The RIPK4-IRF6 signalling axis safeguards epidermal differentiation and barrier function.

The integrity of the mammalian epidermis depends on a balance of proliferation and differentiation in the resident population of stem cells1. The kinase RIPK4 and the transcription factor IRF6 are mutated in severe developmental syndromes in humans, and mice lacking these genes display epidermal hyperproliferation and soft-tissue fusions that result in neonatal lethality2-5. Our understanding of how these genes control epidermal differentiation is incomplete. Here we show that the role of RIPK4 in mouse development requires its kinase activity; that RIPK4 and IRF6 expressed in the epidermis regulate the same biological processes; and that the phosphorylation of IRF6 at Ser413 and Ser424 primes IRF6 for activation. Using RNA sequencing (RNA-seq), histone chromatin immunoprecipitation followed by sequencing (ChIP-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) of skin in wild-type and IRF6-deficient mouse embryos, we define the transcriptional programs that are regulated by IRF6 during epidermal differentiation. IRF6 was enriched at bivalent promoters, and IRF6 deficiency caused defective expression of genes that are involved in the metabolism of lipids and the formation of tight junctions. Accordingly, the lipid composition of the stratum corneum of Irf6-/- skin was abnormal, culminating in a severe defect in the function of the epidermal barrier. Collectively, our results explain how RIPK4 and IRF6 function to ensure the integrity of the epidermis and provide mechanistic insights into why developmental syndromes that are characterized by orofacial, skin and genital abnormalities result when this axis goes awry.

Dorsal lip maturation and initial archenteron extension depend on Wnt11 family ligands.

Wnt11 family proteins are ligands that activate a type of Dishevelled-mediated, non-canonical Wnt signaling pathway. Loss of function causes defects in gastrulation and/or anterior-posterior axis extension in all vertebrates. Non-mammalian vertebrate genomes encode two Wnt11 family proteins whose distinct functions have been unclear. We knocked down Wnt11b and Wnt11, separately and together, in Xenopus laevis. Single morphants exhibited very similar phenotypes of delayed blastopore closure, but they had different phenotypes during the tailbud period. In response to their very similar gastrulation phenotypes, we chose to characterize dual morphants. Using dark field illuminated time-lapse imaging and kymograph analysis, we identified a failure of dorsal blastopore lip maturation that correlated with slower blastopore closure and failure to internalize the endoderm at the dorsal blastopore lip. We connected these externally visible phenotypes to cellular events in the internal tissues by imaging intact fixed embryos stained for anillin and microtubules. We found that the initial extension of the archenteron is correlated with blastopore lip maturation, and archenteron extension is dramatically disrupted by decreased Wnt11 family signaling. We were aided in our interpretation of the immunofluorescence by the novel, membrane proximal location of the cleavage furrow protein anillin in the epithelium of the blastopore lip and early archenteron.

FOUR LIPS plays a role in meristemoid-to-GMC fate transition during stomatal development in Arabidopsis.

Meristemoids, which are stomatal precursor cells, exhibit self-renewal and differentiation abilities. However, the only known core factor associated with meristemoid division termination and fate transition is the heterodimer formed by the basic helix-loop-helix proteins MUTE and SCREAMs (SCRMs). FOUR LIPS (FLP), a well-known transcription factor that restricts guard mother cell (GMC) division, is a direct target of MUTE. Whether FLP involves in meristemoid differentiation is unknown. Through sensitized genetic screening of flp-1, we identified a mute-like (mutl) mutant with arrested meristemoids. The mutant carried a novel allele of the MUTE locus, i.e., mute-4. Intriguingly, mute-4 is a hypomorphic allele that exhibits wild-type appearance with slightly delayed meristemoid-to-GMC transition, whereas it renders an unexpected mutl epidermis with most meristemoids arrested and very few stomata when combined with flp (flp mute-4), suggesting that FLP is a positive regulator during this transition process. Consistently, the expression of FLP increased during GMC commitment, and the number of cells at this stage was markedly increased in flp. flp scrm double mutants produced arrested meristemoids similar to mute, and FLP was able to interact physically with SCRM. Taken together, our results demonstrate that FLP functions together with MUTE and SCRMs to direct meristemoid-to-GMC fate transition.

