Characterization of bone homeostasis in individuals affected by cardio-facio-cutaneous syndrome.

Cardio-facio-cutaneous syndrome (CFCS) is a rare disorder characterized by distinctive craniofacial appearance, cardiac, neurologic, cutaneous, and musculoskeletal abnormalities. It is due to heterozygous mutations in BRAF, MAP2K1, MAP2K2, and KRAS genes, belonging to the RAS/MAPK pathway. The role of RAS signaling in bone homeostasis is highly recognized, but data on bone mineral density (BMD) in CFCS are lacking. In the present study we evaluated bone parameters, serum and urinary bone metabolites in 14 individuals with a molecularly confirmed diagnosis of CFCS. Bone assessment was performed through dual X-ray absorptiometry (DXA); height-adjusted results were compared to age- and sex-matched controls. Blood and urinary bone metabolites were also analyzed and compared to the reference range. Despite vitamin D supplementation and almost normal bone metabolism biomarkers, CFCS patients showed significantly decreased absolute values of DXA-assessed subtotal and lumbar BMD (p ≤ 0.05), compared to controls. BMD z-scores and t-scores (respectively collected for children and adults) were below the reference range in CFCS, while normal in healthy controls. These findings confirmed a reduction in BMD in CFCS and highlighted the importance of monitoring bone health in these affected individuals.

Activating mutations in BRAF disrupt the hypothalamo-pituitary axis leading to hypopituitarism in mice and humans.

Germline mutations in BRAF and other components of the MAPK pathway are associated with the congenital syndromes collectively known as RASopathies. Here, we report the association of Septo-Optic Dysplasia (SOD) including hypopituitarism and Cardio-Facio-Cutaneous (CFC) syndrome in patients harbouring mutations in BRAF. Phosphoproteomic analyses demonstrate that these genetic variants are gain-of-function mutations leading to activation of the MAPK pathway. Activation of the MAPK pathway by conditional expression of the BrafV600E/+ allele, or the knock-in BrafQ241R/+ allele (corresponding to the most frequent human CFC-causing mutation, BRAF p.Q257R), leads to abnormal cell lineage determination and terminal differentiation of hormone-producing cells, causing hypopituitarism. Expression of the BrafV600E/+ allele in embryonic pituitary progenitors leads to an increased expression of cell cycle inhibitors, cell growth arrest and apoptosis, but not tumour formation. Our findings show a critical role of BRAF in hypothalamo-pituitary-axis development both in mouse and human and implicate mutations found in RASopathies as a cause of endocrine deficiencies in humans.

Zygomatic implant survival in 9 ectodermal dysplasia patients with 3.5- to 7-year follow-up.

OBJECTIVE: Ectodermal dysplasia syndrome is a complex group of genetic disorders identified by the abnormal development of the ectodermal structures. The aim of this retrospective clinical case series report was to evaluate the outcomes of the ectodermal dysplasia syndrome patients that underwent zygomatic implant surgery. MATERIALS AND METHODS: A total of 9 ectodermal dysplasia syndrome patients aged between 21 and 56 years (mean age 36.8) with severely atrophic maxilla were included in this study. All the patients were treated with a total of 19 zygomatic implants. The mean follow-up of the patients was 55 months (with a range of 44-84 months). The implant survival rate was evaluated as a primary outcome. The intra- and postoperative complications were evaluated as additional criteria for success. RESULTS: The overall implant survival rate was 100% without any complications. Final or provisional prosthesis was delivered on the same day of surgery, which resulted in an improvement of the quality of life of the patients. CONCLUSION: According to the results of this study, zygomatic surgery can be considered as a viable and safe alternative to conventional treatment modalities for oral rehabilitation of ectodermal dysplasia syndrome patients.

Treatment with the anti-diabetic drug metformin ameliorates betel-nut induced carcinogenesis in a murine model.

