzard Syndrome

I. Overview

• Johanson-Blizzard syndrome (JBS) is a rare autosomal recessive multisystem disorder.
• Clinically characterized by a triad of:
  • Exocrine pancreatic insufficiency (EPI)
  • Nasal wing aplasia or hypoplasia
  • Dental anomalies (oligodontia or hypodontia)
• Other variable features may include:
  • Imperforate anus
  • Congenital deafness
  • Hypothyroidism
  • Short stature
  • Scalp defects
  • Urogenital malformations

II. Epidemiology

• Estimated prevalence: ~1 in 250,000 live births.

III. Pathogenesis

• Caused by biallelic pathogenic variants in the UBR1 gene on chromosome 15q13.
• UBR1 encodes a ubiquitin ligase; mutations lead to severe deficiency and impaired protein degradation.
• Results in near-complete absence of pancreatic acinar cells, replaced by fat and connective tissue.
• Ductal and islet architecture is preserved.
• Pancreatic histology resembles Shwachman-Diamond syndrome but without bone marrow involvement.

IV. Diagnosis

• Clinical recognition of EPI and characteristic facial features is key.
• Confirmed by molecular genetic testing for UBR1 mutations.
• Imaging (CT or ultrasound) shows a fatty pancreas of normal size.

V. Clinical Manifestations

• Core features:
  • EPI: diarrhea, steatorrhea, failure to thrive in infancy
  • Nasal wing aplasia/hypoplasia → “beak-shaped” nose
  • Oligodontia (absence of permanent teeth)
• Other features and prevalence:
  • Hearing impairment (78%)
  • Scalp defects and sparse hair (64%)
  • Cognitive impairment (61%)
  • Short stature (61%)
  • Hypothyroidism (39%)
  • Microcephaly (34%)
  • Intrauterine growth restriction (29%)
  • Congenital heart defects (25%)
  • Imperforate anus (20%)
  • Genital malformations (20%)
  • Renal abnormalities (13%)
  • Diabetes (10%)
  • Growth hormone deficiency and panhypopituitarism (rare)
• Differential clue: Unlike Shwachman-Diamond syndrome, JBS lacks skeletal and bone marrow abnormalities.

VI. Management

• Pancreatic enzyme replacement therapy (PERT)
• Fat-soluble vitamin supplementation
• Multidisciplinary evaluation for associated anomalies (e.g., endocrine, cardiac, renal, auditory, dental)