Frank–ter Haar syndrome

Overview

Frank–ter Haar Syndrome (FTHS) is a rare, inherited genetic disorder characterized by skeletal abnormalities, craniofacial dysmorphism, and cardiovascular defects. The syndrome typically presents in infancy or early childhood and can affect multiple organ systems. FTHS is considered a part of the broader group of congenital connective tissue disorders. It is named after Dr. Yitzchak Frank and Dr. Bo ter Haar, who first described the condition. The disorder is progressive and often associated with significant developmental delays and reduced life expectancy.

Causes

Frank–ter Haar Syndrome is caused by mutations in the SH3PXD2B gene located on chromosome 5. This gene encodes a protein involved in podosome formation and cellular matrix remodeling, which are essential for normal development of the skeleton, eyes, and cardiovascular system. The syndrome follows an autosomal recessive inheritance pattern, meaning both parents must carry and pass on one copy of the mutated gene for their child to be affected.

Symptoms

The clinical features of Frank–ter Haar Syndrome are variable but often include the following key characteristics:

Craniofacial Features

• Prominent forehead (frontal bossing)

• Wide-set eyes (hypertelorism)

• Flat nasal bridge and broad nasal tip

• Full cheeks and a small chin (micrognathia)

Skeletal Abnormalities

• Broad ribs and short limbs

• Joint hypermobility or stiffness

• Abnormal curvature of the spine (scoliosis or kyphosis)

• Delayed ossification or abnormal bone formation

Ocular Features

• Glaucoma (increased pressure in the eye)

• Optic disc anomalies

• Possible visual impairment or blindness

Cardiovascular Issues

• Congenital heart defects (e.g., ventricular septal defect, valvular abnormalities)

• Enlargement of the heart (cardiomegaly)

Neurological and Developmental

• Global developmental delay

• Intellectual disability (variable severity)

• Hypotonia (reduced muscle tone)

Diagnosis

Diagnosis of Frank–ter Haar Syndrome involves a combination of clinical evaluation, imaging studies, and genetic testing. Key diagnostic steps include:

• Physical examination: To identify characteristic facial, skeletal, and cardiac features.

• Radiographic imaging: X-rays and CT scans to assess bone abnormalities and spinal curvature.

• Ophthalmologic evaluation: To check for glaucoma and other eye defects.

• Echocardiogram: To detect congenital heart anomalies.

• Genetic testing: Confirms diagnosis by identifying mutations in the SH3PXD2B gene.

Treatment

There is no cure for Frank–ter Haar Syndrome, and treatment is focused on managing symptoms and preventing complications. A multidisciplinary care approach is essential and may include:

Medical Management

• Intraocular pressure-lowering medications or surgery for glaucoma

• Cardiac surgery or medications for heart defects

Supportive Therapies

• Physical therapy to address joint stiffness and mobility issues

• Occupational therapy for daily function and independence

• Special education services and cognitive support

Surgical Interventions

• Orthopedic surgery for skeletal deformities

• Corrective surgery for craniofacial anomalies if necessary

Prognosis

The prognosis for individuals with Frank–ter Haar Syndrome varies depending on the severity of symptoms, particularly cardiac and ocular involvement. Many affected children experience significant developmental challenges and may require lifelong medical care. Severe cases, particularly those with major heart or respiratory complications, can result in early mortality. Early diagnosis, regular monitoring, and comprehensive supportive care can improve quality of life and potentially extend life expectancy.