Autosomal Recessive Woolly Hair Caused by LIPH Mutations: A Case Series of Six Chinese Patients

Introduction

Autosomal recessive woolly hair/hypotrichosis (ARWH) is a rare congenital alopecia characterized by sparse, tightly curled hair with varying degrees of hypopigmentation and slow hair growth.¹ ARWH has been associated with mutation of several genes, including LIPH (OMIM #607365), LPAR6 (OMIM #609239), KRT25 (OMIM #616760), C3orf52 (OMIM #611956), and ADAM17 (OMIM #603639).^1–5 The LIPH gene encodes lipase H (PA-PLA1α), a key enzyme in the synthesis of lysophosphatidic acid (LPA).⁶ LPA activates the LPAR6 receptor, which regulates hair follicle development through multiple signaling pathways and ultimately modulates the expression of growth factors and their receptors, such as transforming growth factor α (TGF-α) and epidermal growth factor receptor (EGFR).⁷ Pathogenic variants in LIPH impair the enzymatic activity of lipase, resulting in decreased LPA levels in hair follicles and disruption of hair growth via the LIPH/LPA/LPAR6 signaling axis.⁶

Although ARWH has been described in Asian populations, reports in Chinese patients are limited. Studying a Chinese cohort may reveal population-specific or recurrent variants and broaden the phenotypic spectrum. Defining genotype–phenotype correlations is clinically relevant for diagnosis, counseling, and prognosis. This study details the clinical features and genetic mutations of six ARWH patients, providing novel insights into the genetic basis of this condition.

Methods

Genetic Analysis

This study retrospectively reviewed six patients from six unrelated families presenting to our department between 2021 and 2024. Written informed consent for publication of the clinical details and images was obtained from all patients, as well as from the parents of the 7-year-old patient. The study was conducted in accordance with the Declaration of Helsinki. Peripheral blood samples were collected from all six patients, and genomic DNA was extracted for subsequent analysis. Whole-exome sequencing (WES) was performed by Novogene Bioinformatics Technology Co., Ltd. (Beijing, China). Briefly, 0.4 μg of genomic DNA was fragmented to an average size of 180–280bp using a Covaris LE220R-plus (Covaris, USA). DNA fragments were end-repaired, phosphorylated, A-tailed, and ligated with paired-end adapters, followed by PCR amplification. Libraries were captured using the Agilent SureSelect Human All Exon V6 kit (Agilent, USA, Catalog #5190-8864), purified with AMPure XP (Beckman Coulter, USA), assessed for size distribution (Agilent 5400 system), and quantified by real-time PCR (Life Technologies, USA). Qualified libraries were sequenced on Illumina platforms (PE150 strategy).

Sequencing reads were aligned to the human reference genome, and variants were called and filtered. Candidate variants were validated by Sanger sequencing in selected families and compared against the 1000 Genomes, gnomAD, and ExAC databases. Variant interpretation followed the American College of Medical Genetics and Genomics (ACMG) guidelines.

Clinical Evaluation

Trichoscopy was performed in selected patients to evaluate hair shaft and scalp features. Scalp biopsy specimens were obtained for histopathological evaluation of hair follicles.

Protein Structure Modeling

Wild-type and mutant protein structures were generated using SWISS-MODEL. The resulting models were visualized and compared with PyMOL.

Results

Clinical Characteristics

We collected clinical data from six patients with diffuse hair thinning and curly hair since childhood . All patients denied parental consanguinity, and none exhibited abnormalities in other organ systems.

Table 1 Clinical and Genetic Characteristics of Six Patients with LIPH Variants

All six patients exhibited sparse, curly hair since childhood and reported increased hair fragility with easy breakage (Figure 1a), with trichoscopy consistently showing woolly hair patterns (Figure 1b). Sparse eyebrows were observed in most patients (Patients 1# and 3#~6#). Notably, trichoscopy of Patient 4# revealed twisted, irregularly arranged eyebrow hairs with a wavy, woolly pattern (Figure 1c).

Among all six patients, Patient 1# developed progressive, mid-scalp hair thinning after the age of 18, and trichoscopy revealed markedly greater hair shaft diameter diversity at the mid-scalp compared with the occipital region, indicating coexisting female pattern hair loss. Patient 5# reported increased hair shedding over the past two years, and trichoscopy demonstrated upright regrowing hairs, suggestive of chronic telogen effluvium.

Scalp biopsy was done in Patient 2# and Patient 5# for further diagnosis (Figure 1d). Histopathological examination of Patient 2# revealed no significant inflammatory infiltrates, although some follicles showed abnormal morphology. In Patient 5#, follicular abnormalities were more pronounced, and an increased proportion of telogen follicles was observed, consistent with a diagnosis of concomitant telogen effluvium.

