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.

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.

Acquired smooth muscle hamartoma with sebaceous component.

BACKGROUND: Acquired smooth muscle hamartoma (ASMH) is a rare benign lesion characterized clinically by hyperpigmented plaques with hypertrichosis and some follicular papules. The main histologic finding is the presence of disorganized smooth muscle bundles in the dermis. Only 25 cases of ASMH have been reported in the literature. CLINICAL CASE: We present the case of an 18-year-old male who reported a pigmented area and increased hair growth on the left hemifacial with one year of evolution. Clinically, a plaque was observed in the preauricular region and on the left cheek with a linear Blaschkoid path, consisting of hyperpigmentation, hypertrichosis, and some papular lesions, with negative pseudo-Darier sign. Histological analysis showed an increase in the number of smooth muscle bundles in the middle and deep dermis surrounding abundant sebaceous glands and numerous hair follicles in different stages of evolution. CONCLUSIONS: The sebaceous component in this lesion was prominent. Therefore, we considered this lesion part of a spectrum where the acquired smooth muscle hamartoma and folliculosebaceous cystic hamartoma are found at the extremes. This case would fall in the middle of the range, as it combines both histological features.

INTRODUCCIÓN: El hamartoma de músculo liso adquirido (HMLA) es una lesión benigna adquirida, poco frecuente, caracterizada clínicamente por presentar placas hiperpigmentadas, con hipertricosis y algunas pápulas foliculares. El principal hallazgo histológico es la presencia de abundantes haces de músculo liso desorganizados en la dermis. Se han reportado solo 25 casos de HMLA en la literatura. CASO CLÍNICO: Se presenta el caso de un paciente de sexo masculino de 18 años que refirió una zona pigmentada y el aumento de vello en la hemicara izquierda con un año de evolución. Clínicamente se observó una placa en la región preauricular y mejilla izquierda con trayecto lineal blaschkoide, constituida por hiperpigmentación, hipertricosis y algunas lesiones papulares, con signo pseudo-Darier negativo. Histológicamente se encontró un aumento en el número de haces de músculo liso en la dermis media y profunda rodeando abundantes glándulas sebáceas, así como numerosos folículos pilosos en diferentes estadios de evolución. CONCLUSIONES: El componente sebáceo en esta lesión fue muy marcado, por lo que se considera que forma parte de un espectro donde en los extremos se encuentran el hamartoma de músculo liso adquirido y el hamartoma quístico folículo sebáceo. El presente caso se encontraría en medio, ya que combina ambas características histológicas.

Atypical comorbidities in a child considered to have type 1 diabetes led to the diagnosis of SLC29A3 spectrum disorder.

INTRODUCTION: SLC29A3 spectrum disorder is an autosomal, recessively inherited, autoinflammatory, multisystem disorder characterized by distinctive cutaneous features, including hyperpigmentation or hypertrichosis, hepatosplenomegaly, hearing loss, cardiac anomalies, hypogonadism, short stature, and insulin-dependent diabetes. CASE PRESENTATION: Herein, we report a 6-year-old boy who presented with features resembling type 1 diabetes mellitus, but his clinical course was complicated by IgA nephropathy, pure red cell aplasia, and recurrent febrile episodes. The patient was tested for the presence of pathogenic variants in 53 genes related to monogenic diabetes and found to be compound heterozygous for two SLC29A3 pathogenic variants (p. Arg386Gln and p. Leu298fs). CONCLUSION: This case demonstrated that SLC29A3 spectrum disorder should be included in the differential diagnosis of diabetes with atypical comorbidities, even when the distinctive dermatological hallmarks of SLC29A3 spectrum disorder are entirely absent.

Recurrent KCNT2 missense variants affecting p.Arg190 result in a recognizable phenotype.

KCNT2 variants resulting in substitutions affecting the Arg190 residue have been shown to cause epileptic encephalopathy and a recognizable facial gestalt. We report two additional individuals with intellectual disability, dysmorphic features, hypertrichosis, macrocephaly and the same de novo KCNT2 missense variants affecting the Arg190 residue as previously described. Notably, neither patient has epilepsy. Homology modeling of these missense variants revealed that they are likely to disrupt the stabilization of a closed channel conformation of KCNT2 resulting in a constitutively open state. This is the first report of pathogenic variants in KCNT2 causing a developmental phenotype without epilepsy.

Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome.

Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non-LoF variants. This study identifies genotype-phenotype correlations as well as race-facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long-term outcomes in individuals with WSS.

Trio-WES reveals a novel de novo missense mutation of KMT2A in a Chinese patient with Wiedemann-Steiner syndrome: A case report.

