Hypotrichosis 14: novel variants of the LSS gene in five Chinese families and insights from literature review

Abstract

Background

Congenital hypotrichosis 14 is a nonsyndromic form of alopecia associated with pathogenic variants in the lanosterol synthase (LSS) gene. Recent studies have expanded the spectrum of LSS-related phenotypes, including congenital cataracts, alopecia-intellectual disability syndrome, and palmoplantar keratoderma. Currently, investigations into this disease are still limited, and its treatment remains elusive.

Methods

In this study, we aimed to report six Chinese patients who were diagnosed with hypotrichosis 14, whose conditions were attributed to five novel and recurrent variants in the LSS gene identified via whole exome sequencing. Moreover, the reported LSS gene has also been summarized.

Results

We described six patients in five Chinese families with hair loss, and one of whom had a rare accompanying phenotype of hypergonadotropic hypogonadism, which has rarely been reported. Five novel variants were discovered in the LSS gene, including c.919_921del (p.His307del), c.1987 C > T (p.Arg663Trp), c.982 C > T (p.Arg328*), c.1405_1407del (p.Glu469del) and c.193_200dup (p.Pro68Argfs*14).

Conclusions

Our comprehensive summary of phenotypes caused by LSS gene variants not only enriches the existing knowledge on congenital hypotrichosis 14 but also provides crucial guidance for more accurate genetic counseling and potentially new directions for future research in understanding the disease mechanism and developing targeted therapies.

Introduction

Hypotrichosis 14 (OMIM # 618275) is a nonsyndromic hypotrichosis, characterized by sparse to absent lanugo-like scalp hair, eyebrows, eyelashes and body hair [1]. It is caused by homozygous or compound heterozygous pathogenic variants in the lanosterol synthase gene (LSS, OMIM * 600909), which encodes the protein lanosterol synthase (UniprotKB, P48449) [1]. In recent years, with the remarkable progress in sequencing technology, a growing number of variants associated with hypotrichosis 14 have been identified [1–21]. Additionally, pathogenic variants in LSS were reported to be responsible for congenital cataract-44 (OMIM # 616509), alopecia intellectual disability syndrome 4 (APMR4, OMIM # 618840) and palmoplantar keratoderma (PPK, # 144200) [2–4].

However, current research on this disease remains limited. The understanding of the diverse pathogenic variants within the LSS gene and their corresponding phenotypic manifestations remains incomplete. Moreover, the existing treatment options for hypotrichosis 14 are far from satisfactory. Therefore, there is an urgent need for more comprehensive investigations to deepen the knowledge of hypotrichosis 14 and formulate more efficacious management strategies.

Methods

In the present study, we aimed to report six Chinese patients who were diagnosed with hypotrichosis 14, whose conditions were attributed to five novel and recurrent variants in the LSS gene identified via whole exome sequencing (WES) [1–21]. Notably, one patient developed hypergonadotropic hypogonadism, a phenotype that has rarely been reported in the context of hypotrichosis 14 [17].

Subjects

Case 1

Patient 1, a 31-year-old male, was born to a nonconsanguineous family with normal parents and presented with sparse and thin scalp hair. His hair growth was slow, and hair shedding gradually worsened with age. Hair on the limbs, axillary regions and pubic regions was absent. However, his eyebrows, eyelashes, and beard were normal. The hair on the frontal and vertex scalp was sparser than that on the temporal and occipital areas, a pattern that resembled severe male-pattern hair loss (Fig. 1a and b). Atrophy of the right kidney was found in his childhood. External genitalia retardation became evident in his adolescence, and azoospermia was diagnosed by an andrologist. Another hospital reported that no viable sperm was present despite normal semen volume. His height and intelligence were normal, and no cataract or other eye abnormality was identified after the ophthalmic examination. Laboratory investigations revealed elevated serum estradiol levels at 177.50 pmol/L (reference range: 73.43–176.70 pmol/L), follicle-stimulating hormone levels at 31.29 IU/L (reference range: 1.4–18.1 IU/L) and luteinizing hormone levels at 13.11 mIU/mL (reference range: 1.5–9.3 mIU/mL). Other sex hormones, such as testosterone, progesterone and prolactin, were normal. Electroencephalograph and brain MRI were performed without positive results.

