Au-Kline Syndrome
Summary
Clinical characteristics.
Au-Kline syndrome is characterized by developmental delay and hypotonia with moderate-to-severe intellectual disability, and typical facial features that include long palpebral fissures, ptosis, shallow orbits, large and deeply grooved tongue, broad nose with a wide nasal bridge, and downturned mouth. There is frequently variable autonomic dysfunction (gastrointestinal dysmotility, high pain threshold, heat intolerance, recurrent fevers, abnormal sweating). Congenital heart disease, hydronephrosis, palate abnormalities, and oligodontia are also reported in the majority of affected individuals. Additional complications can include craniosynostosis, feeding difficulty, vision issues, osteopenia, and other skeletal anomalies.
Diagnosis/testing.
The diagnosis of Au-Kline syndrome is established in a proband by identification of a heterozygous pathogenic variant in HNRNPK on molecular genetic testing.
Management.
Treatment of manifestations: Physiotherapy support may be helpful for hypotonia; dysautonomia management per neurologist; standard treatment for congenital heart defects; cleft palate treatment per craniofacial specialists; early intervention, individualized education, and therapies for developmental delay; psychiatry referral for those with behavior issues; nasogastric or gastric-tube feeding as needed for significant feeding issues; treatment of hearing loss with hearing aids if necessary; standard treatment for refractive errors and keratopathy; standard dental and/or orthodontic care as needed; orthopedics referral for scoliosis as needed for bracing or surgical intervention; standard management for hypothyroidism; bisphosphonate treatment could be considered for recurrent fractures.
Prevention of secondary complications: Anesthesia consultation is suggested prior to any sedation for surgery given potential airway issues from malocclusion and macroglossia and risk for prolonged intubation and ventilation.
Surveillance: Screen for craniosynostosis in infants at each health visit during the first few months of life; at all health visits and at least annually review developmental milestones and screen for seizure history, symptoms of dysautonomia, behavior concerns, and scoliosis; annual audiologic evaluation; echocardiography to monitor for aortic dilatation with frequency as per cardiologist; ophthalmologic evaluation with frequency as per ophthalmologist; periodic TSH and bone densitometry as needed.
Genetic counseling.
Au-Kline syndrome is inherited in an autosomal dominant manner. All probands reported to date with Au-Kline syndrome have the disorder as a result of a de novo HNRNPK pathogenic variant. Each child of an individual with Au-Kline syndrome has a 50% chance of inheriting the HNRNPK pathogenic variant. Prenatal testing for pregnancies at increased risk is possible if the HNRNPK pathogenic variant in the family is known.
Diagnosis
Formal diagnostic criteria for Au-Kline syndrome (AKS) have not been established.
Suggestive Findings
AKS should be suspected in individuals with the following clinical and imaging findings.
Clinical findings
- Characteristic facial features [Au et al 2015, Au et al 2018] (see Figure 1):
- Long palpebral fissures
- Ptosis
- Shallow orbits
- Deeply grooved tongue
- Broad nose with wide nasal bridge
- Downturned mouth, often described as an "M-shaped" Cupid's bow
- Craniosynostosis; typically sagittal and metopic sutures are affected. Metopic ridging is common.
- Palate abnormalities (e.g., cleft palate, high-arched palate, bifid uvula)
- Congenital heart malformations (e.g., ventricular septal defect, atrial septal defect, bicuspid aortic valve, and more complex malformations)
- Genitourinary anomalies (e.g., hydronephrosis, undescended testes)
- Skeletal anomalies (e.g., vertebral segmentation defects, scoliosis, congenital hip dysplasia)
Figure 1.
Three individuals with Au-Kline syndrome A-C. Proband 1 at age 14 months, age 8 years, and age 19 years. Note long palpebral fissures, prominent eyes and shallow orbits, broad nasal ridge, and "M-shaped" Cupid's bow to upper lip. D. High-arched palate (more...)
Imaging findings
- Brain MRI. Individuals with AKS can have variable brain anomalies identified on MRI. More common findings include gray matter heterotopia and hypoplasia of the corpus callosum [Lange et al 2016, Au et al 2018].
- Radiographs of the spine may show vertebral segmentation defects [Au et al 2015, Au et al 2018].
- Spine MRI. Spinal syrinx may be identified, especially if scoliosis is present.
