Loose Anagen Hair Research Articles

Noonan syndrome and Noonan-like syndrome with loose anagen hair: rare phenotypes may emerge during follow-up.

Noonan syndrome (NS) and Noonan-like syndrome with loose anagen hair (NS/LAH) are neurodevelopmental syndromes resulting from germline mutations in genes that participate in the rat sarcoma/mitogen-activated protein kinases (RAS/MAPK) pathway. The aim of this retrospective study was to describe common and rare manifestations of NS and NS/LAH. We collected and analyzed clinical and genetic data from 25 patients with NS and NS/LAH. The patients' median age was 6.3 years (range, 1-13 years), and the male-to-female ratio was 18:7. In total, 19 patients had NS caused by a mutation in PTPN11. Another causative gene was found in six patients, including two patients with a SHOC2 mutation, one patient with a KRAS mutation, one patient with an LZTR1 mutation, one patient with a BRAF mutation, and one patient with a PPP1CB mutation. Short stature was detected in 100% of the patients. This study provides an overview of the clinical features of NS, including unique facial features, short stature, congenital heart defects, and other manifestations. Notably, systemic lupus erythematosus (SLE) was found in two SHOC2-positive patients. One patient had a posterior urethral valve, which is very rare in NS patients. Our study identified several clinical features that were previously poorly related to NS, including SLE. We concluded that SHOC2-related NS is associated with a particularly high risk of SLE, which may have a significant impact on quality of life, and a posterior urethral valve is a novel phenotype. These findings could be helpful in enhancing the understanding of the clinical spectrum of NS.

The expression of congenital Shoc2 variants induces AKT-dependent crosstalk activation of the ERK1/2 pathway.

The Shoc2 scaffold protein is crucial in transmitting signals within the Epidermal Growth Factor Receptor (EGFR)-mediated Extracellular signal-Regulated Kinase (ERK1/2) pathway. While the significance of Shoc2 in this pathway is well-established, the precise mechanisms through which Shoc2 governs signal transmission remain to be fully elucidated. Hereditary variants in Shoc2 are responsible for Noonan Syndrome with Loose anagen Hair (NSLH). However, due to the absence of known enzymatic activity in Shoc2, directly assessing how these variants affect its function is challenging. ERK1/2 phosphorylation is used as a primary parameter of Shoc2 function, but the impact of Shoc2 mutants on the pathway activation is unclear. This study investigates how the NSLH-associated Shoc2 variants influence EGFR signals in the context of the ERK1/2 and AKT downstream signaling pathways. We show that when the ERK1/2 pathway is a primary signaling pathway activated downstream of EGFR, Shoc2 variants cannot upregulate ERK1/2 phosphorylation to the level of the WT Shoc2. Yet, when the AKT and ERK1/2 pathways were activated, in cells expressing Shoc2 variants, ERK1/2 phosphorylation was higher than in cells expressing WT Shoc2. In cells expressing the Shoc2 NSLH mutants, we found that the AKT signaling pathway triggers the PAK activation, followed by phosphorylation of Raf-1/MEK1/2 and activation of the ERK1/2 signaling axis. Hence, our studies reveal a previously unrecognized feedback regulation downstream of the EGFR and provide additional evidence for the role of Shoc2 as a "gatekeeper" in controlling the selection of downstream effectors within the EGFR signaling network.

A case of loose anagen hair syndrome associated with trichotillomania in a 14-year-old girl

Loose anagen hair syndrome (LAHS) and trichotillomania (TTM) are two distinct conditions. LAHS is a rare condition characterized by easily removable anagen hair without any sensation of pain. It primarily affects young girls and is associated with a sparse hair growth and a delicate hair texture. LAHS can occur spontaneously or be inherited in an autosomal recessive manner. On the other hand, TTM, also known as hair pulling disorder, is an obsessive-compulsive disorder characterized by the recurrent, overwhelming urge to repeatedly pull out one’s hair. Hair pulling can occur anywhere on the body but is most common on the scalp, eyebrows, and eyelashes and subsequently results in bald patches. It is linked to psychosocial impairment and a decrease in the overall quality of life. We present a case of 14-year-old female with a longstanding history of sparse and disorderly hair since childhood due to LAHS associated with TTM. Treatment involved topical minoxidil and psychiatric counseling, resulting in significant improvement initially. However, a relapse was observed a year later, emphasizing the complexity of managing this dual pathology.

Natural history and outcomes in paediatric RASopathy-associated hypertrophic cardiomyopathy.