Fig. 1.

Patient 1: (a, b) The hairs of Patient 1 on the frontal and vertex scalp were sparser than those in the temporal and occipital areas, which mimicked the distribution of severe male pattern hair loss. Patient 2: (c, d) Sparse vellus hair of Patient 2 was observed, and there was no terminal hair. Patient 3: (e) Patient 3 showed involvement of the eyebrows and eyelashes. Patient 4: (f, g) Sparse vellus hair and follicular papules were found. Patient 5: (h) Patient 5 had sparse hair over the entire scalp. Patient 6: (i, j) Patient 6 also had sparse hair over the entire scalp

Case 2

Patient 2, a 15-year-old boy, presented with sparse vellus hair at birth, and no terminal hair had developed (Fig. 1c and d). He was misdiagnosed with ectodermal dysplasia at the age of two, with no hair regrowth after the application of topical minoxidil. He reached puberty at the age of 15, without any beard. He did not have atopy or recurrent infections, including upper respiratory, otitis media, or pneumonia. On physical examination, trachyonychia with periungual erythema, scaling, and hyperkeratosis was noted on all his fingers. Diffuse black dots with vellus hairs were visualized via dermoscopy on his scalp. His total serum immunoglobulin E level was elevated above 412.4 IU/mL (normal range: < 200 IU/mL).

Case 3

An 11-year-old boy from a nonconsanguineous family with normal parents had a normal scalp with sparse hair at birth. The length of his hair extended to 2 mm at most. He had previously been misdiagnosed as alopecia areata, he failed to respond to oral baritinib 2 mg daily after 6 months. Skin examination revealed that his scalp hair, eyebrows and eyelashes were almost absent (Fig. 1e). Black dots were found via dermoscopy on his scalp. Congenital cataract was previously diagnosed several years ago.

Case 4

Patient 4 was a 13-year-old boy with a history of 13 years of recurrent scalp hair loss (Fig. 1f and g). He was born with no scalp hair. White vellus hair began growing when he was one year old. After growing to 1–2 cm, the hair fell out spontaneously. Follicular papules, some resembling folliculitis, were observed on his scalp. The child complained of scalp itchiness. Dermoscopy examination revealed broken hairs, black dots, and yellow dots on his scalp. High levels of interleukin (IL)-4 at 23.73 pg/mL (≤ 4.19 pg/mL), IL-10 at 6.35 pg/mL (≤ 4.50 pg/mL), IL-1β at 3.83 pg/mL (≤ 3.40 pg/mL) and IL-17 A at 5.43 pg/mL (≤ 4.74 pg/mL) in the serum were detected. Scalp pathological examination revealed a decreased number of hair follicles in the dermis (Fig. 2a and d).

Fig. 2.

Patient 4: (a-d) Scalp pathological examination revealed a decreased number of hair follicles in the dermis in Patient 4

Case 5 and case 6

Both Patient 5, a 10-year-old girl, and her brother (Patient 6), a 5-year-old boy, were born into a nonconsanguineous family with normal parents and were both born with no scalp hair. Their hair did not start to grow until they were approximately one month old and then fell out spontaneously. It was easy to pluck out their hair without much pain. On physical examination, the girl’s thin and weak hair was sparse over the entire scalp (Fig. 1h), whereas her brother’s hair was even sparser (Fig. 1i and j). Their eyebrows and eyelashes were normal. They were otherwise normal. These patients were diagnosed with congenital hypotrichosis and failed to respond to 5% topical minoxidil twice a day.

