Introduction
Nagar syndrome is a rare genetic disorder known as acrofacial systosis. A combination of craniofacial and limb anomalies are the main characteristics of this disorder. It was named after the Swiss radiologist Franz Nagar, who was the first to describe this condition in 1948. Nagar syndrome presents a major challenge for diagnosis and differentiation from other syndromes with common abnormal features. Early and accurate diagnosis is vital for good management and effective treatment. This article aims to provide a comprehensive and detailed overview of the diagnostic process for Nagar syndrome and highlight the key considerations in differential diagnosis.
Symptoms and clinical presentation
A distinct range of craniofacial and limb abnormalities are the main characteristics of Nagar syndrome. The clinical features can vary tremendously among the affected individuals, making the diagnosis step challenging1
The most common craniofacial characters are below:
- Malar hypoplasia: a hallmark of this syndrome; is undevelopment of the checkbones, leading to a flattened midface appearance
- Downword slanting palpebral fissures: the eyes are often slanted downwards, making the distinct facial appearance
- Micrognathia: a common feature of the small jaw, which leads to difficulties in feeding and breathing in infants
- Cleft palate: Most of the babies born with this syndrome show this abnormality, which affects speech ability and feeding
- Ear anamolies: external ear abnormalities and small or absent ear canals that lead to conductive hearing loss
- Respiratory issues: due to the craniofacial anomalies, respiratory airway obstruction and breathing difficulties are common in newborn babies.
The upper limbs in particular have limb anomalies that are also a significant aspect of Nagar syndrome. These include:
- Radial ray anomalies: the thumb and forearm are missing
- Ulnar defects: shortened or absent ulnae
- Limited elbow extension: reduced range of motion in the elbows
Additional features may include short stature, scoliosis, and various congenital heart defects, though these are less common. The variability in the anomalies presence requires a thorough and systematic approach for the right diagnosis.2
Genetic basis and pathophysiology
The primary cause of nager syndrome is a mutation in the SF3B4 gene, which encodes a part of the splicing factor 3b complex. The pre-mRNA splicing process is essential for the expression of genes, which is carried out by this complex. Mutations in SF3B4 disrupt normal splicing, leading to the abnormal development of the craniofacial structure and limbs.
The inheritance pattern of nager syndrome is typically autosomal dominant, though many cases arise from denovo mutation, meaning they occur spontaneously rather than being inherent in parents. This genetic information is essential for an accurate diagnosis and genetic counseling for affected families.3
Diagnostic approach
Diagnosing nager syndrome requires an all-encompassing, multidisciplinary method. It is imperative to integrate radiographic imaging, genetic testing, and clinical examinations due to the presence of variable clinical presentations.4
- Clinical evaluation
A thorough physical examination with an emphasis on limb abnormalities and craniofacial traits. The severity of limb deformities such as radial ray anomalies and face dysmorphisms such malar hypoplacia, micrognathia, and cleft palate will be evaluated by physicians5
- Imaging studies
Skeletal anomalies can be seen by radiographic imaging, such as CT scans, MRIs, or x-rays. These imaging examination can help with diagnosis and surgical planning by giving specific information about the degree of limb and craniofacial abnormalities6
- Genetic testing
It is imperative to perform confirmatory testing for the SF3B4 mutation utilising techniques such as sanger sequencing or next-generation sequencing (NGS).
