Ichthyosis follicularis, alopecia, and photophobia (IFAP) syndrome

The IFAP syndrome is a rare X-linked genetic disorder reported in nearly 40 patients. It is characterized by the triad of Ichthyosis Follicularis, Alopecia, and Photophobia from birth. Other features such as short stature, intellectual disability, and seizures may develop in the first few years of life. Skin histopathology is non-specific and consists of dilated hair follicles with keratin plugs extending above the surface of the skin, decreased or absent sebaceous glands, and decreased desmosomes in number and size. The disorder results from mutations in the MBTPS2 gene that impairs cholesterol homeostasis and the ability to cope with endoplasmic reticulum stress. Follicular hyperkeratosis can be treated using topical keratolytics, emollients and urea preparations. A moderate response to acitretin therapy has been noted in some patients. Intensive lubrication of the ocular surface is essential. Life expectancy in patients with IFAP syndrome can vary from death in the neonatal period to normal surviving. Cardiopulmonary complications remain the major cause of death

An Autosomal-Recessive Form of Cutis Laxa Is Due to Homozygous Elastin Mutations, and the Phenotype May Be Modified by a Heterozygous Fibulin 5 Polymorphism

Cutis laxa (CL) is a heterogeneous group of connective tissue disorders characterized by loose, sagging skin and variable involvement of other organs. Autosomal-dominant forms are relatively mild, and may be caused by mutations in the elastin gene, whereas the more severe recessive forms have been associated with mutations in the fibulin 4 and fibulin 5 genes, as well as in a vesicular ATPase subunit. We describe here a previously unreported autosomal-recessive form of CL caused by homozygous recessive mutations in exon 12 of the elastin gene (p.P211S) in three patients from two related consanguineous Syrian families. Furthermore, we found that the presence of a polymorphism in the fibulin 5 gene in one of the patients seems to modify the phenotype, producing more severe symptoms. This polymorphism (p.L301M) was associated with mild symptoms in the mother of the patient, who was heterozygous for both the elastin and fibulin 5 mutations. To our knowledge, autosomal-recessive CL owing to homozygous mutations in the elastin gene has not been reported previously

Heterochromatic Genes Undergo Epigenetic Changes and Escape Silencing in Immunodeficiency, Centromeric Instability, Facial Anomalies (ICF) Syndrome

Immunodeficiency, Centromeric Instability, Facial Anomalies (ICF) syndrome is a rare autosomal recessive disorder that is characterized by a marked immunodeficiency, severe hypomethylation of the classical satellites 2 and 3 associated with disruption of constitutive heterochromatin, and facial anomalies. Sixty percent of ICF patients have mutations in the DNMT3B (DNA methyltransferase 3B) gene, encoding a de novo DNA methyltransferase

Amyloidosis in familial Mediterranean fever patients: correlation with MEFV genotype and SAA1 and MICA polymorphisms effects

BACKGROUND: Familial mediterranean fever (FMF) is a recessively inherited disease characterized by recurrent crises of fever, abdominal, articular and/or thoracic pain. The most severe complication is the development of renal amyloidosis. Over 35 mutations have been discovered so far in the gene responsible for the disease, MEFV. This article aims at determining a correlation between the MEFV genotype and the occurence of amyloidosis in FMF patients, in addition to the study of the modifying effects of the SAA1 (type 1 serum amyloid A protein) and MICA (Major Histocompatibility Complex (MHC) class-I-chain-related gene A) genes on this severe complication. METHODS: Fourteen MEFV mutations were screened and the SAA1 and MICA polymorphisms tested in 30 FMF patients with amyloidosis and 40 FMF patients without amyloidosis. RESULTS: The M694V and V726A allelic frequencies were, respectively, significantly higher and lower in the group with amyloidosis, compared to the control FMF group. The beta and gamma SAA1 alleles were more frequently encountered in the group without amyloidosis, whereas the alpha allele was significantly more observed in FMF patients with amyloidosis (p < 0.025). All the MICA alleles were encountered in both patients' groups, but none of them was significantly associated with amyloidosis. CONCLUSIONS: The results suggest a protective effect of the SAA1 beta and gamma alleles on the development of amyloidosis and show the absence of a MICA modifying effect on amyloidosis development. Testing these polymorphisms on a larger sample will lead to more definite conclusions

Germline genes hypomethylation and expression define a molecular signature in peripheral blood of ICF patients: implications for diagnosis and etiology.

International audienceBACKGROUND: Immunodeficiency Centromeric Instability and Facial anomalies (ICF) is a rare autosomal recessive disease characterized by reduction in serum immunoglobulins with severe recurrent infections, facial dysmorphism, and more variable symptoms including mental retardation. ICF is directly related to a genomic methylation defect that mainly affects juxtacentromeric heterochromatin regions of certain chromosomes, leading to chromosomal rearrangements that constitute a hallmark of this syndrome upon cytogenetic testing. Mutations in the de novo DNA methyltransferase DNMT3B, the protein ZBTB24 of unknown function, or loci that remain to be identified, lie at its origin. Despite unifying features, common or distinguishing molecular signatures are still missing for this disease. METHOD: We used the molecular signature that we identified in a mouse model for ICF1 to establish transcriptional biomarkers to facilitate diagnosis and understanding of etiology of the disease. We assayed the expression and methylation status of a set of genes whose expression is normally restricted to germ cells, directly in whole blood samples and epithelial cells of ICF patients. RESULTS: We report that DNA hypomethylation and expression of MAEL and SYCE1 represent robust biomarkers, easily testable directly from uncultured cells to diagnose the most prevalent sub-type of the syndrome. In addition, we identified the first unifying molecular signatures for ICF patients. Of importance, we validated the use of our biomarkers to diagnose a baby born to a family with a sick child. Finally, our analysis revealed unsuspected complex molecular signatures in two ICF patients suggestive of a novel genetic etiology for the disease. CONCLUSIONS: Early diagnosis of ICF syndrome is crucial since early immunoglobulin supplementation can improve the course of disease. However, ICF is probably underdiagnosed, especially in patients that present with incomplete phenotype or born to families with no affected relatives. The specific and robust biomarkers identified in this study could be introduced into routine clinical immunology or neurology departments to facilitate testing of patients with suspected ICF syndrome. In addition, as exemplified by two patients with a combination of molecular defects never described before, our data support the search for new types of mutations at the origin of ICF syndrome

Eisenstein Congruences for SO(4, 3), SO(4, 4), Spinor, and Triple Product L-values

We work out instances of a general conjecture on congruences between Hecke eigenvalues of induced and cuspidal automorphic representations of a reductive group, modulo divisors of certain critical L-values, in the case that the group is a split orthogonal group. We provide some numerical evidence in the case that the group is SO(4, 3) and the L-function is the spinor L-function of a genus 2, vector-valued, Siegel cusp form. We also consider the case that the group is SO(4, 4) and the L-function is a triple product L-function

“Fork and bracket” syndrome expands the spectrum of SBF1-related sensory motor polyneuropathies

Charcot-Marie-Tooth neuropathy type 4 (CMT4) comprises a large group of genetically heterogeneous progressive sensory motor neuropathies characterized by autosomal recessive inheritance. Among these, CMT4B includes 3 forms related to genes of the myotubularin family, namely CMT4B1 (MTMR2), CMT4B2 (MTMR13/SBF2), and CMT4B3 (MTMR5/SBF1)