Genetic Mutations: CHROMOSOMAL ABNORMALITIES IN HUMANS

CHROMOSOMAL ABNORMALITIES IN HUMANS

 

Monosomies

• 5p deletion

Definition

Cri du Chat Syndrome (CdCS) is a genetic disease resulting from a deletion of the short arm of chromosome 5 (5p-). Its clinical and cytogenetic aspects were first described by Lejeune et al. in 1963. The most important clinical features are a high-pitched cat-like cry (hence the name of the syndrome), distinct facial dysmorphism, microcephaly and severe psychomotor and mental retardation. The size of the deletion ranges from the entire short arm to the region 5p15. Simmons et al. reported a deletion size ranging from 5 to 40 Mb.

Epidemiology

CdCS is a rare disease with an incidence ranging from 1:15,000 to 1:50,000 live-born infants. Niebuhr found a prevalence of around 1:350 among over 6,000 mentally retarded people, Duarte et al. found a prevalence of 1:305 among 916 patients attending genetic counselling services and analysed cytogenetically.

 

 

 

Clinical Signs and Symptoms in CdCS

• Crying that resembles that of a kitten; high-pitched and mewling
• Hypotonia in infancy (may be severe)
• Impaired vocalization and/or speech development 
• Intellectual disability, mild to severe
• Delayed motor milestones, balance problems, falls, and/or clumsiness
• Rounded face in infancy 
• Elongated face with maturation; may be asymmetric
• Micrognathia 
• Wide-set eyes
• Eyes may be markedly slanted in infancy 
• Epicanthal folds in infancy
• Flattened nasal bridge 
• Tantrums, aggression, and/or self-harming        behaviors (hairpulling, biting, or head-banging)
• Dental/palate abnormalities; high, arched palate and/or dental malocclusions, often anterior open bite
• Prematuryly grey hair
• Low birthweight
• Failure to thrive
• Feeding/swallowing difficulties and constipation
• Deformities of the hands; brachydactyly, syndactyly, clinodactyly, and/or single palmar creases.
• Deformities of the feet; pes varus, or talipes deformities (club foot)
• Ears which are deformed or low-set
• Hyperacusis (sensitivity to sound in particular frequency ranges)

They include congenital heart defects (several types), palate deformities, kidney defects, brainstem abnormalities which may be observed via MRI, hip problems, hypermobile joints or flat feet, sleep disorders, hypogonadism or undescended testicles (in males), hyperactivity, respiratory distress or frequent infections, and abnormal curvatures of the spine.

 

Developmental and behavioural profile

The limited data available about the psychomotor development indicated a severe psychomotor and mental retardation in all patients. Prognosis is better for homereared patients who underwent an early educational program. This test showed the percentile distribution of patients on the basis of the age of achievement of developmental milestones. A specific psychomotor development -chart has been established. Data from the Italian series show that half of the patients walk by themselves at three years old and that all learn to walk later; with regard to the language, 25% of the children are able to make short sentences at 4.5 years old, 50% at 5.5 and almost all the children make short sentences before the age of 10; 50% of the patients feed themselves with a spoon at 3.5 years old and dress at 5. Although these patients have a range of severe developmental retardation, they can achieve many skills in childhood and continue to learn.

Aetiology

The introduction of molecular cytogenetic analysis has allowed the cytogenetic and phenotypic map of 5p to be defined. Analysis of 80 patients and 148 parents from the Italian Registry of CdCS revealed: a 5p terminal deletion (62 patients: 77.5%), an interstitial deletion (seven patients: 8.75%), a de novo translocation (four patients: 5%), a familial translocation (three patients: 3.75%), a mosaic with two rearranged cell lines (three patients: 3.75%) and a deletion originating from a paternal inversion (one patient: 1.25%). The breakpoints range from p13 to p15.2. This region contains a large number of repetitive sequences that may account for its instability.

Diagnostic methods

The diagnosis is first of all clinical, based on typical characteristics such as facial dysmorphisms (facial gestalt), transverse flexion creases, hypotonia in combination with the peculiar cat-like cry. The first test to perform is karyotype analysis, which will confirm the diagnosis. In doubtful cases, when there is a conflict between the clinical suspicion and an apparently normal karyotype result, FISH analysis should be performed recent techniques, such as array CGH and quantitative PCR, mainly used for research purposes, allow a more precise definition of breakpoints and microrearrangements.

Antenatal diagnosis

Prenatal diagnosis by cytogenetic and molecular cytogenetic analyses has been reported in some cases with previous CdCS child, in which the syndrome resulted from a familial balanced translocation.

 

 

 

 

 

Prognosis

After the first years of life, the survival expectation is high and morbidity is low. The mortality in the series studied by Niebuhr was about 10%, 75% of which occurred during the first months of life, and up to 90% within the first year.

 

 

 

Bibliography:

AURORA APARICIO MANRIQUE. (S/f). Mutations. 05/10/15, de biology 2 website: http://ies.rosachacel.colmenarviejo.educa.madrid.org/aurora.pdf

Jose s. ramil. (S/f). Mutations. 12/10/15, de ciencias Sitio web: http://www.tirsoferrol.org/ciencias/pdf/a10_mutacion.pdf

Paola Cerruti Mainardi. (2006). Orphanet Journal of Rare Diseases. BioMed Central, 33, 1-9.

Enrique Gómez Galán. (S / F). Turner syndrome. 23.10.15, Spanish Association of Pediatrics Website: http://www.spao.es/documentos/biblioteca/entrada-biblioteca-fichero-60.pdf

 

Health Secretary. (2007). National Center for Gender Equity and Reproductive Health. 30 / October / 2015, of Children's Rehabilitation Center Telethon, the Group of Birth Studies AC, John Langdon down Foundation, AC Website: http://www.salud.gob.mx/unidades/cdi/documentos/Sindrome_Down_lin_2007.pdf