CONCURRENT OCCURRENCE OF NEUROFIBROMATOSIS TYPE 1 AND TURNER SYNDROME: A PEDIATRIC CASE REPORT WITH COMPREHENSIVE LITERATURE REVIEW

Abstract

Introduction

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that typically presents in childhood and involves multiple organ systems. Turner syndrome (TS) is a chromosomal condition resulting from complete or partial loss of one X chromosome. Both disorders can independently cause short stature and pubertal delay.

Case Report

We present a 9-year-old girl diagnosed with NF1 at age 6, based on widespread café-au-lait macules and a positive family history. She was referred to our pediatric endocrinology clinic for evaluation of severe short stature. Physical examination revealed TS stigmata, including height SDS: -4.07, cubitus valgus, webbed neck, low posterior hairline, and widely spaced nipples. Karyotype analysis confirmed mosaic TS: 45,X[12]/46,X,del(X)(p11.2)[18]. Cranial magnetic resonance imaging revealed hamartomatous lesions, an empty sella, and an optic pathway glioma, for which she had received chemotherapy. Laboratory findings were consistent with hypergonadotropic hypogonadism. Estrogen replacement therapy was initiated; however, recombinant human growth hormone treatment was declined by the family after counseling.

Conclusions

This co-occurrence is exceedingly rare, with only a few pediatric cases having been reported in the literature. This dual diagnosis poses diagnostic and therapeutic challenges and necessitates a personalized approach to growth assessment, pubertal induction, and long-term tumor surveillance in pediatric endocrine care.

INTRODUCTION

Neurofibromatosis type 1 (NF1), commonly known as von Recklinghausen disease, is an autosomal dominant genetic disorder caused by pathogenic variants in the NF1 gene, which encodes the tumor suppressor protein neurofibromin (1). The condition exhibits variable expressivity, and approximately half of the cases arise from de novo mutations. It’s estimated incidence is between 1 in 2.500 and 1 in 3.000 individuals (1). Clinical diagnosis is made according to the National Institute of Health (NIH) criteria, which include multiple characteristic features such as café-au-lait macules (>5 mm in prepubertal or >15 mm in postpubertal individuals), two or more neurofibromas or one plexiform neurofibroma, axillary or inguinal freckling, optic pathway glioma, two or more Lisch nodules, distinctive osseous lesions (e.g., sphenoid wing dysplasia), or a first-degree relative with a confirmed diagnosis NF1 (2).

Turner syndrome (TS) is a common sex chromosome abnormality seen in approximately 1 in 2.500 live-born females (3, 4). It is typically caused by partial or complete absence of one X chromosome and is associated with short stature, primary ovarian insufficiency, and a variety of congenital malformations and comorbid conditions (4).

The co-occurrence of NF1 and TS is exceptionally rare, with only a small number of cases reported in the literature (5). This rare overlap is of clinical relevance to pediatric endocrinologists, as both conditions independently impact linear growth, pubertal timing, and endocrine-metabolic status. When present together, their overlapping and potentially confounding clinical features may complicate diagnosis and require highly individualized follow-up and treatment plans.

We report a striking and exceptionally rare case of a girl diagnosed with both NF1 and TS, underscoring the diagnostic challenges and the need for a multidisciplinary approach in such overlapping syndromic presentations.

CASE REPORT

Presentation

A 9-year-old girl with a known diagnosis of NF1 was referred to the pediatric endocrinology clinic for evaluation of short stature. She had been born at term via cesarean section, with a birth weight of 3750 grams. At six years of age, she was diagnosed with NF1 after presenting with widespread hyperpigmented macules across her body. At that time, physical examination revealed multiple café-au-lait spots, and her family history was notable for NF1 in her father, who had died at the age of 33 due to an intracranial tumor.

At presentation, her height was 108.9 cm [standard deviation score (SDS): -4.07], weight 20.4 kg (SDS: -2.15), and body mass index (BMI) was 17.2 kg/m² (SDS: +0.3). Physical examination showed several dysmorphic features, including cubitus valgus, webbed neck, low posterior hairline, and widely spaced nipples. She also had extensive café-au-lait macules on the trunk and extremities, along with axillary and inguinal freckling (Fig. 1). She was prepubertal at the time of evaluation (Tanner stage I).

Figure 1.

