Pathogenic variants in KMT2C result in a neurodevelopmental disorder distinct from Kleefstra and Kabuki syndromes.

Trithorax-related H3K4 methyltransferases, KMT2C and KMT2D, are critical epigenetic modifiers. Haploinsufficiency of KMT2C was only recently recognized as a cause of neurodevelopmental disorder (NDD), so the clinical and molecular spectrums of the KMT2C-related NDD (now designated as Kleefstra syndrome 2) are largely unknown. We ascertained 98 individuals with rare KMT2C variants, including 75 with protein-truncating variants (PTVs). Notably, ∼15% of KMT2C PTVs were inherited. Although the most highly expressed KMT2C transcript consists of only the last four exons, pathogenic PTVs were found in almost all the exons of this large gene. KMT2C variant interpretation can be challenging due to segmental duplications and clonal hematopoesis-induced artifacts. Using samples from 27 affected individuals, divided into discovery and validation cohorts, we generated a moderate strength disorder-specific KMT2C DNA methylation (DNAm) signature and demonstrate its utility in classifying non-truncating variants. Based on 81 individuals with pathogenic/likely pathogenic variants, we demonstrate that the KMT2C-related NDD is characterized by developmental delay, intellectual disability, behavioral and psychiatric problems, hypotonia, seizures, short stature, and other comorbidities. The facial module of PhenoScore, applied to photographs of 34 affected individuals, reveals that the KMT2C-related facial gestalt is significantly different from the general NDD population. Finally, using PhenoScore and DNAm signatures, we demonstrate that the KMT2C-related NDD is clinically and epigenetically distinct from Kleefstra and Kabuki syndromes. Overall, we define the clinical features, molecular spectrum, and DNAm signature of the KMT2C-related NDD and demonstrate they are distinct from Kleefstra and Kabuki syndromes highlighting the need to rename this condition.

Missense variants causing Wiedemann-Steiner syndrome preferentially occur in the KMT2A-CXXC domain and are accurately classified using AlphaFold2.

Wiedemann-Steiner syndrome (WDSTS) is a neurodevelopmental disorder caused by de novo variants in KMT2A, which encodes a multi-domain histone methyltransferase. To gain insight into the currently unknown pathogenesis of WDSTS, we examined the spatial distribution of likely WDSTS-causing variants across the 15 different domains of KMT2A. Compared to variants in healthy controls, WDSTS variants exhibit a 61.9-fold overrepresentation within the CXXC domain-which mediates binding to unmethylated CpGs-suggesting a major role for this domain in mediating the phenotype. In contrast, we find no significant overrepresentation within the catalytic SET domain. Corroborating these results, we find that hippocampal neurons from Kmt2a-deficient mice demonstrate disrupted histone methylation (H3K4me1 and H3K4me3) preferentially at CpG-rich regions, but this has no systematic impact on gene expression. Motivated by these results, we combine accurate prediction of the CXXC domain structure by AlphaFold2 with prior biological knowledge to develop a classification scheme for missense variants in the CXXC domain. Our classifier achieved 92.6% positive and 92.9% negative predictive value on a hold-out test set. This classification performance enabled us to subsequently perform an in silico saturation mutagenesis and classify a total of 445 variants according to their functional effects. Our results yield a novel insight into the mechanistic basis of WDSTS and provide an example of how AlphaFold2 can contribute to the in silico characterization of variant effects with very high accuracy, suggesting a paradigm potentially applicable to many other Mendelian disorders.

Cutaneous findings in patients with acromegaly and its relationship with concomitant endocrinopathies.