BACKGROUND: Wiedemann-Steiner Syndrome (WSS) is an autosomal dominant genetic condition caused by mutations in the KMT2A gene. Lysine methyltransferase, encoded by KMT2A, plays critical roles in the regulation of gene expression during early development. METHODS: Trio-based whole exome sequencing (Trio-WES) was performed on a 15 months old Chinese girl and her two parents by MyGenostics (Beijing, China) using the Illumina HiSeq X ten system. Variants were confirmed with Sanger sequencing. She exhibited mild/moderate intellectual disability (ID), hypotonia, hypertrichosis cubiti, hypertrichosis on the back, dysmorphic facies, psychomotor retardation, growth delay, small and puffy hands, fat pads anterior to calcanei, and palmar/plantar grooves. RESULTS: Trio-WES revealed a novel de novo mutation of KMT2A gene (NM_001197104.1: c.3566G>T, p.Cys1189Phe). WSS was diagnosed based on WES and clinical features. CONCLUSION: Our findings expand the phenotypic and mutation spectra of WSS.

Hypertrichotic patches as a mosaic manifestation of Proteus syndrome.

BACKGROUND: Proteus syndrome is an overgrowth disorder caused by a mosaic activating AKT1 variant. Hair abnormalities in Proteus syndrome have rarely been reported, and frequencies of such findings have not been elucidated. OBJECTIVE: To define the types and frequencies of hair findings in individuals with Proteus syndrome. METHODS: A cross-sectional study was conducted of individuals with clinical features of Proteus syndrome and a confirmed pathogenic variant in AKT1 evaluated between November 1996 and June 2019 at the National Institutes of Health Clinical Center. Medical records were reviewed for patterning, density, and color of hair on the body and scalp. RESULTS: Of 45 individuals evaluated, 29 (64%) had asymmetric hypertrichosis on the body. This included unilateral blaschkoid hypertrichotic patches overlying normal skin or epidermal nevi in 16 (36%), unilateral nonblaschkoid hypertrichotic patches in 11 (24%), and unilateral limb hypertrichosis in 10 (22%). Diffuse, scattered, or patchy changes in scalp hair density or color were present in 11 individuals (24%). LIMITATIONS: The retrospective, observational design, and limited longitudinal follow-up. CONCLUSIONS: Asymmetric variations in hair distribution, thickness, length, and color contribute to the overall mosaic appearance of the skin in Proteus syndrome, an observation that provides novel insights into the role of phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) signaling in skin appendage development.

Hypertrichosis, trichomegaly, and androgenic alopecia related to cetuximab treatment.

Anti-epidermal growth factor receptor (EGFR) antibodies are mainly used in the treatment of advanced stages of solid tumors as a targeted therapy to inhibit tumor proliferation. They cause many dermatological adverse reactions through inhibition of EGFR pathway in the skin. A 39-year-old female patient diagnosed with metastatic colon adenocarcinoma received oxaliplatin, fluorouracil, and folinic acid regimen with cetuximab. The patient noticed increase in fairy hair especially at facial area as well as in the whole body beginning after the first few cycles of treatment, after 3 months. Obvious hypertrichosis, androgenic alopecia, and trichomegaly were observed. Blood tests for androgenetic alopecia and hirsutism were studied. Hormonal levels were in normal range. Upper abdominal imaging to rule out any adrenal lesion was also normal. Previous studies reported found that cetuximab may cause alopecia, hypertrichosis on face and body, and trichomegaly. We have not encountered a combination of hypertrichosis, androgenic type alopecia, and trichomegaly in the literature.

Cantú syndrome versus Zimmermann-Laband syndrome: Report of nine individuals with ABCC9 variants.