Experiential grounding of abstract concepts: Processing of abstract mental state concepts engages brain regions involved in mentalizing, automatic speech, and lip movements.

concepts like mental state concepts lack a physical referent, which can be directly perceived. Classical theories therefore claim that abstract concepts require amodal representations detached from experiential brain systems. However, grounded cognition approaches suggest an involvement of modal experiential brain regions in the processing of abstract concepts. In the present functional magnetic resonance imaging study, we investigated the relation of the processing of abstract mental state concepts to modal experiential brain systems in a fine-grained fashion. Participants performed lexical decisions on abstract mental state as well as on verbal association concepts as control category. Experiential brain systems related to the processing of mental states, generating verbal associations, automatic speech as well as hand and lip movements were determined by corresponding localizer tasks. Processing of abstract mental state concepts neuroanatomically overlapped with activity patterns associated with processing of mental states, generating verbal associations, automatic speech and lip movements. Hence, mental state concepts activate the mentalizing brain network, complemented by perceptual-motor brain regions involved in simulation of visual or action features associated with social interactions, linguistic brain regions as well as face-motor brain regions recruited for articulation. The present results provide compelling evidence for the rich grounding of abstract mental state concepts in experiential brain systems related to mentalizing, verbal communication and mouth action.

Incidental finding of a human-like tusavirus in a lamb with lip lesions and fatal pneumonia.

Tusaviruses in the genus Protoparvovirus of family Parvoviridae were first identified in a diarrhoeic Tunisian child in 2014. Thereafter, high prevalence of a genetically similar virus was demonstrated in faeces from caprine and ovine species in Hungary. Here, we describe an investigation into the cause of scabby lip lesions in a 6 month-old lamb, submitted from a farm experiencing weight loss and scouring in lambs in England. Transmission electron microscopy visualised small circular particles of 18 and 22 nm in diameter in lip lesions identified as tusavirus and flumine parvovirus by Next Generation Sequencing. Liver, kidney, lung, small intestine content and faeces were also strongly positive for the tusavirus DNA as well as 10 % of faecal samples of the flock collected 2 months after the initial lip sampling. NS1 and VP1 amino acid sequences of this tusavirus displayed 99.5 and 92.89 % identity to those of a human tusavirus, respectively. These amino acid identities were at 95.5 and 89.68 % when compared to those of a goat tusavirus. Phylogenetic analysis of the NS1 and VP1 also grouped the virus in the genus Protoparvovirus and close to tusaviruses detected in human, ovine and caprine species. Wider surveillance of the virus indicated a broader geographical distribution for the virus in England. Histology of the lip tissue revealed localised areas of epidermal hyperplasia and hyperkeratosis affecting haired skin, with mild leucocyte infiltration of the subjacent dermis, but no changes to implicate virus involvement. Flumine parvovirus was concluded to be an environment contaminant. Broader studies in prevalence of these virus in UK sheep flocks and human population, animal models and experimental infections could provide insights into the pathogenesis of these novel viruses and their zoonotic potential.

A novel, high-performance, low-volume, rapid luciferase immunoprecipitation system (LIPS) assay to detect autoantibodies to zinc transporter 8.