In addition to confirming the diagnosis, genetic testing helps to distinguish nager syndrome from other hereditary conditions that share its characteristics7
Differential diagnosis
Several conditions could be similar in their clinical features to those of nager syndrome, making the differential diagnosis an essential practice. Key conditions to consider are:
- Treacher-Collins syndrome (TCS)
It is also referred to as mandibulofacial dysostosis and shares several craniofacial characteristics with Nager syndrome, including micrognathia and malar hypoplasia. However, TCS doesn’t involve limb anomalies, which differentiates it from nager syndrome. Mutations in the TCOF1, POLR1C, or POLR1D genes cause the Tracey-collins syndrome8
- Miller syndrome
Also known as postaxial acrofacial dysostosis. Facial dysmorphism and limb anomalies are characteristic of Miller syndrome. A mutation in the DHODH gene makes it. The facial features of miller syndrome, including cleftlip/palate and lower eyelid colobomas, can overlap with those of nager syndrome, but detailed genetic analysis can distinguish between the two9
- Goldenhare syndrome
Also referred to as OAVS (oculo-auriculo-vertebral spectrum). Ocular abnormalities, spinal deformities, and craiofacial malformations are the hallmarks of Goldenhare syndrome. Unlike Nager syndrome, Goldenhare syndrome often includes vertebral and cardiac anomalies. The presence of vertebral anomalies can help differentiate goldenhare syndrome from nager syndrome10
- Pierre robin sequence (PRS)
PRS is characterised by micrognathia, glossoptosis (downward displacement or retraction of the tongue), and airway obstruction. PRS can occur in isolation or as part of other syndromes, such as stickler syndrome. The absence of limb anomalies in RPS helps differentiate it from nager syndrome11
- Acrofacial dysostosis rodriguez type
This rare condition presents with severe limb anomalies and craniofacial dysmorphism. Unlike nager syndrome, rodriguez type often includes severe intellectual disability and additional vesseral anomalies12
Management and prognosis
An individualized strategy is needed to manage nager syndrome, taking into account the unique abnormalities that each patient has. For the best care, a multidisciplinary team of audiologists, speech therapists, craniofacial surgeons, orthopedic surgeons, and geneticists is required.13
Key management strategies include:
- Surgical intervention
For limb and craniofacial defects to be corrected, many procedures can be needed. These may involve reconstructive surgery for limb abnormalities, mandibular distraction osteogenesis to stretch the jaw, and cleft palate repair.
- Respiratory management
Newborns with severe macrognathia and airway obstruction may require interventions such as tachoestomy or mandibular distraction to secure the airway
- Hearing management
It is imperative to detect and treat hearing loss early on. Using cochlear implants, bone-anchored hearing aids, or hearing aids could be necessary, depending on the type and extent of hearing loss.
- Speech therapy
Individuals with nager syndrome often require speech therapy to address issues related to a cleft palate and hearing loss
- Genetic counseling
For impacted families to comprehend the inheritance pattern, recurrence risk, and implications for subsequent births, genetic counseling is imperative.
Prognosis
The severity of the abnormalities and the efficacy of the therapeutic techniques used determine a wide range of outcomes for people with nager syndrome. Affected people can greatly enhance their quality of life with an early diagnosis and management. It is frequently vital to have a multidisciplinary team provide lifetime follow-up in order to address ongoing medical and developmental requirements.14
Challenges in diagnosis and management
The phynotypic heterogeneity of nager syndrome poses a significant diagnostic problem. Due to the vast range of clinical presentations, some people may have modest symptoms when they present, while others may have more serious abnormalities that could be fatal. This flactuation can make care more difficult and delay diagnosis.
The condition’s rarity presents another difficulty. Because the ailment is so uncommon, many medical professionals might not be familiar with how to present or treat it. This emphasizes how crucial it is to send patients to specialized facilities with knowledge of genetic and craniofacial problems.
Furthermore, the overlap of the clinical features with other syndromes necessitates a thorough differential diagnosis. Accurate genetic testing is essential to distinguish nager syndrome from other conditions with similar presentations, ensuring that individuals receive appropriate and targeted interventions.15
Future direction
Promising developments in genetic research and diagnostic methods could enhance the identification and treatment of nager syndrome. Early and more precise diagnosis is now possible thanks to the increasing affordability and accessibility of next-generation sequencing and other molecular diagnostic technologies.
New therapeutic strategies may result from ongoing investigation into the underlying mechanisms of the SF3B4 mutation and its effect on development. Gaining insight into how these mutations affect regular gene splicing may pave the way for focused treatments that lessen the disorder’s symptoms.
Furthermore, healthcare professional’s knowledge and education on nager syndrome can help with early diagnosis and referral to specialized medical care. To improve our knowledge and treatment of this complicated illness, geneticists, craniofacial surgeons, and other experts must work together.16
FAQs
What causes nager syndrome?
Nager syndrome is a rare genetic condition where your child is born with underdeveloped bones of the face, hands, and arms.
What are the nager syndrome symptoms?
Children with Nager syndrome have a characteristic appearance due to problems with their cheek bones, jaws, and eye’s sockets.
What is nager syndrome treatment?
Children may need tube feeding and need to have a tracheotomy tube placed to help them breathe.
What is the nager syndrome life expectancy?