Sample sequencing and analysis

Blood samples were obtained from patients and their family members after signing written informed consent. Then, genomic DNA was extracted via Qiagen FlexiGene DNA Kit (Qiagen, Germany) according to the manufacturer’s instructions. WES was performed on these six probands and their parents. Exome capture was carried out with the Agilent SureSelect Human All Exon V6 (Agilent, USA) and the captured exomes were sequenced using the NEXome Core Panel (Nanodigmbio, Singapore).

Sanger sequencing was conducted to verify the results. The primers were designed and synthesized via the Primer website (http://genepipe.ncgm.sinica.edu.tw/primerz/primerz4.do) (forward primer: 5’-AGGGGATGAGTGCGTGAATG-3’; reverse primer: 3’-CCAGGACTCAAGGGATGCAG-5’). In the PCRs, the following conditions were used with a final volume of 50 µl for amplification of the LSS gene: 95 °C for 10 min, followed by 35 cycles of 95 °C for 30 s, 60 °C for 30 s, 72 °C for 45 s, and a final extension at 72 °C for 5 min. The amplified PCR products were purified and directly sequenced on an ABI 3730 automated DNA sequencer (Applied Biosystems, USA).

After the sequences were aligned to the reference human genome GRCh37/hg19 with Burrows–Wheeler Aligner software (v0.7.15), single-nucleotide variants (SNVs) and small insertions or deletions (InDels) were identified via GATK Unified Genotyper (v3.6). ANNOVAR (v2016-02-01) was used for functional annotation.

Pathogenic variants were classified using the American College of Medical Genetics and Genomics (ACMG) guidelines [22]. Common variants (minor allele frequency over 5%) from public databases, including the Human Gene Mutation Database (https://www.hgmd.cf.ac.uk/ac/index.php) and 1000 Genomes Project (http://browser.1000genomes.org) were excluded. The pathogenicity of SNVs was evaluated on the basis of related literature and disease databases, including PubMed (https://www.ncbi.nlm.nih.gov/pubmed/), OMIM (http://www.omim.org) and NCBI Clinvar (https://www.ncbi.nlm.nih.gov/clinvar/?term=lanosterol+synthase). Missense variants were also assessed via function prediction software such as SIFT (https://sift.bii.a-star.edu.sg) and Polyphen2 (http://genetics.bwh.harvard.edu/pph2). Candidate pathogenic variants related to the proband’s phenotypes were validated by Sanger sequencing.

The LSS sequences (wild type, variant types) were searched against the database of sequences from the Protein Data Bank (PDB) via BLAST, respectively [23]. Structural templates were selected by choosing the sequence of known structures with the highest percent identity with the query sequence. Protein structural models for LSS (wild type, variant types) were constructed with PyMOL (V1.3, Schrodinger, LLC).

Results

Disease­associated gene variants in the LSS gene were identified in all patients. To establish a genotype‒phenotype correlation easily, the characteristics of our six patients in LSS variants (Fig. 3a‒3k) were summarized in Table 1. Five novel variants [c.919_921del (p.His307del), c.1987 C > T (p.Arg663Trp), c.982 C > T (p.Arg328*), c.1405_1407del (p.Glu469del) and c.193_200dup (p.Pro68Argfs*14)] were found in these patients. We also analyzed the protein structural models for LSS (Fig. 4).

Fig. 3.

Patient 1: (a) We identified a homozygous missense variant, c.812T > C (p.Ile271Thr), of the LSS gene in Patient 1. Patient 2: (b, c) In Patient 2, the variants c.919_921del (p.His307del) and c.812T > C (p.Ile271Thr) in LSS were revealed in a compound heterozygous state. Patient 3: (d, e) Two heterozygous variants of the LSS gene, c.1025T > G (p.Ile342Ser) and c.934 C > T (p.Arg312Trp), were also identified in Patient 3. Patient 4: (f, g) Two heterozygous variants c.1987 C > T (p.Arg663Trp) and c.982 C > T (p.Arg328*) were identified in Patient 4. Patient 5: (h, i) Two heterozygous variants c.1405_1407del (p.Glu469del) and c.193_200dup (p.Pro68Argfs*14) were identified in Patient 5. Patient 6: (j, k) Two heterozygous variants c.1405_1407del (p.Glu469del) and c.193_200dup (p.Pro68Argfs*14) were identified in Patient 6

Table 1.

