Goldberg–Shprintzen syndrome

Overview

Goldberg–Shprintzen syndrome (GOSHS) is a rare genetic disorder characterized by a combination of craniofacial abnormalities, intellectual disability, Hirschsprung disease (a condition affecting the large intestine), and other congenital anomalies. It was first described by Goldberg and Shprintzen in the 1980s. The syndrome presents at birth or early infancy and affects multiple body systems, particularly the nervous, gastrointestinal, and musculoskeletal systems. Due to its complex presentation, early diagnosis and multidisciplinary management are essential for improving outcomes.

Causes

Goldberg–Shprintzen syndrome is caused by mutations in the KIAA1279 gene, which provides instructions for making a protein involved in neuronal development. The condition is inherited in an autosomal recessive manner, meaning both copies of the gene must be mutated—one inherited from each parent—for the individual to be affected. The KIAA1279 gene plays a crucial role in neuronal cell migration and gastrointestinal tract innervation, explaining the combination of neurological and intestinal symptoms in this syndrome.

Symptoms

The clinical presentation of Goldberg–Shprintzen syndrome is variable, but commonly includes the following features:

Neurological and Developmental Symptoms:

• Intellectual disability, typically moderate to severe

• Delayed developmental milestones

• Hypotonia (low muscle tone)

• Seizures (in some cases)

Gastrointestinal Symptoms:

• Hirschsprung disease: A congenital condition where nerve cells are missing from parts of the large intestine, causing severe constipation or intestinal obstruction

Craniofacial and Structural Features:

• Microcephaly (small head circumference)

• High-arched palate

• Wide nasal bridge

• Long face and prominent jaw

• Low-set ears or dysplastic ear shape

Other Possible Features:

• Speech delay or absence of speech

• Hydrocephalus (accumulation of fluid in the brain, in rare cases)

• Strabismus (misalignment of the eyes)

Diagnosis

Diagnosis of Goldberg–Shprintzen syndrome involves clinical assessment, imaging, and genetic confirmation:

• Clinical evaluation: Based on the presence of characteristic facial features, developmental delays, and signs of Hirschsprung disease

• Rectal biopsy: Confirms the absence of enteric ganglion cells in cases of Hirschsprung disease

• Brain imaging (MRI/CT): To assess structural abnormalities such as microcephaly or hydrocephalus

• Genetic testing: Confirms mutations in the KIAA1279 gene

• Family history: Evaluation of parental carrier status for genetic counseling

Treatment

There is no cure for Goldberg–Shprintzen syndrome, and treatment is aimed at managing individual symptoms and supporting development. A multidisciplinary approach is essential:

• Surgical intervention: Required for Hirschsprung disease, typically through resection of the affected bowel segment

• Developmental support: Early intervention programs including physical, occupational, and speech therapy

• Educational support: Special education tailored to the child’s cognitive needs

• Medical management: Monitoring for seizures, feeding difficulties, and gastrointestinal function

• Genetic counseling: Recommended for families to understand inheritance and recurrence risks

Prognosis

The prognosis for individuals with Goldberg–Shprintzen syndrome varies based on the severity of symptoms, particularly the degree of intellectual disability and presence of Hirschsprung disease. With appropriate surgical and supportive care, some children achieve developmental progress, though lifelong support is often needed. The condition is non-progressive, but complications related to gastrointestinal and neurological issues may impact quality of life. Early diagnosis and coordinated medical and developmental care are key to improving outcomes.