மூலக்கூறு மற்றும் மரபணு மருத்துவம்

Schaf-Yang Syndrome is a rare genetic condition, produced by a mutation in the MAGEL2 gene, located at the level of chromosome 15, in the Prader-Willi Syndrome region, with which it shares some physical similarity. The phenotype is variable and ranges from fetal akinesia to an important neurobehavioral phenotype and contractures of the small finger joints that are very characteristic. The gene has a maternal imprint and the phenotype will only be expressed when the mutated allele has been transmitted parentally. We present the case of a 2-and-a-half-year-old male from Ecuador, whose most prominent signs were in the beginning a marked macroglossia that gave a certain rough facial appearance, as well as bilateral camptodactyly of the 3rd and 4th fingers. The history of a previous sister who died at age 8 with a diagnosis of hypothyroidism, and clinical similarity to this new baby, led the clinical orientation to the screening of a potentially autosomal recessive condition. The genetic tests performed as part of the differential diagnosis where to pathologies such as Becwith-Wiedeman Syndrome, Mucopolysaccharidosis and Congenital Hypothyroidism. The clinical elements of this case are compared with those described in the literature with this rare genetic syndrome, and the clinical evolution of dysmorphic patterns in young children is emphasized in order to achieve a better diagnostic certainty. We emphasize the features of macroglossia as a probably expanding phenotype in this rare condition. The presentation of this clinical case shows that the factors that alter the segregation of simple mutations such as the case of the genetic imprint, found in this patient, constitute an event that hinders the interpretation of inheritance patterns and should always be taken into account in genetic counseling.

Objectives: Donnai–Barrow syndrome (DBS) or facio oculo acoustic renal (FOAR) syndrome, DBS/FOAR (MIM# 227290) is caused by mutations in the LRP2 gene (MIM# 600073). Disease severity and penetrance vary greatly among patients carrying the same pathogenic variant(s) and single-gene variants often do not reliably predict the disease phenotypes.
Background: The LRP2 gene located on chromosome 2q31.1 band encodes megalin, a multi-ligand endocytic receptor. There are less than 50 cases reported worldwide.
Cases presentation: We report two Ecuadorian sisters born from consanguineous parents carrying a homozygous LRP2 mutation in intron 44 NM_004525.2:c.8452+1G>A. Both individuals, aged 23 and 20 years respectively, presented classical clinical features of the DBS/FOAR including craniofacial dysmorphology, hypertelorism, ocular anomalies, cataracts, high myopia, and sensorineural deafness associated with renal dysfunction (proteinuria, hypercalciuria and hypocitraturia). Both sisters were treated with hearing aids, cochlear implants, corrective lenses, cataracts surgery, vitamin D and potassium citrate supplementation, and renal protection with angiotensin II receptor antagonists.
Conclusion: As far as we know, this is the first family of DBS/FOAR resulting from consanguineous parents with a LRP2 splice site mutation NM_004525.2:c.8452+1G>A, with a complete characterization of the renal phenotype and follow-up.

Preimplantation Genetic Testing (PGT) is a special technique in Assisted Reproduction Field that is applied to avoid a variety of hereditary disorders. This case report presents the first experience with rare X-linked Choroideremia disease (CHM), which leads to total blindness in male members of the family. To achieve a live birth in this case a total of 3 IVF procedures and 3 PGT cycles were performed. The data in our case offer the chance to couples suffering from rare genetic ophthalmo-neurological diseases to have healthy offspring. 

Madame F, 55 years old with a story; four miscarriages and two fetal deaths in utero. At 40 years old, she had a brutal motor deficit in the left lower limb and then in the homolateral upper limb associated with left hemifacialparaesthesia with complete recovery 10 years ago. 

Objective: To examine the association of copy number variants (CNV) among fetuses with ultrasound-detected soft markers (USM). 
Methods: This IRB-approved retrospective cohort study of fetuses with prenatal or children with postnatal chromosomal microarray analysis (CMA) sought to examine an association between clinically relevant CNV (classified as pathogenic CNV or variants of uncertain significance (VUS)) and USM in women who delivered at Geisinger between January 2010 and July 2018. The following USM were evaluated: choroid plexus cyst, thickened nuchal fold, absent or hypoplastic nasal bone, echogenic intracardiac focus, echogenic bowel, short long bones, and urinary tract dilation. Fetuses or children with known aneuploidy or a single gene disorder were excluded. Odds ratios (OR) of the association between CNV and USM were reported along with associated 95% confidence intervals (CI) and p-values. P values <0.05 were considered significant. 
Results: Of the 348 fetuses/children, 89 (25.6%) had a clinically relevant CNV. Similar percentages of demographic, delivery and neonate characteristics were noted for those with a clinically relevant CNV and those with a normal microarray analysis. No statistically significant differences were noted among those fetuses/children with a clinically relevant CNV and structural anomaly (p = 0.52; OR 1.18, 95% CI 0.72-1.92), presence of one USM (p = 0.72; OR 1.52, 95% CI 0.79-2.92), or presence of more than one USM (p = 0.79; OR 1.56, 95% CI 0.28-8.72). 
Conclusion: Our data supports a lack of association between a clinically relevant copy number variant and an ultrasound-detected soft marker. A small statistically insignificant increase in odds of a clinically relevant CNV was noted for those fetuses/children with one or more USM. 

