Dermatological manifestations in Costello syndrome: A prospective multicentric study of 31 HRAS-positive variant patients.

BACKGROUND: Data on dermatological manifestations of Costello syndrome (CS) remain heterogeneous and lack in validated description. OBJECTIVES: To describe the dermatological manifestations of CS; compare them with the literature findings; assess those discriminating CS from other RASopathies, including cardiofaciocutaneous syndrome (CFCS) and the main types of Noonan syndrome (NS); and test for dermatological phenotype-genotype correlations. METHODS: We performed a 10-year, large, prospective, multicentric, collaborative dermatological and genetic study. RESULTS: Thirty-one patients were enrolled. Hair abnormalities were ubiquitous, including wavy or curly hair and excessive eyebrows, respectively in 68% and 56%. Acral excessive skin (AES), papillomas and keratotic papules (PKP), acanthosis nigricans (AN), palmoplantar hyperkeratosis (PPHK) and 'cobblestone' papillomatous papules of the upper lip (CPPUL), were noted respectively in 84%, 61%, 65%, 55% and 32%. Excessive eyebrows, PKP, AN, CCPUL and AES best differentiated CS from CFCS and NS. Multiple melanocytic naevi (>50) may constitute a new marker of attenuated CS associated with intragenic duplication in HRAS. Oral acitretin may be highly beneficial for therapeutic management of PPHK. No significant dermatological phenotype-genotype correlation was determined between patients with and without HRAS c.34G>A (p.G12S). CONCLUSIONS AND RELEVANCE: This validated phenotypic characterization of a large number of patients with CS will allow future researchers to make a positive diagnosis, and to differentiate CS from CFCS and NS.

Combination of metformin with liraglutide in treating HAIR-AN syndrome in children: A case report and literature review. / 二甲双胍联合利拉鲁肽治疗儿童HAIR-AN综合征1ä¾‹å¹¶æ–‡çŒ®å¤ä¹ .

Hyperandrogenism-insulin resistance-acanthosis nigricans (HAIR-AN) syndrome is a special and rare subtype of polycystic ovarian syndrome. It can lead to hyperandrogenism (HA), insulin resistance (IR), and acanthosis nigricans (AN) accompanied by acne, hirutism, irregular menstruation, and other androgen excess symptoms. A case of pediatric HAIR-AN syndrome with severe AN was admitted to the Department of Endocrinology, China-Japan Friendship Hospital. The patient's clinical manifestations, laboratory data, imaging features, and gene sequencing were analyzed, and the patient was diagnosed with pediatric HAIR-AN syndrome. Obesity, IR, hyperglycemia, menstrual disorder, and AN were significantly improved after treating with metformin and liraglutide. HAIR-AN syndrome occurs in various forms. When the patient appears unexplained acanthosis nigricans and menstrual disorders, the disease should be considered possible. Early diagnosis and symptomatic supportive treatment can improve the quality of life.

Autosomal dominant familial acanthosis nigricans caused by a C-terminal nonsense mutation of FGFR3.

FGFR3 encodes a transmembrane receptor tyrosine kinase that has six autophosphorylation sites of tyrosine. Among them, Y770 is a negative regulatory site for the downstream signaling of FGFR3. Constitutive active mutations in FGFR3 are involved in human developmental disorders including familial acanthosis nigricans, an autosomal dominant disorder characterized by general hyperpigmentation with mild acanthosis of the epidermis. Here, we report two unrelated cases of familial acanthosis nigricans with a heterozygous c.2302G>T (p.E768*) mutation in FGFR3 (NM_000142.5). FGFR3 mRNA purified from the skin lesion neither showed aberrant splicing nor nonsense-mediated mRNA decay, indicating that the FGFR3 mutant simply lacked the C-terminal 768-806 amino acids including Y770. While all of the known pathogenic mutations were missense mutations in FGFR3 showing autosomal dominant trait, the c.2302G>T mutation of FGFR3 is a unique autosomal dominant nonsense mutation that causes familial acanthosis nigricans probably via loss of negative regulatory autophosphorylation site of FGFR3.

Clinical presentation and molecular characterization of a novel patient with variant POC1A-related syndrome.

