Phosphoglucomutase 3 (PGM3) deficiency is a rare congenital disorder of glycosylation. Most of patients with autosomal recessive hypomorphic mutations in
PGM3
encoding for phosphoglucomutase 3 ...present with eczema, skin and lung infections, elevated serum IgE, as well as neurological and skeletal features. A few PGM3-deficient patients suffer from a more severe disease with nearly absent T cells and severe skeletal dysplasia. We performed targeted next-generation sequencing on two kindred to identify the underlying genetic etiology of a severe combined immunodeficiency with developmental defect. We report here two novel homozygous missense variants (p.Gly359Asp and p.Met423Thr) in
PGM3
identified in three patients from two unrelated kindreds with severe combined immunodeficiency, neurological impairment, and skeletal dysplasia. Both variants segregated with the disease in the two families. They were predicted to be deleterious by in silico analysis. PGM3 enzymatic activity was found to be severely impaired in primary fibroblasts and Epstein–Barr virus immortalized B cells from the kindred carrying the p.Met423Thr variant. Our findings support the pathogenicity of these two novel variants in severe PGM3 deficiency.
Patients with Kallmann syndrome (KS) have hypogonadotropic hypogonadism caused by a deficiency of gonadotropin-releasing hormone (GnRH) and a defective sense of smell related to olfactory bulb ...aplasia. Based on the findings in a fetus affected by the X chromosome–linked form of the disease, it has been suggested that hypogonadism in KS results from the failed embryonic migration of neuroendocrine GnRH1 cells from the nasal epithelium to the forebrain. We asked whether this singular observation might extend to other developmental disorders that also include arrhinencephaly. We therefore studied the location of GnRH1 cells in fetuses affected by different arrhinencephalic disorders, specifically X-linked KS, CHARGE syndrome, trisomy 13, and trisomy 18, using immunohistochemistry. Few or no neuroendocrine GnRH1 cells were detected in the preoptic and hypothalamic regions of all arrhinencephalic fetuses, whereas large numbers of these cells were present in control fetuses. In all arrhinencephalic fetuses, many GnRH1 cells were present in the frontonasal region, the first part of their migratory path, as were interrupted olfactory nerve fibers that formed bilateral neuromas. Our findings define a pathological sequence whereby a lack of migration of neuroendocrine GnRH cells stems from the primary embryonic failure of peripheral olfactory structures. This can occur either alone, as in isolated KS, or as part of a pleiotropic disease, such as CHARGE syndrome, trisomy 13, and trisomy 18.
Fetal phenotype associated with the 22q11 deletion Noël, Anne-Claire; Pelluard, Fanny; Delezoide, Anne-Lise ...
American journal of medical genetics. Part A,
11/2014, Volume:
164A, Issue:
11
Journal Article
WHIM syndrome (WS), a rare congenital neutropenia due to mutations of the CXCR4 chemokine receptor, is associated with Human Papillomavirus (HPV)-induced Warts, Hypogammaglobulinemia, bacterial ...Infections and Myelokathexis. The long term follow up of eight patients highlights the clinical heterogeneity of this disease as well as the main therapeutic approaches and remaining challenges in the light of the recent development of new CXCR4 inhibitors.
This study aims to describe the natural history of WS based on a French cohort of 8 patients.
We have reviewed the clinical, biological and immunological features of patients with WS enrolled into the French Severe Chronic Neutropenia Registry.
We identified four pedigrees with WS comprised of eight patients and one foetus. Estimated incidence for WS was of 0.23 per million births. Median age at the last visit was 29 years. Three pedigrees encompassing seven patients and the fetus displayed autosomal dominant heterozygous mutations of the CXCR4 gene, while one patient presented a wild-type CXCR4 gene. Two subjects exhibited congenital conotruncal heart malformations. In addition to neutropenia and myelokathexis, all patients presented deep monocytopenia and lymphopenia. Seven patients presented repeated bacterial Ears Nose Throat as well as severe bacterial infections that were curable with antibiotics. Four patients with late onset prophylaxis developed chronic obstructive pulmonary disease (COPD). Two patients reported atypical mycobacteria infections which in one case may have been responsible for one patient's death due to liver failure at the age of 40.6 years. HPV-related disease manifested in five subjects and progressed as invasive vulvar carcinoma with a fatal course in one patient at the age of 39.5 years. In addition, two patients developed T cell lymphoma skin cancer and basal cell carcinoma at the age of 38 and 65 years.