BACKGROUND: Metformin, a widely used anti-diabetic drug has gained enormous attention as an anticancer agent. This study seeks to investigate the efficacy of metformin in ameliorating aqueous extract of betel-nut (AEBN) and arecoline induced carcinogenesis in a murine model. METHODS: Swiss albino mice were exposed to AEBN (2 mg ml-1) and arecoline (10 µg ml-1) in drinking water for 16 weeks followed by co-administration of metformin (75 mg kg-1 or 150 mg kg-1) for 4 or 8 weeks. Histological changes and oxidative stress were assessed by haematoxylin and eosin staining, TBARS assay and protein carbonylation assay respectively. Lipid profile was determined using an automated analyzer. Expression of total and phosphorylated AMPK, ACC and p53 were determined by immunoblotting. RESULTS: AEBN and arecoline induced dyslipidemia by downregulating AMPK (Thr-172) and activating ACC (Ser-79); they also downregulated tumor suppressor p53 (Ser-15). Metformin treatment induced AMPK-dependent alleviation of dyslipidemia in a dose and time dependent manner, upregulated p53 (Ser-15), restored tissue architecture and reduced oxidative stress in tissues of AEBN and arecoline treated mice. CONCLUSION: This study establishes that betel nut induces dyslipidemia through its alkaloid, arecoline by inhibition of AMPK (Thr-172) and activation of ACC (Ser-79) and highlights the therapeutic potential of metformin for treatment of betel-nut induced carcinogenesis, indicating the repurposing of the old drug in a new avenue.

Associations between ectodermal dysplasia, psychological distress and quality of life in a group of adults with oligodontia.

OBJECTIVE: The aim of this study was to assess demographics, self-reported signs of ectodermal dysplasia (problems with hair, nails, skin and sweat glands), present teeth, previous dental treatment, psychological distress and QoL in individuals with oligodontia, and to explore the associations between these factors. We also aimed to compare the level of psychological distress and QoL between the study group and normative samples. METHODS: Forty-seven individuals with oligodontia registered at a resource centre in Norway were included in the study. The participants completed self-administered questionnaires on demographics, ED signs, dental treatments, psychological distress and QoL (overall, health-related- and oral health-related QoL). Relevant statistics (independent t-test, correlation analysis and hierarchical multiple regressions) were used. RESULTS: Thirty-five participants reported ED signs. Forty-one participants had tooth replacements (nine had removable dentures). Sixteen had ≤10 present teeth, 13 perceived dry mouth and seven were unemployed. Persons with ≤10 present teeth had higher anxiety- and depression-scores than those having >10 present teeth. Unemployment, dry mouth and removable dentures indicated poor health-related- and oral health related QoL. Compared to a normative sample; the study group had significantly poorer mental health (MH)-related QoL, mean (SD); (51.1(8.2) versus 46.8(9.3), p < .001) and more anxiety, mean (SD); (4.5(3.1) versus 6.7(3.6), p < .001). ED signs and treatments were most important for psychological distress and MH related QoL (MCS), whereas demographic parameters were most important for the other QoL measures. CONCLUSIONS: The psychological burden of oligodontia is significant, emphasizing the importance of a holistic approach by caregivers.

Topical cetirizine and oral vitamin D: a valid treatment for hypotrichosis caused by ectodermal dysplasia.

BACKGROUND: Ectodermal dysplasia is a clinically and genetically heterogeneous group of inherited disorders characterized by abnormal development of two or more of the following ectodermal-derived structures: hair, teeth, nails and sweat glands. The hair is the most frequently affected structure. Hair shaft abnormalities are of great concern to these patients, but no effective treatments are available. METHODS: We describe three girls with congenital hypotrichosis (9, 5 and 6 years old) caused by ectodermal dysplasia treated with topical cetirizine solution (2 mL. once daily) and oral vitamin D supplementation (1000 IU daily). RESULTS: After 6 months of treatment, the density of hair on the scalp increased in all patients. The vellus hair was replaced by terminal hair. Hair regrowth was evaluated both from the clinical and trichoscopic point of view. CONCLUSION: We propose a combination of topical cetirizine and oral vitamin D as a rational treatment of choice in congenital hypotrichosis caused by ectodermal dysplasia.

Ulerythema ophryogenes: updates and insights.