OBJECTIVES: Skin changes in acromegaly are often the first sign of the disease. The aim of this study was to describe the cutaneous findings in patients with acromegaly. In addition, a secondary aim was to investigate the possible association of these findings with remission status and concomitant endocrinopathies. DESIGN, PATIENTS, AND MEASUREMENTS: In this prospective multicenter study, 278 patients over the age of 18 years with acromegaly who were followed up in 14 different tertiary healthcare institutions were included. These patients, who were followed up by the Endocrinology Department, were then referred to a dermatologist for dermatological examination. The frequency of skin lesions was investigated by detailed dermatologic examination. Dermatological diagnosis is reached by clinical, dermatological and/or dermoscopic examination, and rarely skin punch biopsy examinations in suspicious cases. The possible association of the skin findings between remitted and nonremitted patients and with concomitant endocrinopathies were evaluated. RESULTS: The most common skin findings in patients with acromegaly in our study were skin tags (52.5%), cherry angiomas (47.4%), seborrhoea (37%), varicose veins (33%), acneiform lesions (28.8%), hyperhidrosis (26.9%) and hypertrichosis (18.3%). Hypertrichosis was significantly more prevalent in patients nonremitted (p: .001), while xerosis cutis was significantly more prevalent in patients remitted (p: .001). The frequency of diabetes mellitus and hypothyroidism was significantly higher in patients with varicose veins and seborrhoeic keratosis than those without. Additionally, the coexistence of hypothyroidism, hyperthyroidism and galactorrhea was significantly higher in patients with Cherry angioma than in those without Cherry angioma (p-values: .024, .034 and .027, respectively). The frequency of hypogonadism in those with xerosis cutis was significantly higher than in those without (p: .035). CONCLUSIONS: Cutaneous androgenization findings such as skin tag, seborrhoea, acne and acanthosis nigricans are common in patients with acromegaly. Clinicians should be aware that skin findings associated with insulin resistance may develop in these patients. It can be said that the remission state in acromegaly has no curative effect on cutaneous findings. Only patients in remission were less likely to have hypertrichosis. This may allow earlier review of the follow-up and treatment of acromegaly patients presenting with complaints of hypertrichosis. Additionally, it can be said that patients with skin findings such as cherry angioma may be predisposed to a second endocrinopathy, especially hypothyroidism. Including dermatology in a multidisciplinary perspective in acromegaly patient management would be beneficial to detect cutaneous findings earlier.

A recurrent KCNK4 variant in a dominant pedigree with hypertrichosis and gingival fibromatosis syndrome: Variable phenotypic expressivity and insights on patients' dental management.

Abnormal hyperpolarization of the KCNK4 gene, expressed in the nervous system, brain, and periodontal ligament fibroblasts, leads to impaired neurotransmitter sensitivity, cardiac arrhythmias, and endocrine dysfunction, as well as, progressive cell proliferation. De novo gain of function variants in the KCNK4 gene were reported to cause a recognizable syndrome characterized by facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth (FHEIG, OMIM# 618381). FHEIG is extremely rare with only three reported cases in the literature. Herein, we describe the first inherited KCNK4 variant (c.730G>C, p.Ala244Pro) in an Egyptian boy and his mother. Variable phenotypic expressivity was noted as the patient presented with the full-blown picture of the syndrome while the mother presented only with hypertrichosis and gingival overgrowth without any neurological manifestations. The c.730G>C (p.Ala244Pro) variant was described before in a single patient and when comparing the phenotype with our patient, a phenotype-genotype correlation seems likely. Atrial fibrillation and joint laxity are new associated findings noted in our patient extending the clinical phenotype of the syndrome. Dental management was offered to the affected boy and a dramatic improvement was noted as the patient regained his smile, restored the mastication function, and resumed his psychological stability.

Multiple rhabdomyomatous mesenchymal hamartomas in a patient with mosaic Barber-Say syndrome.

Barber-Say syndrome (BSS) is a rare congenital ectodermal dysplasia with few cases reported in the literature. We describe a 9-year-old boy with congenital generalized hypertrichosis and multiple rhabdomyomatous mesenchymal hamartomas (RMHs) on his nose and periocular region. Next-generation sequencing, performed in DNA from a blood sample, and RMH tissue, revealed a pathogenic variant in the TWIST2 gene, which was not detected in a salivary sample of the patient, nor in his parents. Therefore, we consider this variant as de novo mosaicism. To our knowledge, this is the first case of multiple RMHs associated with BSS.