BACKGROUND: Zinc transporter 8 autoantibodies (ZnT8A) are thought to appear close to type 1 diabetes (T1D) onset and can identify high-risk multiple (≥2) autoantibody positive individuals. Radiobinding assays (RBA) are widely used for ZnT8A measurement but have limited sustainability. We sought to develop a novel, high-performance, non-radioactive luciferase immunoprecipitation system (LIPS) assay to replace RBA. METHODS: A custom dual C-terminal ZnT8 (aa268-369; R325/W325) heterodimeric antigen, tagged with a NanoluciferaseTM (Nluc-ZnT8) reporter, and LIPS assay was developed. Assay performance was evaluated by testing sera from new onset T1D (n = 573), healthy schoolchildren (n = 521), and selected first-degree relatives (FDRs) from the Bart's Oxford family study (n = 617; 164 progressed to diabetes). RESULTS: In new-onset T1D, ZnT8A levels by LIPS strongly correlated with RBA (Spearman's r = 0.89; P < 0.0001), and positivity was highly concordant (94.3%). At a high specificity (95%), LIPS and RBA had comparable assay performance [LIPS pROC-AUC(95) 0.032 (95% CI: 0.029-0.036); RBA pROC-AUC(95) 0.031 (95% CI: 0.028-0.034); P = 0.376]. Overall, FDRs found positive by LIPS or RBA had a comparable 20-year diabetes risk (52.6% and 59.7%, respectively), but LIPS positivity further stratified T1D risk in FDRs positive for at least one other islet autoantibody detected by RBA (P = 0.0346). CONCLUSION: This novel, high-performance, cheaper, quicker, higher throughput, low blood volume Nluc-ZnT8 LIPS assay is a safe, non-radioactive alternative to RBA with enhanced sensitivity and ability to discriminate T1D progressors. This method offers an advanced approach to current strategies to screen the general population for T1D risk for immunotherapy trials and to reduce rates of diabetic ketoacidosis at diagnosis.

Utility of labial salivary gland biopsy in the histological diagnosis of neuronal intranuclear inclusion disease.

BACKGROUND AND PURPOSE: Neuronal intranuclear inclusion disease (NIID) poses a diagnostic challenge because of its diverse clinical manifestations. Detection of intranuclear inclusions remains the primary diagnostic criterion for NIID. Skin biopsies have traditionally been used, but concerns exist regarding postoperative complications and scarring. We sought to investigate the diagnostic utility of labial salivary gland biopsy, a less invasive alternative. METHODS: This study included a total of 19 patients and 11 asymptomatic carriers who underwent labial gland biopsies, while 10 patients opted for skin biopsies. All these individuals were confirmed to have pathogenic GGC repeat expansions in the NOTCH2NLC gene. The control group comprised 20 individuals matched for age and sex, all with nonpathogenic GGC repeat expansions, and their labial gland tissue was sourced from oral surgery specimens. RESULTS: Labial gland biopsies proved to be a highly effective diagnostic method in detecting eosinophilic intranuclear inclusions in NIID patients. The inclusions showed positive staining for p62 and ubiquitin, confirming their pathological significance. The presence of uN2CpolyG protein in the labial gland tissue further supported the diagnosis. Importantly, all patients who underwent lip gland biopsy experienced fast wound healing without any noticeable scarring. In contrast, skin biopsies led to varying degrees of scarring and one instance of a localized infection. CONCLUSION: Labial salivary gland biopsy emerged as a minimally invasive, efficient diagnostic method for NIID, with rapid healing and excellent sensitivity.

Histopathologic findings in ointment pseudo-cheilitis: An alert to dermatopathologists.

Ointment pseudo-cheilitis is a recently recognized distinctive type of self-induced cheilitis. Lesions consist of a variable amount of crusts adhered to the vermilion. These crusts consist of dried saliva and dead cells mixed with applied medications attached to the lip surface. Patients are typically severely anxious or depressed; the condition impacts quality of life. Ointment pseudo-cheilitis is frequently misdiagnosed as exfoliative cheilitis or cheilitis glandularis. Biopsy reports are often non-revealing because there are no established histopathological criteria for this disease, and clinicians usually do not formulate the correct diagnostic hypothesis. Here, we present the histopathological findings of four cases of ointment pseudo-cheilitis. The most consistent finding was the presence of laminated parakeratotic material detached from the epithelium in biopsies that are devoid of other significant diagnostic changes. This material at the lip surface possibly represents physiologic labial desquamation mixed with dried saliva and applied medication. With this report, we intend to alert dermatopathologists to the diagnosis of ointment pseudo-cheilitis if they receive biopsies from patients who present clinically exuberant labial lesions that show only minimal histopathological changes.

