Nager acrofacial dysostosis

Nager acrofacial dysostosis
Synonyms	Nager syndrome, mandibulofacial dysostosis with preaxial limb anomalies
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Field	Medical genetics, Orthopedics, Otolaryngology
Symptoms	Craniofacial abnormalities, limb malformations, sensorineural hearing loss, cleft palate, intellectual development usually normal.
Complications	Hearing loss, feeding difficulties due to cleft palate, respiratory issues, orthopedic problems.
Onset	Present at birth.
Duration	Lifelong.
Types	Nager acrofacial dysostosis has no subtypes, though severity varies.
Causes	Genetic mutations, particularly in the **SF3B4** gene.
Risks	Parental inheritance, spontaneous mutations, family history of the disorder.
Diagnosis	Diagnosis is primarily clinical, supported by genetic testing for SF3B4 mutations, and imaging to assess limb and craniofacial anomalies.
Differential diagnosis	Differentiated from other craniofacial and limb malformation syndromes such as Miller syndrome, Goldenhar syndrome, and Treacher Collins syndrome.
Prevention	No known prevention. Early genetic counseling is recommended for at-risk families.
Treatment	No cure. Treatment involves managing symptoms, including speech therapy, surgical intervention for cleft palate, hearing aids, and orthopedic management for limb malformations.
Medication	No specific medication for the disorder, though supportive therapies like hearing aids and speech therapy may be prescribed.
Prognosis	Generally good prognosis with appropriate treatment and management of symptoms. Intellectual development is typically normal, but there may be physical limitations depending on the severity of malformations.
Frequency	Rare; exact incidence unknown, but Nager acrofacial dysostosis is a rare genetic disorder.
Deaths	Few deaths are reported directly due to Nager acrofacial dysostosis, but complications related to malformations may contribute to health challenges.

Alternate names

Mandibulofacial dysostosis, Treacher Collins type, with limb anomalies; Nager syndrome; AFD, Nager type; Preaxial acrofacial dysostosis; Nager acrofacial dysostosis syndrome; Split hand deformity-mandibulofacial dysostosis; Acrofacial dysostosis 1, Nager type

Definition

Nager acrofacial dysostosis is a genetic disorder that affects the limbs and face.

Epidemiology

Nager syndrome is a rare condition. Its prevalence is unknown. More than 75 cases have been reported in the medical literature.

Cause

• More than half of cases of Nager syndrome are caused by mutations in the SF3B4 gene. The cause of the remainder of cases is unknown; other genes are thought to be involved in the condition.
• The SF3B4 gene provides instructions for making the SAP49 protein, which is one piece of a complex called a spliceosome.
• Spliceosomes help process messenger RNA (mRNA), which is a chemical cousin of DNA that serves as a genetic blueprint for making proteins.
• The spliceosomes recognize and then remove regions from mRNA molecules that are not used in the blueprint (which are called introns).
• The SAP49 protein may also be involved in a chemical signaling pathway known as the bone morphogenic protein (BMP) pathway.
• This signaling pathway regulates various cellular processes and is involved in the growth of cells.
• The SAP49 protein is particularly important for the maturation of cells that build bones and cartilage (osteoblasts and chondrocytes).

Gene mutations

• SF3B4 gene mutations that cause Nager syndrome prevent the production of functional SAP49 protein.
• Although the effect of this protein shortage is unknown, researchers suspect that it disrupts spliceosome formation, which may impair mRNA processing and alter the activity of genes involved in the development of several parts of the body.
• A loss of SAP49 may also impair BMP pathway signaling, leading to abnormal development of bones in the face, hands, and arms.

Inheritance

• When caused by mutations in the SF3B4 gene, Nager syndrome follows an autosomal dominant inheritance pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Most cases result from new mutations in the gene and occur in people with no history of the disorder in their family. Less commonly, an affected person inherits the mutation from one affected parent. Autosomal dominant Nager syndrome may also be caused by mutations in other genes.
• Nager syndrome can also be inherited in an autosomal recessive pattern, which means both copies of a gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of a mutated gene, but they typically do not show signs and symptoms of the condition. Nager syndrome is suspected to have an autosomal recessive inheritance pattern when unaffected parents have more than one affected child. The genetic cause in these families is unknown.

