What is Nager syndrome?

Nager syndrome is a type of preaxial acrofacial dysostosis (AFD) characterised by craniofacial and limb (particularly in the thumb and forearm) abnormalities. In early pregnancy, the jaw, eye sockets, and cheekbones of the fetus may not develop properly, resulting in the characteristic appearance of a small jaw and downward-sloping eyes. The normal development of the child’s face, hands and arms is hampered, with the disease varying in severity.¹

Cause

Nager syndrome is a rare condition inherited in an autosomal dominant manner and caused by mutations in the Splicing Factor 3b Subunit 4 (SF3B4) gene. SF3B4 mutation prevents the production of SAP49 protein involved in spliceosome complex formation responsible for mRNA processing. The SAP49 protein may be involved in the bone morphogenetic protein (BMP) pathway, which is responsible for cell growth. SAP49 protein is involved in the maturation of osteoblasts and chondrocytes in bone and cartilage development, respectively. Mutation in the SF3B4 gene can hamper BMP signaling and result in impaired development of bones of the hands, face and arms.

In early pregnancy, there is an alteration in the development of the first and second pharyngeal arches on either side of the head and neck owing to the mutation. These arches eventually develop into the structures of the face and neck, including the nerves and muscles needed to show facial expressions and chewing and the outer and middle ear structures.

Many cases of Nager syndrome occur sporadically due to de novo mutations and with no history of the syndrome in the family, usually occurring in females more often than in males.^1,2

Differential diagnosis

Treacher-Collins syndrome has similar facial features to those observed in Nager syndrome, but limb abnormalities are absent. Postaxial acrofacial dysostosis or Miller syndrome differs from Nager syndrome by the incomplete development, the absence of the fifth digital rays of all the limbs, and the presence of extra nipples. Patients with Fontaine syndrome have cleft palate and micrognathia, which are present in Nager syndrome. However, the hand and feet anomalies differ between these two conditions, such as ectrodactyly and cleft hands and feet.³

Clinical features

The primary clinical features of Nager syndrome include craniofacial, limb and musculoskeletal abnormalities.

Craniofacial abnormalities

• Underdeveloped cheekbones (malar hypoplasia)
• Abnormally small lower jaw (micrognathia)
• Cleft palate and absence of soft palate
• Velopharyngeal insufficiency, referring to when the soft palate of the mouth fails to close properly while speaking
• Choanal atresia (i.e., narrowing of the back of the nasal cavity)
• Internal and external ear malformation, leading to mild abnormality or absence of external ear
• Sagging of upper eyelids, lack of tissue from the lower eyelids, and partial or total absence of lower lid eyelashes^1,3

Limb abnormalities

Limb abnormalities along with facial features are diagnostic for Nager syndrome. Commonly observed limb abnormalities include preaxial anomalies (hypoplastic or absent thumb and radii) and proximal radioulnar synostosis. Thumb anomalies are asymmetrical. Duplicated or triphalangeal thumbs may be present. Clinodactyly (oddly curved fingers), camptodactyly (bent fingers) and syndactyly (merged fingers) can occasionally be present in the disorder.

Various lower limb abnormalities include phocomelia, dislocated hip, talipes equinovarus, absent tibia or fibula and metatarsus varus. Toe abnormalities include overlapping toes, hypoplastic toes, a few cases of absent toes, syndactyly, posteriorly placed hypoplastic halluces, hallux valgus, broad hallux, dorsal angulation of the second toe and medial deviation of the toes. Limb reduction defects have also been observed.^1,3

Skeletal abnormalities

The axial skeleton abnormalities present in Nager syndrome include thoracolumbar scoliosis, and rib and cervical vertebrae anomalies.^1,3

Other structural abnormalities

Various anomalies that occur less frequently in this condition include genitourinary abnormalities, such as unilateral renal agenesis, vesicoureteral reflux, duplicated ureter, external genital hypoplasia and bicornuate uterus; gastrointestinal abnormalities, such as Hirschsprung's disease and gastroschisis; cardiovascular malformations, such as a ventricular septal defect, tetralogy of Fallot and subvalvular muscular obstruction of the right ventricular outflow tract and central nervous system anomalies, such as microcephaly and aqueductal stenosis resulting in hydrocephalus and polymicrogyria.^1,3

Symptoms

Mandibular hypoplasia (smaller lower jaw) along with choanal atresia (a condition in which nasal passages are blocked by tissue or bone) and cleft palate can cause feeding and breathing difficulties in infants with Nager syndrome. Breathing difficulties, if left untreated, can cause serious complications. Patients may have temporomandibular joint dysfunction (TMJ), which can cause jaw, neck and face pain, jaw muscle stiffness and misalignment of the upper and lower teeth while closing the mouth.

