Neurofibromatosis type 1 with unilateral macrodactyly-like overgrowth: a case report

Abstract

Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by benign tumors of the nervous system, typically associated with café-au-lait spots and neurofibromas. Macrodactyly usually is referred to as a rare congenital anomaly with overgrowth of bone and soft tissue. In addition, macrodactyly-like patterns of localized digital overgrowth have been described, including nerve-related segmental overgrowth. We report the case of a 22-year-old woman from northern Tanzania presenting with unilateral macrodactyly-like overgrowth of the non-dominant left hand and clinical features of NF1, including café-au-lait spots and multiple neurofibromas. Surgical excision of redundant soft tissue resulted in an improved hand contour and restoration of the first web space. The postoperative course was uncomplicated with preserved early sensory function; however, meaningful assessment of range of motion and dexterity was not possible due to the limited stay of medical staff until three days postoperatively. Intraoperatively, markedly enlarged digital nerves were observed, and histopathology confirmed a plexiform neurofibroma consistent with NF1‑related nerve‑associated segmental overgrowth rather than classical idiopathic macrodactyly. This rare presentation of NF1 with unilateral macrodactyly-like overgrowth highlights the diagnostic challenge of distinguishing true congenital macrodactyly from NF1-associated nerve-related segmental overgrowth in the absence of modern diagnostic tools. Nevertheless, the case emphasizes the need for further investigation into NF1-associated tissue overgrowth and macrodactyly-like digital enlargement, as well as the role of surgery in improving hand contour, potential function, and quality of life in low-resource settings.

Introduction

NF1 is marked by the development of multiple benign tumors in the nervous system, often affecting both the central and peripheral nervous systems [1]. Common skin manifestations include café-au-lait spots and neurofibromas. Although NF1 primarily impacts the nervous system, its clinical presentation is diverse, complicating both diagnosis and treatment [2,3]. Macrodactyly - usually a congenital anomaly characterized by the excessive growth of the bones and soft tissues of the digits - is rare and remains largely idiopathic, with only few documented cases in the literature [4,5]. Beyond this classical concept, macrodactyly-like patterns of localized digital overgrowth have been described, in which congenital or acquired nerve‑related lesions, such as plexiform neurofibromas in NF1, lead to segmental enlargement that clinically can mimic true macrodactyly [6]. The simultaneous occurrence of NF1 and unilateral macrodactyly-like overgrowth of the hand is exceptionally rare and presents unique challenges in terms of diagnosis, treatment, and understanding the underlying pathophysiology [6,7]. This case report explores this unusual co-presentation and potential pathophysiological association, detailing the patient’s clinical presentation, diagnostic journey, and therapeutic approach under a low-resource setting at a sub-Sahara medical facility. Through this report, we aim to add to the limited body of knowledge on the intersection of these conditions and provide insights for future research and clinical practice.

Case presentation

During the annual aid mission by the Interplast Germany e.V. section Baden-Baden/Bayreuth in Tanga, northern Tanzania, a young woman of 22 years presented with an unusual combination of symptoms. The patient complained of massive excess of soft tissue on her non-dominant left hand. Interestingly, not the entire hand was affected, but rather the thenar and the first interphalangeal fold (Figure 1a–e). The excess tissue was described by the patient as unpleasant and the restriction of usability as moderate. She mainly reported difficulties with activities of daily living that required full fist closure, as well as subjective disfigurement due to the disproportionate size of the hand. Pain and clinical symptoms suggestive of carpal tunnel syndrome in the affected hand were denied. No relevant past medical history was known. The patient explained that the excess tissue had existed her entire life and had increased with her growth. Besides, the patient did not present any other symptoms or clinical findings consistent with generalized macrosomia or acromegaly. Unfortunately, no standard radiographs of the hand were available in the low‑resource setting, so potential osseous hypertrophy of the phalanges or metacarpals could not be systematically assessed. The clinical diagnosis of macrodactyly‑like overgrowth was therefore primarily based on life‑long enlargement and soft‑tissue excess. Due to unclear parental status no meaningful family history could be acquired.

Figure 1.

Preoperative photodocumentation.