Establishing the Diagnosis
The diagnosis of Au-Kline syndrome is established in a proband by identification of a heterozygous pathogenic variant in HNRNPK on molecular genetic testing (see Table 1).
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing, exome array) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Au-Kline syndrome is often recognizable, individuals with the distinctive findings described in Suggestive Findings may be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of Au-Kline syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of Au-Kline syndrome, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.
- Single-gene testing. Sequence analysis of HNRNPK detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.Note: Given the rarity of Au-Kline disorder, single-gene testing for HNRNPK may not be clinically available. A custom multigene panel or comprehensive genomic testing, or reanalysis of previous genomic testing data may be required for HNRNPK analysis.
- A multigene panel that includes HNRNPK and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of Au-Kline syndrome, some panels for intellectual disability may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the diagnosis of Au-Kline syndrome is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible.
Exome array (when clinically available) may be considered if exome sequencing is not diagnostic.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Au-Kline Syndrome
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| HNRNPK | Sequence analysis 3 | 16/17 4 |
| Gene-targeted deletion/duplication analysis 5 | 1/17 6 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Au et al [2015]; Lange et al [2016]; Miyake et al [2017]; Au et al [2018]; Dentici et al [2018]; Author, personal communication
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by Pua et al [2014], Hancarova et al [2015], and Au et al [2018]) may not be detected by these methods.
- 6.
Au et al [2018]
Clinical Characteristics
Clinical Description
Au-Kline syndrome, a recently described syndrome affecting multiple organ systems, is associated with moderate-to-severe intellectual disability. This section summarizes information from 20 individuals with Au-Kline syndrome (AKS), including published and unpublished reports [Au et al 2015; Lange et al 2016; Au et al 2018; Dentici et al 2018; Author, personal communication].
Growth. Most neonates with AKS have normal growth parameters. Approximately 50% of individuals demonstrate growth deficiency over time, affecting both height and weight. Age of onset of growth restriction has been variable. One third of individuals have microcephaly, and some may acquire microcephaly, which is usually noted by early childhood. Overgrowth has been observed in only two individuals [Au et al 2018].
Neurologic. Hypotonia has been reported in all known individuals with AKS. Reflexes are typically reduced or absent. Some individuals describe muscle weakness and/or easy fatigability. Muscle biopsy may be abnormal and has not been pursued in most individuals. Histologic findings have not been consistent, and have included type 1 fiber atrophy and mitochondrial complex 1 deficiency. Brain anomalies have been identified in several individuals. The most common abnormalities were heterotopia and thinning of the corpus callosum. Seizures have been reported in three individuals; absence seizures were reported in one individual and partial complex epilepsy in another. Seizures were controlled with antiepileptic medication in both individuals. The third individual had seizures that resolved. Several individuals have been diagnosed with autonomic dysfunction, presenting with gastrointestinal dysmotility, high pain threshold, heat intolerance, recurrent fevers, and abnormal sweating.
Cardiovascular. Congenital heart disease is present in approximately 75% of individuals with AKS. Ventricular septal defects are the most common anomaly. Complex congenital heart defects are rarely reported. Aortic dilatation has been identified in three individuals; the natural history of aortic dilatation in AKS is unclear.
Genitourinary. Hydronephrosis is present in up to 75% of individuals with AKS. It is often identified prenatally and typically associated with vesicoureteral reflux disease or obstructive uropathy. It can sometimes be severe, as in one individual who was affected with prune belly sequence [Au et al 2018].
Craniofacial. Craniosynostosis is present in approximately one third of individuals with AKS. Sagittal and metopic sutures are typically affected, and many individuals have metopic ridging without obvious or confirmed synostosis. Early detection and intervention for craniosynostosis may help with neurocognitive outcomes [Renier et al 1996], but this is unclear for AKS specifically. Approximately half of individuals with craniosynostosis have required surgical intervention.
Palate abnormalities, which include cleft palate, high-arched or narrow palate, and bifid uvula, are common.