Biallelic pathogenic variants in POC1A result in SOFT (Short-stature, Onychodysplasia, Facial-dysmorphism, and hypoTrichosis) and variant POC1A-related (vPOC1A) syndromes. The latter, nowadays described in only two unrelated subjects, is associated with a restricted spectrum of variants falling in exon 10, which is naturally skipped in a specific POC1A mRNA. The synthesis of an amount of a POC1A isoform from this transcript in individuals with vPOC1A syndrome has been believed as the likely explanation for such a genotype-phenotype correlation. Here, we illustrate the clinical and molecular findings in a woman who resulted to be compound heterozygous for a recurrent frameshift variant in exon 10 and a novel variant in exon 9 of POC1A. Phenotypic characteristics of this woman included severe hyperinsulinemic dyslipidemia, acanthosis nigricans, moderate growth restriction, and dysmorphisms. These manifestations overlap the clinical features of the two previously published individuals with vPOC1A syndrome. RT-PCR analysis on peripheral blood and subsequent sequencing of the obtained amplicons demonstrated a variety of POC1A alternative transcripts that resulted to be expressed in the proband, in the healthy mother, and in controls. We illustrate the possible consequences of the two POC1A identified variants in an attempt to explain pleiotropy in vPOC1A syndrome.

De novo mutation in ELOVL1 causes ichthyosis, acanthosis nigricans, hypomyelination, spastic paraplegia, high frequency deafness and optic atrophy.

BACKGROUND: Very long-chain fatty acids (VLCFAs) are essential for functioning of biological membranes. ELOVL fatty acid elongase 1 catalyses elongation of saturated and monounsaturated C22-C26-VLCFAs. We studied two patients with a dominant ELOVL1 mutation. Independently, Kutkowska-Kazmierczak et al. had investigated the same patients and found the same mutation. We extended our study towards additional biochemical, functional, and therapeutic aspects. METHODS: We did mutation screening by whole exome sequencing. RNA-sequencing was performed in patient and control fibroblasts. Ceramide and sphingomyelin levels were measured by LC-MS/MS. ELOVL1 activity was determined by a stable isotope-labelled [13C]malonyl-CoA elongation assay. ELOVL1 expression patterns were investigated by immunofluorescence, in situ hybridisation and RT-qPCR. As treatment option, we investigated VLCFA loading of fibroblasts. RESULTS: Both patients carried an identical heterozygous de novo ELOVL1 mutation (c.494C>T, NM_001256399; p.S165F) not deriving from a founder allele. Patients suffered from epidermal hyperproliferation and increased keratinisation (ichthyosis). Hypomyelination of the central white matter explained spastic paraplegia and central nystagmus, while optic atrophy was causative for reduction of peripheral vision and visual acuity. The mutation abrogated ELOVL1 enzymatic activity and reduced ≥C24 ceramides and sphingomyelins in patient cells. Fibroblast loading with C22:0-VLCFAs increased C24:0-ceramides and sphingomyelins. We found competitive inhibition for ceramide and sphingomyelin synthesis between saturated and monounsaturated VLCFAs. Transcriptome analysis revealed upregulation of modules involved in epidermal development and keratinisation, and downregulation of genes for neurodevelopment, myelination, and synaptogenesis. Many regulated genes carried consensus proliferator-activated receptor (PPAR)α and PPARγ binding motifs in their 5'-regions. CONCLUSION: A dominant ELOVL1 mutation causes a neuro-ichthyotic disorder possibly amenable to treatment with PPAR-modulating drugs.

A Molecular Perspective on the Potential Benefits of Metformin for the Treatment of Inflammatory Skin Disorders.