Photos a–e: Clinical presentation of the patient’s left hand with excessive soft tissue predominantly at the thenar and the first interdigital fold

Photos f, g: Clinical presentation of multiple Café-au-lait spots and neurofibromas

A thorough physical examination was conducted, and multiple skin lesions were noted. These café-au-lait spots were seen in several places, predominantly on the torso. In addition, various, widely distributed small neurofibromas could be examined (Figure 1f and g). After relevant examination and consolidation of the findings, a suspected diagnosis of unilateral macrodactyly-like overgrowth of the hand in a patient with NF1 was made.

The patient was informed about the clinical picture and requested surgical therapy of the enlarged parts of the hand, the primary aim being the reconstruction of the first interdigital fold and improved functionality of the hand.

During surgery, substantial amounts of soft tissue and skin were excised (13.2 cm × 9.4 cm × 1.6 cm) while sparing the vessels and nerves (Figure 2d and e). The digital nerves were first identified proximally to the lesion and carefully traced distally to avoid accidental transection. Intraoperatively, anatomical atypia of the nerve tissue became apparent, with the digital nerves presenting a markedly increased caliber, as shown in the intraoperative photographs (Figure 2a). In addition, the transverse carpal ligament was released, although the patient had not reported any preoperative symptoms suggestive of carpal tunnel syndrome. After removal of the excess tissue, a significantly narrower hand contour and a well-defined first interdigital fold could be achieved. (Figure 2b and c).

Figure 2.

Intraoperative photodocumentation.

Photo a: Intraoperative view on anatomical atypia including abundant, fibrous subdermal soft tissue (red arrow) and significantly enlarged digital nerves (yellow arrow)

Photo b, c: Intraoperative result after excision of excessive soft tissue resulting in a significantly slimmed contour of the thenar and hand and a reconstructed, clearly identifiable first interdigital fold.

Photos d, e: Resected skin and soft tissue for histological examination

In the postoperative examination, the patient showed no loss of sensitivity compared to the opposite side. The two-point discrimination was 4 mm on both hands. Due to the brevity of the stay of the foreign medical staff and the patient living in a remote area, the final postoperative check-up took place on the third postoperative day with a so far uncomplicated recovery (Figure 3a–d). Due to postoperative swelling and pain-related restriction of movement, no meaningful Kapandji-score or finger-palm distance could be measured. Thus, only early contour and sensory findings, but not definitive functional outcomes, could be documented at this time point. Despite the planned follow-up visit the following year, the patient did not re-present to our team, so that no further clinical or functional examination could be conducted.

Figure 3.

Postoperative photodocumentation on the third postoperative day:

Photos a,c: Postoperative result after removal of easy-flow drainages showing a reconstructed first interdigital fold and a significantly slimmer thenar and thumb compared with the preoperative presentation.

Photo c: Comparison of the operated left hand with its right counterpart showing an improved symmetry despite postoperative swelling.

Photo d: Comparison of moveability of both hands showing a restricted closure of the operated, still swollen left hand compared to the right hand.

Pathohistological analysis of the resected tissue was conducted at the department for pathology at the Klinikum Bayreuth GmbH in Bayreuth, Germany. Histological examination revealed nodular proliferates of spindle-cells in dermal and subcutaneous layers. Furthermore, these proliferates were found to be positive in S-100 and CD34 staining. Therefore, suggesting a neurofibroma of the plexiform type associated with neurofibromatosis.

Discussion

Neurofibromatosis, including its three forms NF1, NF2 and schwannomatosis, is known to cause a diverse spectrum of neuronal tumors [3,8,9]. NF1 accounts for more than 90% of all neurofibromatosis cases [3]. With a prevalence of approximately 1 in 3,000–4,000 individuals, NF1 is considered a rare disease according to European Union standards (<5:10,000) [10]. The genetic locus on chromosome 17q11.2 encodes neurofibromin, a Ras-GTPase activating protein. Point mutations are the most common mechanism (≈90%), while deletions account for about 5–11% [11]. More than 2800 pathogenic NF1 variants have been identified, which explains the high variability of clinical manifestations [12]. Although NF1 is inherited in an autosomal-dominant fashion, up to 50% of cases result from de novo mutations [13].

The established clinical diagnostic criteria for NF1 include combinations of café-au-lait macules, neurofibromas (including plexiform subtypes), axillary or inguinal freckling, optic gliomas, osseous lesions, and genetic confirmation [14]. Our patient presented with multiple café-au-lait spots, numerous cutaneous neurofibromas, and histologically confirmed plexiform neurofibroma, fulfilling the criteria for NF1.