Lip color diversity: An intricate study.

BACKGROUND: Lip investigations and characterizations in the literature are less prevalent than for skin, particularly on the topic of color diversity. However, as the consumer demand increases for a nude lip makeup result, that is, shades close to the bare lip color, the identification and modification of lip color is essential for the cosmetic industry. OBJECTIVE: The objective was to highlight lip color diversity among three ethnicities (Caucasian, African and Hispanic), through the use of a spectral color measurement device especially adapted to the lip area, and to consider lip color ethnic specificities and overlaps. MATERIALS AND METHODS: The inferior natural lip color was measured with a full-face hyperspectral imaging system, SpectraFace (Newtone Technologies, Lyon, France), on 410 healthy women aged 19 to 68 (Caucasian French, Caucasian American, African American, and Hispanic American women). A hierarchical ascending classification, was deployed to determine clusters based on the lip colorimetric parameters along two strategies to identify the best statistical analysis to preserve the lip color diversity. RESULTS: Lip color is a continuous color space, with great intra-ethnic and inter-ethnic diversity, especially for African American women in terms of chroma and lightness. Among the two strategies of data analysis, our two-step statistical clustering analysis yielded 11 groups (i.e., 11 lip tones), revealing an accurate representation of the scope of diversity, but also of the overlaps. CONCLUSION: The 11 lip tones/colors could potentially serve as target shades for the development of a more diverse and inclusive range of lip cosmetics, such as nude lipsticks.

Image-based investigation of lip aging features in a large number of Korean women.

BACKGROUND: The lips play a significant role in shaping facial aesthetics. Due to the distinct attributes of lips in contrast to other facial skin, a unique approach is imperative for managing lip aging. We analyzed lip characteristics (morphology, wrinkles, and color) to investigate visual changes and distinctive attributes of aging lips. METHODS: By utilizing image data processing methods, including facial landmark detection, pattern recognition, and color quantification, we extracted 11 lip characteristic indices (four morphological indices, four wrinkle indices, and three color indices) from high-resolution images of 1000 Korean women aged 20-69. Correlation tests were conducted to assess the relationship between lip characteristic indices and age, and also between lip morphological and wrinkle indices. RESULTS: Lip height significantly decreased, while lip width and lip ratio (lip width divided by the sum of the upper and lower lip height) significantly increased with aging. Lip wrinkles significantly increased with aging, whereas lip colors (redness and yellowness) decreased. The lip wrinkle indices, which are segmented for the first time in this study, exhibited significant correlations with lip width, and three of them additionally were correlated with lip ratio (p < 0.05). The results imply such morphological changes can be associated with wrinkle formation of human lips. CONCLUSION: The indices suggested in this study can be used for assessing lip aging characteristics, and the study results can contribute to deeper understanding of lip aging.

Why do marionette lines appear? Exploring the anatomical perspectives and role of thread-based interventions.