The characteristics of our cases in LSS pathogenic variants

Variables	Patient 1	Patient 2	Patient 3	Patient 4	Patient 5	Patient 6
Age (years)	31	15	11	13	10	5
Sex	male	male	male	male	female	male
Family history	negative	negative	negative	negative	negative	negative
Variant type	homozygous missense	compound heterozygous	heterozygous missense	heterozygous missense	heterozygous missense	heterozygous missense
DNA and amino acids changes	c.812T > C (p.Ile271Thr) (likely pathogenic)	c.919_921del (p.His307del) (uncertain significance)	c.1025T > G (p.Ile342Ser) (likely pathogenic)	c.1987 C > T (p.Arg663Trp) (uncertain significance)	c.1405_1407del (p.Glu469del) (uncertain significance)	c.1405_1407del (p.Glu469del) (uncertain significance)
	/	c.812T > C (p.Ile271Thr) (uncertain significance)	c.934 C > T (p.Arg312Trp) (uncertain significance)	c.982 C > T (p.Arg328*) (likely pathogenic)	c.193_200dup (p.Pro68Argfs*14) (pathogenic)	c.193_200dup (p.Pro68Argfs*14) (pathogenic)
Hair	scalp hair: sparse and thin; hair on the limbs, axillary regions and pubic regions: absent; otherwise: normal	scalp hair: sparse vellus hair; otherwise: normal	scalp hair, eyebrows and eyelashes: almost absent; otherwise: normal	scalp hair: sparse; otherwise: normal	scalp hair: thin and weak, sparse over the entire scalp; otherwise: normal	scalp hair: sparse; otherwise: normal
Diagnose	HHS, atrophy of the right kidney, azoospermia, hypergonadotropic hypogonadism	HHS, periungual erythema, scaling, and hyperkeratosis on all fingers	HHS, cataract	HHS, scalp folliculitis, itchiness	HHS	HHS
Dermoscopy	/	diffuse black dots with vellus hairs	black dots	broken hairs, black dots, and yellow dots	/	/
Pathology	/	/	/	decreased number of hair follicles in the dermis	/	/

Notes: HHS, hereditary hypotrichosis simplex

Fig. 4.

We analyzed the protein structural models for the wild type of LSS

In Patient 1, the likely pathogenic variant (PM1, PM2, PP3, PP4) c.812T > C (p.Ile271Thr) were identified using ACMG guidelines. It was predicted to be “deleterious”, “probably damaging” and “disease causing” by SIFT, PolyPhen2 and MutationTaster. In the wild type of Patient 1, p.Ile271 was in a random coil and formed two hydrogen bonds with p.Asp267 and p.Trp273 (Fig. 5a), whereas p.Ile271Thr was also in a random coil and formed the same hydrogen bonds with p.Asp267 and p.Trp273 (Fig. 5b). Patient 1 was finally diagnosed with hypotrichosis 14 and hypergonadotropic hypogonadism.

Fig. 5.

The forms of the wild type (a, c, e, g, i, k, m and o) and the mutated types (b, d, f, h, j, l, n and p) of our six patients are present

In Patient 2, no variants in the genes responsible for sexual development were identified. The uncertain significance variant (PM2, PP3) c.812T > C (p.Ile271Thr) and the uncertain significance variant (PM2, PM4) c.919_921del (p.His307del) were identified according to ACMG guidelines. The variant c.812T > C (p.Ile271Thr) was predicted to be “deleterious”, “probably damaging” and “disease causing” by SIFT, PolyPhen2 and MutationTaster. In the wild type of Patient 2, His307 was in the random coil (Fig. 5c), whereas p.His307del led to the deletion of His (Fig. 5d). In the wild type, p.Ile271 was in the random coil and formed two hydrogen bonds with p.Asp267 and p.Trp273 (Fig. 5a), whereas p.Ile271Thr was also in the random coil and formed the same hydrogen bonds with p.Asp267 and p.Trp273 (Fig. 5b). Patient 2 was subsequently diagnosed with hypotrichosis 14.