This study aimed to describe the natural history and predictors of all-cause mortality and sudden cardiac death (SCD)/equivalent events in children with a RASopathy syndrome and hypertrophic cardiomyopathy (HCM). This is a retrospective cohort study from 14 paediatric cardiology centres in the United Kingdom and Ireland. We included children <18years with HCM and a clinical and/or genetic diagnosis of a RASopathy syndrome [Noonan syndrome (NS), NS with multiple lentigines (NSML), Costello syndrome (CS), cardiofaciocutaneous syndrome (CFCS), and NS with loose anagen hair (NS-LAH)]. One hundred forty-nine patients were recruited [111 (74.5%) NS, 12 (8.05%) NSML, 6 (4.03%) CS, 6 (4.03%) CFCS, 11 (7.4%) Noonan-like syndrome, and 3 (2%) NS-LAH]. NSML patients had higher left ventricular outflow tract (LVOT) gradient values [60 (36-80) mmHg, P=0.004]. Over a median follow-up of 197.5 [inter-quartile range (IQR) 93.58-370] months, 23 patients (15.43%) died at a median age of 24.1 (IQR 5.6-175.9) months. Survival was 96.45% [95% confidence interval (CI) 91.69-98.51], 90.42% (95% CI 84.04-94.33), and 84.12% (95% CI 75.42-89.94) at 1, 5, and 10years, respectively, but this varied by RASopathy syndrome. RASopathy syndrome, symptoms at baseline, congestive cardiac failure (CCF), non-sustained ventricular tachycardia (NSVT), and maximal left ventricular wall thickness were identified as predictors of all-cause mortality on univariate analysis, and CCF, NSVT, and LVOT gradient were predictors for SCD or equivalent event. These findings highlight a distinct category of patients with Noonan-like syndrome with a milder HCM phenotype but significantly worse survival and identify potential predictors of adverse outcome in patients with RASopathy-related HCM.

Minoxidil oral en alopecias no androgénicas

For several years minoxidil has been used in medicine and trichology. Its mechanism of action remains unclear, it prolongs anagen, modulates angiogenesis and increases hair shaft thickness. New research suggests an antiandrogenic and immunomodulatory role. Low-dose oral minoxidil has proven to be an alternative for alopecia. The optimal dose for this purpose has not been established, it is probably different for children, women and men. Androgenic alopecia has been the most widely studied condition, there are other pathologies such as telogen effluvium, traction alopecia, alopecia areata, chemotherapy-induced alopecia, loose anagen hair syndrome, monilethrix, and scarring alopecia (fibrosing frontal alopecia and lichen planus pilaris). This literature review aims to expose the mechanism of action, pharmacokinetics, safety and efficacy of oral minoxidil in different types of non-androgenic alopecia.

A very mild phenotype in six individuals of a three-generation family with the novel HRAS variant c.176C > G p.(Ala59Gly): Emergence of a new HRAS-related RASopathy distinct from Costello syndrome.

Costello syndrome is a clinically recognizable, severe neurodevelopmental disorder caused by heterozygous activating variants in HRAS. The vast majority of affected patients share recurring variants affecting HRAS codons 12 and 13 and a relatively uniform phenotype. Here, we report the unique and attenuated phenotype of six individuals of an extended family affected by the HRAS variant c.176C>T p.(Ala59Gly), which, to our knowledge, has never been reported as a germline variant in patients so far. HRAS Alanine 59 has been previously functionally investigated as an oncogenic hotspot and the p.Ala59Gly substitution was shown to impair intrinsic GTP hydrolysis. All six individuals we report share a phenotype of ectodermal anomalies and mild features suggestive of a RASopathy, reminiscent of patients with Noonan syndrome-like disorder with loose anagen hair. All six are of normal intelligence, none have a history of failure to thrive or malignancy, and they have no known cardiac or neurologic pathologies. Our report adds to the previous reports of patients with rare variants affecting amino acids located in the SWITCH II/G3 region of HRAS and suggests a consistent, attenuated phenotype distinct from classical Costello syndrome. We propose the definition of a new distinct HRAS-related RASopathy for patients carrying HRAS variants affecting codons 58, 59, 60.

Promising Results with 2% Minoxidil Solution in Loose Anagen Hair Syndrome in a Pediatric Age Group: A Case Report

Promising Results with 2% Minoxidil Solution in Loose Anagen Hair Syndrome in a Pediatric Age Group: A Case Report

Loose anagen hair syndrome

Loose anagen hair syndrome

M-type phospholipase A2 receptor-associated membranous nephropathy in a patient with Noonan-like syndrome with loose anagen hair.