Macrodactyly is a rare congenital disorder characterized by abnormal overgrowth of digits due to hypertrophy of both bone and soft tissue [4–6]. From a clinical perspective and according to recent reviews, macrodactyly is often classified into a static form, in which the affected digit grows proportionally with overall somatic growth, and a progressive form, in which the overgrowth is disproportionate and may become massive over time. In addition, a distinction has been made between nerve territory–oriented macrodactyly, where enlargement follows the distribution of a specific digital nerve, and more diffuse involvement of a ray or extremity [6,15]. Macrodactyly-like patterns of localized digital overgrowth have been described, in which congenital or acquired nerve-related lesions, including somatic overgrowth in NF1, lead to segmental enlargement that can mimic true macrodactyly but may not fulfill all classical criteria [16]. In our case, the overgrowth had been present since early childhood and increased in parallel with the patient’s growth. Intraoperatively, the digital nerves supplying the affected area were markedly enlarged, which is compatible with nerve territory–oriented macrodactyly-like overgrowth rather than unequivocal classical macrodactyly.

Most cases of clinical macrodactyly occur as isolated fibrolipomatosis (macrodystrophia lipomatosa). This entity typically presents with prominent fibrofatty overgrowth of soft tissues and characteristic adipose proliferation on imaging and histology [17,18]. In contrast, our case showed abundant fibrous tissue and, more importantly, a plexiform neurofibroma with S100- and CD34-positive spindle cell proliferations in the dermis and subcutis, together with grossly enlarged digital nerves. S100 immunoreactivity supports a Schwann cell/neural crest origin of the tumour cells, whereas CD34 positivity is frequently seen in neurofibromas and helps to distinguish them from other peripheral nerve sheath and soft tissue tumours [19]. This clinicopathological constellation is therefore less compatible with classical macrodystrophia lipomatosa and more in keeping with NF1-associated, nerve-related digital overgrowth.

The coexistence of NF1 and macrodactyly has only been reported very rarely. Inglis (1950) first described local gigantism as a possible manifestation of NF1, and further isolated reports have suggested that NF1-associated peripheral nerve changes may contribute to segmental overgrowth [6,7]. Nevertheless, the overall paucity of published cases indicates that such an association, if present, is at most exceptional and not an established clinical pattern.

A pathophysiological link between NF1 and digital overgrowth, however, remains poorly understood [6]. NF1-associated loss of neurofibromin function results in dysregulated Ras signaling and uncontrolled cellular proliferation [20,21]. While this mechanism explains the formation of neurofibromas, it remains speculative whether it also contributes to localized digital overgrowth [6]. In our case, the intraoperative finding of enlarged digital nerves and histological confirmation of plexiform neurofibroma may suggest that NF1-related nerve pathology could have contributed to the development of the unilateral macrodactyly-like overgrowth of the hand in our patient [7,22]. However, given the single-case nature of this report and the absence of molecular or advanced imaging studies, any causal relationship must be interpreted with caution and regarded as hypothetical rather than definitive.

This case report has several limitations. Advanced diagnostic tools such as ultrasound, MRI, extended histological and genetic testing were not available due to the low-resource setting. A particularly important limitation is the lack of standardized radiographs of the affected hand, which precludes a definitive assessment of bony hypertrophy and limits our ability to clearly interpret the nature of the segmental overgrowth. Long-term follow-up was not possible, as the patient resides in a remote rural area and could only be examined perioperatively and up to three days postoperatively. While early postoperative assessment confirmed preserved sensibility and an improved hand contour, postoperative swelling and pain prevented meaningful evaluation of range of motion and dexterity. Therefore, any conclusions regarding long-term functional outcome must remain speculative, and potential late complications or recurrence cannot be assessed at this stage.

Taken together, the clinical presentation, intraoperative nerve findings and histopathological confirmation support the interpretation of NF1-associated, nerve-related digital overgrowth with a macrodactyly-like appearance in this patient, while falling short of establishing a definitive causal relationship.

Conclusion

In summary, our case adds to the limited body of literature on the unusual co-presentation of NF1 and a macrodactyly-like phenotype. It emphasizes the importance of considering NF1 in patients with (congenital) digital overgrowth and illustrates how surgical management can improve hand contour and may contribute to functional improvement and quality of life, even in low-resource environments.

Patient consent

Written informed consent was obtained from the patient for publication of this case report and accompanying images.

Disclosure statement

No potential conflict of interest was reported by the author(s).