Diffuse neurofibroma with hypertrichosis in a toddler.

Diffuse neurofibroma is a rare type of neurofibroma uncommonly reported in infancy. It is a slow growing tumor originating in the peripheral nerve sheath. We present the case of a 17-month-old boy with diffuse neurofibroma of the scalp associated with hypertrichosis. His genetic and clinical workup for neurofibromatosis was negative.

Vascular KATP channel structural dynamics reveal regulatory mechanism by Mg-nucleotides.

Vascular tone is dependent on smooth muscle KATP channels comprising pore-forming Kir6.1 and regulatory SUR2B subunits, in which mutations cause Cantú syndrome. Unique among KATP isoforms, they lack spontaneous activity and require Mg-nucleotides for activation. Structural mechanisms underlying these properties are unknown. Here, we determined cryogenic electron microscopy structures of vascular KATP channels bound to inhibitory ATP and glibenclamide, which differ informatively from similarly determined pancreatic KATP channel isoform (Kir6.2/SUR1). Unlike SUR1, SUR2B subunits adopt distinct rotational "propeller" and "quatrefoil" geometries surrounding their Kir6.1 core. The glutamate/aspartate-rich linker connecting the two halves of the SUR-ABC core is observed in a quatrefoil-like conformation. Molecular dynamics simulations reveal MgADP-dependent dynamic tripartite interactions between this linker, SUR2B, and Kir6.1. The structures captured implicate a progression of intermediate states between MgADP-free inactivated, and MgADP-bound activated conformations wherein the glutamate/aspartate-rich linker participates as mobile autoinhibitory domain, suggesting a conformational pathway toward KATP channel activation.

Cases with the H syndrome presenting with skin and bone findings.

BACKGROUND: The H syndrome is an autosomal recessive disease characterized by hyperpigmentation, hypertrichosis and sensorineural hearing loss. METHODS: A mutation in the coding of the human equilibrative nucleoside transporter 3 (hENT3) within the SLC29A3 gene on chromosome 10q22 leads to the manifestation of this disease. In this report, we present two cases of H syndrome. RESULTS: The first patient exhibits hyperpigmentation, hypogonadism, Type 1 diabetes mellitus, arthritis and osteoporosis. The second patient experiences hyperpigmentation, hypertrichosis, osteopenia and hypogonadism. CONCLUSION: Our objective is to broaden the clinical spectrum of H syndrome, highlighting the involvement of arthritis, hyperinflammation and low bone mineral density in individuals with this disorder.

What are the Factors That Induce Paradoxical Hypertrichosis After Laser Hair Removal?

BACKGROUND: Laser hair removal (LHR) is one of the most requested cosmetic procedures worldwide. A rare side effect is the appearance of excess hair around previously treated areas, known as paradoxical hypertrichosis. OBJECTIVES: The aim of this study was to retrospectively identify the cause of this side effect. METHODS: This study included all patients who underwent LHR at our center between November 2018 and November 2020. Alexandrite laser hair removal (HR) or diode laser super hair removal (SHR) was performed in 70% and 30% of cases, respectively. Clinical features and daily habits of patients with and without postlaser hypertrichosis were compared. RESULTS: Of the 7381 patients who received LHR, 25 patients (0.34%) demonstrated an increase in hair growth compared to baseline. Of these 25 patients, 24 had been treated with alexandrite laser HR (P < .01). The most common site was the upper arm, followed by the periareolar area. Daily sun protection was associated with a significantly lower incidence of hypertrichosis (P < .05), as was confirmed and shown to be independent of Fitzpatrick skin type by binary logistic regression analysis (odds ratio = 0.41, P < .05). CONCLUSIONS: In our clinic, we observed paradoxical hypertrichosis after laser hair removal in a small minority of cases, as described by others. We did not observe differences in incidence related to skin type, but daily sun protection and LHR with diode laser SHR were associated with significant reductions in incidence rates. In addition to previously reported common sites, we also identified the periareolar area as a high-risk region.

[Clinical characteristics and genetic analysis of a child with Cantú syndrome due to variant of ABCC9 gene].

