Conradi–Hünermann syndrome

Overview

Conradi–Hünermann syndrome, also known as Conradi–Hünermann–Happle syndrome or chondrodysplasia punctata type 2, is a rare genetic disorder that affects skeletal development, skin, and eyes. It is classified as a type of chondrodysplasia punctata, which involves abnormal calcium deposits in the cartilage and bones. The condition is typically present at birth and primarily affects females due to its X-linked dominant inheritance pattern. Males with the condition usually do not survive pregnancy, making it extremely rare in male infants.

Causes

Conradi–Hünermann syndrome is caused by mutations in the EBP gene, which is located on the X chromosome. The EBP gene provides instructions for making an enzyme involved in cholesterol biosynthesis. Disruption of cholesterol metabolism leads to abnormal development of bones, skin, and other tissues. The condition is inherited in an X-linked dominant manner. Because males have only one X chromosome, the disorder is usually lethal in male fetuses, while females with one mutated copy can survive and manifest the disease.

Symptoms

Symptoms and severity can vary widely, even among affected females. Common features of Conradi–Hünermann syndrome include:

• Stippled epiphyses (chondrodysplasia punctata): Calcium deposits in cartilage visible on X-rays, especially in infancy

• Asymmetric limb shortening: One side of the body may grow more slowly than the other, leading to limb length discrepancy

• Ichthyosis or skin abnormalities: Thick, scaly, or red skin, often following a pattern along Blaschko’s lines

• Patchy alopecia: Areas of hair loss on the scalp

• Cataracts: Clouding of the lens in one or both eyes, often present at birth

• Scoliosis: Curvature of the spine

• Facial asymmetry: Mild differences in the appearance of the face

• Nail and dental anomalies: Underdeveloped or ridged nails and widely spaced teeth

Most symptoms are present at birth, though some (such as scoliosis) may become more apparent with age.

Diagnosis

Diagnosis of Conradi–Hünermann syndrome is based on clinical findings, radiologic imaging, and genetic testing. Diagnostic methods include:

• Physical examination: Observation of asymmetrical growth, skin patterns, and other characteristic features

• X-rays: Reveal stippled calcifications in cartilage and asymmetrical limb development

• Ophthalmologic exam: To detect cataracts and other eye abnormalities

• Genetic testing: Identification of pathogenic variants in the EBP gene confirms the diagnosis

• Cholesterol testing: May show elevated levels of specific cholesterol intermediates

Treatment

There is no cure for Conradi–Hünermann syndrome, so treatment focuses on managing individual symptoms and improving quality of life. A multidisciplinary approach is often required. Treatment strategies include:

• Orthopedic management: Monitoring and correcting scoliosis or limb length discrepancies with braces or surgery

• Dermatologic care: Use of moisturizers and keratolytic agents to manage dry, scaly skin

• Ophthalmologic treatment: Surgical removal of cataracts if vision is impaired

• Dental care: Regular dental visits and possible orthodontic treatment

• Physical therapy: To support motor function and mobility

• Genetic counseling: For affected families to understand inheritance and recurrence risks

Prognosis

The prognosis for individuals with Conradi–Hünermann syndrome is generally good. While the condition is lifelong, many symptoms can be managed effectively with appropriate medical care. Intellectual development is typically normal, and life expectancy is not significantly reduced. Early diagnosis and coordinated care from specialists can help maximize functional outcomes and ensure a good quality of life.