Topical minoxidil for alopecia in trichorhinophalangeal syndrome type 1

Dear Editor,

Trichorhinophalangeal syndrome (TRPS) is a rare disorder caused by mutations in the TRPS1 gene, affecting the hair, skeleton and overall development. It was first described by Giedion in 1966, who defined its core triad of hair, facial and digital anomalies.¹ While the clinical and genetic features of TRPS are well-documented, reports on the successful management of its associated alopecia remain limited. Herein, we report the case of a young girl with TRPS type 1 who was successfully treated with a combination of 2% minoxidil and 0.1% halcinonide. An ethical waiver was granted for the off-label use of topical minoxidil.

A 6-year-old girl presented with a history of sparse, hypopigmented hair since birth that failed to grow long, with no spontaneous improvement observed with age. She also demonstrated global developmental delay. However, detailed milestones were unavailable as no prior paediatric consultation had been sought. The parents were non-consanguineous, but the mother had a history of sparse hair. Her physical examination revealed short stature, sparse lateral eyebrows [Figure 1a], a pear-shaped nose [Figure 1b] and brachydactyly of the fingers [Figure 1c]. The child had sparse hair density in the fronto-vertical and occipital scalp [Figures 2a and b]. Trichoscopy performed using a video dermatoscope (Videodermatoscope-HX-8000; Hongxin Medical, Beijing, China) revealed prominent hair shaft diameter variability (mean diameter: 46.06 μm[normal:50-70μm]), reduced overall hair density (96.81/cm²[normal:>150/cm²]), a vellus-to-terminal hair ratio of approximately 3.3[normal:<0.25/cm²], numerous yellow dots and the presence of pigtail hairs [Figures 2c and d]. These features are indicative of congenital hypotrichosis and consistent with TRPS type 1. Based on these characteristic clinical findings, the patient was referred to a genetics clinic for further evaluation. Family-based whole-exome sequencing analysis revealed a heterozygous c.1870C>T (p.Arg624*) variant in the TRPS1 gene. Sanger sequencing confirmed the same heterozygous variant in her mother, establishing a diagnosis of autosomal dominant TRPS type 1 [Figure 2e]. The patient was advised to consult the department of paediatrics for a comprehensive systemic evaluation including skeletal examination.

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Figure 1a: A child of TRPS-1 having very sparse eyebrows.

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Figure 1b: Child showing pear-shaped nasal deformity with pyriform nasal contour (red arrows).

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Figure 1c: Short fingers (brachydactyly) in the child with TRPS 1.

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Figure 2a: Sparse hair density in occipital region in the child before treatment.

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Figure 2b: Sparse hair density over fronto-vertical scalp before treatment.

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Figure 2c: Baseline trichoscopic image of vertex hair showing predominant vellus hairs (red arrows) (non-polarised, 40x).

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Figure 2d: Baseline trichoscopic image of hair whorl showing thin hair shafts (red stars), (non-polarised, 40x)

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Figure 2e: Whole-exome sequencing confirming a heterozygous nonsense variant in the TRPS1 gene in both the patient and her mother. The red arrows indicate a heterozygous c.1870C>T (p.Arg624*) variant in the TRPS1 gene.

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For the treatment of alopecia, considering the patient’s young age and reports of potential systemic side effects to minoxidil with more frequent dosing, we opted for a conservative regimen: a 6:1 mixture of 2% minoxidil and 0.1% halcinonide, 1ml applied once daily. Halcinonide was incorporated to mitigate the risk of minoxidil-induced contact dermatitis, thereby enhancing cutaneous tolerability to minoxidil during long-term application. The child was followed up every three months over a planned one-year period. After six months of treatment, a diffuse increase in scalp hair density was observed both clinically and trichoscopically. Clinically, there was noticeable hair elongation at three and six months, although precise length measurements were not performed [Figures 2f-i]. Trichoscopy revealed numerous regrowing hairs with mean hair density increasing to 200.06/cm², mean shaft diameter to 54.25 μm and a vellus-to-terminal hair ratio of approximately 1.5 [Figures 2j-m]. There were no signs of local or distant hypertrichosis, nor were any other treatment-related adverse reactions during the follow-up period.