OBJECTIVE: To explore the clinical characteristics and pathogenic variant in a child with Cantú syndrome (CS). METHODS: A male who was admitted to the Children's Hospital Affiliated to Zhengzhou University on February 23, 2022 was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples of the child and his parents were collected and subjected to whole-exome sequencing (WES). Candidate variant was verified by Sanger sequencing. This study was approved by the Children's Hospital Affiliated to Zhengzhou University (Ethics No. 2023-K-087). RESULTS: The child, a 3-year-and-2-month-old male, was born with hirsutism, with heavy hair all over the body and peculiar facial features. Routine echocardiography 1 month before had discovered atrial septal defect. Sequencing revealed that the child has harbored a heterozygous c.2438G>C (p.S813T) variant of the ABCC9 gene, which was de novo in origin. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.2438G>C variant was classified as likely pathogenic (PS2+PM2_Supporting+PP3). CONCLUSION: The heterozygous c.2438G>C variant of the ABCC9 gene probably underlay the pathogenesis of CS in this child.

Patients with DeSanto-Shinawi syndrome: Further extension of phenotype from Italy.

Here we describe three patients with neurodevelopmental disorders characterized by mild-to-moderate intellectual disability, mildly dysmorphic features, and hirsutism, all of which carry de novo sequence variants in the WW domain-containing adaptor of the coiled-coil (WAC) gene; two of these-c.167delA, p.(Asn56I1efs*136) and c.1746G>C, p.(Gln582His)-are novel pathogenic variants, and the third-c.1837C>T, p(Arg613*)-has been previously described. Diseases associated with WAC include DeSanto-Shinawi syndrome; to date, de novo heterozygous constitutional pathogenic WAC variants have caused a syndromic form of intellectual disability and mild dysmorphic features in 33 patients, yet potential associations with other clinical manifestations, such as oligomenorrhea and hyperandrogenism, remain unknown, because the phenotypic spectrum of the condition has not yet been delineated. The patient bearing the novel c.167delA WAC gene variant presented a normal psychomotor development, oligomenorrhea, hyperandrogenism, and hirsutism, and hirsutism was also observed in the patient with the c.1746G>C WAC gene variant. Hypertrichosis and hirsutism have been described in nine DeSanto-Shinawi patients, only in 17 of the 33 aforementioned patients thus far reported this aspect, and no hormonal-pattern data are available. In conclusion, we note that the pathogenic c.167delA WAC variant may be associated with a mild phenotype; and in addition to the neurodevelopmental problems nearly all DeSanto-Shinawi patients experience (i.e., intellectual disability and/or developmental delay), we recommend the addition of mild dysmorphic features, hirsutism, and hypertrichosis to this clinical presentation.

Combination 1550 nm non-ablative fractional resurfacing and laser hair removal for treatment of Becker's nevi in skin types III-VI.

OBJECTIVES: Becker's nevus is a cosmetically bothersome benign hamartoma typically associated with basal layer hyperpigmentation and hypertrichosis. We herein present the largest case series characterizing treatment parameters and clinical outcomes of combined 1550 nm non-ablative fractional resurfacing and laser hair removal (long-pulsed neodymium-doped yttrium aluminum garnet or alexandrite) in the treatment of Becker's nevus. This is also the largest case series of laser treatment of Becker's nevus in Fitzpatrick skin types V and VI. METHODS: We performed a retrospective review of patients treated between 2016 and 2021. Clinical photographs were graded by three independent physicians using a 5-point visual analog scale. RESULTS: Twelve patients (mean age: 24.8 years, Fitzpatrick skin types III-VI) were treated for Becker's nevus on the face (4) or the trunk and/or extremities (8). Four patients were Fitzpatrick skin types V or VI. On average, patients received 5.3 treatments in 1-4-month intervals. Ten of the 12 patients had concomitant laser hair removal preceding same-day non-ablative fractional resurfacing (n = 7 with long-pulsed 1064 nm neodymium-doped yttrium aluminum garnet and n = 3 with long-pulsed 755 nm alexandrite). The number of treatments with each modality was determined by patient satisfaction with improvement in hyperpigmentation and hypertrichosis. At follow-up, which ranged from 6 to 40 weeks (mean 10.5 weeks), patients were given a mean improvement score of 51%-75%. No long-term adverse events were encountered in either group. Limitations include a small sample size and a lack of long-term follow-up. CONCLUSION: Combination 1550 nm non-ablative fractional resurfacing and laser hair removal is safe and efficacious in the cosmetic reduction of hyperpigmentation and hypertrichosis associated with Becker's nevus, including those with Fitzpatrick skin types V and VI.

