Paciente con Síndrome de Cri-Du-Chat y de Beckwith-Wiedemann originado por un derivado de translocación paterna

Abstract

Cri-du-Chat syndrome (CdCS) is one of the most common deletion syndromes (1/15,000-1/50,000 live births) caused by the loss of material from the short arm of chromosome 5 (5p). Although the breakpoints are variable, the CdCS critical region has been shown to be located at 5p15.2 as microdeletions of this region as well as larger deletions of varying sizes, produce the phenotype associated with this syndrome. Patients born with CdCS usually present with microcephaly, round face, hypertelorism, epicanthic folds, micrognathia, large nasal bridge, growth delay, and severe psychomotor retardation. However, the main distinguishing feature of this syndrome is the characteristic cry: a high-pitched, monotonous, cat-like cry. Approximately 80% of patients with CdCS have “de novo” deletions, 10% present with a derivative chromosome from a parental translocation that results in monosomy 5p with trisomy of the other chromosome involved in the rearrangement, and 10% are caused by rarer chromosome alterations, such as inversions. The second disorder of interest, Beckwith-Wiedemann syndrome (BWS), has a frequency of 1 in 13,700 live born children and is the most common of the overgrowth syndromes. It is characterised by macrosomia, hemihyperplasia, macroglossia, abdominal wall defects (omphalocele, umbilical hernia, diastasis recti), earlobe creases, visceromegaly, neonatal hypoglycemia, and a predisposition to embryonal malignancies such as hepatoblastoma, neuroblastoma, rabdomyosarcoma, and Wilms tumour. The etiology of BWS is very complex, involving genetic and epigenetic processes within the p15 region in the short arm of chromosome 11. Up to 60 % of patients with BWS have an epigenetic error in one of the imprinting centers in 11p15 (caused by loss or gain of methylation), approximately 20% have uniparental disomy (UPD), 10% have mutations of the CDKN1C gene, and only 2% of cases have chromosome rearrangements affecting 11p. The majority of these alterations result from the unbalanced segregation of a parental translocation or inversion, and when the disorder is caused by the inheritance of a balanced rearrangement, the alteration is always maternallyderived. To assess the recurrence risk, it is very important to identify the type of mechanism causing the syndrome, although in 10-15% patients the etiology for BWS remains unidentified. In this article, we present a newborn female with a derivative chromosome 5, resulting from a paternal translocation involving chromosomes 5 and 11. This has resulted in the proband having partial monosomy for 5p and partial trisomy for 11p, producing a clinical picture in which the features of both CdCS and BWS are observed. The baby presented with a strange cry, dysmorphics features, (including epicanthic folds, long palpebral fissures, broad nasal bridge with small nose, and microretrognathia), macroglossia, short neck, bell-shaped thorax with widely-spaced, asymmetrical nipples, single-palmar crease on both hands, long feet with malposition of the toes, and interiorly displaced anus. She also showed generalized hypotonia and neonatal persistent hypoglycemia. Although high-resolution G-banded chromosome studies showed an apparently normal, female karyotype, a FISH screening of the subtelomeric regions of all chromosomes showed monosomy for 5p and trisomy for 11p. Further FISH investigation with a probe specific for the CdCS critical region confirmed this locus to be deleted. Parental studies detected the presence of an apparently balanced translocation between chromosomes 5 and 11 in the father. Molecular analysis using microsatelites was carried out showing a deletion of 15.93 Megabases (Mb) on chromosome 5 and a deletion of 10.87 Mb on chromosome 11, both of paternal origin. Although there are six previous published cases that originated from similar paternal translocations, the altered chromosome regions are of different sizes, and the current infant seems to be the first in which the clinical characteristics of both CdCS and BWS are recognized.