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Figure 2f: Clinical image of occipital scalp at 3-month follow-up after topical minoxidil treatment, demonstrating increased hair density.

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Figure 2g: Clinical image of vertex hair at 3-month follow-up after topical minoxidil treatment, demonstrating increased hair density compared to baseline.

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Figure 2h: Clinical image of occipital scalp at 6-month follow-up, demonstrating sustained and significant improvement in hair density compared to the 3-month follow-up.

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Figure 2i: Clinical image of fronto-vertical scalp at 6-month follow-up, demonstrating sustained and significant improvement in hair density compared to the 3-month follow-up.

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Figure 2j: Trichoscopic image of vertex hair at 3-month follow-up, showing decreased vellus hair percentage (red arrows), (non-polarised, 40x).

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Figure 2k: Trichoscopic image of hair whorl at 3-month follow-up, showing thickened hair shafts (red stars) and decreased number of single-hair follicles, (non-polarised, 40x).

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Figure 2l: Trichoscopic image of vertex hair at 6-month follow-up, showing a further increase in hair thickness and a marked reduction in vellus hair percentage, (red arrows indicate thickened hair shafts) (non-polarised, 40x).

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Figure 2m: Trichoscopic image of hair whorl at 6-month follow-up, showing a further increase in hair density and a marked reduction in vellus hair percentage, (red stars indicate thickened hair shafts) (non-polarised, 40x).

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Typical hair characteristics in TRPS patients include fine, soft and sparse hair, a high anterior hairline, often lighter hair colour and thinning of the lateral eyebrows with thickening of the medial eyebrows,² a phenomenon also observed in our patient. Auxiliary examinations such as trichoscopy, reflectance confocal microscopy (RCM) and scanning electron microscopy (SEM) can provide supportive evidence for diagnosis of TRPS. A multicentre retrospective study indicated that a high occipital hairline, along with trichoscopic features such as non-terminal hairs and low hair density, are common findings in TRPS patients.³ Another study using RCM showed scalp skin of TRPS patients to have increased number of empty hair follicles, sebaceous gland atrophy and surrounding fibroblastic infiltration.⁴ Under SEM, hair shafts were found to be slender with irregularly arranged, partially folded and indistinctly bordered cuticular cells.⁴ The trichoscopic findings in our case, including yellow dots and hair shaft variability, clinically reflect the follicular and structural abnormalities described in these RCM and SEM studies.

Previous studies have confirmed that the TRPS1 gene influences hair follicle development and the hair cycle by regulating the Wnt and bone morphogenetic protein (BMP) signalling pathways, as well as androgen metabolism.^5,6 We hypothesise that topical minoxidil may ameliorate alopecia in TRPS-I patients through its ability to activate the Wnt pathway and prolong the anagen phase of the hair cycle. To date, only two other paediatric cases of TRPS type 1 treated with different concentrations and formulations of topical minoxidil have been reported, both demonstrating improvement in hair density and length [Table 1].^7,8 Furthermore, for TRPS patients unresponsive to conventional treatments like minoxidil and finasteride, autologous hair transplantation has been reported as an effective alternative that can yield long-term, satisfactory cosmetic results.

In conclusion, TRPS type 1 is a rare genetic disorder characterised by distinctive alopecia with approximately 200 cases reported to date. Diagnosis relies on a combination of clinical and trichoscopic features,with genetic testing being the gold standard for confirmation. This case demonstrates the efficacy and safety of a combined regimen of once-daily topical 2% minoxidil with 0.1% halcinonide for treating alopecia in a young child with TRPS-1. This approach successfully promoted hair regrowth without inducing hypertrichosis associated with more frequent dosing reported in a prior study. However, a limitation of this case is that while clinical signs of systemic absorption (like hypertrichosis in non-treated areas and scalp irritation) were monitored through parental observation and follow-up, clinical examinations, hemodynamic parameters (like blood pressure and heart rate) were not specifically assessed. Despite this, we propose this regimen as an initial management option for alopecia, emphasising the need for careful surveillance of local reactions and systemic vital signs. Future studies are needed to validate its long-term efficacy.