Alazami syndrome

Alazami syndrome in short

• A rare form of primordial dwarfism, frequently associated with microcephaly, characterized by short stature, global developmental delay, varying degrees of intellectual disability, and distinctive facial dysmorphism.
• Common facial features include a triangular-shaped face, prominent forehead, deeply set eyes, low-set ears, broad nose, underdeveloped cheekbones (malar hypoplasia), wide mouth, thick lips, and widely spaced teeth.

Synonyms

• Microcephalic primordial dwarfism
• Alazami type

Prevalence: <1 / 1 000 000

Inheritance: Autosomal recessive

Age of onset: Antenatal, Neonatal

What are the symptoms of Alazami syndrome?

Very frequent symptoms

• Deeply set eye
• Intellectual disability, severe
• Postnatal growth retardation 
• Wide mouth
• Wide nose
• Widely spaced teeth

Frequent symptoms

• Abnormal eating behavior
• Abnormal repetitive mannerisms
• Anxiety
• Cutis marmorata 
• Low-set ears
• Malar flattening
• Mild microcephaly
• Narrow palpebral fissure
• Short palpebral fissure
• Short philtrum 
• Sparse eyebrow
• Thick vermilion border
• Thickened skin 
• Triangular face

Occasional symptoms

• Abnormality of the orbital region
• Atrial septal defect
• Prominent forehead
• Scoliosis
• Seizure
• Self-mutilation
• Sleep abnormality
• Sleep apnea
• Slender long bone
• Stereotypical hand wringing
• Strabismus

Clinical description

Alazami syndrome is a rare genetic developmental disorder characterized by a range of features including mild to severe short stature, head circumference below the 50th percentile, and microcephaly in about half of affected individuals. Global developmental delay is common, typically accompanied by moderate to severe intellectual disability. Speech may be absent or significantly delayed, with expressive language more affected than receptive skills in milder cases.

Short stature and reduced head circumference are usually noticeable at birth and tend to progress with age. Endocrine evaluations are generally normal, though some individuals may show slightly decreased levels of IGF-1.

Distinctive facial features are frequently observed and may include a triangular face, prominent forehead, deep-set eyes (often with narrow palpebral fissures), low-set ears, a broad nose, malar hypoplasia, a wide mouth, thick lips, and widely spaced teeth.

Additional findings may include scoliosis and strabismus in about one-third of cases. Autistic traits and maladaptive behaviors, such as stereotypies resembling hand-washing, are also reported. There is notable inter- and intrafamilial variability in the presentation of features.

Other variable features can include:

• Congenital heart defects (e.g., pulmonary artery stenosis, atrial septal defect)
• Seizures
• Brain anomalies (e.g., agenesis or hypoplasia of the corpus callosum, other MRI abnormalities)
• Advanced bone age

Less commonly reported features are:

• Cleft palate
• Brachydactyly
• Prominent interphalangeal joints
• 2-3 toe syndactyly
• Metaphyseal dysplasia
• Hydronephrosis due to ureteropelvic junction stenosis
• Hypospadias

How common is this condition?

• To date, fewer than 30 affected individuals have been reported worldwide, with approximately half of the cases occurring in a small number of consanguineous families.

What causes Alazami syndrome?

• The syndrome is caused by biallelic loss-of-function variants in the LARP7 gene (located at 4q25), which encodes a protein that plays a role in RNA transcription and splicing regulation.
• Although at least one variant with partial residual protein function has been identified, no clear genotype-phenotype correlation has been established.

How is this condition diagnosed?

• Diagnosis is primarily based on clinical evaluation and can be confirmed through molecular genetic testing, specifically sequencing of the LARP7 gene.
• While chromosomal microarray analysis may also be considered to detect potential large deletions involving LARP7, such deletions have not been reported in affected individuals to date.

Antenatal diagnosis

• Prenatal diagnosis can be offered for at-risk pregnancies if a pathogenic variant has been previously identified in an affected family member.

Differential diagnosis

• Differential diagnosis includes other syndromes characterized by intellectual disability and short stature.

Genetic counseling

• Alazami syndrome is inherited in an autosomal recessive manner, with both homozygous and compound heterozygous variants reported. The condition is more likely to occur in populations with a high rate of consanguinity. Genetic counseling is recommended for at-risk couples who are both carriers of a disease-causing variant, as each pregnancy carries a 25% risk of producing an affected child.

How is this condition treated?

• Management is multidisciplinary and tailored to the individual’s clinical features, with the need for lifelong follow-up.
• Most patients will require varying levels of support for daily living activities. Interventions such as neuropsychiatric care, speech therapy, and educational support can be beneficial in improving function and quality of life.

What is the prognosis?

• Life expectancy for individuals with this condition is currently unknown. Some affected individuals have been reported to survive into early adulthood, and only a limited number of associated clinical features are considered potentially life-threatening.
• A single report has suggested a possible increased risk of tumor development.
• The degree of independence largely depends on the severity of intellectual disability and the extent of language impairment.