Introduction

Van Der Woude Syndrome (VWS) and Popliteal Pterygium Syndrome (PPS) are two autosomal dominant disorders arising from a genetic mutation and share common symptoms. Both VWS and PPS present with a craniofacial cleft lip, but PPS is additionally characterised by abnormal genitals, syndactyly (fusion) of the fingers and toes, and toenail dysplasia.¹

Van der woude syndrome 

VWS affects approximately 2 children per 100,000 each year and is diagnosed in 1% or 2% of children with cleft palate. Children with VWS tend to have a combination of a cleft lip and cleft palate in addition to a slit on their lower lips. VWS may be caused by various mutations on the IRF6 gene on chromosome 1 which is mainly involved in the formation of the roof of the mouth as well as other structures during development. The lip slits may be small and barely noticeable or they may be wide and prominent. These slits connect to salivary glands underneath the dermis layer of the skin which allows saliva to drain through the opening. This may be why children with VWS appear to be drooling. 

Due to the role of the IRF6 gene in the formation of the roof of the mouth and other structures, children with VWS may experience additional problems, such as hypodontia (missing teeth). The upper and lower premolars may be the most common missing teeth in cases of VWS. Anomalies outside the orofacial region are not observed with this condition.²

Genetic etiology

VWS commonly presents with a cleft lip, but there is a variety within patients, even though it is an autosomal dominant disorder. Lip pits are thought to develop from the notching of the lip during early stages of labial development, with tissue fixation at the base of the notch, or from incomplete union of the embryonic lateral sulci of the lip. These pits persist and eventually develop into permanent lip pits. Penetrance of the disorder is 80% but some cases have reported 100% penetrance.³  

Clinical manifestations

VWS can be diagnosed through blood or genetic tests which look for the IRF6 mutation. Prenatal ultrasounds can also detect cleft lips and/or palate. Additional prenatal screening methods, such as chorionic villus sampling (CVS) and genetic amniocentesis, can be performed while the baby is still in the womb to screen for VWS. 

Surgery is required to correct the cleft lip, typically performed when the baby is between 2 and 6 months old. Cleft palate repairs are usually done when the child is older, around 9 and 18 months old. Surgery is also needed to repair the lip pits and prevent saliva and mucus from being secreted. Both surgeries are often performed simultaneously. 

The following are symptoms associated with VWS:⁴

• Cleft lip, cleft palate, or both
• Low pits (depressions) or mounds (raised bumps) on one or both sides of the lower lip
• Moist or wet-looking lower lip - due to the salivary or mucus glands which are connected to the area beneath the lower lip
• Missing teeth (hypodontia) or missing teeth enamel (dental hypoplasia) 
• Developmental delay in children
• Mild cognitive impairment
• Speech and language delays 

Popliteal pterygium syndrome 

As mentioned previously, PPS presents similarly to VWS in that both conditions have a cleft lip and/or palate. However, PPS also presents with additional features, such as:

• Syndactyly (webbing of the hands and feet)
• Webs of skin across the back of the legs around the knee joint
• Triangular-shaped folds of skin over the nails of the large toes
• Tissue connecting the upper and lower eyelids or the upper and lower jaw

Individuals affected with PPS may also have abnormal genital development. Unlike VWS, PPS does not involve growth delays or cognitive impairment, and intelligence is usually normal. Similar surgical treatments are provided for both.⁵

Clinical manifestations

A cleft lip and/or palate may be detected as early as the first trimester through ultrasound, which 91-97% of patients present with. Some patients may also have lower lip pits or sinuses. The skin webbing may extend from the ischial tuberosities (the sit bones) to the heels. This webbing may impair mobility depending on the severity. 

Genital abnormalities may present with a bifid scrotum, which is when the two scrotal sacs are widely separated with a laid open urethra. The scrotal raphe will not be detected. Minor forms of a bifid scrotum may have a split or wide scrotal raphe alongside other symptoms. People assigned male at birth (AMAB) may also present with cryptorchidism where at least one testicle is missing from the scrotum. Patients assigned female at birth (AFAB) may present with hypoplasia of the labia majora, where one or both sides of the labia do not form properly during puberty, fingers and/or toe syndactyly, and skin abnormalities around the nails. 

Additional symptoms associated with PPS include:⁶ 

• Spina bifida occulta: Incomplete formation of the baby’s backbone during pregnancy leading to gaps in the spinal bones. Often causes no health problems
• Retrognathia: Defined as an unusual position of the mandible from deficient growth. Often, the mandible will be posterior to and behind where it is supposed to be located 
• Accessory medial meniscus (bands of cartilage attached to the shinbone which act as shock absorbers and stabilise the knees)
• Talipes: Also known as clubfoot which is when a foot, or both feet, turn in and under with the sole of the foot facing backwards. It happens when the Achilles tendon is too short, but can be corrected 

Diagnosis

PPS occurs when there is a mutation in the IRF6 gene which is involved in the formation of epithelial tissues and other structures mentioned previously. For a physician to diagnose PPS, the clinical symptoms must be present and then subsequent genetic testing can be performed. These tests will detect a missense mutation in the DNA binding domain of IRF6 that alter residues which are predicted to interact directly with DNA. Because of the clinical overlap with VWS, PPS and VWS are considered differential diagnoses to one another. Amniocentesis and CVS can detect PPS prenatally.⁶ 

Treatment options and management

Cleft lip and/or palate should be treated surgically to manage the salivary and mucus gland overflow, similar to VWS. Speech therapy, audiological, and dental assessments should also be provided. Corrective surgery may also be used to fix lip pits, popliteal pterygium, and syndactyly. Abnormal genitalia are not often considered for surgical intervention but some rare and extreme cases may be considered. Physical activity may be considered on a case-by-case basis as it depends on the severity of the pterygium and the success of corrective surgery.⁶    

Most patients face difficulties walking and other activities of daily life depending on the severity of their case. Surgical resection of the pterygium is possible and it involves cutting (tenotomy) or removing (full resection) the superficial fibrous band. Neighbouring tissues may also require lengthening or grafting to function with the new range of motion of the knee joint. The sciatic nerve may be grafted or the local tendons may be lengthened as part of this treatment. Skin grafting may also be needed to cover the back of the leg once knee extension is achieved. 

Proper treatment involves restoring normal joint orientation either through acute correction with soft tissue release (with or without cutting the bone), or gradual correction using an external fixator. The goal is to achieve a straight and stable knee, amenable to ambulation, with both of these approaches.⁷ 

Summary

Van der Woude syndrome (VWS) and Popliteal pterygium syndrome (PPS) both belong to the IRF6 category of disorders, but they differ in their clinical presentations. While VWS is associated with developmental delays and mild cognitive impairment, PPS does not typically affect intellectual functioning, and children with PPS generally have normal cognitive abilities. However, PPS patients may experience syndactyly (webbing), abnormal genitalia, and other physical impairments that are not present in VWS. This may limit their physical abilities to a certain extent but may be corrected with surgery. 

Both conditions can be treated with surgical intervention in early infancy. This surgery often fixes the cleft lip and/or palate and prevents salivary/mucus overflow. Additionally, both PPS and VWS can be detected through genetic testing and prenatal testing such as chorionic villus sampling. Despite the potential impairments associated with these diagnoses, children with either condition can often lead healthy and fulfilling lives.