M-type phospholipase A2 receptor-associated membranous nephropathy in a patient with Noonan-like syndrome with loose anagen hair.

Central nervous system involvement in individuals with RASopathies.

Central nervous system (CNS) anomalies are common in individuals with RASopathies. While certain findings, including relative or absolute macrocephaly, are typical for most RASopathies, other findings are more common in certain conditions, with rare low-grade gliomas in Noonan syndrome (NS); Chiari 1 malformation and tethered cord in Costello syndrome (CS); and variable structural anomalies including heterotopia and hydrocephalus in cardio-facio-cutaneous syndrome (CFC). We performed a literature review and present aggregate data on the common and uncommon CNS manifestations in individuals with RASopathies. A gene-based approach to defining risk for specific abnormalities may be considered. However, limited information on the CNS findings of rare RASopathies, such as autosomal recessive LZTR1-related NS or PPP1CB-related NS with loose anagen hair (NSLH), is currently available. Thus, consideration of the RASopathies as a group of distinct syndromic conditions with shared underlying causes and overlapping clinical presentations remains relevant, and individuals with a RASopathy are at risk for many findings seen in these conditions.

Dermatological manifestations, management, and care in rasopathies.

RASopathies are rare genetic disorders caused by germline pathogenic variants in genes belonging to the RAS/MAPK pathway, which signals cell proliferation, differentiation, survival and death. The dysfunction of such signaling pathway causes syndromes with overlapping clinical manifestations. Skin and adnexal lesions are the cardinal clinical signs of RASopathies, such as cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, formerly known as LEOPARD syndrome, Costello syndrome, neurofibromatosis (NF1), Legius syndrome, Noonan-like syndrome with loose anagen hair (NSLH) and Noonan syndrome. As NF1, one of the most common RASopathies, described in 1882, has its clinical features well delineated, we will focus on the dermatological diagnosis, management and care of non-NF1 RASopathies, which are less known and more recently described. Dermatological manifestations are important clinical diagnostic elements that can aid differential diagnosis among RASopathies. They can affect dermis and epidermis, causing pigmented lesions (melanocytic nevi, café-au-lait spots, and lentigines), hyperkeratosis (keratosis pilaris, ulerythema ophryogenes, and palmoplantar keratosis) or hyperplasia. To date there are rare known links to malignancy, but oftentimes skin lesions require close attention because they can highly affect quality of life.

Clinical overview on RASopathies.

RASopathies comprise a group of clinically overlapping developmental disorders caused by genetic variations affecting components or modulators of the RAS-MAPK signaling cascade, which lead to dysregulation of signal flow through this pathway. Noonan syndrome and the less frequent, clinically related disorders, Costello syndrome, cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, and Noonan syndrome-like disorder with loose anagen hair are part of the RASopathy spectrum and share a recognizable pattern of multisystem involvement. This review describes the "Noonan syndrome-like" phenotype as a common phenotypic signature of generalized developmental RAS pathway dysregulation. Distinctive features of the different entities are revisited against the background of the understanding of underlying genetic alterations and genotype correlations, which has evolved rapidly during the past 20 years, thereby leading to suggestions regarding the nosology of RASopathies.

Shoc2 controls ERK1/2-driven neural crest development by balancing components of the extracellular matrix

The extracellular signal-regulated kinase (ERK1/2) pathway is essential in embryonic development. The scaffold protein Shoc2 is a critical modulator of ERK1/2 signals, and mutations in the shoc2 gene lead to the human developmental disease known as Noonan-like syndrome with loose anagen hair (NSLH). The loss of Shoc2 and the shoc2 NSLH-causing mutations affect the tissues of neural crest (NC) origin. In this study, we utilized the zebrafish model to dissect the role of Shoc2-ERK1/2 signals in the development of NC. These studies established that the loss of Shoc2 significantly altered the expression of transcription factors regulating the specification and differentiation of NC cells. Using comparative transcriptome analysis of NC-derived cells from shoc2 CRISPR/Cas9 mutant larvae, we found that Shoc2-mediated signals regulate gene programs at several levels, including expression of genes coding for the proteins of extracellular matrix (ECM) and ECM regulators. Together, our results demonstrate that Shoc2 is an essential regulator of NC development. This study also indicates that disbalance in the turnover of the ECM may lead to the abnormalities found in NSLH patients.

