Monosomy 5p

A rare developmental defect during embryogenesis, resulting from partial or total deletion of the short arm of chromosome 5, classically characterized by a high-pitched, monotone, cat-like cry (cri du chat) present since birth, associated with varying degrees of intellectual disability, developmental delay, microcephaly, and facial dysmorphism.

Epidemiology

Monosomy 5p prevalence at birth ranges from 1/15,000 to 1/45,000, with females being slightly more affected than males.

Clinical description

Newborns typically exhibit low birthweight and microcephaly, as well as asphyxia cyanotic crises, and impaired suction. The disorder shows high phenotypic variability that evolves over time. Craniofacial dysmorphism includes microcephaly, round face, broad nasal bridge, hypertelorism, epicanthic folds, strabismus, downward-slanting palpebral fissures, low-set ears, down-turned corners of mouth, high-arched palate, microretrognathia, and malocclusion. Psychomotor delay and intellectual disability usually become evident in the first year of life and recurrent respiratory and intestinal infections may be observed during infancy. Pre- and postnatal growth delay, with weight more affected than height, is reported. With increasing age, the following features develop: hypotonia changes to hypertonia, face becomes long and narrow and supraorbital arch prominent, dental malocclusions arise, palpebral fissures tend to become horizontal, and premature grey hair appears.

Etiology

The disorder is due to a partial or total deletion of the short arm of chromosome 5, with the critical region located between 5p15.2 and 5p15.3. The deletion size may range from 0.5 to 40 Mb. Deletions may be terminal (most frequent), interstitial, or due to an unbalanced translocation. In approximately 80% of cases, the deletion is a de novo event.

Diagnostic methods

Diagnosis is suspected based on clinical characteristics, in particular the typical cry. Karyotype analysis can confirm the diagnosis. In doubtful cases, when there is conflict between the clinical suspicion and an apparently normal karyotype result, FISH analysis, quantitative PCR and/or CMA should be performed.

Differential diagnosis

Differential diagnosis includes Mowat-Wilson and Wolf-Hirschhorn syndromes, 1p36 monosomy, 17q21 microdeletion, and other chromosomal anomalies.

Antenatal diagnosis

Prenatal diagnosis is possible by ultrasonographic observation of structural abnormalities. Some cases present with cerebellar abnormalities. Chorionic villus sampling or amniocentesis, with karyotype, FISH or CMA analysis may reveal deletion of the critical region on chromosome 5p. However, in some cases, ultrasound can be normal. Noninvasive prenatal testing (NIPT) is currently commercially available in some countries and can be used as a screening method for some microdeletion syndromes, including Cri-du-chat syndrome. In families with an already known translocation involving 5p, preimplantation genetic testing for chromosomal structural rearrangement (PGT-SR) is possible.

Genetic counseling

Genetic counseling, including communication of risk of recurrence, family orientation, and anticipatory supervision for common complications, is possible for cases with a diagnosis of Cri-du-chat syndrome. Parents should be tested in order to rule out a balanced translocation. The recurrence risk for a de novo deletion is negligible.

Management and treatment

No specific treatment exists, however, rehabilitation, initiated early-on, has proven to be beneficial as it seems to improve prognosis and social adaptation. During the neonatal period, physical therapy should be started in the first week of life to help with any difficulty in swallowing and suction. Physical therapy, psychomotricity, and speech therapy are suggested for psychomotor and speech retardation. Patients often have sensorineural deafness; therefore, audiometric examinations should be routinely carried out. Malformations, including congenital heart disease and renal abnormalities, should be rule out as soon as the diagnosis is suspected. Periodic general check-up is recommended, including ENT, ophthalmological and dental assessments.

Prognosis

It is reported a 10% mortality, with 75 - 90% of the cases within the first year of life. The type, size, and location of the deletion greatly influence the severity and prognosis of the disease, with patients with larger deletions typically being more severe. Early diagnosis greatly influences prognosis as early detection allows for the prompt implementation of therapeutic measures, thus improving the outcome of physical and psychomotor development and helping with social adaptation.