Due to its anti-hyperglycemic effect, metformin is the first-line medication for the treatment of type 2 diabetes, particularly in people who are obese. However, metformin is a drug with a very wide range of pharmacological properties and reports of its therapeutic effect on diseases including inflammation and cancer are increasing. Numerous research groups have reported that metformin has beneficial effects on a variety of inflammatory skin disorders including psoriasis, acanthosis nigricans, acne, hidradenitis suppurativa, and allergic contact dermatitis. According to these reports, in addition to the well-known action of metformin, that is, its anti-hyperglycemic effect, NF-kB inhibition and the resulting alteration to the cytokine network may be the potential targets of metformin. Its anti-hyperandrogenism effect has also been confirmed as the major action of metformin in some inflammatory skin diseases. Moreover, novel regulatory mechanisms, including autophagy and antioxidant processes, have been suggested as promising mechanisms of action for metformin in inflammatory skin disorders.

Acanthosis nigricans in a Chinese girl with FGFR3 K650 T mutation: a case report and literature review.

BACKGROUND: Acanthosis nigricans (AN) is a clinical manifestation featured by velvety brown plaques in skin folds that occurs in some hereditary and syndromic disorders. Fibroblast growth factor receptor 3 (FGFR3) mutations have been identified as one of the genetic causes of inherited AN. CASE PRESENTATION: A 17-year-old Chinese female had presented generalized acanthosis nigricans since she was 4 years old. She yielded no family history of short stature or AN. Apart from a short stature, no skeletal defects, neurological defects or other abnormalities were found. To identify the aetiology of the clinically diagnosed AN, we screened the proband for genetic mutations using whole exome sequencing. A heterozygous mutation (c.1949A > C, p.Lys650Thr) in FGFR3 was found in the proband. To date, 26 cases of AN harbouring this specific gene mutation have been reported in the literature, and only one child carried a de novo mutation instead of inheriting the specific mutation from their parents. The present case is the first-reported Chinese patient with isolated AN with a de novo K650 T mutation in FGFR3. CONCLUSIONS: We reported a new case of AN caused by a heterozygous mutation (c.1949A > C, p.K650 T) in FGFR3, and review the past reports of AN with the same gene mutation. Sequencing of the FGFR3 gene is a feasible approach to identify the aetiology of AN, especially for early onset extensive AN.

Mutational analysis of epidermal and hyperproliferative type I keratins in mild and moderate psoriasis vulgaris patients: a possible role in the pathogenesis of psoriasis along with disease severity.

BACKGROUND: Mutations in keratin proteins have been vastly associated with a wide array of genodermatoses; however, mutations of keratins in psoriasis have not been fully investigated. The main aim of the current research was to identify the mutation in K14, K10, K16, and K17 genes in two stages of psoriasis patients. METHODS: Ninety-six psoriatic skin biopsies were collected. mRNA transcript of K14, K10, K16, and K17 was prepared, amplified, and sequenced. Sanger sequences of all keratins were further validated for mutational analysis using Mutation Surveyor and Alamut Visual. Then, in silico analysis of protein stability and protein and gene expression of all keratins was performed and validated. RESULTS: Out of 44 mutations, about 75% of keratins are highly pathogenic and deleterious. Remaining 25% mutations are less pathogenic and tolerated in nature. In these 33 deleterious mutations were immensely found to decrease keratin protein stability. We also found a correlation between keratin and Psoriasis Area and Severity Index score which added that alteration in keratin gene in skin causes severity of psoriasis. CONCLUSIONS: We strongly concluded that acanthosis and abnormal terminal differentiation was mainly due to the mutation in epidermal keratins. In turn, disease severity and relapsing of psoriasis are mainly due to the mutation of hyperproliferative keratins. These novel keratin mutations in psoriatic epidermis might be one of the causative factors for psoriasis.

Topical sirolimus therapy for epidermal nevus with features of acanthosis nigricans.

We present a 4-year-old developmentally appropriate boy with short stature and widespread expanding epidermal nevus with features of acanthosis nigricans. He was found to have a mosaic mutation in FGFR3, the R248C variant. Despite several therapies, he continued to have growth, fissuring, and bleeding of the affected skin. Ultimately, topical sirolimus was attempted and found to improve thickness and overall symptoms.

Acanthosis nigricans, hypochondroplasia, and FGFR3 mutations: Findings with five new patients, and a review of the literature.

