The rare association of congenital glaucoma, giant melanocytic nevus, alopecia, and hypospadias in an Egyptian child with neurofibromatosis type 1: a case report

Abstract

Background

Neurofibromatosis type 1 (NF1) is a multisystem genetic disorder that commonly involves skin, nerves, and skeletal system with increased neoplastic predisposition. This disease has been rarely associated with multiple congenital anomalies. Herein, we describe an Egyptian child with NF1 and coexistent bilateral congenital glaucoma, giant congenital melanocytic nevi (GCMN), alopecia, and hypospadias.

Case presentation

A 2.5-year-old boy presented with developmental delay, back swelling, and multiple congenital anomalies. His father and two sisters were known to have NF1. The child was diagnosed with bilateral primary congenital glaucoma at the age of 3.5 months and underwent trabeculectomy with mitomycin C therapy. Examination at the age of 5 months revealed marked hypotonia, multiple GCMN, scanty café-au-lait macules, left upper eyelid plexiform neuroma and trichomegaly, hypertrichosis of left eyebrow, hypertelorism, depressed nasal bridge, left frontal scalp alopecia, and distal penile hypospadias. At the age of 8 months, brain imaging depicted a markedly dilated left lateral ventricle, and he underwent ventriculoperitoneal shunt surgery. The child developed back swelling at the age of 2.5 years, and a spinal magnetic resonance image showed bilateral multiple spinal neurofibromas in the paraspinal region with intraspinal extensions. A whole exome sequencing identified a heterozygous missense variant NM_001042492.3:c.1466A > G (NP_001035957.1:p.Tyr489Cys) in NF1 gene.

Conclusions

The present case report adds to the knowledge of the phenotypic spectrum and variability of NF1 by reporting the association of multiple unusual congenital anomalies. Importantly, such congenital anomalies could be the first presenting features in patients with NF1 since cafe´-au-lait macules and other typical diagnostic criteria may not be apparent in the neonatal period and early infancy. Accordingly, NF1 should be considered in newborns with congenital glaucoma, GCMN, scalp alopecia, and hypospadias.

Background

Neurofibromatosis type 1 (NF1; OMIM 162200) is a common genetic multisystem disorder that affects 1 per 3000 individuals worldwide. This disease results from pathogenic variants in NF1 gene and is inherited in an autosomal dominant manner, although about half of patients have de novo NF1 variants [1, 2]. NF1 manifests a broad spectrum of characteristic features of variable severity and progression, commonly involving skin, nerves, and skeletal system. Moreover, patients with NF1 are prone to developing benign and malignant neoplasms. Other less common abnormalities include skeletal, vasculopathy, gastrointestinal, endocrine, and pulmonary diseases [3, 4]. The diagnosis of NF1 relies on meeting National Institutes of Health (NIH) diagnostic criteria, as revised by Legius et al.[4] in 2021.

Several congenital anomalies have been described in patients with NF1, including cardiac, vascular, musculoskeletal, gastrointestinal, and urinary defects [5]. A population registry study indicated that children with NF1 have threefold higher odds of having at least one congenital anomaly [5]. However, the constellation of multiple congenital anomalies in association with NF1 has been rarely reported [6,7,8]. In this case report, we describe an Egyptian child with NF1 associated with bilateral congenital glaucoma, giant congenital melanocytic nevi (GCMN), alopecia, and hypospadias.

Case presentation

A 2.5-year-old boy presented to our hospital in southern Egypt with developmental delay, back swelling, and multiple congenital anomalies. He was the youngest of five children whose parents were first cousins of Arab descent from Egypt (Fig. 1). The child was delivered vaginally at full term (birth weight of three kg) with no remarkable events during gestation or labor. At the age of 3.5 months, the mother sought an ophthalmology clinic because her infant had excessive tearing since birth. Examination revealed increased horizontal corneal diameter (left eye 14.5 mm, right eye 14 mm), high intraocular pressure (left eye 32 mmHg, right eye 30 mmHg), corneal edema, and optic disk cupping. The child was diagnosed with bilateral primary congenital glaucoma and underwent trabeculectomy with mitomycin C therapy for both eyes (interspersed by 1.5-month duration). However, the operation was complicated by recession of the conjunctival flap and baring of the scleral flap in one eye, which required operative revision. Furthermore, corneal edema and increased intraocular pressure were detected following the operation at 3 months for one eye and at one year for the other eye, which were managed by combined dorzolamide and timolol eye drops.

