Clinical Guidance

Based on the limited number of reported individuals with AKS, it appears that individuals with missense pathogenic variants may have a reduced burden of major organ malformations compared to individuals with loss-of-function pathogenic variants . Additionally, individuals with loss-of-function pathogenic variants (protein truncating or haploinsufficient) are very likely to meet suggested clinical diagnostic criteria, whereas some individuals with missense pathogenic variants may only meet criteria for "possible AKS." This may be due to the fact that all known individuals with loss-of-function pathogenic variants have the recognizable facial gestalt, whereas approximately 70% of individuals with missense pathogenic variants have the recognizable facial gestalt.

Source: GeneReviews — "Au-Kline Syndrome"

Diagnostic Criteria

Clinical diagnostic criteria for Au-Kline syndrome (AKS) have been proposed .

Suggestive Findings

AKS should be suspected in individuals with at least four of the following six characteristic facial features :

• Long palpebral fissures

• Ptosis

• Shallow orbits

• Deeply grooved tongue

• Broad nose with wide nasal bridge and thick alae nasi

• Downturned mouth, often described as an M-shaped Cupid's bow

AND

• Global developmental delay or intellectual disability (defined as a DQ or IQ score below 70)

• Hypotonia

A diagnosis is considered highly likely in an individual with at least five of the six characteristic facial features in addition to global developmental delay/ intellectual disability and hypotonia ; however, molecular genetic testing is still recommended. Further supportive features may include:

Source: GeneReviews — "Au-Kline Syndrome"

Differential Diagnosis

Table 3.

Disorders to Consider in the Differential Diagnosis of Au-Kline Syndrome

Gene(s) | Disorder | MOI | Clinical Features of Disorder

Overlapping w/AKS | Distinguishing from AKS

KDM6A

KMT2D

| Kabuki syndrome | ADXL1 | • Postnatal growth deficiency

• Congenital heart defects

• Genitourinary anomalies

• Elongated palpebral fissures, large, prominent ears, cleft palate, dental anomalies

• ID (mild to moderate)

• Skeletal anomalies

| • Arched broad eyebrows; short columella w/depressed nasal tip2

• Cleft lip or lip pits

• Immunodeficiency

• Craniosynostosis is rare.

BRAF

KRAS

LZTR1

MAP2K1

Management Guidelines

No clinical practice guidelines for Au-Kline syndrome (AKS) have been published.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with AKS, the evaluations summarized (if not performed as part of the evaluation that led to diagnosis) are recommended.

Table 4.

Au-Kline Syndrome: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Constitutional

| Measure weight, length/height, head circumference. | To assess for growth restriction microcephaly

Development

| Developmental assessment | • To incl motor, adaptive, cognitive, speech-language eval

• Eval for early intervention/ special education

Neurobehavioral/

Psychiatric

| Neuropsychiatric eval | For persons age 12 mos: screening for concerns incl ADHD, anxiety, /or findings suggestive of ASD

Neurologic

| Neurologic eval to incl assessment for seizures dysautonomia | • Brain MRI could be considered if neurologic symptoms (e.g., seizure) are present.

• Consider EEG if seizures are a concern.

• Consider referral to neurologist.

Craniofacial

| In infants, evaluate for craniosynostosis w/clinical exam imaging as needed. | Referral to neurosurgeon if craniosynostosis is suspected

ENT eval | To identify palate anomalies malocclusion

Cardiovascular

| Cardiac eval w/echocardiography | To evaluate for structural defects, dilatation of aorta, cardiomyopathy

Genitourinary

| Renal ultrasound | To evaluate for hydronephrosis

Source: GeneReviews — "Au-Kline Syndrome"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Au-Kline Syndrome"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended. Table 6. Au-Kline Syndrome: Recommended Surveillance

Source: GeneReviews — "Au-Kline Syndrome"