Robinow syndrome

Overview

Robinow syndrome is a rare genetic disorder that affects skeletal development, facial structure, and genital formation. It is characterized by distinctive facial features, short stature, limb shortening (especially in the forearms and lower legs), and abnormalities of the spine and ribs. The facial appearance is often described as “fetal-like,” with a broad forehead, wide-set eyes (hypertelorism), a short nose with an upturned tip, and a wide mouth.

There are two main forms of Robinow syndrome, each with differing severity and patterns of inheritance:

• Autosomal recessive Robinow syndrome (RRS): The more severe form, often associated with significant skeletal abnormalities and growth retardation.

• Autosomal dominant Robinow syndrome (DRS): A milder form with less pronounced skeletal abnormalities.

First described in 1969 by Dr. Meinhard Robinow, the syndrome has since been linked to mutations in genes that regulate skeletal and embryonic development.

Causes

Robinow syndrome is caused by mutations in genes that play a role in the WNT signaling pathway, which is essential for proper development of the skeleton and organs during embryogenesis.

Known Causative Genes:

• ROR2: Mutations in this gene cause the autosomal recessive form.

• DVL1, DVL3: Mutations in these genes cause the autosomal dominant form.

• NXN, FZD2, WNT5A: Additional genes also associated with the dominant type in some cases.

Inheritance Patterns:

• Autosomal recessive: Both parents carry one copy of the mutated gene but are unaffected. Affected individuals inherit two copies.

• Autosomal dominant: Only one copy of the mutated gene is needed to cause the disorder. It may be inherited or occur as a new (de novo) mutation.

Symptoms

The symptoms of Robinow syndrome vary depending on the type (recessive or dominant) and individual genetic mutations, but there is significant overlap in key features.

Craniofacial Features:

• Broad and prominent forehead

• Wide-set, prominent eyes (hypertelorism)

• Short, upturned nose with a flattened bridge

• Wide mouth with prominent lips and gums

• Small or recessed jaw (micrognathia)

• Low-set ears

Skeletal and Growth Abnormalities:

• Short stature with proportionate or disproportionate limb shortening

• Mesomelic limb shortening (middle segments of limbs)

• Short fingers and toes (brachydactyly)

• Spinal abnormalities, including scoliosis or hemivertebrae

• Delayed bone age and underdeveloped vertebrae and ribs

Genitourinary Abnormalities:

• In males: underdeveloped genitals (micropenis, undescended testes)

• In females: small labia or clitoris

Other Possible Features:

• Dental anomalies: delayed eruption, crowded teeth, misalignment

• Hearing loss (in some individuals)

• Heart defects (especially in the recessive form)

• Delayed motor milestones or mild intellectual disability (more common in the recessive form)

Diagnosis

Diagnosis of Robinow syndrome is based on physical findings, radiological imaging, and genetic testing. It is often suspected due to characteristic facial features and limb abnormalities present at birth or in early childhood.

Clinical Evaluation:

• Detailed medical and family history

• Physical examination of facial features, limbs, spine, and genitalia

Radiologic Imaging:

• X-rays of the spine, limbs, and skull to detect bone abnormalities

• Spinal imaging to identify hemivertebrae or fused vertebrae

Genetic Testing:

• Targeted mutation analysis for ROR2, DVL1, DVL3, and other associated genes

• Whole exome or genome sequencing if specific mutations are not initially identified

Other Diagnostic Tools:

• Cardiac ultrasound to check for congenital heart defects

• Hearing tests and developmental assessments

Treatment

There is no cure for Robinow syndrome. Treatment is symptomatic and supportive, aimed at addressing developmental delays, physical deformities, and organ-specific complications. Management typically involves a team of specialists.

1. Orthopedic Interventions:

• Monitoring and treatment of spinal abnormalities such as scoliosis

• Corrective surgeries for severe limb deformities

• Physical therapy to improve mobility and muscle strength

2. Craniofacial and Dental Care:

• Orthodontic treatment for dental malocclusion

• Speech therapy if jaw or palate anomalies affect speech

3. Genitourinary Management:

• Hormonal or surgical treatment for genital abnormalities, especially in males

• Monitoring for potential fertility issues later in life

4. Developmental and Educational Support:

• Early intervention programs for speech, occupational, and motor delays

• Special education services if learning difficulties are present

5. Regular Monitoring and Support:

• Routine hearing and vision screenings

• Cardiology follow-ups for patients with heart defects

• Psychosocial support for families and caregivers

Prognosis

The prognosis for individuals with Robinow syndrome varies widely based on the type and severity of symptoms. Those with the autosomal dominant form generally have a normal life expectancy and may lead relatively typical lives with some medical support. Physical appearance and short stature are often the most persistent features.

Individuals with the autosomal recessive form tend to have more severe skeletal and organ involvement, including heart defects and potential developmental delays, which may impact quality of life and life expectancy. However, with comprehensive care and early intervention, many children with Robinow syndrome can achieve improved functional outcomes.

Ongoing research into the genetic pathways involved in skeletal development may offer future therapies or interventions for this and similar disorders.