Background: Perlman syndrome is an uncommon genetic disorder grouped with overgrowth syndrome in which an abnormal increase in the size of the body or a body part of the infant often noticed at birth. The disorder, usually affects the kidneys as main findings. Perlman syndrome inherited as an autosomal recessive pattern. People with this condition are generally born with renal abnormalities also called renal hamartomas, nephroblastomatosis also been grouped with Renal cell carcinoma. The characteristic features include polyhydramnios, fetal overgrowth, including macrocephaly, neonatal macrosomia, visceromegaly mainly hepatomegaly and nephromegaly, dysmorphic facial features, and an increased risk for Wilms’ tumor at an early age. The prognosis of Perlman syndrome is poor with high morbidity and mortality rate.
Material and Methods: We report 3 months old female infant from Saudi origin product of consanguineous marriage with prenatal sonographic signs suggestive of Perlman Syndrome specifically polyhydramnios, bilateral nephromegaly with fetal ascites. The clinical course was marked by neonatal respiratory distress, cyanosis and refractory hypoxemia with chylothorax required mechanical ventilation. Frequent hospitalization since that due to frequent attacks of apnea and chest infections.
Discussion and Conclusion: The constellation of clinical presentation and radiological finding confirmed by Molecular investigations showed a homozygous variant c.1810C>T p.(Gln604*) in the DIS3L2 gene (OMIM : 614184 ) which is consistent with Autosomal Recessive Perlman syndrome.

Background: The chromosomal aneuploidy described as Cytogenetic condition characterized by abnormality in numbers of the chromosome. Aneuploid patient either trisomy or monosomy, can occur in both sex chromosomes as well as autosome chromosomes. However, double aneuploidies involving both sex and autosome chromosomes relatively a rare phenomenon. In present study, we reported a double aneuploidy (Down-Klinefelter syndrome) in infant from Saudi Arabia.

Materials and Methods: In the present investigation, chromosomal analysis (standard chromosomal karyotyping) and fluorescence in situ hybridization (FISH) were performed according to the standard protocols.

Results: Here, we report a single affected individual (boy) having Saudi origin, suffering from double chromosomal aneuploidy. The main presenting complaint is the obvious dysmorphic features suggesting Down syndrome. Chromosomal analysis and FISH revealed 48,XXY,+21, show the presence of three copies of chromosome 21, two copies of X chromosome and one copy of Y chromosome chromosomes.

Conclusion: Patients with Down syndrome must be tested for other associated sex chromosome aneuploidies. Hence, proper diagnosis is needed for proper management and the cytogenetic tests should be performed as the first diagnostic approach.

Introduction: Differential diagnosis of polyglobulia/erythrocytosis which is caused by deregulated erythropoiesis with an overproduction of red blood cells resulting in elevated hemoglobin and hematocrit levels is a diagnostic challenge.

Case Report: A 31-year-old man was referred to us with a suspected diagnosis of polycythemia vera (a clonal myeloproliferative neoplasm) because of erythrocytosis. One year before, he suffered from an ischemic central retinal vein occlusion of unknown cause. Aspirin treatment was initiated. His mother was diagnosed with a JAK2V617F negative polycythemia vera years earlier and treated with phlebotomies as well as aspirin. Apart from erythrocytosis, laboratory analysis showed a normal white blood cell and platelet counts. The differential blood picture and lactate dehydrogenase were within the normal ranges. Molecular testing for BCR-ABL, JAK2V617F and Calreticulin gene mutations by PCR was negative. Bone marrow biopsy was normal without signs for a myeloproliferative neoplasm. As almost all patients with polycythemia vera carry the phenotype-driver mutation JAK2V617F, further genetic testing for congenital causes of erythrocytosis was conducted. Mutations in the EPO-receptor gene were not found, but a very rare heterozygous point mutation in the beta-globin-chain [exon 2 (c.119A>C) leading to a change in codon 40 (CAG>CCG)] was detected by next generation sequencing. This rare variant belongs to the high oxygen affinity hemoglobinopathies leading to a reduction of oxygen supply in tissues and an increase in red cell production.

Conclusion: The diagnosis of a JAK2 mutation negative polycythemia vera must always be questioned and congenital causes of erythrocytosis excluded as the therapeutic and prognostic consequences are immense. Rare variants of hemoglobinopathies, particularly those with high oxygen affinity need to be excluded by molecular testing.