Early development of extensive acanthosis nigricans (AN) is a key feature in some patients who have hypochondroplasia (HCH) in association with FGFR3 mutations. We here report regarding five new patients with HCH who exhibited AN, and we compare their characteristics to the eight patients previously described in the literature. In these patients, the AN lesions began in childhood, and they were extensive. These lesions were located on the torso, the abdomen, and the face, in addition to the typical skin fold sites. Other skin lesions were frequently reported: café-au-lait macules, melanocytic nevi, lentigines, and seborrheic keratosis. The Lys650Thr mutation was the predominant reported mutation of FGFR3.

Acanthosis nigricans in achondroplasia.

Acanthosis nigricans (AN) in those with achondroplasia has been reported occasionally in the literature previously. Other disorders arising from constitutive activation of FGFR3 also manifest AN at various frequencies. We assessed the prevalence of AN in a sequential series of 477 individuals with achondroplasia. Using a REDCap database, we collected and analyzed what other features or medical issues may co-occur with AN in those with achondroplasia. AN arises in approximately 10% of individuals with achondroplasia. It usually first appears in preadolescence or adolescence, is more likely in the non-White population and in those who are obese. It is not severe and generally will need no treatment. It is not associated with any evident risk for neither hyperinsulinemic states nor malignancy, and therefore, no special investigations are warranted when it is recognized. Thus, clinicians should not be surprised or concerned upon discovering this finding in those with achondroplasia. In addition, the mechanisms and genetic causes of AN are detailed.

Crouzon with Acanthosis Nigricans and Odontogenic Tumors: A Rare Form of Syndromic Craniosynostosis.

Crouzon syndrome with acanthosis nigricans (CAN) is caused by a mutation in the fibroblast growth factor receptor ( FGFR) 3 gene that presents clinically as Crouzonoid craniofacial features in association with other anomalies such as acanthosis nigricans and benign odontogenic tumors. Diagnosis through the use of genetic mutational analysis is critical, as it alerts the surgeon to the need for careful screening for jaw tumors so that timely treatment in the form of curettage or segmental resection can be provided.

Mild achondroplasia/hypochondroplasia with acanthosis nigricans, normal development, and a p.Ser348Cys FGFR3 mutation.

Pathogenic allelic variants in the fibroblast growth factor receptor 3 (FGFR3) gene have been associated with a number of phenotypes including achondroplasia, hypochondroplasia, thanatophoric dysplasia, Crouzon syndrome with acanthosis nigricans (Crouzonodermoskeletal syndrome), and SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans). Crouzon syndrome with acanthosis nigricans is caused by the pathogenic variant c.1172C>A (p.Ala391Glu) in the FGFR3 gene. The p.Lys650Thr pathogenic variant in FGFR3 has been linked to acanthosis nigricans without significant craniofacial or skeletal abnormalities. Recently, an infant with achondroplasia and a novel p.Ser348Cys FGFR3 mutation was reported. We describe the clinical history of an 8-year-old child with a skeletal dysplasia in the achondroplasia-hypochondroplasia spectrum, acanthosis nigricans, typical development, and the recently described p.Ser348Cys FGFR3 mutation.

Molecular mechanisms of insulin resistance in 2 cases of primary insulin receptor defect-associated diseases.

BACKGROUND: Defects of the insulin receptor gene ( INSR ) cause wide spectra of congenital insulin resistance. Monoallelic defects result in milder insulin-resistant diabetes mellitus with acanthosis nigricans (IRAN, type A). Whereas, leprechaunism (Donahue syndrome), the most severe condition with lethality during the infantile period is caused by biallelic defects of INSR . MATERIALS AND METHODS: We detected 2 missense mutations in 2 cases of leprechaunism and IRAN, type A, and reduced mRNA expression in the leprechaunism case. We performed an in vitro analysis to confirm that the 2 missense mutations are causative. RESULTS: The heterozygote mutations c.3436G>A (p.Gly1146Arg) and c.294C>A (p.Ser98Arg) were identified in a male patient with IRAN, type A and a female patient with leprechaunism, respectively. Gly1146Arg was previously reported in a diabetic case without precise functional analyses, and Ser98Arg is a novel mutation. Gly1146 and Ser98 are located on the tyrosine kinase domain and ligand-binding domain of INSR, respectively, and in vitro analyses (assay for insulin binding and phosphorylation) revealed that each mutation disrupted protein functions and properties. In the leprechaunism case, mutations in INSR other than Ser98Arg were not identified, and qRT-PCR analysis revealed that mRNA expression of INSR in lymphocytes was reduced in the leprechaunism case. CONCLUSION: Our study indicates that the 2 missense mutations of INSR , Gly1146Arg, and Ser98Arg, are responsible for insulin resistance, and, suggests that mutations not contained within INSR , but leading to decreased INSR expression should be considered for the patients who show insulin resistance without any mutations in the coding sequence of INSR.