Loose anagen hair syndrome: take a closer look!

Loose anagen hair syndrome: take a closer look!

Behavioral phenotype of Noonan-like syndrome with loose anagen hair

IntroductionNoonan-like syndrome with loose anagen hair (NSLH MIM 607721) is associated to mutations in PTPN11, RAF1, BRAF and SHOC2 genes.ObjectivesHere, we report behavioral phenotype of a child suspected to have NSLH.MethodsA 2-years-old Tunisian child harboring severe pulmonic valvular stenosis was referred to our genetic counselling for genetic assessment. Medical dysmorphology, cytogenetic analysis as well as genetic exploration of RAS-MAPK pathway genes were conducted.ResultsThe child had short stature and ectodermal features including ichthyotic skin and thin-soft nails. He has specific hair appearance associated to NS features. In fact, he had a small nasal tip, thick lips and sticking-out rotated ears. He harbored typical nasal voice and loose anagen hair with ungrowing thin hair, sparse and pale scalp hair and eyebrows. He showed cognitive deficits with mental retardation and hyperactive behavior. Considered as having NSLH, cytogenetic analysis revealed a 46,XY formula, but molecular screening of PTPN11, RAF1, BRAF, RIT1 and SHOC2 genes was negative.Conclusions Mutations within the RAS‐MAPK signaling pathway affect neurophysiologic activity in brain regions underlying attention and executive functions. Children with rasopathies demonstrated higher rates of attention deficit-hyperactivity (ADHD) and autism spectrum disorders. However, no studies have examined specifically the aspects of behavioral attention in the various types of Rasopathies. A recent study demonstrated that ADHD seems to be higher in children with NSLH and SHOC2 mutation, which is the case of our patient. We suggest that assessment of inattentive and hyperactivity symptoms in children should consider Rasopathies with specific molecular screening.DisclosureNo significant relationships.

Proteins of the ubiquitin system in the Shoc2 ‐ ERK1/2 signaling axis and Noonan‐like syndrome with loose anagen hair (NSLAH) RASopathy

The ERK1/2 signaling pathway is critical in organismal development and tissue morphogenesis. Deregulation of this pathway leads to congenital abnormalities with severe developmental dysmorphisms, i.e. RASopathies. The core ERK1/2 cascade relies on scaffold proteins such as Shoc2 to guide and fine‐tune its signals. Mutations in shoc2 lead to the development of the pathology termed Noonan‐like Syndrome with Loose Anagen Hair (NSLAH) RASopathy. However, the mechanisms underlying the functions of Shoc2 and its contributions to disease progression remain unclear.We found that Shoc2 assembles an elegant multi‐component complex that incorporates several proteins of the ubiquitin system. To fine‐tune the amplitude of ERK1/2 signal transmitted via the complex, Shoc2 tethers the E3 ligase HUWE1, the (AAA+) ATPases, PSMC5 and VCP/p97, and the deubiquitinating enzyme, USP7. All of these enzymes are integral to the intricate feedback mechanism.Our recent studies demonstrated that ERK1/2 pathway activation triggers the interaction of Shoc2 with the ubiquitin‐specific protease USP7. We identified that in the Shoc2 module, USP7 functions as a molecular “switch” that controls the E3 ligase HUWE1 and the HUWE1‐induced regulatory feedback loop. We also found that disruption of Shoc2‐USP7 binding leads to aberrant activation of the Shoc2‐ERK1/2 axis. The zebrafish vertebrate model was then used to show that Shoc2 congenital mutations affecting Shoc2 interaction with USP7 lead to aberrant Shoc2 ubiquitination and signal transmission. Thus, our studies reveal a role for USP7 in the pathogenic mechanisms underlying NSLAH extending our understanding of how ubiquitin‐specific proteases regulate intracellular signaling.In summary, our studies are the first to demonstrate that the Shoc2 scaffold employs multi‐protein enzymatic machinery to govern the amplitude of Shoc2‐ERK1/2 signals. We also uncover novel molecular mechanisms underlying the pathogenesis of Noonan‐like syndrome with loose anagen hair. Overall, these studies significantly advance our understanding of the mechanisms by which non‐enzymatic scaffolds regulate the specificity and dynamics of the ERK1/2 signaling networks.