Individuals born with nager syndrome have normal to above-average intelligence. Even though surgeries are often in the future, they can have a typical life span.
What is the differential diagnosis of nager syndrome?
Differential diagnoses to consider include:
- Treacher-Collins syndrome: similar facial features but lacks limbs abnormality
- Miller syndrome: similar facial features and limb abnormalities particularly affect the hands and feet
- Goldenhar syndrome: facial asymmetry and ear abnormalities, often with spinal and rib anomalies
- Acrofacial dysostosis: a group of disorders, including nager and miller syndromes, with facial and limb abnormalities
Summary
Diagnosing nager syndrome requires precision due to its varied manifestation and similarities to other craniofacial and limb disorders. Comprehensive evaluation, including imaging, genetic testing, and clinical assessment, is crucial for accuracy. Differentiating nager syndrome from similar conditions ensures proper treatment and care. This approach optimizes patient outcomes and quality of life. Ongoing research promises refined diagnostic methods and therapies, offering hope for enhanced management of this complex disorder. As scientific understanding develops, so does the potential for improved care and support for those affected by nager syndrome.
References
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- Oberg KC. Classification of congenital upper limb anomalies: towards improved communication, diagnosis, and discovery. Journal of Hand Surgery European Volume [Internet]. 2018 Sep 30;44(1):4–14. Available from: https://doi.org/10.1177/1753193418801280
- Cadieux‐Dion M, Hughes S, Engleman K, Rush ET, Saunders C. Nager syndrome in patient lacking acrofacial dysostosis: Expanding the phenotypic spectrum of SF3B4‐related disease. American Journal of Medical Genetics Part A [Internet]. 2021 Feb 8;185(5):1515–8. Available from: https://doi.org/10.1002/ajmg.a.62113
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- Zerounian S, Delrue M, Rypens F, Codsi E, Wavrant S. EP17.10: Early diagnosis of Nager syndrome in dichorionic twins. Ultrasound in Obstetrics and Gynecology [Internet]. 2019 Sep 30;54(S1):336. Available from: https://doi.org/10.1002/uog.21451
- Drendel HM, Wilson C, Sagaribay P, Casey R, Barnes E, Davidson K, et al. 14. Prenatal diagnosis of Acrofacial Dysostosis type 1 (Nager syndrome) by chromosomal microarray at the exon level. Cancer Genetics [Internet]. 2021 Apr 1;252–253:S5. Available from: https://doi.org/10.1016/j.cancergen.2021.01.025
- Kubo S, Horinouchi T, Kinoshita M, Yoshizato T, Kozuma Y, Shinagawa T, et al. Visual diagnosis in utero: Prenatal diagnosis of Treacher-Collins syndrome using a 3D/4D ultrasonography. Taiwanese Journal of Obstetrics and Gynecology [Internet]. 2019 Jul 1;58(4):566–9. Available from: https://www.sciencedirect.com/science/article/pii/S1028455919301287
- Veduta A, Duta S, Ciobanu AM, Botezatu R, Gica N, Peltecu G, et al. Fetal Skeletal Dysplasias that Involve the Face: Binder Syndrome and Nager Syndrome. PubMed [Internet]. 2021 Mar 1; Available from: https://pubmed.ncbi.nlm.nih.gov/34221170
- Jangra B. Goldenhar Syndrome: A Case Report with Review. Jaypee’s International Journal of Clinical Pediatric Dentistry [Internet]. 2016 Jan 1;9(3):278–80. Available from: https://doi.org/10.5005/jp-journals-10005-1377
- Rosa RFM, Guimarães VB, Beltrão LA, Trombetta JS, Lliguin KLP, De Mattos VF, et al. Nager syndrome and Pierre Robin sequence. Pediatrics International [Internet]. 2015 Mar 25;57(2). Available from: https://doi.org/10.1111/ped.12562
- Drivas TG, Taylor JA, Zackai EH. The final demise of Rodriguez lethal acrofacial dysostosis: A case report and review of the literature. American Journal of Medical Genetics Part A [Internet]. 2019 Mar 28;179(6):1063–8. Available from: https://doi.org/10.1002/ajmg.a.61121
- Contact. Nager syndrome | Information & support | Contact [Internet]. Contact. 2022. Available from: https://contact.org.uk/conditions/nager-syndrome/
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