Diagnosis of Neonatal Neurofibromatosis Type 1: a case report and review of the literature

doi:10.21203/rs.3.rs-2347068/v1

Download PDF

Case Report

Diagnosis of Neonatal Neurofibromatosis Type 1: a case report and review of the literature

https://doi.org/10.21203/rs.3.rs-2347068/v1

This work is licensed under a CC BY 4.0 License

Journal Publication

published 24 May, 2023

Read the published version in BMC Pediatrics →

You are reading this latest preprint version

Background: Neurofibromatosis Type 1 (NF1) is a rare genetic disorder characterized with the development of multiple benign tumors on the nerves and skin.

Case presentation: This report described a case of a neonate with a large mass observed on the left side of the maxillofacial region and cervical region at birth. Meantime, multiple cafe-au-lait macules (CALMs) were also seen on the trunk and both lower extremities.

Conclusions: In this case, ultrasonography was used as a diagnostic method to discuss the ultrasonographic and clinical features of the tumor.

neurofibromatosis type 1

neonate

ultrasound

imaging

case report

As an autosomal dominant disorder, Neurofibromatosis Type 1 (NF1) has a neonatal morbidity of around 1/3000 (1). NF1 gene mutation is the direct genetic cause of NF1. Located on chromosome 17q11.2, NF1 is a tumor suppressor gene that encodes a neurofibromin, involved in the transduction cascade of multiple signals such as Ras/RAF/MEK/ERK, Akt/mTOR and AC/cAMP, and associated with cell proliferation and differentiation (2). Typical clinical manifestations of NF1 are cutaneous neurofibromas, cafe-au-lait macules (CALMs), freckles, and Lisch nodules (iris malformations). Some cases are characterized clinically by seizures, learning and cognitive impairments, autism spectrum disorders, vascular diseases, cardiac malformations, central nervous system (CNS) tumors, skeletal abnormalities and other syndromes (3). Some cases missed diagnosis due to the lack of any symptoms, and some wasted the best time due to late onset. For patients without family history, only 46% were diagnosed before 2 (4). Among them, neonatal cases are even rarer. This report discussed a case of a neonate with a large mass on maxillofacial region and cervical region, as well as its ultrasound imaging features and clinical presentations.

A newborn, female, 4 days old, born at 39 weeks of gestational age, was admitted to our hospital with a mass of progressive enlargement in the left maxillofacial region. The child was born naturally due to premature rupture of membranes, with the umbilical cord around the neck one loop, and no abnormality found in placenta and amniotic fluid. Apgar score at birth was 10 at 1 minute, 5 minutes and 10 minutes respectively. Physical examination after admission showed edema on the left facial region and left eyelid region, ectropion of the left eyelid, conjunctival congestion, and faint yellow secretion. No nodular protuberance was seen on the bilateral iris. The mass on the left cervical region to the facial region was slightly tough by palpation, with low local skin temperature, average mobility and no rupture. The number of CALMs seen on the trunk and both lower extremities was more than 6, with the largest greater than 11cm. Her father also had CALMs. The lung respiratory sound was coarse, and sputum sound was heard.

CT showed enormous space occupying in the maxillofacial and cervical region, oppression of airway, involvement of left cavernous sinus and local encasement of optic nerve (Fig. 1). CT suspected neurofibromatosis. MRI showed enormous irregular soft tissue space occupying in the left maxillofacial and cervical region with unclear borders, encasing the left carotid sheath, oppressing the airway, involving the left parotid gland, the left cavernous sinus, and extending into the left orbit. Enhanced MR scanning showed significantly more uniform enhancement, with some nodular and lumpy enhancement (Fig. 1). MR suspected neurogenic tumor or Kaposi's hemangioendothelioma.

The sonography showed a large irregular and substantial hypoechoic mass in the deep facial space besides the left cervical spine, around 6.6×6.0×5.5 cm. The lower edge of the mass was equal to the level of the thyroid gland, and the inner upper edge reached the level of the skull base, and the upper edge had unclear boundaries with the submandibular gland and parotid gland. Echo within the mass was uneven. The mass wrapped around the entire extracranial segment of the internal carotid artery to the cranial base level, external carotid artery and branches. The jugular veins were compressed to become narrow. Color Doppler revealed dotted blood flow signals within the mass. Contrast-enhanced ultrasound displayed rapid hyperenhancement with slow contouring within the mass, without obvious non-enhancement areas (Fig. 2A-D). Ultrasound diagnosis showed large substantial space occupying lesions on the left cervical and maxillofacial region, and thus neurofibromatosis was considered.

After 2 days of observation, the child demonstrated extent of the lesion, accompanied by trachea compression. Considering low possibility of complete resection and high risk, ultrasound-guided mass puncture was performed (Fig. 2E). Immunohistochemical analysis of tumor cells showed S-100 protein (+) and CD34 (+). Histologic examinations were consistent with neurofibromatosis (Fig. 2F). Combined with the child's medical history, neurofibromatosis type 1 (NF 1) was suspected. Then whole exome genetic test was conducted on her parents and the child. The results showed that the child had NF1 gene variation, but her parents did not have NF1 gene variation. It was a de novo mutation. The child was discharged from the hospital without further treatment for family reasons and has been alive up to now after 6 months of follow-up.

