Diagnosis of neonatal neurofibromatosis type 1: a case report and review of the literature
BMC Pediatrics volume 23, Article number: 259 (2023)
Neurofibromatosis Type 1 (NF1) is a rare genetic disorder characterized with the development of multiple benign tumors on the nerves and skin.
This report described a neonatal case with a large mass observed on the left side of the maxillofacial and cervical region at birth. Meantime, multiple cafe-au-lait macules (CALMs) were seen on the trunk and both lower extremities.
In this case, the clinical features of the rare NF1 neonate are discussed along with its ultrasound findings.
As an autosomal dominant disorder, Neurofibromatosis Type 1 (NF1) has a neonatal morbidity of around 1/3000 . NF1 gene mutation is the direct 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 . 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 . Many patients are usually undiagnosed or miss the best treatment opportunity due to the lack of symptoms or late onset. Only 46% of patients without family history are diagnosed before age 2 . Among them, neonatal cases are even rarer. This report discussed a neonatal case with a large mass on the maxillofacial and cervical region, as well as its ultrasound imaging features and clinical presentations.
A 4-day-old female infant with gestational age of 39 weeks 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 in 1 min, 5 and 10 min 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. The mass on the left side of the maxillofacial to cervical region was slightly tough, with low local skin temperature, average mobility and without rupture (Fig. 1). The number of CALMs seen on the trunk and both lower extremities was more than 6, with the largest greater than 11 cm. The lung respiratory sound was coarse, and sputum sound heard. The family history of the newborn was normal, except that her father suffered from CALMs.
CT showed a large mass occupying in the maxillofacial and cervical region that compressed the airway, involving the left cavernous sinus and locally encircling the optic nerve (Fig. 2A-C). CT suspected neurofibromatosis. MRI also showed an enormous irregular mass 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 (Fig. 2D, E). Contrast enhanced MRI revealed a more homogeneous enhancement of the mass as a whole, with some nodular and mass-like enhancement (Fig. 2F). For these, the MRI diagnosis was suspected neurogenic tumor or Kaposi’s hemangioendothelioma.
The ultrasound 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, 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 ultrasound 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. 3A-D). Ultrasound diagnosis showed large substantial space occupying lesions on the left cervical and maxillofacial region, and thus neurofibromatosis was considered.
Due to the compression of the trachea by the cervical mass, the child was urgently intubated and ventilated with a ventilator. After 2 days of observation, ultrasound-guided puncture of the mass was performed (Fig. 3E). The pathological findings of the swelling puncture biopsy (hematoxylin-eosin staining) showed that the puncture tissue consisted mainly of spindle cells. The nuclei were oval or short spindle-shaped, with inconspicuous heterogeneity, and no obvious nuclear division was seen. The cytoplasm of the cells was lightly stained or lightly pink stained (Fig. 3F). Immunohistochemical analysis of tumor cells showed S-100 protein (+) and CD34 (+). Histologic examinations were consistent with neurofibromatosis. In light of the child’s medical history, NF1 was suspected. Then whole exome genetic test was conducted on her parents and the child. The results showed a heterozygous variant in their NF1 gene with the mutation locus c.2540T > C (p.L847P), which is a pathogenic mutation. As no mutation at this locus was found in either of her parent, this was a spontaneous germline mutation. Given the extent of the lesion and the low tolerability of the neonate, the possibility of complete surgical resection was low and the risk was high, so the child received conservative treatment temporarily. The child was discharged for family reasons and treated outside hospital, where he survived 6 months, and the family refused to provide treatment details.
Discussion and conclusions
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 . This has no family history of NF1 and is a spontaneous mutation. CALMs are early clinical features of NF1 . According to the uniform diagnostic criteria of National Institutes of Health (NIH) for NF1 in 1988, six or more CALMs are diagnostic . Generally, normal people also carry 1–3 CALMs sometimes, which could explain the coffee milk spots on the father.
In the past 3 decades, there have been few reports on neonatal NF1 (Table 1) [7,8,9,10,11,12,13,14]. 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 . PNF can be limited, nodular, or diffuse and seen in the paravertebral region of the trunk (31%), head & neck (31%) and extremities (25%) . 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. However, the Color Doppler flow signals can have many different presentations that have no specificity . 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. The ultrasound contrast enhancement pattern with 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 . 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 . 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 .
Neonatal NF1 is rare. Diagnosis is more challenging if it is 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, ultrasound-guided aspiration biopsy has provided a reliable basis for the diagnosis of neurofibromatosis.
Maxillofacial and cervical mass in neonates accompanied by CALMs should consider NF1. The combination use of contrast-enhanced ultrasound and ultrasound-guided puncture biopsy can ensure the diagnosis of this disease.
Availability of data and materials
The datasets used and analysed during the current study are available from the corresponding author upon reasonable request.
Neurofibromatosis Type 1
Central nervous system
National Institutes of Health
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):1082–6.
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):5139–45.
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):465–73.
Blakeley JO, Plotkin SR. Therapeutic advances for the tumors associated with neurofibromatosis type 1, type 2, and schwannomatosis. Neuro Oncol. 2016;18(5):624–38.
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.
National Institutes of Health Consensus Development Conference Statement: neurofibromatosis. Bethesda, Md., USA, July 13–15, 1987. Neurofibromatosis. 1988;1(3):172–178.
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):645–6.
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):e495-7.
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):318–20.
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):211–4.
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):1444–52.
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):504–8.
Farschtschi S, Mautner VF, McLean ACL, Schulz A, Friedrich RE, Rosahl SK. The Neurofibromatoses. Dtsch Arztebl Int. 2020;117(20):354–60.
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.
We sincerely appreciate all members of the Department of Ultrasound, Neonatology, and Radiology, Shenzhen Children’s Hospital, Shenzhen, China.
This study has been supported by Guangdong High-level Hospital Construction Fund and Shenzhen High-level Hospital Construction Fund.
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.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Zheng, Q., Xia, B., Zhao, X. et al. Diagnosis of neonatal neurofibromatosis type 1: a case report and review of the literature. BMC Pediatr 23, 259 (2023). https://doi.org/10.1186/s12887-023-04077-z
- Neurofibromatosis type 1
- Case report