In Patient 3, the likely pathogenic variant (PM1, PM3, PM2_Supporting, PP4) c.1025T > G (p.Ile342Ser) and uncertain significance variant (PM3, PM2_Supporting, PP4) c.934 C > T (p.Arg312Trp) were identified using ACMG guidelines. The variant c.1025T > G (p.Ile342Ser) was predicted to be “0.45”, “deleterious”, “possibly damaging” and “disease causing” by REVEL, SIFT, PolyPhen2 and MutationTaster, respectively. The variant c.934 C > T (p.Arg312Trp) was predicted to be “0.511”, “deleterious”, “probably damaging” and “disease causing” by REVEL, SIFT, PolyPhen2 and MutationTaster, respectively. In the wild type of Patient 3, p.Ile342 was in the α-helix and formed three hydrogen bonds with p.Ile338, p.Leu345 and p.Val346 (Fig. 5e). Moreover, p.Ile342Ser was also in the α-helix and formed three hydrogen bonds with p.Ile338, p.Leu345 and p.Val346 (Fig. 5f). In the wild type, p.Arg312 was in the α-helix and formed seven hydrogen bonds with p.Glu304, p.Ser308, p.Val316 and p.Glu214 (Fig. 5g). Then p.Arg312Trp was also in the α-helix and formed three hydrogen bonds with p.Ser308, p.Ala315 and p.Val316 (Fig. 5h). Hypotrichosis 14 and cataract were diagnosed.

In Patient 4, the likely pathogenic variant (PVS1_VeryStrong, PM2_Supporting) c.982 C > T (p.Arg328*) and uncertain significance variant (PM2_Supporting) c.1987 C > T (p.Arg663Trp) were identified according to ACMG guidelines. The variant c.1987 C > T (p.Arg663Trp) was predicted to be “0.361”, “0.06”, “deleterious”, “probably damaging” and “disease causing” by REVEL, SpliceAI, SIFT, PolyPhen2 and MutationTaster. The variant c.982 C > T (p.Arg3288) was predicted to be “disease causing automatic” by MutationTaster. In the wild type of Patient 4, p.Arg663 was in the random coil and formed four hydrogen bonds with p.Leu659, p.Met660 and p.Ala661 (Fig. 5i), whereas p.Arg663Trp was also in the random coil and formed one hydrogen bond with Met660 (Fig. 5j). In the wild type, p.328Arg was in the α-helix and formed one hydrogen bond with p.Val324 (Fig. 5k), whereas the p.Arg328Ter variant caused the protein to terminate prematurely because the amino acid was mutated into a stop codon (Fig. 5l). Therefore, the diagnosis of hypotrichosis 14 and folliculitis was established.

In Patients 5 and 6, the pathogenic variant (PVS1_VeryStrong, PM2_Supporting, PP4) c.193_200dup (p.Pro68Argfs*14) and uncertain significance variant (PM4, PM2_Supporting, PP4) c.1405_1407del (p.Glu469del) were identified using ACMG guidelines. In the wild type of Patients 5 and 6, p.Glu469 was in the α-helix and formed three hydrogen bonds with p.Leu465, p.Lys546 and p.Arg547 (Fig. 5m), whereas p.Glu469del caused the deletion of the amino acid Glu (Fig. 5n). In the wild type, p.Pro68 was in a random coil (Fig. 5o). However, the p.Pro68Argfs*14 variant caused the protein to terminate prematurely due to the insertion of amino acids resulting in the movement of the reading frame (Fig. 5p). Hypotrichosis 14 was subsequently diagnosed.

