15q24 Microdeletion Syndrome

15q24 microdeletion syndrome is a rare chromosomal anomaly characterized cytogenetically by a 1.7-6.1 Mb deletion in chromosome 15q24 and clinically by pre- and post-natal growth retardation, intellectual disability, distinct facial features, and genital, skeletal, and digital anomalies.

Epidemiology

The prevalence of 15q24 deletion syndrome is unknown. To date, 19 cases with clinical data and detailed mapping of genomic breakpoints have been reported.

Clinical description

At birth, approximately 1/3 of patients have low birth weight consistent with intrauterine growth retardation. Feeding difficulties and failure to thrive are reported in about 20%. In later childhood, 30% show growth retardation and short stature and 17% obesity. Growth hormone (GH) deficiency may be present. Growth delay, feeding difficulties, and distinct facial features (long face with high anterior hairline, epicanthal folds, hypertelorism, downslanting palpebral fissures, sparse and broad medial eyebrows, broad and/or depressed nasal bridge, long smooth philtrum, and small mouth with full lower lip) are the most common early presenting symptoms. Most patients (90%) have digital deformities (proximally implanted and/or hypoplastic thumbs, clinodactyly, brachydactyly, overriding toes, toe syndactyly, small hands). Approximately 60% have skeletal complications (joint laxity and scoliosis). Hernias are found as well as hypotonia (60%). Eye abnormalities are common (nystagmus and strabismus). Ear abnormalities are variable but common (large ears, ear lobe pits, anteverted ear lobes, and protuberant ears). Genital abnormalities are common in males (60%). Mild to moderate developmental delay is found in all patients. Behavior abnormalities, such as autism, hyperactivity, aggression, and attention deficit are reported in 37%. Approximately 50% of patients have abnormal brain imaging on magnetic resonance imaging (MRI). Nearly 40% have a history of recurrent infections. Recurrent ear infections may be a predisposing factor to hearing loss (25%). Microcephaly is uncommon (20%). Other congenital malformations, while rare, can be severe and include cardiovascular malformations, congenital diaphragmatic hernia, intestinal atresia, imperforate anus, and myelomeningocele (see these terms).

Etiology

The syndrome is caused by a microdeletion of 1.7 to 6.1 Mb in size in chromosome 15q24 which usually results from nonallelic homologous recombination (NAHR). The smallest region of overlap (SRO) spans a 1.2 Mb region including several candidate genes that may predispose to many of the clinical features: CYP11A1, SEMA7A, CPLX3, ARID3B, STRA6, SIN3A and CSK.

Diagnostic methods

Oligonucleotide array CGH (aCGH) with confirmation by fluorescent in-situ hybridization (FISH) detects most, if not all, deletions of 15q24. Karyotypes are typically normal.

Differential diagnosis

Differential diagnoses include other genetic syndromes, particularly monosomy 22q11, Prader-Willi, and Noonan syndromes (see these terms).

Antenatal diagnosis

Deletion of 15q24 can be detected in amniotic fluid or chorionic villi samples. Since routine karyotyping is not sufficient to detect the deletion, aCGH should be performed.

Genetic counseling

The deletion occurred as a de novo event in all reported patients when parents were available for testing. Parental aCGH and/or FISH studies are recommended to provide accurate genetic counseling.

Management and treatment

Management should be multi-disciplinary with the primary care physician and clinical geneticist playing crucial roles in appropriate screening, surveillance, and care. At the time of diagnosis, baseline echocardiograms, audiologic, ophthalmologic, and developmental assessments are needed. Growth and feeding should be monitored closely.

Prognosis

The prognosis is variable and depends on the severity and extent of congenital malformations.