The scaffold protein Shoc2 controls ERK1/2‐driven neural crest development by balancing the expression of extracellular matrix components

Dysregulation of the extracellular‐signal‐regulated kinase 1/2 (ERK1/2) pathway results in common developmental syndromes – RASopathies. Our lab studies a RASopathy called Noonan syndrome with loose anagen hair (NSLAH). This RASopathy is caused by mutations in a critical regulator of the ERK1/2 pathway, Shoc2. Patients harboring shoc2mutations have structural deficiencies common among RASopathies (e.g., altered pigmentation, craniofacial defects, valve disorders). Many NSLAH features could involve defects in the development of neural crest (NC).Zebrafish provide an excellent system for studying neural crest development because of their transparency and highly conserved molecular pathways. Therefore, we utilized the zebrafish model to study the role of Shoc2‐mediated signals in NC development. We found that the loss of Shoc2 affects the expression of the transcription factors prdm1a, pax7, and foxd3‐ all required for the neural plate border formation in zebrafish. The loss of Shoc2 also led to the irregular expression of sox10, the global regulator of NC formation. Moreover, embryos depleted of Shoc2 displayed altered expression of dlx2a, a key transcription factor for the maintenance of cranial NCCs and their migration. We observed that loss of Shoc2 impaired the expression of the transcription factor inducing commitment to cartilage fate, promoting the activation of cartilage‐specific genes in the forebrain and the pharyngeal arch regions, and regulating chondrocyte stacking, sox9a. Moreover, the loss of the Shoc2‐ERK1/2 axis hindered the terminal differentiation of NCCs and resulted in the reduced number of NCC‐derived Schwann cells and pigment cells, including iridophores. Finally, our global assessment of the transcription programs affected by the loss of the Shoc2‐ERK1/2 signals revealed striking differences in the expression of a significant number of extracellular matrix proteins and proteoglycans, including collagen2aI, and aggrecans a and b ‐ all of which are critical for chondrocyte differentiation and maturation.Together, our data suggest that the Shoc2‐ERK1/2 signaling axis is critical for the development, specification/differentiation, and morphogenesis of the NC‐derived tissues. Our study is the first to define that Shoc2‐mediated ERK1/2 signals regulate NC development. Future inquiries into the mechanisms by which Shoc2 controls embryogenesis will significantly advance our understanding of the mechanisms underlying pathological causes of NSLAH and, ultimately, other RASopathies.

Low-dose oral minoxidil for treatment of androgenetic alopecia and telogen effluvium in a pediatric population: A descriptive study

Low-dose oral minoxidil for treatment of androgenetic alopecia and telogen effluvium in a pediatric population: A descriptive study

EP108: PPP1CB-related Noonan syndrome with loose anagen hair presenting with focal cortical dysplasia and epilepsy

Noonan syndrome with loose anagen hair (NS-LAH) is a rasopathy originally associated with a single recurrent missense SHOC2 variant. More recently, variants in PPP1CB have also been described in a number of patients with symptoms resembling those of NS-LAH including relative macrocephaly, low set, posteriorly rotated ears, developmental delay and slow growing or sparse hair. Many patients have a recurrent NM_206876.1:c.146C>G, p.Pro49Arg pathogenic variant, but a few other variants have been described as well.

The RASopathies: Biology, genetics and therapeutic options.

The RASopathies are a group of genetic diseases in which the Ras/MAPK signaling pathway is inappropriately activated as a result of mutations in genes encoding proteins within this pathway. As their causative mutations have been identified, this group of diseases has expanded to include neurofibromatosis type 1 (NF1), Legius syndrome, Noonan syndrome, CBL syndrome, Noonan syndrome-like disorder with loose anagen hair, Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, gingival fibromatosis and capillary malformation-arteriovenous malformation syndrome. Many of these genetic disorders share clinical features in common such as abnormal facies, short stature, varying degrees of cognitive impairment, cardiovascular abnormalities, skeletal abnormalities and a predisposition to develop benign and malignant neoplasms. Others are more dissimilar, even though their mutations are in the same gene that is mutated in a different RASopathy. Here, we describe the clinical features of each RASopathy and contrast them with the other RASopathies. We discuss the genetics of these disorders, including the causative mutations for each RASopathy, the impact that these mutations have on the function of an individual protein and how this dysregulates the Ras/MAPK signaling pathway. As several of these individual disorders are genetically heterogeneous, we also consider the different genes that can be mutated to produce disease with the same phenotype. We also discuss how our growing understanding of dysregulated Ras/MAPK signaling had led to the development of new therapeutic agents and what work will be critically important in the future to improve the lives of patients with RASopathies.