The pathogenesis of marionette lines involves a complex interplay of anatomical, physiological, and age-related factors leading to the development of wrinkles around the oral commissures. This exploration delves into the distinct anatomical predispositions observed among different ethnicities, emphasizing the role of compact modiolus structures and muscle compositions. Notably, individuals of East Asian descent exhibit inherent facial structures that predispose them to pronounced sagging around the oral commissures during aging. The emergence of distinct facial lines, such as the commissural line and the melolabial fold, contributes to the formation of marionette lines. This specific wrinkle pattern, resembling a marionette puppet's mouth contours, is influenced by various factors like bone resorption, gravitational forces, fat compartment variations, muscle compression, ligament tethering, and skin aging. Treatment strategies for marionette lines encompass diverse interventions, including filler injections, botulinum neurotoxin, surgeries targeting fat reduction, thread lifting, and volumizing fillers. These approaches aim to address the underlying causes and mitigate the appearance of marionette lines. Botulinum neurotoxin injections, for instance, weaken specific facial muscles, reducing downward strain and aiding in tissue retraction. Anatomical considerations during procedures are crucial to avoid nerve or vascular damage. Delicate manipulation and precise entry points are essential to prevent inadvertent injuries, particularly concerning blood vessels like the facial artery and nerves like the mental nerve. Technical guidelines for procedures targeting marionette lines involve specific techniques like cogged thread reverse methods and volumizing thread placements. Attention to entry points, tissue engagement, and the direction of threads is crucial for effective treatment outcomes, minimizing complications, and ensuring patient safety.

A Comparison Between Hyaluronic Acid Filler and Dermofat Grafts With or Without Tie-Over Dressing for Lip Augmentation.

BACKGROUND: There are many different autologous grafts used for lip augmentation, such as fat, fascia, or dermofat grafts (DFG). However, filling with synthetic materials such as hyaluronic acid (HA) fillers is the most preferred method. OBJECTIVE: The authors aimed to compare DFG with HA fillers regarding cost, permanence, complication rate, gained volume, and satisfaction rate. The authors investigated the effect of tie-over dressings on the viability of DFG. PATIENTS AND METHODS: Patients who received hyaluronic acid fillers were referred to as Group H. Patients who received grafts without tie-over and with tie-over dressings formed Groups D1 and D2, respectively. The lip index (LI) was used for volume comparisons. The viable area of the grafts was measured using ultrasound imaging. RESULTS: At postoperative month 6, the only significant difference was found between Group D1 and Group D2 ( p < .05). At the postoperative first year, Groups D1 and D2 had a statistically higher LI value compared with Group H. Group D2 had a higher viable area than Group D2 ( p < .05). Group H and Group D2 showed higher satisfaction scores than Group D1 ( p < .05). CONCLUSION: Dermofat grafts with or without tie-over dressings can be considered a reliable and inexpensive choice for patients who seek a more permanent procedure. Tie-over dressings increase the predictability of DFG and reduce the need for overcorrection.

Complications, Treatment, and Outcomes of Self-Injecting Substances Into the Face: A Systematic Review.

BACKGROUND: The increased demand for minimally invasive facial cosmetic procedures in tandem with the ease of acquiring injectable cosmetics through direct-to-consumer retailers has led to a rise in self-injecting cosmetics among untrained individuals. OBJECTIVE: To analyze complications, treatments, and outcomes associated with self-injecting fillers into the face. METHODS: A systematic review of the literature from PubMed and Embase databases was performed from inception to September 10, 2022, to identify studies pertaining to self-injection of facial fillers. RESULTS: A total of 15 articles describing 38 complications among 18 patients were included in the data collection. The most commonly injected substance was hyaluronic acid (76.4%). The lips were the most common site of injection (33%). The most reported complication was edema (61%). Severe complications included acute vascular compromise (11%) and acute hearing loss (5%). The most common intervention was use of hyaluronidase and/or antibiotics (87.5%). Patients generally healed after treatment although residual localized hyperpigmentation was noted among 11% of patients. CONCLUSION: Injecting commercially available substances into the face is associated with potentially irreversible aesthetic, infectious, and vascular complications, especially in the hands of untrained consumers. Patients and providers should be aware of this dangerous trend.

Reconstruction of Broad Lower Lip Defects Using Karapandzic-Type Flaps.