Signs and symptoms

The signs and symptoms of Nager acrofacial dysostosis vary among affected individuals, even among those in the same family.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Aplasia/Hypoplasia of the thumb(Absent/small thumb)
• Delayed speech and language development(Deficiency of speech development)
• Downslanted palpebral fissures(Downward slanting of the opening between the eyelids)
• Hearing impairment(Deafness)
• Hypoplasia of the maxilla(Decreased size of maxilla)
• Hypoplasia of the zygomatic bone(Cheekbone underdevelopment)
• Micrognathia(Little lower jaw)
• Skeletal dysplasia

30%-79% of people have these symptoms

• Abnormal nasal morphology(Abnormal of nasal shape)
• Aplasia/Hypoplasia of the eyebrow(Absence of eyebrow)
• Atresia of the external auditory canal(Absent ear canal)
• Cleft palate(Cleft roof of mouth)
• Hypoplasia of the radius(Underdeveloped outer large forearm bone)
• Joint stiffness(Stiff joint)
• Lower eyelid [[coloboma](Cleft lower eyelid)
• Microtia(Small ears)
• Ptosis(Drooping upper eyelid)
• Respiratory insufficiency(Respiratory impairment)
• Sparse lower eyelashes(Scanty lower eyelashes)
• Wide mouth(Broad mouth)

5%-29% of people have these symptoms

• Abnormality of cardiovascular system morphology
• Abnormality of the lower limb(Lower limb deformities)
• Low-set, posteriorly rotated ears
• Non-midline cleft lip
• Patent ductus arteriosus
• Phocomelia
• Triphalangeal thumb(Finger-like thumb)
• Unilateral renal agenesis(Absent kidney on one side)
• Ventricular septal defect(Hole in heart wall separating two lower heart chambers)

Diagnosis

The diagnosis of Nager acrofacial dysostosis (NADS) is primarily clinical, based on the presence of characteristic features such as craniofacial abnormalities, limb malformations, and hearing impairment. Diagnosis is confirmed through a detailed physical examination, family history, and genetic testing.

Clinical Features 

Key features include:

• Craniofacial abnormalities: Micrognathia (small jaw), underdeveloped cheekbones, and a small head (microcephaly).
• Limb malformations: Typically, affected individuals have shortened forearms and hands, with additional radial abnormalities and occasionally syndactyly (fusion of fingers or toes).
• Hearing loss: Sensorineural hearing loss is common in individuals with Nager acrofacial dysostosis.
• Cleft palate: Some individuals may have a cleft lip or cleft palate.
• Other features: Intellectual development is usually normal, although the severity of malformations varies significantly between individuals.

Genetic Testing 

Genetic testing can be used to confirm the diagnosis and identify the specific mutations responsible for Nager acrofacial dysostosis. Mutations in the SF3B4 gene have been associated with the condition. This gene is involved in the splicing of pre-messenger RNA, and mutations can disrupt normal development.

• Molecular genetic testing: Identifying mutations in the SF3B4 gene is essential for confirming the diagnosis in patients where clinical features are present but a definitive diagnosis is unclear.

Differential Diagnosis 

Nager acrofacial dysostosis shares some features with other craniofacial and limb malformation syndromes, and it is important to distinguish it from:

• Miller syndrome: Characterized by similar craniofacial anomalies, but caused by mutations in the DHODH gene.
• Goldenhar syndrome: This syndrome also presents with craniofacial abnormalities but typically lacks the limb defects seen in Nager acrofacial dysostosis.
• Treacher Collins syndrome: A genetic disorder that affects craniofacial development but does not involve limb anomalies to the same degree.

Imaging 

• X-rays and CT scans: Imaging studies are often used to assess limb abnormalities, the degree of limb shortening, and any other skeletal malformations.
• MRI: Used to evaluate the craniofacial malformations and to rule out other structural abnormalities.

Diagnosis often involves a combination of clinical evaluation, genetic testing, and imaging studies to differentiate from similar disorders.

Treatment

In infants with Nager acrofacial dysostosis who experience respiratory distress require immediate attention and may require a tracheostomy. A tracheostomy is a surgical procedure on the neck that opens a direct airway through an incision in the windpipe. Infants with feeding difficulties may require surgery and/or placement of a feeding tube (gastrostomy). Surgery can be performed to repair cleft palate and often micrognathia. Cosmetic surgery, especially for eyelids, can be performed to ensure complete closure of eyelids at night in order to prevent injury of the cornea. Surgical treatment is best accomplished at a craniofacial center with expertise in plastic surgery, otolaryngology, orthodontics, and dentistry. Hearing aids for individuals with conductive hearing loss should be offered.

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