NF1 refers to germline mutation of the NF1 gene originating from chromosome 17q11.2. The mutation can be de novo or familial, characterized by autosomal dominant inheritance. Approximately 50% of NF1 patients are spontaneously mutated (4). The patient has no family history of NF1 and is a spontaneous mutation. CALMs are early clinical features of NF1 (5). In the past 3 decades, there have been few reports on neonatal NF1 (Table 1) (6–13).

Table 1

Reports on Neonatal NF1 in the past 30 years.
Author	Article Year	Age at diagnosis (d)	Gender	Family history	Presence of CALMs	Location of neurofibroma	Treatment
Berthin C et al. (6)	2019	21d	Male	Unknown	Yes	Eye	Unknown
Sadhukhan M et al. (7)	2017	8d	Female	Unknown	Yes	Retropharyngeal and paraspinal	Taking MEK inhibitors
Day KM, et al. (8)	2020	1d	Female	Unknown	Unknown	Neck	Microlaryngoscopy, bronchoscopy and tracheotomy plus trametinib chemotherapy
Goyal S et al. (9)	2014	6d	Female	Yes	No	Eye	Local excision
Hatanaka K et al. (10)	2013	1d	Male	No	Yes	Posterior mediastinum	Surgery
Colás-Tomás T et al. (11)	2010	1d	Male	Yes	Yes	Posterior ocular	Ahmed glaucoma flap implantation
Stewart H et al. (12)	2008	1d	Female	No	No	Diffuse, most severely involving the head and neck, and the mass found involving almost every tissue at autopsy	Died 42h after birth
Payne MS et al. (13)	2014	1d	Female	No	None at birth, present at 10w	Paracervical spine	Local excision

Subcutaneous neurofibroma and plexiform neurofibroma (PNF) are present in 30–50% of NF1 patients. Usually congenitally benign, PNF grows in a reticular pattern to replace normal tissue (14). PNF can be limited, nodular, or diffuse and seen in the paravertebral region of the trunk (31%), head & neck (31%) and extremities (25%) (5). Previous ultrasound reports showed that PNF was an irregularly lobulated hypoechoic mass, which ran along the nerve axis on the longitudinal image diagram and displayed target ring sign on the transverse image, with high echo in the center and low echo around. Cystic changes can be seen in about 70% of the masses. Color Doppler flow signals showed different conditions (15). The ultrasonography findings in this case were consistent with previous reports. In addition, after the literature review, we found that this case was the first report of using contrast-enhanced ultrasound and ultrasound-guided puncture biopsy to diagnose neurofibromatosis in the left maxillofacial and cervical region. Ultrasonography with characteristics of quick-in-and-out has been previously reported in a 35-year-old male with non-NF1 pancreatic neurofibroma and a 4-year-old with a giant retroperitoneal neurofibroma (16). The enhancement pattern in this child was quick in-slow out. The exact cause of such discrepancy could not be demonstrated due to the lack of big data statistics, but this case has accumulated experience for this rare disease.

PNF usually grows rapidly in early childhood at a volume of ≥ 20% per year (4). In this case, the mass was large enough to compress the trachea, and thus tracheal intubation was required. This case suggested that the diagnosis of rare diseases should be made with caution and suspicion. Early diagnosis and treatment may improve the long-term prognosis (8).

Neonatal NF1 is rare. Diagnosis is more challenging if it is of non-familial inheritance. In this case, the left mass was large enough to compress the airway and surround the blood vessels. Life-threatening conditions such as respiratory and cardiac arrest could occur at any time. Ultrasonic examination, which is convenient and multi-directional, is particularly necessary for early diagnosis. With a high success rate, ultrasonic-guided aspiration biopsy has provided a reliable basis for the diagnosis of neurofibromatosis.

Maxillofacial and cervical mass in neonates accompanied by CALMs should consider neurofibromatosis type 1. The combination use of contrast-enhanced ultrasound and ultrasound-guided puncture biopsy can ensure the diagnosis of this disease.

NF1: Neurofibromatosis Type 1; CALMs: Cafe-au-lait macules; CNS: Central nervous system; PNF: Plexiform neurofibroma.

Ethics approval and consent to participate

The studies involving human participants were reviewed and approved by the Ethics Committee of Shenzhen Children's Hospital.

Consent for publication

The parents of this patient consented to the publication of the case and any accompanying images with written informed consent.

Availability of data and materials

The datasets used and analysed during the current study are available from the corresponding author upon reasonable request.

Competing interests

The authors report no conflicts of interest in this work.

Funding

This research received no external funding; no funds, no grants, or other support were received.

Authors' contributions

QZ made substantial contributions to the conception and design of this study. QZ and RW wrote the manuscript. FX and XZ collected the data. LL critically reviewed the manuscript and supervised the whole study process. All authors read and approved the final manuscript. All authors agreed to be accountable for all aspects of the work.