Characterization of membrane protein interactions in plasma membrane derived vesicles with quantitative imaging Förster resonance energy transfer.

Here we describe an experimental tool, termed quantitative imaging Förster resonance energy transfer (QI-FRET), that enables the quantitative characterization of membrane protein interactions. The QI-FRET methodology allows us to acquire binding curves and calculate association constants for complex membrane proteins in the native plasma membrane environment. The method utilizes FRET detection, and thus requires that the proteins of interest are labeled with florescent proteins, either FRET donors or FRET acceptors. Since plasma membranes of cells have complex topologies precluding the acquisition of two-dimensional binding curves, the FRET measurements are performed in plasma membrane derived vesicles that bud off cells as a result of chemical or osmotic stress. The results overviewed here are acquired in vesicles produced with an osmotic vesiculation buffer developed in our laboratory, which does not utilize harsh chemicals. The concentrations of the donor-labeled and the acceptor-labeled proteins are determined, along with the FRET efficiencies, in each vesicle. The experiments utilize transient transfection, such that a wide variety of concentrations is sampled. Then, data from hundreds of vesicles are combined to yield dimerization curves. Here we discuss recent findings about the dimerization of receptor tyrosine kinases (RTKs), membrane proteins that control cell growth and differentiation via lateral dimerization in the plasma membrane. We focus on the dimerization of fibroblast growth factor receptor 3 (FGFR3), a RTK that plays a critically important role in skeletal development. We study the role of different FGFR3 domains in FGFR3 dimerization in the absence of ligand, and we show that FGFR3 extracellular domains inhibit unliganded dimerization, while contacts between the juxtamembrane domains, which connect the transmembrane domains to the kinase domains, stabilize the unliganded FGFR3 dimers. Since FGFR3 has been documented to harbor many pathogenic single amino acid mutations that cause skeletal and cranial dysplasias, as well as cancer, we also study the effects of these mutations on dimerization. First, we show that the A391E mutation, linked to Crouzon syndrome with acanthosis nigricans and to bladder cancer, significantly enhances FGFR3 dimerization in the absence of ligand and thus induces aberrant receptor interactions. Second, we present results about the effect of three cysteine mutations that cause thanatophoric dysplasia, a lethal phenotype. Such cysteine mutations have been hypothesized previously to cause constitutive dimerization, but we find instead that they have a surprisingly modest effect on dimerization. Most of the studied pathogenic mutations also altered FGFR3 dimer structure, suggesting that both increases in dimerization propensities and changes in dimer structure contribute to the pathological phenotypes. The results acquired with the QI-FRET method further our understanding of the interactions between FGFR3 molecules and RTK molecules in general. Since RTK dimerization regulates RTK signaling, our findings advance our knowledge of RTK activity in health and disease. The utility of the QI-FRET method is not restricted to RTKs, and we thus hope that in the future the QI-FRET method will be applied to other classes of membrane proteins, such as channels and G protein-coupled receptors.

Successful rhIGF1 treatment for over 5 years in a patient with severe insulin resistance due to homozygous insulin receptor mutation.

