An Unusual Association: Triple X, 2Q Duplication, and Charge Syndrome

Presenter: V. Comito (e-mail: [e-mail])

Introduction: CHARGE syndrome is a genetic disease caused by mutations in a single gene, the CHD7 gene, located on the long arm of chromosome 8, and inherited in an autosomal dominant manner. Major criteria for the diagnosis of CHARGE syndrome are ocular coloboma, choanal atresia and hypoplasia of semicircular canals. Other minor features, less specific, are hypothalamo-hypophyseal dysfunction, ear malformations, mediastinal organ malformations, mental retardation. Triple X syndrome is associated with an increased risk of learning disabilities and delayed development of speech and language skills.

Materials and Methods: D. E. was born by CS at 38 + 5 weeks of gestation after an uneventful pregnancy and normal ultrasound scans. Due to previous spontaneous abortion of a malformed fetus, amniocentesis was performed and a karyotype of 47 chromosomes “XXX” was found. At birth the baby appeared small for gestational age; her weight and height were below the 3rd centile, her cranial circumference between 10th and 25th centile. She showed several craniofacial dysmorphisms, such as square face with broad prominent forehead, small nose with anteverted nostrils, left epicanthic folds, ocular hypertelorism, micrognathia, bilateral severe malformed ears, hypoplastic helix. Other anomalies were laryngomalacia, velopharyngeal deficiency with swallowing problem, bilateral congenital cataract, presence of eleven ribs and patent ductus arteriosus. The MRI pointed out mild cerebral atrophy with increased fluid spaces and no malformations of inner and middle ears. Baby underwent surgery several times: gastrostomy and tracheostomy were performed to support her vital functions, PDA had to be surgically closed and the bilateral cataract corrected. This baby’s follow-up has been characterized by growth failure, mild neurodevelopmental retardation and visual deficit. The association of cranial dysmorphisms (specifically, the outer ear malformations), ocular and cardiac pathological features led us to the suspicion of CHARGE syndrome. A FISH test was first conducted and resulted negative as no chromosome 8 alterations were evident. On the other hand, on the array-CGH a partial duplication of the long arm of chromosome 2 was found. However, this mutation, “de novo,” had not been associated to a known phenotypical picture so far and could not explain baby’s dysmorphisms. Sanger DNA sequence of the entire CHD7 coding sequence (36 exons) and adjacent exon/intron junctions was also performed with a negative outcome. CHD7 intragenic deletions have been described in a minority (~5%) of bona fide CHARGE individuals; therefore an additional genetic test, namely MLPA, was performed. The MLPA results show the occurrence of an heterozygous de novo deletion of the entire exon 1 of CHD7, finally confirming our clinical suspicion of CHARGE syndrome.

Conclusion: This case report shows that a combination of clinical expertise in genetic syndromes and knowledge of laboratory tests can help in the diagnosis of a genetic disease, especially at birth. A tight collaboration between clinicians and medical laboratory scientists should be always part of the diagnostic process in genetics and neonatology, supporting the resolution of difficult cases.

Keywords: cranial dysmorphisms, charge, genetic laboratory tests