Clinical features of NF1. (Left) Café-au-lait macule on the abdomen. (Right) Axillary freckling and additional café-au-lait spots. These pigmentary supported the initial clinical suspicion of NF1.

Investigation

Laboratory tests revealed hypergonadotropic hypogonadism, with elevated gonadotropin levels and low estradiol concentrations (Table 1). Chromosomal analysis revealed a mosaic karyotype: 45,X[12]/46, X,del(X)(p11.2)[18], confirming the diagnosis of TS. Cardiac echocardiography and renal ultrasonography (USG) revealed no abnormalities. Pelvic USG demonstrated a hypoplastic uterus measuring 36 × 15.5 × 8.5 mm with a linear endometrial echo, while both ovaries were not visualized. Pituitary magnetic resonance imaging (MRI) showed an empty sella. Cranial MRI revealed multiple hamartomatous lesions consistent with NF1. Additionally, an optic pathway glioma was detected, for which the patient had previously received chemotherapy with vincristine and carboplatin (Fig. 2). Skeletal radiography demonstrated mild dextroconvex scoliosis of the thoracic spine. Vertebral Dual X-ray Absorptiometry showed a Z-score of -2.95.

Table 1.

Laboratory investigations and radiology findings

Parameter	Values	Reference range
Hb (g/dl)	12.3	12-16
WBC count (103/ul)	9.66	4.37-9.68
Platelet count (103/ul)	291	150-450
Glucose (mg/dl)	76	74-106
Creatinine (mg/dl)	0.55	0.5-0.9
ALT (U/L)	21	<33
Albumin (g/L)	47.38	35-52
HbA1c%	5.2	4-6
Insulin (mU/L)	18.2	2.6-24.9
Lipid profile	Total cholesterol 163 mg/dl LDL cholesterol 84 mg/dl HDL cholesterol 56.3 mg/dl Triglycerides 148 mg/dl	<200 <100 45-65 < 150
Serum calcium (mg/dl)	9.56	8.6-10
Serum phosphorus (mg/dl)	3.68	2.5-4.5
Alkaline phosphatase (U/L)	64	35-104
25(OH)D (ng/ml)	29.9	30-100
FSH (mIU/ml)	88.6	3.5-12.5
LH (mIU/ml)	21.7	2.4-12.6
Estradiol (pg/ml)	10.5	30.9-232
Thyroid function tests	TSH (mIU/L): 4.8 Free T4 (ng/dl): 1.26 Free T3 (ng/L): 3.56 Anti-thyroid peroxidase antibody (U/ml): 354 Anti-thyroglobulin antibody (U/ml): 223	0.51 – 4.3 0.93 – 1.63 2.56 – 5.01 < 26 < 64
IGF-1 (ng/ml)	152	117-323
Bone Age (Left hand X ray)	8 years and 10 months
Vertebral DXA	Z-score at AP spine (L1 – L4): -2.95

Hb: Hemoglobin; WBC: white blood cell; ALT: alanine aminotransferase; HbA1c: hemoglobin A1c; LDL: low-density lipoprotein; HDL: high-density lipoprotein; FSH: follicle-stimulating hormone; LH: luteinizing hormone; TSH: thyroid stimulating hormone; IGF-1: insulin-like growth factor 1; DXA: Dual X-ray Absorptiometry; bone mineral density.

Figure 2.

Cranial MRI findings of the patient demonstrating NF1-associated lesions. A) T2-weighted cranial MRI showing hyperintense hamartomatous lesions. B) Orbital section demonstrating fusiform thickening of the left optic nerve, consistent with an optic glioma. These radiological features strengthened the diagnostic of NF1 and guided follow-up planning.

Treatment

Pubertal induction was initiated due to hypergonadotropic hypogonadism secondary to gonadal dysgenesis, which is characteristic of TS. Pubertal induction was achieved through estrogen therapy. During follow-up, she was started on estradiol valerate 2 mg daily, and subsequently received cyclic medroxyprogesterone acetate 10 mg daily for 10 days each month, which resulted in regular menstrual cycles. Due to her severe short stature, the patient was also assessed for potential recombinant human growth hormone (rhGH) treatment. However, following a detailed discussion of the potential benefits and risks, the family opted against initiating rhGH therapy. Oral calcium and vitamin D supplementation were prescribed for the management of osteoporosis.