Continuous prophylactic anti-infective measures, when started in early childhood, seem to effectively prevent further bacterial infections and the consequent development of COPD. Long-term follow up is needed to evaluate the effect of early anti-HPV targeted prophylaxis on the development of skin and genital warts.
Asphyxiating Thoracic Dysplasia (ATD) belongs to the short rib polydactyly group and is characterized by a narrow thorax, short long bones and trident acetabular roof. Other reported features include ...polydactyly, renal, liver and retinal involvement. To date, mutations in IFT80, DYNC2H1, TTC21B and WDR19 have been reported in ATD. The clinical and molecular heterogeneity leads to difficulties in the evaluation of the long-term prognosis.
We investigated 53 ATD cases (23 living cases and 30 fetuses) from 39 families. They benefited from a combined approach of deep phenotyping and IFT80 and DYNC2H1 molecular screening.
Among the 23 postnatal cases, pulmonary insufficiency was noted in 60% of cases, with tracheotomy requirement in five cases. Renal and liver diseases occurred respectively in 17% and 22% of cases, whereas retinal alteration was present in 50% of cases aged more than 5 years. We identified DYNC2H1 mutations in 23 families (59%) and IFT80 mutations in two families (5%). However, in six families, only one heterozygote mutation in either IFT80 or DYNC2H1 was identified. Finally, the two genes were excluded in 14 families (36%).
We conclude that DYNC2H1 is a major gene responsible for ATD, while IFT80 is rarely involved. The presence of only one mutation in six families and the exclusion of the two genes in 14 families support the involvement of other causal cilia genes. The long-term follow up emphasizes that the pulmonary prognosis is probably less pejorative and retinal involvement more frequent than previously thought.
Matthew-Wood, Spear, PDAC or MCOPS9 syndrome are alternative names used to refer to combinations of microphthalmia/anophthalmia, malformative cardiac defects, pulmonary dysgenesis, and diaphragmatic ...hernia. Recently, mutations in STRA6, encoding a membrane receptor for vitamin A-bearing plasma retinol binding protein, have been identified in such patients. We performed STRA6 molecular analysis in three fetuses and one child diagnosed with Matthew-Wood syndrome and in three siblings where two adult living brothers are affected with combinations of clinical anophthalmia, tetralogy of Fallot, and mental retardation. Among these patients, six novel mutations were identified, bringing the current total of known STRA6 mutations to seventeen. We extensively reviewed clinical data pertaining to all twenty-one reported patients with STRA6 mutations (the seven of this report and fourteen described elsewhere) and discuss additional features that may be part of the syndrome. The clinical spectrum associated with STRA6 deficiency is even more variable than initially described.
The molecular mechanisms that orchestrate the development of the human dentate gyrus are not known. In this study, we characterized the formation of human dentate and fimbrial progenitors and ...postmitotic neurons from 9 gestational weeks (GW9) to GW25. PAX6+ progenitor cells remained proliferative until GW16 in the dentate ventricular zone. By GW11, the secondary dentate matrix had developed in the intermediate zone, surrounding the dentate anlage and streaming toward the subpial layer. This secondary matrix contained proliferating PAX6+ and/or TBR2+ progenitors. In parallel, SOX2+ and PAX6+ fimbrial cells were detected approaching the dentate anlage, representing a possible source of extra-dentate progenitors. By GW16, when the granule cell layer could be delineated, a hilar matrix containing PAX6+ and some TBR2+ progenitors had become identifiable. By GW25, when the 2 limbs of the granule cell layer had formed, the secondary dentate matrix was reduced to a pool of progenitors at the fimbrio-dentate junction. Although human dentate development recapitulates key steps previously described in rodents, differences seemed to emerge in neuron layer markers expression. Further studies are necessary to better elucidate their role in dentate formation and connectivity.
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