Fig. 1

Pedigree chart. The proband is depicted by the black arrow

At the age of five months, the mother sought medical advice because her infant was floppy. Developmental assessment showed social smiling and cooing sounds but no head support. On neurological examination, the child had generalized hypotonia with preserved deep tendon reflexes and no tongue fasciculation. Regarding anthropometric measures, his weight was 4.5 kg (5th centile), length 66 cm (50th centile), and head circumference 43.5 cm (75th centile). Skin examination showed a hairy GCMN encircling the left thigh and scanty café-au-lait macules. Furthermore, examination of the face and head revealed left exophthalmos, left upper eyelid plexiform neuroma and trichomegaly, hypertrichosis of left eyebrow, hypertelorism, depressed nasal bridge, and left frontal scalp alopecia. Last, distal penile hypospadias was detected (Fig. 2). Regarding family history, the father and two sisters were known to have NF1 (Fig. 1); the father had multiple café-au-lait macules, several cutaneous neurofibromas, and right upper eyelid plexiform neurofibroma, while the two sisters had only café-au-lait patches with no developmental abnormalities.

Fig. 2

Multiple congenital anomalies in a child with neurofibromatosis type 1. a & b Left proptosis, upper eyelid plexiform neuroma (black arrows), trichomegaly (white arrows), brow hypertrichosis (white asterisks), frontal scalp alopecia (black asterisks), hypertelorism, and depressed nasal bridge (black circles); c Hairy giant congenital melanocytic nevus encircling left thigh (white arrow); d Distal penile hypospadias (black arrow)

Brain computed tomography showed bilateral hyperdense basal ganglia especially on the left side, decreased volume of the left cerebral hemisphere, dilated left lateral ventricle, and enlarged pericerebral cerebrospinal fluid (CSF) spaces (Fig. 3a). Magnetic resonance imaging (MRI) of the orbit revealed left sphenoid wing dysplasia with herniation of the temporal lobe and its surrounding CSF spaces leading to exophthalmos (Fig. 3b). Echocardiography showed no remarkable abnormalities. The child was diagnosed with NF1 and started a multidisciplinary management plan. This included growth evaluation and nutritional support, neurodevelopmental evaluation, physiotherapy, regular ophthalmological assessment for intraocular pressure and visual functions, regular screening MRI brain, and blood pressure monitoring [9]. Urological consultation recommended surgical repair for hypospadias at the age of 12 months. Plastic surgeons monitored GCMN and planned for laser management after few months.

Fig. 3

a Axial CT brain at the age of 5.5 months showing bilateral hyperdense basal ganglia particularly on the left side prominent at the thalamus and lentiform nucleus (black arrow) and decreased volume of the left cerebral hemisphere as well as dilated left lateral ventricle (white arrow) and wide perihemispheric CSF spaces (white asterisk); b Axial T2 MRI scan of the orbits at the age of 5.5 months depicting thinning (hypoplasia) of the left sphenoid wing (black arrow) causing deformity of the left orbit which is flattened posteriorly (white arrow). Consequently, the left temporal lobe with the surrounding prominent CSF bulges anteriorly with subsequent proptosis where the whole left eye globe is seen anterior to the interzygomatic line at the level of the lens (black line); c Axial FLAIR MRI sequences at the age of 8 months showing markedly decreased volume of left cerebral hemisphere tissue with reduced brain mantle (residual cortex) (white arrow) and markedly dilated left lateral ventricle (white asterisk)

At the age of 8 months, the infant could smile, know familial people, and put hands in mouth, but still no head support. Exam showed a progressive increase in the head circumference (48 cm; > 97th centile). MRI brain showed marked dilatation of the left lateral ventricle and significantly reduced volume of the left cerebral hemisphere with no detectable obstructive lesions (Fig. 2c). Subsequently, the child underwent left ventriculoperitoneal shunt surgery. Unfortunately, the parents missed scheduled follow-up visits for several months.

