Continuing Education Activity

Pterygium syndrome, also known as multiple pterygium syndrome, is a rare congenital disorder that primarily affects neuromuscular and skeletal functions. It occurs due to disrupted communication between nerve and muscle cells during early fetal development. The syndrome presents in two clinical forms, with the severity of symptoms varying between individuals. Multiple pterygium syndrome is typically inherited in an autosomal recessive pattern. Patients with this syndrome commonly exhibit multiple skin webbing, musculoskeletal anomalies, and distinctive facial features. This activity provides an overview of the etiology, classification, clinical manifestations, evaluation, and management of multiple pterygium syndrome. It emphasizes the importance of an interprofessional or multidisciplinary team in assessing and treating patients with this condition. Early diagnosis and management are critical in improving outcomes for affected individuals.

Objectives:

• Differentiate between the lethal and nonlethal (Escobar) subtypes of pterygium syndrome based on clinical and genetic factors to guide appropriate management approaches.
• Implement appropriate diagnostic evaluations, including genetic testing and imaging studies, to confirm the diagnosis of pterygium syndrome and assess its severity.
• Select and monitor appropriate pharmacological interventions, including pain management and symptomatic relief, to alleviate discomfort and improve the quality of life for individuals with pterygium syndrome.
• Coordinate long-term follow-up and multidisciplinary care plans for patients with pterygium syndrome to optimize outcomes and monitor for potential complications or associated comorbidities.

Introduction

Pterygium syndrome, alternatively called multiple pterygium syndrome (MPS), is a rare group of different genetic congenital disorders characterized by numerous webbing (pterygia) of the parts of the body (the neck, axilla, antecubital, elbow, interdigital, and popliteal regions), multiple joint contractures (arthrogryposis), and skeletal abnormalities or deformities.[1]

Two clinically and genetically different variants of multiple pterygium syndrome exist prenatally, lethal and nonlethal (Escobar) subtypes. The lethal subtype is most severe and diagnosed prenatally with fetal ultrasound during the second trimester with multiple pterygia, hygroma colli, and sometimes stillbirth. The nonlethal variant is Escobar syndrome, which includes numerous pterygia, joint contractures, and distinctive facial features.[2][3][4]

Etiology

A genetic cause of this syndrome has been identified for both variants due to homogenous or heterogenous CHRNG gene mutations, which encode the acetylcholine receptor (AChR) gamma subunit on chromosome 2q37. In addition, genomewide linkage testing of some families also detected a locus on chromosome 2q36.[5][2] 

The identified germline-inactivating mutation of the AChR gamma subunits suggests the role of acetylcholine receptor dysfunction in the etiology of both types of MPS. Dysfunction of the receptor leads to AChR protein malfunction, interrupting communication between nerve cells and muscle cells in the developing fetus. The absence of signaling between the nerves and muscles causes absent or reduced fetal movements and pterygia in-utero. Also, the impaired signaling contributes to several findings of MPS.[2][6]

Epidemiology

The incidence rate and racial predilection of MPS have not been established because of the condition's rarity. However, males and females are equally affected, with a male-to-female ratio of 1:1. Based on many reports of affected siblings and twins with normal parents, there were postulations of genetic susceptibility to mostly autosomal recessive inheritance and increased susceptibility in consanguineous marriages.[4][7] 

Autosomal dominant, X-linked dominant, X-linked recessive, and sporadic cases have also been demonstrated and reported in some case reports for same-sex siblings.[1] However, autosomal recessive is the inheritance pattern most documented for MPS.

History and Physical

The clinical history and findings of MPS depend on what variant of the syndrome is involved. However, a history of consanguinity and sibling affectation with similar phenotypic presentations are usually present. The lethal variant (lethal multiple pterygium syndrome, LMPS) presents in-utero with fetal cystic hygroma colli (FCHC) by the presence of a thin-walled, multiseptate cystic mass between the fetal head and neck diagnosed in the second trimester with ultrasonography and subsequently, can lead to fetal hydrops, intrauterine death, or stillbirth.[5][8] 

The first concern reported by most pregnant mothers is reduced fetal movement, which is observable on fetal ultrasonography. Other findings include pterygia of large joints, joint contractures, reduced fetal movements, hypertelorism, palpebral fissures slanting, flattened nasal bridge and underdeveloped nasal alae, micrognathia, cleft palate, and lung hypoplasia. In addition, cerebral anomalies and muscular atrophy have been recognized in several cases.[8][9]

The Escobar variant usually manifests with different features, some present at birth and certain features past infancy. Clinical features consist mainly of multiple body pterygia (neck, axillae, antecubital, digital, popliteal, and intercrural regions), arthrogryposis multiplex congenita involving the spine (scoliosis, kyphosis, cervical vertebrae fusion, clefting of the vertebral bodies), pelvis (dislocation), hands (syndactyly, camptodactyly, arachnodactyly), and limb abnormalities (absent or dysplastic patella, radial head dislocation, talipes equinovarus, rocker-bottom feet, and flexion contractures).[10][11] 