Cantú syndrome (CS) is a rare developmental disorder characterized by a coarse facial appearance, macrocephaly, hypertrichosis, skeletal and cardiovascular anomalies and caused by heterozygous gain-of-function variants in ABCC9 and KCNJ8, encoding subunits of heterooctameric ATP-sensitive potassium (KATP) channels. CS shows considerable clinical overlap with Zimmermann-Laband syndrome (ZLS), a rare condition with coarse facial features, hypertrichosis, gingival overgrowth, intellectual disability of variable degree, and hypoplasia or aplasia of terminal phalanges and/or nails. ZLS is caused by heterozygous gain-of-function variants in KCNH1 or KCNN3, and gain-of-function KCNK4 variants underlie the clinically similar FHEIG (facial dysmorphism, hypertrichosis, epilepsy, intellectual disability/developmental delay, and gingival overgrowth) syndrome; KCNH1, KCNN3 and KCNK4 encode potassium channels. Within our research project on ZLS, we performed targeted Sanger sequencing of ABCC9 in 15 individuals tested negative for a mutation in the ZLS-associated genes and found two individuals harboring a heterozygous pathogenic ABCC9 missense variant. Through a collaborative effort, we identified a total of nine individuals carrying a monoallelic ABCC9 variant: five sporadic patients and four members of two unrelated families. Among the six detected ABCC9 missense variants, four [p.(Pro252Leu), p.(Thr259Lys), p.(Ala1064Pro), and p.(Arg1197His)] were novel. Systematic assessment of the clinical features in the nine cases with an ABCC9 variant highlights the significant clinical overlap between ZLS and CS that includes early developmental delay, hypertrichosis, gingival overgrowth, joint laxity, and hypoplasia of terminal phalanges and nails. Gain of K+ channel activity possibly accounts for significant clinical similarities of CS, ZLS and FHEIG syndrome and defines a new subgroup of potassium channelopathies.

"Electrifying dysmorphology": Potassium channelopathies causing dysmorphic syndromes.

Potassium channels are a heterogeneous group of membrane-bound proteins, whose functions support a diverse range of biological processes. Genetic disorders arising from mutations in potassium channels are classically recognized by symptoms arising from acute channel dysfunction, such as periodic paralysis, ataxia, seizures, or cardiac conduction abnormalities, often in a patient with otherwise normal examination findings. In this chapter, we review a distinct subgroup of rare potassium channelopathies whose presentations are instead suggestive of a developmental disorder, with features including intellectual disability, craniofacial dysmorphism or other physical anomalies. Known conditions within this subgroup are: Andersen-Tawil syndrome, Birk-Barel syndrome, Cantú syndrome, Keppen-Lubinsky syndrome, Temple-Baraitser syndrome, Zimmerman-Laband syndrome and a very similar disorder called Bauer-Tartaglia or FHEIG syndrome. Ion channelopathies are unlikely to be routinely considered in the differential diagnosis of children presenting with developmental concerns, and so detailed description and photographs of the clinical phenotype are provided to aid recognition. For several of these disorders, functional characterization of the genetic mutations responsible has led to identification of candidate therapies, including drugs already commonly used for other indications, which adds further impetus to their prompt recognition. Together, these cases illustrate the potential for mechanistic insights gained from genetic diagnosis to drive translational work toward targeted, disease-modifying therapies for rare disorders.

Post-zygotic ACTB mutations underlie congenital smooth muscle hamartomas.

BACKGROUND: Congenital smooth muscle hamartomas (CSMHs) are benign lesions that share clinical and histopathological features with Becker nevus, a mosaic disorder associated with post-zygotic ACTB mutations. Given the clinical and histopathological overlap between CSMH and Becker nevus, we hypothesized that post-zygotic mutations in ACTB may underlie CSMH. METHODS: Direct sequencing of ACTB gene in affected and unaffected tissue isolated from one case of hemihypertrichosis and hemihypertrophy corresponding to giant segmental CSMH and hemihypertrophy. This was followed by direct sequencing with and without enrichment assay for hotspot ACTB mutations in affected tissue from 12 samples of isolated CSMH from unrelated individuals. RESULTS: In total we identified somatic missense ACTB mutations in 9 out of 13 CSMHs (69%). Mutations were either novel or previously reported in Becker nevi and Becker nevus syndrome. CONCLUSIONS: CSMHs result from post-zygotic ACTB mutations. This study proves that CSMHs and Becker nevi are nosologically related, and expand the phenotypic spectrum of ACTB mutations.

Skin and hair abnormalities of Cantu syndrome: A congenital hypertrichosis due to a genetic alteration mimicking the pharmacological effect of minoxidil.

Cantu syndrome is an autosomal dominant disorder, first described by Cantu in 1982, that is characterized by congenital hypertrichosis, characteristic facial anomalies and cardiomegaly. Recent investigations have revealed that this syndrome is caused by mutations of ABCC9, which encodes a regulatory subunit of SUR2, an adenosine triphosphate-mediated potassium channel opener, expressed not only in smooth muscle but also in hair follicles. However, the abnormalities of skin and hair in patients with Cantu syndrome have not been well explored. We herein report three Japanese patients with Cantu syndrome and describe their specific skin manifestations and alterations in the histopathology of their hair follicles and sebaceous glands. Similar alterations were shared among those three patients and may be related to the function of SUR2, namely the regulation of hair follicle growth, because SUR2 is a known pharmacological target of minoxidil.