An international advisory group met at the National Institutes of Health in Bethesda, Maryland in 2017, to discuss a new classification system for the ectodermal dysplasias (EDs) that would integrate ...both clinical and molecular information. We propose the following, a working definition of the EDs building on previous classification systems and incorporating current approaches to diagnosis: EDs are genetic conditions affecting the development and/or homeostasis of two or more ectodermal derivatives, including hair, teeth, nails, and certain glands. Genetic variations in genes known to be associated with EDs that affect only one derivative of the ectoderm (attenuated phenotype) will be grouped as non-syndromic traits of the causative gene (e.g., non-syndromic hypodontia or missing teeth associated with pathogenic variants of EDA "ectodysplasin"). Information for categorization and cataloging includes the phenotypic features, Online Mendelian Inheritance in Man number, mode of inheritance, genetic alteration, major developmental pathways involved (e.g., EDA, WNT "wingless-type," TP63 "tumor protein p63") or the components of complex molecular structures (e.g., connexins, keratins, cadherins).
Generalized pustular psoriasis is a life-threatening disease of unknown cause. It is characterized by sudden, repeated episodes of high-grade fever, generalized rash, and disseminated pustules, with ...hyperleukocytosis and elevated serum levels of C-reactive protein, which may be associated with plaque-type psoriasis.
We performed homozygosity mapping and direct sequencing in nine Tunisian multiplex families with autosomal recessive generalized pustular psoriasis. We assessed the effect of mutations on protein expression and conformation, stability, and function.
We identified significant linkage to an interval of 1.2 megabases on chromosome 2q13-q14.1 and a homozygous missense mutation in IL36RN, encoding an interleukin-36-receptor antagonist (interleukin-36Ra), an antiinflammatory cytokine. This mutation predicts the substitution of a proline residue for leucine at amino acid position 27 (L27P). Homology-based structural modeling of human interleukin-36Ra suggests that the proline at position 27 affects both the stability of interleukin-36Ra and its interaction with its receptor, interleukin-1 receptor-like 2 (interleukin-1 receptor-related protein 2). Biochemical analyses showed that the L27P variant was poorly expressed and less potent than the nonvariant interleukin-36Ra in inhibiting a cytokine-induced response in an interleukin-8 reporter assay, leading to enhanced production of inflammatory cytokines (interleukin-8 in particular) by keratinocytes from the patients.
Aberrant interleukin-36Ra structure and function lead to unregulated secretion of inflammatory cytokines and generalized pustular psoriasis. (Funded by Agence Nationale de la Recherche and Société Française de Dermatologie.).
Neonatal ichthyosis and sclerosing cholangitis (NISCH) syndrome is an extremely rare entity with only 19 patients described in the literature. We report an extended family with the disorder and ...investigate the association of neurodevelopmental symptoms. Patients with CLDN1 mutations, and specifically « the Moroccan» c.200_201delTT deletion, may be an increased risk for neurodevelopmental symptoms such as learning disabilities, mental retardation, and language delay.
In epithelia, claudin proteins are important components of the tight junctions as they determine the permeability and specificity to ions of the paracellular pathway. Mutations in CLDN10 cause the ...rare autosomal recessive HELIX syndrome (Hypohidrosis, Electrolyte imbalance, Lacrimal gland dysfunction, Ichthyosis, and Xerostomia), in which patients display severe enamel wear. Here, we assess whether this enamel wear is caused by an innate fragility directly related to claudin‐10 deficiency in addition to xerostomia. A third molar collected from a female HELIX patient was analyzed by a combination of microanatomical and physicochemical approaches (i.e., electron microscopy, elemental mapping, Raman microspectroscopy, and synchrotron‐based X‐ray fluorescence). The enamel morphology, formation time, organization, and microstructure appeared to be within the natural variability. However, we identified accentuated strontium variations within the HELIX enamel, with alternating enrichments and depletions following the direction of the periodical striae of Retzius. These markings were also present in dentin. These data suggest that the enamel wear associated with HELIX may not be related to a disruption of enamel microstructure but rather to xerostomia. However, the occurrence of events of strontium variations within dental tissues might indicate repeated episodes of worsening of the renal dysfunction that may require further investigations.
Our study investigates a third molar collected from a HELIX (Hypohidrosis, Electrolyte imbalance, Lacrimal gland dysfunction, Ichthyosis and Xerostomia) female patient, by microanatomical and physicochemical approaches. The enamel morphology, formation time, organization, microstructure and overall elemental composition appear to be within the natural variability. However, accentuated strontium variations are found within the enamel and dentin, with alternating enrichments and depletions following the direction of the periodical striae of Retzius. This suggests that the CLDN10 mutation, responsible for the HELIX syndrome, does not alter enamel formation. The strontium marked events may reflect the renal dysfunction and the resulting ionic imbalance.
