Alazami Syndrome
A rare form of primordial dwarfism, often microcephalic, characterized by short stature, global developmental delay, variable intellectual disability and recognizable dysmorphic facial features (triangular face, prominent forehead, deeply set eyes, low-set ears, wide nose, malar hypoplasia, wide mouth, thick lips, and widely spaced teeth).
Epidemiology
To date, less than 30 affected individuals reported worldwide, about half of which belong to a few consanguineous families.
Clinical description
Alazami syndrome is a genetic developmental defect characterized by mild to severe short stature, head circumference below the 50th centile, microcephaly in half of the individuals, and global developmental delay with moderate to severe intellectual disability. Speech can be absent or delayed (mainly expressive rather than receptive language delay in milder cases). Short stature and reduced head circumference are progressive, but usually already apparent at birth; endocrinological testing is normal in the majority of examined patients, with only a slight reduction of IGF-1 in some. Most individuals have distinctive facial features: triangular face, prominent forehead, deeply set eyes (often with narrow palpebral fissures), low-set ears, wide nose, malar hypoplasia, wide mouth, thick lips, widely spaced teeth. Scoliosis and strabismus are reported in one third of affected individuals. Several patients display autistic and/or maladaptive behaviors, including stereotypies similar to hand-washing. All features show inter- and intrafamilial variability. Additional, variable features may also include congenital heart defects such as pulmonary artery stenosis or atrial septal defect, seizures, aplasia/hypoplasia of the corpus callosum or other brain MRI anomalies, and accelerated skeletal maturation. Features more rarely reported include cleft palate, brachydactyly, prominent interphalangeal joints, 2-3 toe syndactyly, metaphyseal dysplasia, hydronephrosis due ureteropelvic junction stenosis, and hypospadias.
Etiology
The syndrome is caused by biallelic loss-of-function variants in the LARP7>/i> gene (4q25), which encodes a protein involved in the regulation of RNA transcription and splicing. At least one variant retaining partial protein function has been described, but no specific genotype-phenotype correlation could be established. DIAGNOSTIC METHODS Diagnosis is based on clinical examination and can be confirmed by molecular testing through sequencing. Chromosomal microarrays may also be considered since large deletions encompassing LARP7 cannot be excluded, although none have been reported in affected individuals to date.
Diagnostic methods
Diagnosis is based on clinical examination and can be confirmed by molecular testing through sequencing. Chromosomal microarrays may also be considered since large deletions encompassing LARP7 cannot be excluded, although none have been reported in affected individuals to date.
Differential diagnosis
Differential diagnosis includes other syndromes characterized by intellectual disability and short stature.
Antenatal diagnosis
Prenatal diagnosis is available for at-risk pregnancies, if a pathogenic variant has been identified in a member of the affected family.
Genetic counseling
Alazami syndrome is an autosomal recessive disorder, with homozygous and compound heterozygous variants described. It is expected to have increased frequency in populations where consanguineous couples are frequent. Genetic counseling should be offered to at-risk couples (both carriers of a disease-causing variant) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Management is multidisciplinary, based on the clinical manifestations, with lifelong follow-up. Most patients will require various degrees of assistance with day-to-day activities. Neuropsychiatric assistance, speech therapy and educational support may be effective.
Prognosis
Life expectancy is currently unknown. Affected individuals have been reported to live into early adulthood, and only a few of the known associated clinical features can pose a life-threatening risk. There is only one report indicating a possible increase in tumor susceptibility. The level of autonomy is dependent on the severity of intellectual disability and language delay.