Acknowledgements

We sincerely appreciate all members of the Department of Ultrasound, Neonatology, and Radiology, Shenzhen Children’s Hospital, Shenzhen, China.

Kallionpaa RA, Uusitalo E, Leppavirta J, Poyhonen M, Peltonen S, Peltonen J: Prevalence of neurofibromatosis type 1 in the Finnish population. Genet Med 2018, 20(9):1082-1086.
He Q, Jiang J, Yang J, Zeng J, Zhang H, Zhang Z: A novel mutation of the NF1 gene in a Chinese family with neurofibromatosis type 1. Am J Transl Res 2022, 14(7):5139-5145.
Hernandez-Martin A, Duat-Rodriguez A: An Update on Neurofibromatosis Type 1: Not Just Cafe-au-Lait Spots and Freckling. Part II. Other Skin Manifestations Characteristic of NF1. NF1 and Cancer. Actas Dermosifiliogr 2016, 107(6):465-473.
Blakeley JO, Plotkin SR: Therapeutic advances for the tumors associated with neurofibromatosis type 1, type 2, and schwannomatosis. Neuro Oncol 2016, 18(5):624-638.
Sang NV, Ninh TP, Thanh DT, Thinh NC: A case report of mesenteric involvement in neurofibromatosis type 1. J Clin Imaging Sci 2022, 12:43.
Berthin C, Hugny-Larroque C, Heran F, Misery L, Abasq-Thomas C: Image Gallery: Swelling of the upper eyelid with trichomegaly revealing neurofibromatosis type 1. Br J Dermatol 2019, 181(3):e61.
Sadhukhan M, Conry B, Bhaduri B: Extensive Retropharyngeal and Spinal Plexiform Neurofibromas in a Neonate with Type 1-Neurofibromatosis. Indian J Pediatr 2017, 84(8):645-646.
Day KM, Roward S, Gillispie A, Attra J, Kelley P: Early Diagnosis and Intervention for Airway-Obstructing Neonatal Plexiform Neurofirbomatosis. J Craniofac Surg 2020, 31(5):e495-e497.
Goyal S, Park A, Zeglam A, Brown H, Pemberton JD: Choroidal Ganglioneuroma and Orbital Plexiform Neurofibroma Presenting as Buphthalmos in an Infant With Neurofibromatosis Type 1. Ophthalmic Plast Reconstr Surg 2016, 32(4):e87-89.
Hatanaka K, Yoshioka T, Tasaki T, Tanimoto A: Pulmonary rhabdomyomatous dysplasia of the newborn in neurofibromatosis type 1. Pathol Res Pract 2014, 210(5):318-320.
Colas-Tomas T, Gutierrez-Diaz E, Tejada-Palacios P, Barcelo-Mendiguchia A, Mencia-Gutierrez E: Management of congenital glaucoma in neurofibromatosis type 1: a report of two cases. Int Ophthalmol 2010, 30(2):211-214.
Stewart H, Bowker C, Edees S, Smalley S, Crocker M, Mechan D, Forrester N, Spurlock G, Upadhyaya M: Congenital disseminated neurofibromatosis type 1: a clinical and molecular case report. Am J Med Genet A 2008, 146A(11):1444-1452.
Payne MS, Nadell JM, Lacassie Y, Tilton AH: Congenital glaucoma and neurofibromatosis in a monozygotic twin: case report and review of the literature. J Child Neurol 2003, 18(7):504-508.
Farschtschi S, Mautner VF, McLean ACL, Schulz A, Friedrich RE, Rosahl SK: The Neurofibromatoses. Dtsch Arztebl Int 2020, 117(20):354-360.
Bouimetarhan L, Bellamlih H, En-Nafaa I, Fenni JE, Amil T, Radouane B: [Plexiform cervical neurofibroma: about a case]. Pan Afr Med J 2018, 30:41.
Song L, Jiang Z, Cui J, Gao B, Luo Y: Benign Pancreatic Neurofibroma with Malignant Imaging Features: A Case Report and Literature Review. Front Surg 2022, 9:874006.

No competing interests reported.

Download PDF

Journal Publication

published 24 May, 2023

Read the published version in BMC Pediatrics →

Editorial decision: Major revision
28 Mar, 2023
Reviews received at journal
16 Mar, 2023
Reviewers agreed at journal
08 Mar, 2023
Reviewers agreed at journal
03 Mar, 2023
Reviewers agreed at journal
28 Feb, 2023
Reviewers invited by journal
28 Dec, 2022
Editor assigned by journal
22 Dec, 2022
Editor invited by journal
12 Dec, 2022
Submission checks completed at journal
12 Dec, 2022
First submitted to journal
05 Dec, 2022

You are reading this latest preprint version

Diagnosis of Neonatal Neurofibromatosis Type 1: a case report and review of the literature

Status:

Journal Publication

Version 1

Abstract

Figures

Background

Case Presentation

Discussion And Conclusions

Abbreviations

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1