BACKGROUND: Congenital insulin resistance syndromes are caused by biallelic mutations within the insulin receptor gene (INSR). Recombinant human insulin-like growth factor (rhIGF1) has been used with mixed success; however, rigorous assessment of its efficacy is lacking. Here, we describe a child with a homozygous mutation in INSR successfully treated with rhIGF1 for more than 5 years. CASE REPORT: The patient presented with osmotic diabetes symptoms and was noted to have dysplastic dentition, hypertrichosis, coarse and dysmorphic facial features. Acanthosis nigricans, skin tags and rugated hyperkeratosis were also evident on the posterior neck, axilla and groin. A homozygous INSR essential splice site mutation (c.1268 + 2T > C, p.G374 fs*12) was identified, for which both parents were found to be heterozygous. The patient was treated with twice daily injections of rhIGF1 and metformin for more than 5 years with improvement in her acanthosis nigricans, hyperkeratosis and hypertrichosis. A dramatic fall in fasting insulin, HOMA-IR and HbA1c has been maintained over the entire course of treatment without adverse effects. Her linear growth velocity has remained on target for her predicted adult height. DISCUSSION: Our case demonstrates the effectiveness of rhIGF1 as an early treatment in a patient with a biallelic mutation within INSR without evidence of fluid retention, retinopathy, muscle pain, heart failure, cerebral infarcts or benign intracranial hypertension. Her case suggests rhIGF1 can and should be considered as an initial treatment option instead of as a final option in those with INSR mutations.

Fibroblast growth factor receptor signaling in kidney and lower urinary tract development.

Fibroblast growth factor receptors (FGFRs) and FGF ligands are highly expressed in the developing kidney and lower urinary tract. Several classic studies showed many effects of exogenous FGF ligands on embryonic renal tissues in vitro and in vivo. Another older landmark publication showed that mice with a dominant negative Fgfr fragment had severe renal dysplasia. Together, these studies revealed the importance of FGFR signaling in kidney and lower urinary tract development. With the advent of modern gene targeting techniques, including conditional knockout approaches, several publications have revealed critical roles for FGFR signaling in many lineages of the kidney and lower urinary tract at different stages of development. FGFR signaling has been shown to be critical for early metanephric mesenchymal patterning, Wolffian duct patterning including induction of the ureteric bud, ureteric bud branching morphogenesis, nephron progenitor survival and nephrogenesis, and bladder mesenchyme patterning. FGFRs pattern these tissues by interacting with many other growth factor signaling pathways. Moreover, the many genetic Fgfr and Fgf animal models have structural defects mimicking numerous congenital anomalies of the kidney and urinary tract seen in humans. Finally, many studies have shown how FGFR signaling is critical for kidney and lower urinary tract patterning in humans.

Effective treatment by glycolic acid peeling for cutaneous manifestation of familial generalized acanthosis nigricans caused by FGFR3 mutation.

BACKGROUND: Acanthosis nigricans (AN) can occur as a cutaneous manifestation of genetic diseases, one of which is associated with activating mutations of the fibroblast growth factor receptor 3 gene (FGFR3). OBJECTIVE: We explored familial AN patients with FGFR3 mutations and examined the effectiveness of glycolic acid (GA) peeling in improving their skin manifestations. METHODS: Sanger sequencing was performed for the genomic DNA extracted from leucocytes of the family members involving familial AN. GA peeling was carried out for the two patients of familial AN once every 2 weeks. RESULTS: Heterozygous c.1949A>C (p.K650T) mutation in FGFR3 was identified for the affected family members examined, whereas the wild-type sequence was found for two unaffected individuals. Hyperpigmentation and coarseness of the skin were improved by GA peeling at regular intervals with few adverse effects. CONCLUSION: We diagnosed our cases as familial generalized AN caused by heterozygous c.1949A>C (p.K650T) mutation of FGFR3. We propose that GA peeling is a useful and safe therapeutic option to treat familial AN.

MORFAN Syndrome: An Infantile Hypoinsulinemic Hypoketotic Hypoglycemia Due to an AKT2 Mutation.

We report a child with hypoinsulinemic hypoglycemia and distinctive facies, with a diagnosis of the previously described MORFAN (Mental retardation, pre- and post-natal Overgrowth, Remarkable Face, and Acanthosis Nigricans) syndrome of unknown etiology. Whole-exome sequencing revealed a de novo AKT2 mutation. Although AKT2 has been implicated in four patients with hypoinsulinemic hypoglycemia, our report expands phenotypic spectrum to include MORFAN syndrome characteristics.