What Do We Know About Hair Growth Induced by Wounding and Its Therapeutic Applications?

BACKGROUND: Many studies have reported the role of hair follicles (HFs) in the wound healing response, and vice versa, the creation of superficial injuries may stimulate hair growth, which has encouraged new treatments for hair loss. OBJECTIVE: To review the phenomenon of wound-induced hair growth and the usefulness of therapeutic procedures based on skin wounding in androgenetic alopecia (AGA). METHODS: A literature search was conducted to review cases of localized hypertrichosis induced by wounds and the role of microneedling, fractional laser, and scalp threading as monotherapy for AGA. RESULTS: Localized hypertrichosis has been extensively reported after bone fractures, burn injury, chronic venous ulcer, etc. Only 2 cases of wound-induced hair neogenesis in humans have been reported. As monotherapy for AGA, 1 of 3 studies of microneedling, 4 of 6 of fractional lasers, and 2 of 3 studies of scalp threading show good efficacy. CONCLUSION: Certain types of wounds seem to stimulate localized hair growth in humans, but the underlying mechanism is unclear. Reports on wound-induced HF neogenesis in humans are anecdotal and questions remain as to whether this is a true phenomenon in humans. Further clinical studies are needed before recommending wound-induced hair growth procedures as therapies for AGA.

Multiple vascular anomalies and refractory pericardial effusion in a young patient with Cantu syndrome: a case report and review of the literature.

BACKGROUND: Cantu syndrome is a rare and complex multisystem disorder characterized by hypertrichosis, facial dysmorphism, osteochondroplasia and cardiac abnormalities. With only 150 cases reported worldwide, Cantu syndrome is now gaining wider recognition due to molecular testing and a growing body of literature that further characterizes the syndrome and some of its most important features. Cardiovascular pathology previously described in the literature include cardiomegaly, pericardial effusion, vascular dilation and tortuosity, and other congenital heart defects. However, cardiovascular involvement is highly variable amongst individuals with Cantu syndrome. In some instances, it can be extensive and severe requiring surgical management and long term follow up. CASE PRESENTATION: Herein we report a case of a fourteen-year-old female who presented with worsening pericardial effusion of unknown etiology, and echocardiographic findings of concentric left ventricular hypertrophy, a mildly dilated aortic root and ascending aorta. Her medical history was notable for hemoptysis and an episode of pulmonary hemorrhage secondary to multiple aortopulmonary collaterals that were subsequently embolized in early childhood. She was initially managed with Ibuprofen and Colchicine but continued to worsen, and ultimately required a pericardial window for the management of refractory pericardial effusion. Imaging studies obtained on subsequent visits revealed multiple dilated and tortuous blood vessels in the head, neck, chest, and pelvis. A cardiomyopathy molecular studies panel was sent, and a pathogenic variant was identified in the ABCC9 gene, confirming the molecular diagnosis of autosomal dominant Cantu syndrome. CONCLUSIONS: Vascular anomalies and significant cardiac involvement are often present in Cantu syndrome, however there are currently no established screening recommendations or surveillance protocols in place. The triad of hypertrichosis, facial dysmorphism, and unexplained cardiovascular involvement in any patient should raise suspicion for Cantu syndrome and warrant further investigation. Initial cardiac evaluation and follow up should be indicated in any patient with a clinical and/or molecular diagnosis of Cantu syndrome. Furthermore, whole body imaging should be utilized to evaluate the extent of vascular involvement and dictate long term monitoring and care.