In P63‐related ectodermal dysplasias (ED), the clinical characteristics focus on extra‐cutaneous manifestations. The dermatological phenotype remains incompletely characterized. We report the ...dermatological features of 22 patients carrying a TP63 mutation. Erosions, erythroderma and pigmentary anomalies are characteristics of P63‐related ED. Our data suggest that patients might be classified into two major P63‐related disorders: AEC and EEC. RHS and ADULT represent mild AEC and EEC forms, respectively.
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare life-threatening mucocutaneous reactions most often induced by drugs. To date, no large pharmacovigilance study has been ...conducted in the paediatric population.
To describe the spectrum of drugs associated with SJS-TEN in children through the analysis of cases reported in the WHO pharmacovigilance database (VigiBase).
Disproportionality study using data from VigiBase. All paediatric (age under 18 years) cases reported between January 1, 1967, and July 6, 2022, were included. For each molecule, a case-non-case study was performed to assess a potential pharmacovigilance signal by computing the lower end of the 95% credibility interval for the information component (IC
). We performed sensitivity analyses, (i) taking into account only cases reported by physicians and (ii) taking into account only cases reported in the last 10 years.
Among 31,376,783 adverse drug reactions reported in VigiBase, 2,248,727 were paediatric cases and 7342 were encoded as paediatric SJS-TEN. Significant statistical pharmacovigilance signals were observed for 165 drugs. The two most represented drug classes were antiepileptics and anti-infectious drugs. The five drugs with the highest IC
were lamotrigine (IC
4.99), carbamazepine (IC
4.88), phenobarbital (IC
4.67), phenytoin (IC
4.52) and nimesulide (IC
4.23). Acetaminophen was significantly associated with paediatric SJS-TEN (IC
2.85) and we also described various new suspected drugs. Vaccines had no significant pharmacovigilance signal. These results were confirmed with the sensitivity analyses.
This study updates the spectrum of drugs potentially associated with paediatric SJS-TEN.
Palmoplantar plaque psoriasis is a frequent clinical subtype of childhood psoriasis. This study evaluated the effectiveness of biologic therapies in children with palmoplantar plaque psoriasis using ...data from the two Biological treatments for Pediatric Psoriasis (BiPe) cohorts.
Data for all 170 patients included in the BiPe cohorts were analyzed. Data on the effectiveness (PGA, PASI between baseline and 3 months of treatment) of biologic therapies were then compared between children with palmoplantar plaque psoriasis (n = 20) and those with generalized plaque psoriasis (n = 136). Clinical and demographic data were also analyzed.
Children in the palmoplantar group were more likely to be male (p = .04), with an earlier age of psoriasis onset (p < .001), and more frequent nail involvement (p < .001). After 3 months of biologic treatment, mean PGA scores were higher in the palmoplantar group than in the generalized plaque psoriasis group (p = .004). In the palmoplantar group, continuation rates were higher for adalimumab than for etanercept or ustekinumab (p = .01). Primary inefficacy was a more frequent reason for stopping biologic therapies in the palmoplantar group (p = .01), and disease remission was less frequent (p = .05). Combined systemic and biologic therapies were more frequently used in palmoplantar plaque psoriasis (p < .001).
This study demonstrated the treatment-resistant nature of palmoplantar plaque psoriasis and indicated that adalimumab could be the most effective biologic treatment. Larger studies are needed to allow therapeutic algorithms for palmoplantar plaque psoriasis to be proposed in pediatric psoriasis management guidelines.
The PIK3CA‐related overgrowth spectrum (PROS) encompasses various conditions caused by mosaic activating PIK3CA variants. PIK3CA somatic variants are also involved in various cancer types. Some ...generalized overgrowth syndromes are associated with an increased risk of Wilms tumor (WT). In PROS, abdominal ultrasound surveillance has been advocated to detect WT. We aimed to determine the risk of embryonic and other types of tumors in patients with PROS in order to evaluate surveillance relevance. We searched the clinical charts from 267 PROS patients for the diagnosis of cancer, and reviewed the medical literature for the risk of cancer. In our cohort, six patients developed a cancer (2.2%), and Kaplan Meier analyses estimated cumulative probabilities of cancer occurrence at 45 years of age was 5.6% (95% CI = 1.35%–21.8%). The presence of the PIK3CA variant was only confirmed in two out of four tumor samples. In the literature and our cohort, six cases of Wilms tumor/nephrogenic rests (0.12%) and four cases of other cancers have been reported out of 483 proven PIK3CA patients, in particular the p.(His1047Leu/Arg) variant. The risk of WT in PROS being lower than 5%, this is insufficient evidence to recommend routine abdominal imaging. Long‐term follow‐up studies are needed to evaluate the risk of other cancer types, as well as the relationship with the extent of tissue mosaicism and the presence or not of the variant in the tumor samples.
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