Discussion

Hereditary hypotrichosis simplex (HHS) is nonsyndromic hypotrichosis, in which individuals experience progressive hair loss or sparse hair from birth or early childhood without any associated systemic abnormalities [24]. To date, we have identified multiple types of HHS characterized by different genetic pathogenic variants and clinical manifestations such as hypotrichosis 1 (OMIM # 605389; APCDD1), hypotrichosis 2 (OMIM # 146520; CDSN), hypotrichosis 11 (OMIM # 615059; SNRPE), hypotrichosis 12 (OMIM # 615885; RPL21) and hypotrichosis 14 (OMIM # 618275; LSS) [24]. Among these types, congenital hypotrichosis 14 is associated with the LSS gene variants [1]. The understanding of the diverse pathogenic variants within the LSS gene and the existing treatment options for hypotrichosis 14 are far from satisfactory. Therefore, a literature search of hypotrichosis 14 was conducted through Pubmed, Embase (Elsevier) and Web of Science up to January 2025. The database was searched using the following keywords: “Alopecia,” “Hypotrichosis,” “Hereditary hypotrichosis simplex,” “lanosterol synthase gene,” or “LSS”.

LSS-associated diseases are highly heterogeneous with a broad phenotypic spectrum. Biallelic pathogenic variants in the LSS gene were first demonstrated to be causative for congenital cataracts by Zhao et al. [4]. Subsequently, Chen et al. reported a phenotype of congenital cataracts with hypotrichosis caused by heterozygous pathogenic variants in the LSS gene [6]. Various pathogenic variants in LSS were subsequently found to be associated with hypotrichosis 14 and intellectual disability [2]. In recent studies, pathogenic variants in LSS have been identified in patients with PPK [3, 21]. The genotypes of the LSS gene in PubMed, OMIM and NCBI Clinvar have been searched. There were 431 reported variants in the LSS gene as follows (as for 27 Apr 2025): *Frameshift (4), *Missense (132), *Nonsense (5), *Splice site (6), and *UTR (24). These phenotypes included cataract alone, cataract with hypotrichosis 14, hypotrichosis 14 alone, APMR4 and palmoplantar keratoderma-congenital alopecia syndrome type 2 (PPKCA2) and PPK. We reported five novel variants, enriching the knowledge on congenital hypotrichosis 14. Moreover, hypogenitalism was reported by Elbendary et al. in 2023 [17], while hypergonadotropic hypogonadism was found in one of our patients, which had rarely been reported.

Pathogenic variants of the LSS gene cause hypotrichosis 14 and other diseases by influencing the lanosterol biosynthesis pathway. The LSS gene encodes lanosterol synthase, a key enzyme that catalyzes the conversion of (S)-2,3-epoxysqualene to lanosterol, the rate-limiting step in the biosynthetic pathway of cholesterol, steroid hormones and vitamin D [18]. Lipid metabolism is critical to hair follicle biology, and cholesterol is suspected to be associated with hair growth [25]. Wada et al. revealed that the loss-of-function in LSS was responsible for hypotrichosis and cataracts in LSS knockout mice [10]. Through in vitro studies, Yang et al. reported that pathogenic variants led to reduced levels of LSS and lanosterol in palmoplantar keratoderma-congenital alopecia syndrome type 2 (PPKCA2) patients, suggesting a decrease in enzymatic activity [3]. However, evidence showed that there was no significant decrease in the level of cholesterol or cholesterol intermediates when comparing affected families with their normal counterparts [7]. Romano et al. reported that missense pathogenic variants did not impair the production of the LSS protein but caused mutant LSS to be mislocated within the reticulum [7].