Ulerythema ophryogenes is a rare cutaneous atrophic disorder that occasionally is associated with Noonan syndrome, de Lange syndrome, Rubinstein-Taybi syndrome, and cardiofaciocutaneous (CFC) syndrome. Often presenting in pediatric patients, the pathogenesis of ulerythema ophryogenes remains unclear, though several genetic causes have been suggested. Treatment recommendations remain anecdotal, but clearance has been noted as the patient ages. Although topical agents have been the mainstay of therapy, recent advancement in laser intervention for treatment of ulerythema ophryogenes is promising.

[Rickets-like genetic diseases].

This paper summarizes the clinical features, causative genes and treatment progress of patients with rickets-like genetic diseases, including X-linked hypophosphatemic rickets (XLH), hypophosphatasia, achondroplasia, vitamin D-dependent rickets, pycnodysostosis and ectodermal dysplasia, who visited the pediatric or child health clinic due to the symptoms of rickets, including bow legs, delayed closure of the anterior fontanelle, and sparse hair. Children with XLH usually go to hospital for bow legs and short stature, and biochemical evaluation reveals significantly low serum phosphorus so it is easily diagnosed. This disease is treated using phosphate mixture and 1,25(OH)2D3, which is different from the treatment of nutritional vitamin D deficiency rickets. Hypophosphatasia is characterized by a significant decrease in serum alkaline phosphatase, as well as normal serum calcium and phosphorus. The disease is caused by mutations in TNSALP gene. Patients with achondroplasia show short-limbed dwarfism and special face in addition to bow legs, but with normal serum calcium, phosphorus and alkaline phosphatase. Bone X-ray and FGFR3 gene test contribute to the diagnosis. Vitamin D-dependent rickets is an autosomal recessive disease, and active vitamin D supplement is effective in treatment of the disease. Patients with pycnodysostosis may be first seen at hospital because of large anterior fontanelle; in addition, they also show obtuse mandibular angle, dental abnormalities and dysplastic nails, which are caused by mutations in TSK gene. Children with ectodermal dysplasia may see a doctor for sparse hair, and they are easily misdiagnosed with nutritional vitamin D deficiency rickets. Ectodermal dysplasia is related to EDA, EDAR, EDARADD and WNT 10A genes.

Rickets-like genetic diseases / 中国当代儿科杂志

This paper summarizes the clinical features, causative genes and treatment progress of patients with rickets-like genetic diseases, including X-linked hypophosphatemic rickets (XLH), hypophosphatasia, achondroplasia, vitamin D-dependent rickets, pycnodysostosis and ectodermal dysplasia, who visited the pediatric or child health clinic due to the symptoms of rickets, including bow legs, delayed closure of the anterior fontanelle, and sparse hair. Children with XLH usually go to hospital for bow legs and short stature, and biochemical evaluation reveals significantly low serum phosphorus so it is easily diagnosed. This disease is treated using phosphate mixture and 1,25(OH)2D3, which is different from the treatment of nutritional vitamin D deficiency rickets. Hypophosphatasia is characterized by a significant decrease in serum alkaline phosphatase, as well as normal serum calcium and phosphorus. The disease is caused by mutations in TNSALP gene. Patients with achondroplasia show short-limbed dwarfism and special face in addition to bow legs, but with normal serum calcium, phosphorus and alkaline phosphatase. Bone X-ray and FGFR3 gene test contribute to the diagnosis. Vitamin D-dependent rickets is an autosomal recessive disease, and active vitamin D supplement is effective in treatment of the disease. Patients with pycnodysostosis may be first seen at hospital because of large anterior fontanelle; in addition, they also show obtuse mandibular angle, dental abnormalities and dysplastic nails, which are caused by mutations in TSK gene. Children with ectodermal dysplasia may see a doctor for sparse hair, and they are easily misdiagnosed with nutritional vitamin D deficiency rickets. Ectodermal dysplasia is related to EDA, EDAR, EDARADD and WNT 10A genes.