Outcome and follow-up

She is currently 20 years old and has attained a final height of 138 cm, which is significantly below her target height of 164 cm. Despite her short stature, her BMI remains within the normal range (21.7 kg/m²). During estrogen–progesterone therapy, the patient was closely monitored for the emergence of new neurofibromas, but none of these findings developed during the two-year follow-up. To limit progesterone exposure, given its proposed role in neurofibroma proliferation, daily combined estrogen-progesterone pills were not recommended. During follow-up, she exhibited mildly elevated HbA1c levels, which normalized with lifestyle modifications. Autoimmune thyroiditis was diagnosed based on thyroid ultrasound findings of heterogeneous echogenicity and positive thyroid autoantibodies. The patient is being regularly monitored through a multidisciplinary team including, endocrinology, neurology, ophthalmology, and medical genetics. To date, no additional endocrine abnormalities have been detected.

DISCUSSION

The coexistence of NF1 and TS in the same patient is extremely rare and represents a unique clinical challenge. In our case, the presence of typical TS stigmata in a girl already diagnosed with NF1, highlighted the importance of maintaining a high index of suspicion for dual pathologies, especially in the context of severe short stature and dysmorphic features.

The simultaneous occurrence of TS and NF1 has been documented in only a small number of cases. According to Mondal et al. (5), their case represents the sixth known report of this rare association. Other authors, including El Qadiry et al. (6), have cited up to seven previously published cases, while Vieira et al. (7) noted that fewer than ten cases have been described in total.

Although the number of reported cases has gradually increased, the concurrent diagnosis of NF1 and TS remains exceedingly rare. While each condition independently affects growth, pubertal development, and tumor risk, their overlapping clinical features, such as short stature, webbed neck, and dysmorphic facial characteristics, can create diagnostic uncertainty and complicates management strategies. A comparative summary of previously reported pediatric cases with NF1 and TS is provided in Table 2. This diagnostic ambiguity underscores the importance of karyotyping and comprehensive radiological assessment in syndromic patients presenting with unexplained findings.

Table 2.

Comprehensive comparison of reported cases with concurrent NF1 and TS

Reference	Age at TS diagnosis (years)	Age at NF1 diagnosis (years)	Karyotype	NF1 features	TS features	GH therapy	Order of diagnosis
Schorry et al., 1996 (18)	NA	NA	NA	Overlap of TS and NF1 features	NA	NA	NA
Suttur et al., 2009 (19)	NA	NA	45, X	NF1 + TSC findings	NA	NA	NA
Gengel & Marshall, 2017 (13)	6 years	8 years	45, X	CALMs, axillary freckling, Lisch nodules	Short stature, TS features	Yes	TS → NF1
Dermitzaki et al., 2020 (20)	~2 years	~2 years	Mosaic TS (presumed)	Optic glioma, CALMs	TS features	NA	Simultaneous
El Qadiry et al., 2022 (6)	16 years	16 years	45, X	CALMs, inguinal freckling, Lisch nodules	Webbed neck, short stature	No	Simultaneous
Vieira et al., 2022 (7)	16 years	Earlier	45, X	CALMs, learning difficulties, optic glioma	Hypergonadotropic hypogonadism	No	NF1 → TS
Mondal et al., 2023 (5)	16.5 years	Same age	45, X/46, X, i(Xq)	CALMs, lentigines	Amenorrhea, short stature, scoliosis	No	NF1 → TS
Present case 2025	9 years	6 years	45, X[12]/46, X, del(X) (p11.2)[18]	CALMs, axillary/inguinal freckling, optic glioma, scoliosis	Webbed neck, short stature, cubitus valgus, hypoplastic uterus	Declined	NF1 → TS

CALMs: café-au-lait macules; GH: growth hormone; NA: not available; NF1: neurofibromatosis type 1; TS: Turner syndrome; TSC: tuberous sclerosis complex.

In earlier reports, TS and NF1 were often diagnosed at different time points. For example, Mondal et al. initially diagnosed NF1 based on café-au-lait macules and Lisch nodules, with TS later confirmed due to delayed puberty and short stature (5). In contrast, El Qadiry et al. described a child first diagnosed with TS, in whom the later development of neurocutaneous signs led to the NF1 diagnosis (6). Vieira et al. highlighted that mosaic karyotypes may result in subtler TS phenotypes, delaying diagnosis when NF1 manifestations are more overt (7). In addition to the timing and sequence of diagnoses, the age at which each diagnosis is established may also be an important consideration. In our case, NF1 was diagnosed at age 6 and TS at age 9, which is relatively early compared to some previous reports where mosaic TS remained unrecognized until adolescence due to its subtle phenotype and overshadowing NF1 features (5–7). Our case is distinctive in that both syndromes were clinically suspected based on simultaneous phenotypic features, including extreme short stature, dysmorphic signs (webbed neck, cubitus valgus), widespread café-au-lait spots, and optic glioma. This constellation of findings prompted early clinical suspicion of a dual diagnosis, allowing for timely hormonal evaluation and genetic confirmation.