There is a typical facial gestalt in AKS (see Figure 1). The face is often long. Orbits are often shallow. Palpebral fissures are long in almost 100% of individuals. There can be lateral lid eversion similar to Kabuki syndrome, but typically lid eversion is more subtle. Ptosis is common and can be asymmetric. Ears can be protruding, with a simplified helix. Preauricular pits are common. The nose often has a characteristic shape with broad nasal bridge and tip, and occasionally hypoplastic alae nasi. The mouth is frequently downturned and held in open position. The upper lip is often described as an "M-shaped" Cupid's bow [Dentici et al 2018]. Many individuals have a deep midline groove in the tongue, and bifid tip to the tongue has also been described. Many individuals also have macroglossia. Facial features may appear coarse.
Development. Individuals with loss-of-function HNRNPK variants typically have moderate-to-severe intellectual disability. More detailed developmental information is available for eight older individuals who were evaluated from age eight years to young adulthood. Independent ambulation was achieved by 5/8 individuals, although some still required assistive devices for longer distances. Seven individuals were able to communicate verbally, typically with single words. Four individuals were able to use phrases. Most older children and adults were able to use signs (up to several hundred) and devices to supplement their communication [Au et al 2018]. For example, of five individuals older than age eight years, one was able to speak in phrases and the others all had single words. 4/5 used signs, 5/5 used communication devices. Autism appeared to be rare. The neurodevelopmental outcomes for individuals with missense HNRNPK variants are not yet clear due to the limited number of individuals reported [Miyake et al 2017].
Gastrointestinal complications and feeding. Most newborns are able to feed normally. Some individuals struggle with feeding difficulty and may require short- or long-term support with tube feeding. These issues may be associated with bowel dysmotility (e.g., delayed gastric emptying, recurrent vomiting, pseudoobstruction). Constipation is common, and can be mild or severe.
Hearing. Hearing loss is present in approximately one third of individuals. Conductive hearing loss may be due to chronic middle ear effusion, but sensorineural hearing loss also occurs (described in 3 individuals).
Ophthalmologic. Myopia and hyperopia have both been reported in individuals with AKS. Optic nerve anomalies have been identified in several individuals, which may include hypoplasia of the optic nerve or the presence of a coloboma. There is theoretic risk for exposure keratopathy in individuals with particularly shallow orbits and long palpebral fissures, but it has not been observed in individuals with AKS.
Dental. The majority of individuals appear to have malocclusion, and some individuals have an open bite. Oligodontia is common. Bruxism is frequently observed.
Skeletal. More than half of individuals with AKS have scoliosis, which can range from mild to severe and require surgical intervention. Vertebral segmentation anomalies are present in some individuals and are more likely to be associated with severe scoliosis. Congenital hip dysplasia is observed in more than half of individuals with AKS. Talipes equinovarus and pes planus are also common. Some individuals have joint hypermobility.
Endocrine. Osteopenia has been identified in several individuals; fractures have been seen in two individuals with AKS. Hypothyroidism is also present in several individuals.
Respiratory. Most individuals with AKS have had normal sleep studies. One individual was found to hypoventilate at night and requires BiPAP.
Other. Postaxial polydactyly, branchial defects, inverted nipples, and supernumerary nipples have also been identified in individuals with AKS.
Genotype-Phenotype Correlations
At this time there are no clear genotype-phenotype correlations.
Penetrance
There is complete penetrance for AKS for loss-of-function variants in HNRNPK. No sex- or age-related differences have been observed. There is insufficient information regarding penetrance of missense variants in HNRNPK.
Prevalence
Prevalence is currently unknown. AKS is a rare disorder, only recently described in 2015. At this time the authors are aware of at least 25 affected individuals worldwide, with 12 individuals reported in the literature [Au et al 2015, Lange et al 2016, Miyake et al 2017, Au et al 2018, Dentici et al 2018].
Differential Diagnosis
Table 2.
Disorders to Consider in the Differential Diagnosis of Au-Kline Syndrome (AKS)
| Disorder | Gene(s) | MOI | Clinical Features of Differential Diagnosis Disorder | |
|---|---|---|---|---|
| Overlapping w/AKS | Distinguishing from AKS | |||
| Kabuki syndrome | KDM6A KMT2D | AD |
|
|
| Shprintzen-Goldberg syndrome | SKI | AD |
|
|
| Noonan syndrome | PTPN11 SOS1 RAF1 RIT1 KRAS BRAF MAP2K1 3 | AD |
|
|
| Simpson-Golabi-Behmel syndrome type 1 | GPC3 GPC4 | XL |
|
|
AD = autosomal dominant; CHD = congenital heart defect; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked
- 1.
