Association of Topical Minoxidil With Autosomal Recessive Woolly Hair/Hypotrichosis Caused by LIPH Pathogenic Variants

Abstract

This nonrandomized clinical trial evaluates the association of topical minoxidil with hypotrichosis in patients with autosomal recessive woolly hair/hypotrichosis carrying LIPH pathogenic variants.

LIPH pathogenic variants are a major cause of autosomal recessive woolly hair/hypotrichosis (ARWH; OMIM 278150/604379). To our knowledge, there have been no effective treatments for ARWH, although some reports have found topical minoxidil to improve hypotrichosis.¹ We report the results of a prospective nonrandomized clinical trial involving 8 Japanese patients with ARWH carrying LIPH pathogenic variants.

Methods

This 1-year, single-center, 2-armed, open-label, prospective interventional study enrolled patients from the dermatology outpatient clinic of Nagoya University Hospital in Aichi, Japan (see the trial protocol in the Supplement). Eight patients in the intervention arm have LIPH pathogenic variants. One patient in the other arm has non-LIPH variations causing hypotrichosis. Written informed consent was obtained from all participants prior to participation, and this study was approved by the institutional review board at the Nagoya University. Genomic analysis was performed as previously described,² and detected 2 recurrent variations of LIPH: c.736T>A and c.742C>A, in the patients with ARWH. All participants eligible for the trial received topical 1% minoxidil solution (2 mL) twice daily to the whole scalp for 1 year. The participants visited the hospital every month. At each visit, the scalp hair and hair shafts were photographed using a single-lens reflex camera (EOS Kiss X7, manual mode, ISO 400, f-number 5.0, shutter speed 1/60; Canon) and dermoscopic camera. During the trial, the participants were not allowed to use other hair growth stimulants or hair care products on the scalp, and haircuts were prohibited.

We evaluated the associations of the topical minoxidil with hair changes from 2 aspects: the rates of scalp areas appearing black in images (hair area percentage; HAP) and the diameter of hair shafts. The HAP score was calculated by taking the average of the values obtained from the vertex (area^vert) and lateral (area^lat) views, using the following formula³: HAP = (1 × area^vert + 2 × area^lat)/3. Dermoscopic images were recorded for the temporal and the occipital regions, and we measured the diameter of 30 randomly selected hair shafts by using ImageJ (https://imagej.nih.gov/ij/). Analysis was done by Student t test. Statistical significance was defined as P value less than .01. All results are expressed as mean (SD). The statistical analysis program used was MEPHAS (http://www.gen-info.osaka-u.ac.jp/MEPHAS/welcome.html).

Results

Eight patients with LIPH pathogenic variants, 4 male and 4 female, were enrolled. The patients’ ages ranged from 4 to 38 years. Patients 1, 3, and 6 were compound heterozygotes of c.736T>A and c.742C>A, and patients 2, 4, 5, 7, and 8 were homozygotes of c.736T>A. Patients 2, 4, and 7 were from 1 family. A 31-year-old female patient, patient 9, with trichorhinophalangeal syndrome type 1 (TRPS1) carrying a TRPS1 pathogenic variant⁴ was also enrolled.

By the end of the present study, the hypotrichosis of every participant with LIPH pathogenic variants had improved (Figure 1). Their HAP scores gradually increased, and the hypotrichosis in the patient with TRPS1 did not improve (Figure 2A). Hair shaft diameters were increased in every participant with LIPH pathogenic variants (Figure 2B and C). There were no serious adverse events, but some mild adverse events were reported (dry skin on the scalp, trichiasis, and mild hypertrichosis on the entire body).

Figure 1. Clinical Features of Patients With Autosomal Recessive Woolly Hair/Hypotrichosis With LIPH Pathogenic Variants Before and After Topical Minoxidil Treatment.

Photographs of 3 patients with LIPH pathogenic variants were taken at baseline (before treatment) and at the end of this study (after treatment with topical minoxidil).

Figure 2. Response of Nine Patients With Hereditary Hypotrichosis to Topical Minoxidil Treatment.

A, Chronological changes in hair area percentage (HAP) for each patient studied. Patients 1-8 are patients with autosomal recessive woolly hair/hypotrichosis with LIPH pathogenic variants, and patient 9 is a patient with trichorhinophalangeal syndrome type 1 (TRPS1) with a TRPS1 pathogenic variant. The hypotrichosis in patients 1-8 with LIPH pathogenic variants all improved with topical minoxidil. Patient 1 dropped out of the study on day 196 because his hair was too long and he wanted to cut it. The hypotrichosis in patient 5 worsened on day 189. Around this period, the patient applied topical minoxidil only once daily. Patient 9 (the patient with TRPS1) showed no improvement throughout the treatment period. The final scores of HAP were clearly divided into 2 groups: HAP > 80 and HAP < 50. Patients in the HAP > 80 group needed a regular haircut, but those in the HAP < 50 group did not. B, Hair shaft diameters in the temporal region. The mean values of hair shaft diameters in patients 1-7 are significantly greater after treatment than before treatment. The hair shaft diameters in patient 9 show almost no difference before vs after treatment. C, Hair shaft diameters in the occipital region. The mean values of hair shaft diameters in patients 1-4 and 6-8 are significantly greater after treatment than before treatment. The hair shaft diameters in patient 9 show almost no difference before vs after treatment.

^aP < .01.

Discussion

Lysophosphatidic acids bind the P2Y5 receptor in the hair follicle epithelium and activate hair growth.⁵ In ARWH due to LIPH pathogenic variants, loss-of-function variants in LIPH lead to a deficiency of lysophosphatidic acids and insufficient activation of P2Y5. The present prospective interventional study suggests that minoxidil could be associated with improvements in hypotrichosis in ARWH owing to LIPH pathogenic variants. There appears to be a binary response to minoxidil, with one group responding better than the other. The data on causative pathogenic variants suggest that it is unrelated to the LIPH pathogenic variants. Among the 8 patients with ARWH due to LIPH pathogenic variants, 5 patients were unrelated, and the other 3 were from 1 family. All 3 members of the family were in the group responding better. Thus, we cannot exclude the possibility that the family had an unknown genetic modifying factor affecting the efficacy of minoxidil. We need to know more about the follicular pathology to understand the pharmacologic response to minoxidil.

Supplement.

Trial Protocol and Statistical Analysis Plan