From an endocrinologic standpoint, TS typically presents with hypergonadotropic hypogonadism requiring timely estrogen replacement to induce puberty, support uterine development, and preserve bone mineralization (4). The influence of sex steroid therapy on neurofibroma behavior is a debated issue in patients with NF1. Progesterone receptors are commonly expressed in neurofibromas and may promote Schwann cell proliferation, whereas estrogen receptors are rarely detected (8, 9). In light of reports suggesting a permissive role of progesterone in tumor growth, including rare case reports describing progression of neurofibromas with depot progesterone methods but not with combined oral pills, our patient was managed with cyclic rather than continuous progestin exposure (10). During two years of follow-up, no progression in neurofibroma size or number, nor any signs of optic glioma progression were observed.

rhGH therapy is widely recommended in TS to improve final height outcomes, especially when initiated before the age of 12 (11). However, in patients with NF1, the use of rhGH remains controversial due to potential concerns about tumor growth, particularly in the presence of optic pathway gliomas or other central nervous system lesions (12). In our case, rhGH therapy was offered but ultimately declined by the family after appropriate counseling. Similarly, a previously reported case of coexisting NF1 and TS received growth hormone therapy, supporting the need for vigilant follow-up regarding the potential effects of hormonal treatments on neurofibroma behavior (13). However, the report did not provide long-term follow-up data regarding growth response or potential adverse effects, limiting conclusions about the safety and efficacy of rhGH in this dual-diagnosis context.

Bone fragility in our patient manifested as osteoporosis, a well-documented comorbidity in both TS and NF1. In TS, hypogonadism–related estrogen deficiency significantly contributes to reduced bone mineral density (BMD) and an elevated fracture risk; estrogen replacement therapy has been shown to improve BMD, while calcium and vitamin D supplementation along with lifestyle measures form the cornerstone of management (14). Although bisphosphonates are widely used in adult osteoporosis, their safety and efficacy in young patients with TS remain inconclusive and are not routinely recommended (15). In NF1, reduced BMD, osteoporosis, and fractures have also been consistently reported, even in pediatric populations; although treatment data are limited, bisphosphonates and vitamin D have shown potential benefits in improving BMD and reducing fracture risk (16,17). In our case, osteoporosis was mild and appropriately managed with calcium supplementation alone, without requiring more aggressive pharmacotherapy.

The co-occurrence of TS and NF1 presents unique challenges that extend beyond diagnosis, requiring individualized, multidisciplinary management. Regular follow-up with endocrinology, neurology, ophthalmology, oncology, and clinical genetics is essential, particularly when neuro-oncologic complications coexist with pubertal failure and significant growth delay.

Finally, the limited number of published cases suggests that this association may be underrecognized, especially in patients with mosaic TS or attenuated phenotypes. Additional case reports are needed to increase clinical awareness, refine diagnostic strategies, and guide evidence-based management of this rare co-occurrence.

In conclusion, although both TS and NF1 are relatively common genetic conditions, their co-occurrence in a single patient is exceedingly rare and may complicate the diagnostic process. Shared phenotypic features, such as short stature or dysmorphic characteristics, can overlap with multiple syndromes and potentially obscure accurate identification. Furthermore, the wide phenotypic variability observed in conditions like NF1 may mask the presence of additional diagnoses.

Given these challenges, clinicians should remain alert to atypical findings that cannot be fully explained by an initial diagnosis. In such cases, a thorough reevaluation, including cytogenetic and radiological investigations, is warranted, regardless of any previously established syndromic label. This case underscores the importance of maintaining a broad differential diagnosis and reinforces the value of pursuing further workup when the clinical picture is incomplete.

Conflict of Interest

The authors declare that they have no conflict of interest.

Patient Consent

Written informed consent was obtained from the patient and/or their parent or legal guardian for the publication of clinical details and/or images.