BACKGROUND: Reconstruction of lower lip defects is challenging because of the functional and aesthetic demands of the lower face. We review the functional and aesthetic outcomes of the Karapandzic-type flaps for reconstructing lower lip defects. METHODS: A retrospective review of patients who underwent repair using Karapandzic-type flaps. RESULTS: Fifty patients with lower lip defects ranging from 20% to 95% (mean 59.2% ± 20%) were included. Eighteen patients (36%) were repaired using a bilateral flap, and 32 (64%) were reconstructed using a unilateral flap design. All patients had preservation of oral competency and a satisfactory aesthetic result. No patient complained of microstomia. A complication rate of 8% was noted ( n = 4) with postoperative wound infection and small areas of dehiscence. There was no statistically significant difference in complication rates in patients older than 75 years, in patients with a history of head/neck radiation, or in defects greater than 70% of lower lip breadth. CONCLUSION: Karapandzic-type flaps are versatile and reliable for the reconstruction of a broad range of lower lip defects. This one-stage procedure can produce superior functional and aesthetic results as compared with other local and distant flaps with minimal risk of functional microstomia.

A Natural Flat Volumized Lips Filler Technique: Retrospective Analysis of 920 Patients.

BACKGROUND: Traditionally, hyaluronidase (HYAL) is used after hyaluronic acid (HA) injection to dissolve the undesired migration of product. OBJECTIVE: To describe a novel lip augmentation technique that uses HA and HYAL simultaneously in patients who previously had HA migration. METHODS AND MATERIALS: Nine hundred twenty female patients were included. In the first group ( n = 793), HA injections were performed in subcutaneous plane of the lips. In the second group who had previous product migration ( n = 127), 7.5 units of HYAL is injected in 4 points in ergotrid area before proceeding with HA injection. RESULTS: The medicis lip fullness scale scores after 2 weeks improved in all patients, while 92% of patients perceived the results as "very much improved" with Global Aesthetic Improvement Scale ( p ˂ .001). There was no difference between 2 groups regarding the patient satisfaction rates ( p ˃.05), while filler migration was seen in 0.2% ( n : 15) of patients in the first group during the follow-up period. CONCLUSION: The new vertical injection approach provided an increased vertical height, optimal eversion, and an incisor display on the lips. The simultaneous use of HYAL before HA injection seems to be a safe and effective practice in 1-stage treatment of the previously injected lips with filler migration into ergotrid area.

Practical surgical technique using the SMISS approach for lip reduction in involuted lip infantile hemangiomas.

BACKGROUND: Lip infantile hemangiomas tend to show less volumetric regression and are more susceptible to visible sequelae in the involuted stage. Some of them still require surgical management after propranolol therapy. This study aimed to evaluate the efficacy and safety of the Stepwise, Multi-Incisional, and Single-Stage (SMISS) approach applied to lip reduction for those with involuted lip hemangiomas. METHODS: A retrospective review was performed to evaluate patients with lip hemangioma who received previous propranolol treatment and underwent the aforementioned procedure. Demographic characteristics, lesion morphology, and medical history were reviewed. The Visual Analog Scale was applied to assess the postoperative appearance. Complications within 12 months postoperatively were recorded. RESULTS: A total of 18 patients with lip hemangioma were eligible. All patients received oral propranolol therapy before surgery, with treatment duration ranging from 6.0 to 23.0 months. Their age at surgery ranged from 2.5 to 9.0 years. The median Visual Analog Scale scores were 8.0, ranging from 4.0 to 10.0. No severe complications were reported. CONCLUSIONS: This modified technique based on the SMISS approach has proven reliable and effective in improving the aesthetic outcome for involuted lip infantile hemangiomas. Practical surgical techniques still play an important part in the propranolol era.

Cocaine-Induced Plasma Cell Orificial "Dermatomucositis": A More Accurate Descriptive Term for a Clearly Dermatological Entity.