Findings that might be present at birth are low-set ears, expressionless flat face, epicanthal folds, small mouth, high-arched palate, difficulty in mouth opening with reduced neonatal sucking after birth, lung hypoplasia with neonatal respiratory distress, chest abnormalities (hypoplastic nipples, fused ribs, long clavicles, diaphragmatic hernia, and diaphragmatic eventration).[12]

Other findings include genitourinary abnormalities (hypospadias and cryptorchidism in males; labia majora absence and small clitoris in females), umbilical hernia, generalized amyoplasia, short stature, conductive hearing loss, and possibly intrauterine death. The median age of walking without support is at fifteen months of age, and many of the patients are ambulatory at a later life. Some clinical features might improve as the child grows, while some may worsen.[13][14][15]

Evaluation

Establishing the diagnosis of MPS clinically through history and physical examination is challenging because features of several clinical conditions and syndromes overlap with the characteristics of MPS. However, the evaluation of patients with suspected MPS should commence with detailed family history, including the presence of consanguinity, which increases the risk of autosomal recessive MPS.

Prenatal ultrasonography is utilized for LMPS and remains the standard method for detecting fetal anatomic abnormalities because it allows excellent visualization of fluid-filled structures in the developing fetus. Skeletal anomalies are detectable on radiographic imaging. In addition, features highly suggestive of MPS should undergo molecular genetic testing to detect gene mutations in MPS, which incorporates whole-exome sequencing and Sanger sequencing for confirmation.[10]

Treatment / Management

There is no specific treatment for MPS. Any child with suspected LMPS detected on prenatal ultrasonography and reaches term should be a high-risk delivery. Therefore, risk assessment and measures should be in place at birth to ensure good transitioning to the immediate post-natal life and avoid post-delivery complications such as respiratory distress from pulmonary hypoplasia or diaphragmatic hernia. Subsequently, affected children must be evaluated by a geneticist and managed by an interprofessional team that targets the complex organ systems involved.[1]

Parents of affected children should be tested to determine the mode of inheritance and counseled on the risk of future pregnancies having MPS depending on genetic testing results. Patients with pterygia, joint contractures, and other orthopedic manifestations will require a surgical referral, evaluation, and treatment. Periodic follow-ups should be established to ensure survival and avoid complications of MPS that might develop. Research is ongoing to explore treatment possibilities and the prevention of inherited and acquired genetic disorders.

Differential Diagnosis

Several other genetic conditions have a constellation of symptoms overlapping with features of MPS. These clinical conditions include:

Turner syndrome: This is a genetic syndrome that occurs when there is complete or partial monosomy of the X chromosome in affected girls. The clinical features of Turner syndrome include being delivered small for gestational age with a webbed neck and redundant nuchal skin, widespread nipples, protruding ears, lymphedema of hands and feet, short stature, gonadal dysgenesis, musculoskeletal defects (cubitus valgus, scoliosis, hip dislocation), learning disabilities, endocrine anomalies (hypothyroidism and type 2 diabetes mellitus), renal anomalies (horse-shoe kidneys), gastrointestinal manifestations (inflammatory bowel disease and celiac disease), ear/nose/throat (ENT) problems (strabismus, cataracts, recurrent otitis media, sensorineural hearing loss), and congenital heart defects (bicuspid aortic valve and coarctation of the aorta). In addition, features of MPS usually overlap with parts of Turner syndrome, but patients with Turner syndrome lack multiple body pterygia and contractures.[16]

Noonan syndrome: It is an inherited genetic condition with heterogeneous clinical manifestations and characteristic features of craniofacial abnormalities, skeletal abnormalities, blood clotting problems, and cardiac anomalies, but not contractures or conductive hearing loss.[17]

Klippel-Fiel syndrome: It is a complex bone formation disorder characterized by abnormal cervical bone fusion (C2 and C3) leading to characteristic features of a short neck, limited neck movements, chronic headaches, and back muscle pains.[18] The musculoskeletal manifestations of MPS closely resemble features of Klippel-Fiel syndrome, but patients with Klippel-Feil syndrome lack pterygia and other dysmorphisms associated with MPS. 

Prune belly syndrome: It is also known as Eagle-Barrett syndrome, a congenital anatomical-radiological condition with a triad of absent abdominal wall musculature, undescended testes (cryptorchidism), and genitourinary abnormalities (unusually large ureters, vesicoureteral reflux, oligohydramnios).[19]

Patients also have other associated features, including recurrent urinary tract infections, ventricular septal defect, malrotation of the gut, and clubfoot. The abnormal abdominal musculature in prune belly syndrome closely resembles the contractures in multiple pterygium syndrome, and both have cryptorchidism as a feature. Still, absent abdominal musculature in MPS has not been reported.