Shallow orbits, coarse features, broad nasal ridge, open downturned mouth with macroglossia, and a deeply grooved tongue would be more suggestive of AKS.
- 2.
See Clinical Description, Craniofacial.
- 3.
Several additional genes associated with a Noonan syndrome-like phenotype in fewer than ten individuals have been identified.
- 4.
Individuals with AKS caused by loss-of-function HNRNPK variants typically have moderate-to-severe intellectual disability.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Au-Kline syndrome (AKS), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with Au-Kline Syndrome
| System/Concern | Evaluation | Comment |
|---|---|---|
| Constitutional | Evaluate growth. | |
| Neurologic | Brain MRI could be considered at time of diagnosis if neurologic symptoms (e.g., seizure); assessment for seizures & dysautonomia | Referral to neurologist as needed |
| Cardiovascular | Cardiac evaluation w/echocardiography | To evaluate for structural defects & dilatation of aorta |
| Genitourinary | Renal US; voiding cystourethrogram if needed | To evaluate for vesicoureteral reflux & obstructive uropathy |
| Craniofacial | In infants, evaluate for craniosynostosis w/clinical exam & imaging as needed. | Referral to neurosurgeon if craniosynostosis is suspected |
| ENT evaluation | To identify palate anomalies & malocclusion | |
| Neurodevelopmental/ Neuropsychiatric | Neuropsychiatric evaluation & assessment of developmental milestones |
|
| Gastrointestinal/ Feeding | Clinical evaluation of feeding | If there are feeding concerns or failure to thrive, consider GI referral & workup for dysmotility. |
| Hearing | Audiologic evaluation | To identify middle ear effusion & sensorineural hearing loss |
| Ophthalmologic | Ophthalmologic evaluation | To identify vision concerns & evaluate for keratopathy |
| Dental | Evaluation for malocclusion, oligodontia, & bruxism | |
| Musculoskeletal |
| Referral to orthopedist for congenital hip dysplasia or moderate-to-severe scoliosis |
| Endocrine | Monitor TSH. | To evaluate for hypothyroidism |
| Bone densitometry | If fractures are reported | |
| Respiratory | Polysomnogram | If concerns for sleep apnea |
| Other | Consultation w/clinical geneticist &/or genetic counselor |
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; ENT = ear, nose, and throat; TSH = thyroid-stimulating hormone; US = ultrasound
Treatment of Manifestations
Treatment of the complications associated with AKS are standard and are not currently different from treatment in the general population.
Table 4.
Treatment of Manifestations in Individuals with Au-Kline Syndrome
| Manifestation/ Concern | Treatment | Considerations/ Other |
|---|---|---|
| Hypotonia | Physiotherapy support may be helpful. | In individuals w/weakness & fatigue: anecdotal reports of benefit from creatine supplementation or mitochondrial vitamin cocktails incl coenzyme Q & carnitine; there is currently no published evidence to support these therapies. |
| Dysautonomia | Referral to neurologist w/experience in management of autonomic dysfunction | Offer strategies for managing heat intolerance & abnormal sweating. |
| Congenital heart defects | Standard treatment as per cardiologist | |
| Hydronephrosis | Referral to pediatric nephrologist & urologist for assessment of renal function & appropriate surgical repair | |
| Craniosynostosis | Referral to neurosurgeon for appropriate surgical intervention | |
| Cleft palate | Treatment by craniofacial team | |
| Developmental delay |
| |
| Behavior concerns | Formal evaluation w/psychiatrist | May be beneficial for children who exhibit more behavioral struggles |
| Feeding difficulties | Nasogastric or gastric-tube feeding may be necessary for significant feeding issues. | |
| Hearing loss | Treatment of SNHL & conductive hearing loss per ENT physician / audiologist; hearing aids if necessary | |
| Vision anomalies | Standard treatment for refractive errors & keratopathy | |
| Dental complications | Standard treatment per dentist &/or orthodontist | |
| Scoliosis | If scoliosis is progressive, referral to orthopedist for bracing or surgical intervention w/instrumentation may be required. | It is unclear at present whether certain interventions are more effective or beneficial for progressive scoliosis. |
| Hypothyroidism | Standard management for hypothyroidism |