Colgajo braquiorraquial en la cobertura de la inserción distal del tendón del bíceps / Brachioradial flap for coverage of the distal insertion of the biceps tendon

El músculo braquiorradial es un músculo flexor accesorio del codo que también se puede utilizar para dar la cobertura sin provocar un déficit funcional. Está indicado en la cobertura de los defectos complejos de la cara anterior y lateral del codo, especialmente cuando existe exposición articular, y también del tercio proximal del antebrazo. Se presenta el caso de un varón de 49 años de edad con un problema de cobertura en la región anterior de codo tras una reinserción de bíceps distal 4 semanas antes, mediante anclaje en tuberosidad bicipital. El colgajo de músculo braquiorradial es seguro, está bien vascularizado y es fácil de realizar, con una mínima morbilidad (AU)

The brachioradial muscle is an accesory flexor muscle of the elbow that may also be used for coverage without causing functional deficit. It is indicated for covering complex defects in the anterior and lateral aspects of the elbow, particularly when joint exposure exists, and also in the proximal third of the forearm. The case of a 49-year-old male with a coverage problem in the anterior elbow region 4 weeks after distal biceps reinsertion by anchoring in the bicipital tuberosity is reported. The brachioradial muscle flap is safe, well vascularized, and easy to perform with minimum morbidity (AU)

Use of a water-vapour permeable polyurethane film (omiderm) in the non-surgical treatment of aplasia cutis congenita.

Aplasia cutis congenita is characterised by congenital absence of all layers of skin, and most commonly affects the scalp. It is often associated with absence of the bone and dura underlining the defective scalp. In this report, we present the result of use of a water-vapour permeable polyurethane film (Omiderm) together with absorbant fine mesh gauze impregnated with 3% bismuth tribromophenate (Xeroform) in the treatment of a cranial defect in a newborn baby of low birth weight, who could not be operated on because of associated medical problems.

Metastatic melanoma in a patient with Clouston syndrome successfully treated with isolated hyperthermic limb perfusion.

BACKGROUND: Clouston syndrome is an autosomal dominant disorder characterized by nail dystrophy, partial or total alopecia, and hyperkeratosis of the palms and soles. OBJECTIVE: Although a variety of unusual cutaneous manifestations have been described, the incidence of melanoma in this population is unknown. METHODS: This article reports a case of in-transit metastatic subungual melanoma in a patient with Clouston syndrome successfully treated with hyperthermic limb perfusion with melphalan. RESULTS: Six months postperfusion, the patient is doing well, with resolution of the extremity erythema and edema. Followup ultrasonography revealed reduction in size of the eight subcutaneous nodules, with the largest measuring 3.3 cm in maximum diameter, representing nearly a 50% reduction in tumor volume postperfusion. CONCLUSION: Although melanoma has also been associated with some forms of ectodermal dysplasia, such as ectrodactyly--ectodermal dysplasia--clefting (EEC) syndrome, the incidence of melanoma in patients with Clouston syndrome is unknown. Thus far, to our knowledge, this is the first case report of melanoma arising in a patient with Clouston syndrome.

Otodental syndrome. A case report.

A 12-year-old boy with characteristic findings of otodental syndrome is presented. Abnormalities of deciduous and permanent dentition included bulbous canines, globe-shaped posterior teeth and agenesis of maxillary premolars. High-frequency sensorineural hearing loss was demonstrated, and results of genetic studies indicated an autosomal dominant trait. This patient presented previously unreported findings, including generalized macrodontia, delayed mineralization of the mandibular premolars, and supplementary permanent maxillary canines.

Calcification of basal ganglia and cerebellar roof nuclei in mentally defective patient with hidrotic ectodermal dysplasia. Analysis of intracranial concretions by electon microprobe.

This report describes, for the first time, an analysis by electron microprobe of concretions in the brain of an individual with striopallidodentate calcification. We also report the unique association of this intracranial syndrome with hidrotic ectodermal dysplasia. An institutionalized male with impaired intellectual function and hidrotic ectodermal dysplasia was known since the age of 3 years to have bilateral radiopaque densities in the region of the basal ganglia on skull roentgenogram. He died at age 29 in congestive heart failure from rheumatic pancarditis. At autopsy, concretions were identified in globus pallidus, caudate nuclei, thalamus, and dentate nuclei. Mineral deposits within the brain, analyzed by energy dispersive x-ray microanalysis, consisted predominately of calcium and phosphorus. Trace amounts of magnesium, iron, and silicon also were detected.