Johanson–Blizzard syndrome

Overview

Johanson–Blizzard syndrome (JBS) is a rare autosomal recessive genetic disorder characterized by a wide range of developmental anomalies affecting multiple organ systems. The hallmark features include exocrine pancreatic insufficiency, nasal wing hypoplasia (underdeveloped nostrils), hearing loss, and intellectual disability. Other abnormalities may involve the endocrine system, craniofacial structures, and the urogenital tract. The syndrome was first described in 1971 by Drs. Johanson and Blizzard.

Causes

Johanson–Blizzard syndrome is caused by mutations in the UBR1 gene located on chromosome 15. The UBR1 gene encodes a protein involved in the N-end rule pathway of protein degradation, which is essential for normal cellular function. Loss-of-function mutations in this gene lead to disrupted cellular processes in various tissues, particularly the pancreas and brain. JBS follows an autosomal recessive inheritance pattern, meaning that an individual must inherit two defective copies of the gene (one from each parent) to develop the disorder.

Symptoms

The clinical presentation of Johanson–Blizzard syndrome is highly variable but often includes:

• Exocrine pancreatic insufficiency: Leading to malabsorption, steatorrhea, and failure to thrive

• Nasal wing hypoplasia: A distinct craniofacial feature with underdeveloped or absent alae nasi

• Sensorineural hearing loss: Usually bilateral and permanent

• Intellectual disability: Varies from mild to severe

• Delayed motor and speech development

• Dental anomalies such as hypodontia or abnormal tooth shape

• Scalp defects or aplasia cutis (absence of skin)

• Endocrine abnormalities including hypothyroidism or growth hormone deficiency

• Urogenital malformations in some cases

Diagnosis

Diagnosis of JBS is based on clinical findings and confirmed by genetic testing. Diagnostic steps include:

• Physical examination revealing characteristic facial features and developmental delays

• Hearing tests (audiometry or ABR) confirming sensorineural hearing loss

• Fecal elastase or pancreatic function tests to assess exocrine insufficiency

• Thyroid function tests and other hormonal evaluations

• Brain imaging (MRI/CT) to detect structural abnormalities

• Genetic testing to identify biallelic pathogenic mutations in the UBR1 gene

Treatment

There is no cure for Johanson–Blizzard syndrome, and treatment focuses on managing symptoms and improving quality of life through a multidisciplinary approach. Management may include:

• Pancreatic enzyme replacement therapy to manage malabsorption and nutritional deficiencies

• Hearing aids or cochlear implants for sensorineural hearing loss

• Speech, occupational, and physical therapy to support developmental progress

• Hormone replacement therapy for endocrine dysfunctions such as hypothyroidism

• Dental care for managing dental anomalies

• Educational support and individualized learning plans for intellectual disability

• Regular monitoring by pediatricians, endocrinologists, audiologists, and genetic counselors

Prognosis

The prognosis of Johanson–Blizzard syndrome varies widely depending on the severity of organ involvement and the effectiveness of supportive care. With early intervention and comprehensive management, many children can achieve improved growth, development, and quality of life. However, individuals with severe complications such as profound intellectual disability or multiple organ dysfunction may face greater challenges. Lifelong monitoring and support are typically required to address evolving health needs.