The child presented again at the age of 2.5 years because his mother noticed a new-onset back swelling. His weight was 10.5 kg (< 3rd Centile), length 91 cm (50th centile), and head circumference 51.5 cm (95th Centile). The child manifested severe developmental delay with no head support or spoken words. Besides the previously described abnormalities, examination showed multiple, non-tender, mobile, beaded, subcutaneous mass extending from the left midthoracic paravertebral area to the lateral side of the thoracic cage compatible with plexiform neurofibromas. MRI spine showed bilateral multiple spinal neurofibromas in the paraspinal region with intraspinal extension (Fig. 4). A follow-up MRI brain showed no new abnormalities. Unfortunately, the child died three months later due to severe acute gastroenteritis complicated by septic shock.

Fig. 4

a Coronal T2 whole spine MRI sequence showing bilateral multiple spinal neurofibromas in the paraspinal region (straight white arrows) with intraspinal extension through wide neural foramina (black arrow). Intercostal neurofibromas are also noted on the left side (black asterisk). Mild right scoliosis is also seen (bent white arrows); b Sagittal T2 whole spine MRI scan depicting multiple spinal neurofibromas in the paraspinal region (white asterisks) with intraforaminal extension (white arrow) and intraspinal component of hyperintense signal with central hypointensity (target sign) (black arrow)

A whole exome sequencing (WES) was performed at the age of 2.5 years using high molecular weight genomic DNA extracted from whole blood samples using QIAamp DNA Blood Mini Kit (QIAGEN, Germantown, MD, USA). WES was performed following the CAP/CLIA validated standard operating protocol. Briefly, exome capture was performed using xGen Exome Research Panel v2 (Integrated DNA Technologies, Coralville, IA, USA) and sequencing was performed using the NovaSeq platform (Illumina, San Diego, CA, USA) as 150 bp paired-end reads. Sequencing data were aligned to the GRCh37/hg19 human reference genome using BWA-MEM and processed for variant calling by GATK v.3 [10, 11]. Copy number variants were called using CoNIFER v0.2.2, and 3bCNV, an internally developed tool that uses depth-of-coverage information of each exon [12]. Variants were then annotated by Ensembl Variant Effect Predictor (VEP) and filtered and classified by EVIDENCE following the American College of Medical Genetics and Genomics guideline [13, 14]. The filtered and classified variant list was manually reviewed by medical geneticists and physicians. The most likely variants that can explain the patient’s phenotype were selected for reporting. WES identified a heterozygous missense variant NM_001042492.3:c.1466A > G (NP_001035957.1:p.Tyr489Cys) in NF1 gene (Fig. 5); no other clinically significant variants were found.

Fig. 5

Integrative Genomic Viewer image for 17-29,541,542-A-G (GRCh37), NM_001042492.3:c.1466A > G (NP_001035957.1:p.Tyr489Cys)

Discussion

This is the first case reported from Egypt for a child with NF1 and associated multiple rare congenital anomalies. The diagnosis of NF1 in this case relied on meeting the revised diagnostic criteria for NF1 [4], including plexiform neurofibroma, sphenoid dysplasia, heterozygous pathogenic NF1 variant, and a parent meeting diagnostic criterion of NF1. Other typical features included scoliosis, café-au-lait macules, hydrocephalus, and spinal neurofibromas. Moreover, the child had a constellation of several unusual abnormalities: bilateral congenital glaucoma, giant congenital melanocytic nevi, scalp alopecia, and distal penile hypospadias. A few reports exist on the rare association of each of these congenital anomalies with NF1. However, the constellation of multiple congenital abnormalities in a single NF1 patient has not been reported. Importantly, associated congenital anomalies could be the presenting features in patients with NF1 since typical diagnostic features of NF1 may not be apparent in the neonatal period and early infancy.

The underlying mechanism linking these diverse congenital anomalies with NF1 is likely the disruption of Ras/mitogen-activated protein kinase (MAPK) pathway, which plays a pivotal role in the regulation of cell cycle. NF1 is a tumor suppressor gene encoding neurofibromin. Neurofibromin is a GTPase-activating protein (also called RasGAP), which downregulates the RAS/MAPK pathway [15]. Accordingly, NF1 shares multiple clinical manifestations and congenital anomalies with other RASopathies, such as Noonan (MIM 163950), Costello (MIM 218040), LEOPARD (MIM 151100), Cardiofaciocutaneous (MIM 115150), Legius (MIM 611431), and capillary malformation-arteriovenous malformation (CMAVM; MIM 608354) syndromes [16]. Indeed, vascular and nevi malformations, ocular anomalies, hair abnormalities, and urogenital anomalies are among the reported congenital anomalies in patients with RASopathies [15, 17].