Pathogenic variants in the LSS gene lead to a wide range of phenotypic variations, but the exact mechanism underlying the relationship between genotypes and phenotypes remains unknown. Romano et al. proposed the hypothesis that pathogenic variants occurring in the N-terminus and C-terminus of LSS might separately give rise to alopecia and cataracts [9]. However, with the increasing number of cases of pathogenic variants in the LSS gene, this rule did not seem to apply to all patients [17]. Recently, Murata et al. speculated that the combination of pathogenic variants might determine the severity of phenotypes, such as severe loss-of-function pathogenic variants on both alleles, which might lead to syndromic forms [11]. Further studies suggested that one or two truncation variants in patients caused more severe phenotypes than those with two missense pathogenic variants [7, 8, 9, 10, 11, 12]. The differences between Patient 1 and Patient 2 in our study could also be explained by this theory, providing additional evidence for this conclusion. Compared with Patient 1, Patient 2 presented a more severe form of alopecia, characterized by a decrease in the density and length of scalp hair, in addition to the lack of eyebrows and eyelashes. The more severe manifestation of the phenotype in Patient 2 could be attributed to the frameshift variant c.919_921del (p.His307del), which was a type of truncation variant and might cause a more severe degree of loss-of-function. Additionally, Patient 1, harboring a homozygous pathogenic variant of c.812T > C (p.Ile271Thr), presented a novel accompanying HHS phenotype. Epigenetic modifications and other modifier genes might also play a role in phenotypic heterogeneity [12].

Treating genetic hair loss disorders is challenging. In our study, topical minoxidil was not effective for alleviating hair loss. However, oral minoxidil with growth factors has been reported to be effective in a 14-year-old girl with hypotrichosis [26]. Adding lanosterol synthase by local injection may be an option in the future. To our knowledge, reports on the local injection of lanosterol synthase have not been published. This approach might be an interesting and promising treatment for hypotrichosis 14, although it should be attempted in an LSS animal model considering its safety and efficiency.

A limitation inherent to this study lies in the lack of rigorous functional validation at the protein level. Specifically, immunoblot-based analyses—methodologies that would have enabled assessment of LSS expression in peripheral blood mononuclear cells across both patient and control cohorts—were not performed due to constraints related to sample availability. To enhance the mechanistic rigor and empirical robustness of the findings, subsequent studies should prioritize implementing such protein-level validation protocols, thereby strengthening the evidentiary foundation underlying the current observations.

Conclusion

In conclusion, our comprehensive summary of phenotypes caused by LSS gene variants not only enriches the existing knowledge on congenital hypotrichosis 14 but also provides crucial guidance for more accurate genetic counseling and potentially new directions for future research in understanding the disease mechanism and developing targeted therapies.

Abbreviations

ACMG

American College of Medical Genetics and Genomics

APMR4

Alopecia intellectual disability syndrome 4

HHS

Hereditary hypotrichosis simplex

IL

Interleukin

InDels

Small insertions or deletions

LSS

Lanosterol synthase

PPK

Palmoplantar keratoderma

PPKCA2

Palmoplantar keratoderma-congenital alopecia syndrome type 2

SNVs

Single-nucleotide variants

WES

Whole exome sequencing

Author contributions

Yujing Zhang, Mengxi Zhao, Cheng Zhou and Cong Yu designed the study. Yujing Zhang, Mengxi Zhao, Xiangqian Li, Yongping Zhao and Jianzhong Zhang collected and analyzed clinical and genetic data. Yujing Zhang and Yijie Sun used computer software to analyze the variation. Yujing Zhang and Mengxi Zhao wrote the manuscript. Cheng Zhou, Cong Yu and Xiangqian Li made substantial contribution during study conception and manuscript improvements. All authors read and approved the final manuscript.

Funding

This study was supported by the National Natural Science Foundation of China (No.82304051 and No. 82373504).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

This study was approved by the Institutional Ethics Committee of Peking University People’s Hospital (2021PHB400-001), and all family members or legal guardians of patients under 18 years of age signed a written informed consent. The data in this study were anonymized, or treated confidentially, and did not affect the diagnosis or treatment of the patients.

Consent for publication

The authors affirm that human research participants provided informed consent for publication of the images in Fig. 1.

Competing interests

The authors declare no competing interests.