Van der Woude syndrome: This is a rare congenital condition primarily affecting the mouth and palate. Patients present with pitted cleft lips and palates, and the condition lacks multiple pterygia or contractures. Patients typically have problems with feeding, speech articulation, and recurrent ear infections if not treated early.[20]

Arthrogryposis multiplex congenita: It is a general term used for patients that develop nonprogressive contractures in multiple areas of the body in-utero. Multiple joints are affected, mainly the extremities. It has been known to occur in isolation or with numerous clinical conditions and syndromes, including multiple pterygium syndrome. Mutations in various genes have been associated with arthrogryposis multiplex congenita. If arthrogryposis multiplex congenita occurs in isolation without multiple pterygia, skeletal deformities, or other features of MPS, MPS can be ruled out by genetic testing.[21][22]

Prognosis

MPS is an extremely rare condition, and the prognosis depends on the severity and complexity of the presenting symptoms. The LMPS usually results in stillbirths and intrauterine fetal death. Most newborns that survive through pregnancy may have hypotension, bradycardia, respiratory failure, or early neonatal death in the immediate postnatal life.[23] 

The Escobar variant has a better prognosis than the LMPS. Several reports have noted the development of skeletal anomalies such as kyphoscoliosis during childhood that required surgical evaluation and treatment.[2] Due to amyoplasia, affected children may or may not have muscle weaknesses and can ambulate well later in life with physical and occupational therapy if commenced early.[12] 

Overall, the prognosis of MPS depends on the severity of the presenting symptoms and the promptness of intervention.

Complications

Possible complications include the following:

• Respiratory impairment and failure from restrictive lung disease from multiple contractures of the intercostal muscles and fused ribs
• Pulmonary hypoplasia and respiratory distress syndrome at delivery
• Conductive hearing loss
• Speech delay
• Immobility from restricted joint movements
• Poor feeding and malnutrition from inadequate feeding or cleft palate in the immediate post-natal life
• Cardiac failure from hypoplastic cardiac development
• Death in-utero

Consultations

The following specialists may be needed for consultation in pterygium syndrome cases:

• Genetics
• Orthopedic surgery
• Neonatology (at delivery)
• Anesthesiology 
• Developmental pediatrics
• Physical and occupational therapy
• Pulmonology
• Cardiology
• Audiology
• Otolaryngology/ENT
• Radiology
• Endocrinology
• Urology

Deterrence and Patient Education

Caregivers of patients with multiple pterygium syndrome should be aware and know that it is a lifelong diagnosis and will need continuous outpatient follow-ups. In addition, the associated complications should be relayed to the parents so they know they might need multiple referrals when needed. Proper patient counseling and education are paramount to the care of these children.

Pearls and Other Issues

• Genetic testing is required to diagnose the Escobar variant of multiple pterygium syndrome, including a thorough history and physical examination.
• Multiple problems and complications are associated with MPS needing different interprofessional teams and specialists. The difficulties include immobility, short stature, hearing loss, cryptorchidism, scoliosis, and other orthopedic problems. 
• These problems must be followed up for life to avoid possible complications and ensure good outcomes.

Enhancing Healthcare Team Outcomes

Clinicians and healthcare providers should have a high index of suspicion and be familiar with the clinical symptoms and presentation of multiple pterygium syndrome (MPS), regardless of its rarity. Diagnosing MPS can be challenging due to overlapping symptoms with other medical conditions, necessitating the need to rule out other differential diagnoses through additional genetic testing to reach a definitive diagnosis.

Early confirmation of MPS is crucial for effective management and favorable patient outcomes. Children with multiple organ system involvements should be referred for evaluation and appropriate treatment. Parents and caregivers should be actively involved, supported, and provided with extensive counseling on managing MPS, particularly if other siblings are affected.

While the primary care physician plays a central role in managing and following up on the child's care, an interprofessional team is essential. This team may include geneticists, orthopedic surgeons, developmental pediatricians, physical and occupational therapists, pulmonologists, cardiologists, audiologists, ENT specialists, radiologists (if necessary), endocrinologists, and urologists.

Nurses should possess familiarity with MPS, and those trained in genetics can provide optimal patient education, facilitate communication regarding appointments and referrals, and coordinate care with other healthcare professionals. Pharmacists dispensing prescribed medications should review therapeutic options and communicate the best treatment choices to the primary care physician and other relevant specialties. Delivering excellent and high-quality healthcare is crucial in determining patients' survival and long-term outcomes with multiple pterygium syndrome.