Glaucoma has been found in about 1–2% of patients with NF1. However, the presence of eyelid plexiform neurofibroma, like in our case, is associated with ipsilateral glaucoma in up to 50% of NF1 patients [18, 19]. Possible mechanisms of primary glaucoma associated with NF1 include RAS/MAPK-mediated developmental abnormalities in the iridocorneal angle; direct infiltration of anterior chamber angle by neurofibromas; secondary angle closure due to infiltration of ciliary body and choroid by neurofibromas; and fibrovascularization causing synechial angle closure and neovascular glaucoma [19, 20]. The presence of glaucoma at birth suggests a developmental abnormality of the iridocorneal angle, while onset at an older age indicates infiltration of the anterior chamber angle by neurofibromas or other mechanisms. There have been several reports on children with NF1 who had congenital glaucoma as the first presenting feature [18, 21,22,23,24]. Furthermore, glaucoma has been described in patients with other RASopathies, such as Noonan syndrome and oculocutaneous mosaic RASopathies [25,26,27]. Interestingly, NF1 patients with congenital glaucoma commonly have progressive globe enlargement even after control of intraocular pressure; this could be attributed to local growth factors secreted by neurofibromatous tissue or ptosis-related disruption of normal emmetropization with subsequent development of axial myopia [19, 28]. Management is challenging due to the common coexistence of bone dysplasia and tumors in the eyelid and orbit, leading to generally poor visual prognosis [19, 23].

GCMN has been described in several NF1 children with an estimated prevalence of 5% [29,30,31]. Furthermore, Ekure et al.[6] reported an African NF1 child with GCMN, ambiguous genitalia, and ventricular septal defect. Of note, neurofibromas and GCMN arise from Schwann cells and melanocytes, respectively, both of which have a common origin from the neural crest stem cells [29, 30]. This indicates the important role of RAS/MAPK pathway in neural crest development [15]. Indeed, vascular and melanocytic nevus malformations are common features among other RASopathies, such as CMAVM syndrome, cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, and oculocutaneous mosaic RASopathies [15,16,17, 26]. Importantly, NF1 and GCMN are individually associated with increased risk for neural crest malignancies, including melanoma [3, 30,31,32]. Therefore, patients with coexistent NF1 and GCMN likely have a cumulatively higher risk of malignancy.

Alopecia has rarely been reported in association with NF1. Mizukami et al.[33] reported a 52-year-old man with NF1 presented with alopecia areata. Furthermore, two NF1 children have been reported with alopecia areata, one of whom had associated autoimmune thyroiditis and the other had vitiligo, suggesting an association between NF1 and autoimmunity [34, 35]. However, alopecia in our case was present since birth, which indicates congenital etiology rather than autoimmunity. Similarly, Ghosh et al.[7] reported an NF1 child with right frontal congenital alopecia in association with proptosis, facial dysmorphism and hemihypertrophy, vocal cord palsy, and plexiform neurofibroma. We speculate that alopecia in this case may be related to NF1 variant-mediated dysregulation of RAS/MAPK pathway, which serves a crucial role in hair development and growth [36]. Indeed, hair abnormalities have been described in other RASopathies, such as synophrys and trichomegaly in Costello syndrome [36], sparse scalp hair in Noonan syndrome [17], and scalp alopecia in Noonan syndrome with loose anagen hair syndrome, cardiofaciocutaneous syndrome, and oculocutaneous mosaic RASopathies [17, 26].

Hypospadias is one of the most frequent congenital anomalies in males, which may occur as an isolated anomaly or be associated with other genetic defects [37]. The association of hypospadias and NF1 has been reported once in a Colombian male child with a coexistent pathogenic NR5A1 variant that is associated with sex disorders [38]. Of note, Ras-MAPK pathway is critical for the differentiation of male external genitalia [37]. Urogenital anomalies have been demonstrated in patients with other RASopathies, such as Noonan and LEOPARD syndromes [16]. Interestingly, certain variants in BRAF gene, which is the causal gene for several RASopathies, have been associated with hypospadias through reducing the transcription of SRY gene [37]. Taken together, the rare association between hypospadias and NF1 reported herein indicates a potential role of NF1 in urogenital development, although further studies are warranted to elucidate the underlying functional mechanisms.