Pinnae and facial hypertrichosis induced by cetuximab.

INTRODUCTION: Anti-EGFR targeted anti-cancer treatment is associated with various skin adverse events. Cetuximab is often associated with acneiform papules and skin disorders. Hypertrichosis cited in face pinnae and eyelash trichomegaly are seldom described. CASE REPORT: A 72-year-old female cancer patient presented deteriorating facial-pinnae hypertrichosis and eyelash prolongation post cetuximab infusion. MANAGEMENT AND OUTCOME: Consecutive cetuximab administration led to exaggerating hairy skin side effects, fully alleviated when the drug was discontinued. DISCUSSION: To the best of our knowledge, this is the first reported case of an anti-EGFR-associated diffuse pinnae hypertrichosis presentation in a female patient in literature. This distinct entity can be easily diagnosed and manipulated with early drug withdrawal. An extensive review of relevant basic molecular research is provided to increase physicians' awareness.

A child with generalized hypertrichosis due to secondary topical minoxidil exposure.

Hypertrichosis is defined as excessive hair growth anywhere on the body in either males or females. It may be caused by genetic conditions, endocrinological disorders, exposure to specific medications (including phenytoin, minoxidil and diazoxide) and other less frequent causes. We report the case of a 1-year-old boy with a family history of thyroid disease and alopecia areata who presented with generalized hypertrichosis due to secondary exposure to topical minoxidil. We discuss an uncommon cause of hypertrichosis and the importance of considering a wide differential diagnosis.

Low dose oral minoxidil and the conundrum of cardiovascular complications.

In recent months, the general public has become more cognizant of the potential of oral minoxidil to promote hair growth; this was promulgated, in part, by an article published in the New York Times entitled, "An Old Medicine Grows New Hair for Pennies a Day, Doctors Say." Minoxidil was added to the pharmacologic armamentarium as an antihypertensive nearly 60 years ago and was found to trigger hypertrichosis in many patients, but its use dropped sharply as cardiologists observed a number of adverse cardiovascular events including ischemic heart disease, left ventricular hypertrophy, pleural effusions, and pericardial effusions. Studies in the realm of dermatology have explored the utility and safety of low dose oral minoxidil (LDOM) for management of alopecia. This article highlights potential clinical conundrums posed by these rare but severe cardiovascular complications and the importance of collaboration between cardiologists and dermatologists when employing this agent in patients with cardiorenal or cardiovascular risk factors.

Juvenile Dermatomyositis With Rare Cutaneous Manifestation: Generalised Hypertrichosis.

Juvenile dermatomyositis (JDM) is a rare autoimmune disease characterised by inflammation of muscles and skin with extra muscular involvement of joints, heart, intestine, and liver. Pathogenesis of JDM is believed to be due to vasculopathy. Along with classic cutaneous features of JDM, rare findings include hypertrichosis, lipoatrophy, photosensitivity, bullous lesions, and hyperhidrosis. We present, here, a case of JDM with hypertrichosis as very few cases have been reported previously.

[A case of Oliver-McFarlane syndrome caused by PNPLA6 gene mutation].

Oliver-McFarlane syndrome is a rare genetic disorder characterized by long eyelashes, choroidoretinal atrophy, and multiple pituitary hormone deficiencies. The patient in this case is a 29-year-old female who has suffered from night blindness, low vision, and long eyelashes since childhood. Through genetic sequencing, she was diagnosed with compound heterozygous variaton in the PNPLA6 gene, indicating Oliver-McFarlane syndrome based on her comprehensive clinical presentation.

KATP channels in lymphatic function.

KATP channels function as negative regulators of active lymphatic pumping and lymph transport. This review summarizes and critiques the evidence for the expression of specific KATP channel subunits in lymphatic smooth muscle and endothelium, the roles that they play in normal lymphatic function, and their possible involvement in multiple diseases, including metabolic syndrome, lymphedema, and Cantú syndrome. For each of these topics, suggestions are made for directions for future research.