Genetic Findings

Sequencing revealed that all six patients carried variants in the LIPH gene on chromosome 3 (Table 1). Patient 1# harbored compound heterozygous variants c.742C>A (p.H248N) and c.686delAinsGTAGAACCCAACCTGGCT (p.Asp229Glyfs*37), while Patient 2# carried compound heterozygous variants c.742C>A (p.H248N) and c.454G>A (p.G152R). Patient 3# was homozygous for c.454G>A (p.G152R). Patients 4#, 5#, and 6# were homozygous for c.742C>A (p.H248N), and segregation analysis in Patient 3#, 4# and 6# confirmed parental inheritance. According to the genome aggregation database (gnomAD v2.1.1, East Asian subset), c.742C>A (p.H248N) shows an allele frequency of 0.125% (25/19952), and c.454G>A (p.G152R) has a frequency of 0.010% (5/19952), while c.686delAinsGTAGAACCCAACCTGGCT (p.Asp229Glyfs*37) was not detected in East Asian population. According to the ACMG guidelines, all variants were classified as pathogenic except c.454G>A (p.G152R), which was considered likely pathogenic.

Figure 1 Clinical, Trichoscopic, Histopathological, and Genetic Characteristics of Patients with LIPH-Related Woolly Hair (a) Clinical presentation and whole-exome sequencing results of six patients with woolly hair; (b) Trichoscopy of Patient 2# reveals numerous fine, soft hairs exhibiting a curly pattern, resembling a wavy hair texture; (c) Trichoscopy of Patient 4# shows the eyebrows with a curved, irregular arrangement; (d) Histopathological findings of Patients 2# and 5#. Longitudinal sections showed no inflammatory cell infiltrates, while horizontal sections at the isthmus level demonstrated reduced follicle counts with some follicles showing abnormal morphology and triangular-shaped outer root sheaths. In Patient 5 #, an increased proportion of telogen follicles was noted, consistent with chronic telogen effluvium.

Discussion

In our study, Patient 3#, who was homozygous for the c.454G>A (p.G152R) variant, showed relatively preserved hair density, although the patient still reported fragile hair prone to breakage. Furthermore, Patient 2#, with compound heterozygous variants of c.742C>A (p.H248N) and c.454G>A (p.G152R), also showed less severe hair loss compared to patients with the homozygous c.742C>A (p.H248N) variant (Patients 4# and 6#).

Previous bioinformatics analyses demonstrated that the glycine at position 152 is highly conserved across species, and both SIFT and PolyPhen-2 predict the G152R substitution as deleterious or probably damaging, respectively.⁸ The c.454G>A (p.G152R) variant has previously been functionally validated and implicated in disease pathogenesis.⁸ Homology modeling showed that Ser154, Asp178, and His248 form the catalytic triad of PA-PLA1α (Figure 2).⁸ The G152R substitution is positioned adjacent to the catalytic serine and is predicted to disturb the geometry of the active site. Previous functional studies demonstrated that this variant causes secretion defects and loss of enzymatic activity, supporting the structural prediction.⁸ In our cohort, the affected patient exhibited mildly reduced hair density but presented with hair shaft fragility. This observation raises the possibility that the variant may primarily affect hair shaft integrity, while exerting a comparatively smaller impact on follicular density. Nevertheless, further studies are required to substantiate this hypothesis.

Figure 2 Structural modeling of the PA-PLA1α p.G152R variant. Homology modeling illustrates that Ser154, Asp178, and His248 form the catalytic triad, and the G152R substitution lies near the catalytic site, potentially affecting enzymatic activity.

Numerous studies have reported a high prevalence of LIPH mutation in populations from Japan,⁹ the Volga-Ural region of Russia,¹ and Pakistan.^10–12 To date, no comprehensive population-based studies on the carrier frequency of LIPH mutation have been conducted in China. Based on present reported cases (Table 2), approximately 49% of ARWH patients in China harbor the c.742C>A (p.H248N) variant, while 12% carry the c.736T>A (p.C246S) variant, and 15% carry the c.454G>A (p.G152R) variant.^8,13,14 In the current study, among the six patients analyzed, the c.454G>A (p.G152R) variant was found in 25% of all alleles. This finding suggests that the c.454G>A (p.G152R) variant may represent a mutation with a potentially broader affected population in China, although this assumption requires further confirmation. By comparison, population-based studies in Japan have already established two founder variants, c.736T>A (p.C246S) and c.742C>A (p.H248N), which are known to be prevalent in the general population.

Table 2 Reported Variants in Autosomal Recessive Woolly Hair Patients in China

Limitation

For Patients 1#, 2#, and 5#, Sanger sequencing of the parents was not performed due to personal reasons. In addition, Patient 1# had previously been diagnosed with female pattern hair loss, while Patient 5# was also diagnosed with chronic telogen effluvium during the clinical visit. While these conditions added complexity to the differential assessment, they are unlikely to confound the diagnosis of congenital woolly hair.

Conclusion

In conclusion, our study expands the spectrum of LIPH mutation associated with woolly hair in the Chinese population and further underscores the critical role of LIPH in regulating human hair growth and texture.