Spinal neurofibromas occur in about 40% of patients with NF1, most of which are asymptomatic particularly in infancy and early childhood. These lesions are more likely associated with missense or splice-site germline mutations [3, 39]. In a large cohort of 514 adult patients with NF1, 28% had intraspinal tumors (affecting cervical, lumbosacral, and thoracic regions in descending order of frequency) while 21.8% had extraspinal tumors [40]. However, severe symmetric involvement is less commonly reported particularly at this young age [39]. In a study on 53 children with NF1, spinal MRI detected spinal neurofibromas in seven (13.2%), all of which were asymptomatic [41]. The presence of multiple bilateral spinal tumors but only a few NF1 criteria suggest spinal neurofibromatosis subtype, although this condition may also occur in typical NF1 such as in our case report [1, 2, 42, 43]. Early onset and extensive spinal neurofibromas such as in our case are usually associated with severe motor and sensory impairment and poor prognosis at later age [41]. No definitive chemotherapy is currently available for spinal neurofibromas; surgical excision is typically reserved for severe cases, considering the anatomical site, extent of invasion, risk of recurrence, and patient preference [41,42,43].

The case reported herein had hydrocephalus, hypotonia, and developmental delay, which have been previously reported in patients with NF1. Hydrocephalus affects approximately 5% of children with NF1 and is commonly obstructive due to tumors (mostly gliomas) or aqueduct stenosis; idiopathic aqueduct stenosis may occur in 1.5–2% of patients with NF1 [44]. Hypotonia and muscle weakness are frequent features in children with NF1 as well as other RASopathies [45]. This has been classically attributed to nerve dysfunction; however, evidence from mouse studies indicates that NF1 is associated with low levels of key mitochondrial lipid transporters leading to lipid storage-like myopathy [46]. Finally, the developmental delay in this case may be secondary to several causes, including nerve affection, NF1-associated myopathy, severe hydrocephalus, and extensive spinal neurofibromatosis.

WES of this case revealed a heterozygous c.1466A > G NF1 variant, which has been previously reported as pathogenic with strong evidence in several patients with no specific genotype–phenotype correlation (ClinVar ID: VCV000000354.80) [47, 48]. The nucleotide change creates a cryptic splice donor site, resulting in skipping of the last 62-bp (c.1466_1527del) at exon 13 with the formation of a stop codon at amino acid 489 [47]. Although NF1 is usually diagnosed on clinical grounds, genetic testing is an important means for the diagnosis of cases with atypical features and the provision of genetic counseling. Furthermore, genetic testing could have prognostic implications since certain NF1 variants seem to correlate with clinical phenotype [1, 3].

The present case report has some limitations. First, while our case had normal chromosomal karyotyping and no other clinically significant variants in WES, the possibility of having coexistent intronic or other complex genetic abnormalities contributing to some of patients’ manifestations cannot be absolutely excluded. Another limitation is related to the irregular patient follow-up, which did not allow complete characterization of patient’s features over time. Last, this case report did not include advanced laboratory and functional studies to unravel the underlying pathophysiological mechanisms by which the identified c.1466A > G NF1 variant could contribute to the described multiple congenital anomalies. Additional large and longitudinal follow-up studies are required to better delineate atypical features of NF1. Furthermore, functional studies should investigate how the effects of NF1 variants on RAS/MAPK pathway and other genes’ expression/function could contribute to diverse congenital anomalies.

In conclusion, the present case report adds to the knowledge of the phenotypic spectrum and variability of NF1 by reporting the association of multiple unusual features in an Egyptian child with NF1. Importantly, such congenital anomalies could be the first presenting features in patients with NF1 since cafe´-au-lait macules and other typical diagnostic criteria may not be apparent in the neonatal period and early infancy. Accordingly, NF1 should be considered in newborns with congenital glaucoma, GCMN, alopecia, and hypospadias.