Ear malformations cause conductive hearing loss of varying degrees, with hearing loss contributing to speech development delays.

Limb abnormalities present in this condition can make the forearms appear short. Due to limitations in the range of elbow movement, patients may also experience difficulty straightening their arms. A few patients who are severely affected may exhibit very short upper limbs. Additionally, the missing or underdeveloped radial bone can cause the hand to bend inwards, affecting the bones and tissues on the upper limb’s radial side. The absence or underdevelopment thumbs, could lead patients to experience difficulty with grip and fine motor skills.¹

Diagnosis

A detailed clinical evaluation, patient medical history and physical examination forms the basis of diagnosing this syndrome. The abnormalities seen in Nager syndrome are mostly congenital. 

Molecular genetic testing to determine mutation of SF3B4 can confirm the diagnosis of Nager syndrome. Genetic testing is also required to rule out other disorders with similar symptoms of Nager syndrome. The disorder caused by new mutations requires further analysis of the following genes: POLR1D, TCOF1, POLR1B, POLR1C, EFTUD2 and DHODH.

Imaging studies, such as X-rays, computed tomography, and magnetic resonance imaging can show micrognathia, malar hypoplasia and mandibular hypoplasia. Imaging can also be used to examine the internal structure of the ear in addition to hearing tests to determine hearing loss. The characteristic features of Nager syndrome can also be diagnosed via a prenatal ultrasound, which can be helpful when there is no family history of the disorder.^1,4,5

Treatment

The treatment of Nager syndrome is focused on the specific symptoms of the patient, this is usually a long process that starts in the neonatal period up to the age of 20. It requires a multidisciplinary approach involving paediatricians, oral and plastic surgeons, ophthalmologists, otolaryngologists, otologists, audiologists and psychologists.

A tracheostomy may be required by creating a small opening in the throat and inserting a tube through it for breathing assistance. Surgery may be required to create a small opening in the stomach to insert a feeding tube to provide adequate nutrition for infants experiencing feeding difficulties. Surgical intervention may also be needed for correcting jaw, eyes and limb abnormalities, cleft palate, skeletal abnormalities (e.g., stiffness of elbow), and congenital heart defects. 

Early initiation of physical, speech, and occupational therapies can help affected children achieve their full potential. Physical therapy, such as increasing the mobility of the TMJ, myofascial release techniques, sensory training and food and drink intake training, and occupational therapy will help children walk and use their hands. Speech developmental delays due to hearing loss can be improved using speech therapy. Hearing loss can be corrected by using hearing aids or surgically implanting ear tubes.

Genetic counselling and psychosocial support is essential for the affected individuals and their families, as it can help them understand the disorder and provide the necessary support for their child. Parents or guardians must be provided specific guidelines and instructions to help their child perform exercises at home, particularly after surgery.⁴

Summary

Nager syndrome is a rare disorder characterised by limb and craniofacial abnormalities. It is caused by the mutation in the SF3B4 gene, which leads to abnormal differentiation during the first and second pharyngeal arches and limb bud development. Diagnosis is based on the clinical features present at birth, genetic testing and imaging studies, which aid in planning the treatment of patients.

Many cases of Nager syndrome are caused by non-inherited genetic mutations, and in these cases, further diagnosis may be required by analysing the following genes: POLR1D, TCOF1, POLR1B, POLR1C, EFTUD2 and DHODH. The discovery of new mutations can improve diagnostic accuracy. Treatment is based on the severity of the condition and the type of abnormalities. Surgery and physical, speech and occupational therapies are used to improve the quality of life of the patient.