ABSTRACT: Although the involvement of the nasal passages and nasal septum in cocaine users has been known for decades, a new presentation affecting the nostrils and upper lip with an inflamed appearance has recently been documented. The authors who identified this presentation termed it "cocaine-related plasma cell mucositis" due to the abundance of plasma cells in the infiltrate. In this article, we present a second case and emphasize the dermal involvement of the lip, leading us to consider the condition as a genuine dermatomucositis.

Nasolabial morphological changes in patients with unilateral cleft lip and palate using a Korat-modified nasoalveolar moulding appliance with primary correction.

OBJECTIVE: The objective of this study is to measure the morphological changes of the nose and lip in patients with unilateral cleft lip and palate before and after cheiloplasty with primary rhinoplasty (primary correction) in conjunction with Korat-NAM usage. DESIGN: Longitudinal cohort study. SETTING: Cleft Center Maharat Nakhon Ratchasima Hospital, Nakhon Ratchasima, Thailand. SUBJECTS: Twenty-six patients with unilateral cleft lip and palate. INTERVENTIONS: Control group: only active obturator before primary correction. Experimental group: an active obturator and Korat-NAM I before primary correction. A customized endotracheal tube was retained in the nostril for 3 weeks before switching to Korat-NAM II for 1 year. MAIN OUTCOME MEASURES: Six measurements comprising nostril rim length, nostril height, nostril sill width, columella angle, vertical lip height, and horizontal lip length were measured from the patients' photographs. All measurements, except the columella angle, were reported as the cleft side/non-cleft side value ratio. Measurements were taken at the initial appointment, immediately before, 3 weeks after, and 1 year after primary correction. RESULTS: Nostril rim length ratio, nostril height ratio, nostril sill width ratio, columella angle on the cleft side, and vertical lip height ratio were improved using Korat-NAM before and 3 weeks after primary correction. Nostril rim length and height ratios were significantly better than the control group. CONCLUSIONS: Korat-NAM improved nose and lip morphology before primary correction. An overcorrection improved the nose and lip morphology on the cleft side. The nostril rim length and vertical lip height on the cleft side also improved with Korat-NAM II 1 year after primary correction.

Effects of nasoalveolar molding on nasolabial aesthetics in patients with cleft lip and palate during pre-adolescence: A systematic review and meta-analysis of retrospective studies.

This study aims to analyze long-term effects of nasoalveolar molding (NAM) as a part of cleft primary management protocols on nasolabial aesthetics for patients with non-syndromic cleft lip and palate by conducting a systematic review and meta-analysis. Six electronic databases and two journals were searched up to July 2023. Studies comparing nasolabial outcomes between NAM and non-NAM protocols were selected for further analysis. Nasolabial aesthetics were the outcome of interest. Data extraction, methodological quality assessment, risk of bias assessment, meta-analysis and subgroup analysis were performed. Seven retrospective cohort studies were selected for a qualitative review and four for a quantitative analysis. The risk of bias assessment was moderate for most studies. Only studies utilizing the Asher-McDade rating (AMR) were included for meta-analyses. The protocols with NAM exhibited a significantly lower AMR score for vermillion border than other protocols. AMR scores for nasal form and nasal symmetry from protocols with NAM were significantly lower than protocols without any pre-surgical infant orthopaedics (PSIO) but not significantly different from protocols with other PSIO techniques. The AMR score for nasolabial profile from protocols with NAM was not significantly different from other protocols. However, subgroup analysis demonstrated that protocol combining NAM and primary rhinoplasty significantly lowered AMR scores for nasal form, nasal symmetry and nasolabial profile. For patients with unilateral cleft lip with or without palate (UCLP), this study found that a protocol combining NAM and primary rhinoplasty improved nasolabial outcomes while a protocol with NAM alone offered only limited benefits. For patients with BCLP, the available evidence remains inconclusive. Performing NAM in combination with primary rhinoplasty improves nasolabial aesthetics in patients with UCLP. PROSPERO (CRD4202128384).