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 a pregnancy at increased risk is possible if the HNRNPK pathogenic variant in the family is known.

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).

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 anti-seizure 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].

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.

Treatment of Manifestations

Treatment of the complications associated with AKS are standard and are not currently different from treatment in the general population.

Prevention of Secondary Complications

Anesthesia consultation is suggested prior to any sedation for surgery given potential airway issues from malocclusion and macroglossia. There is also potential risk that prolonged intubation and ventilation will be required, as occurred in one individual after surgery [Au et al 2018].

Surveillance

Evaluation of Relatives at Risk

Asymptomatic family members are not at risk for AKS.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

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.

Mode of Inheritance

Au-Kline syndrome (AKS) is inherited in an autosomal dominant manner and is typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• All probands reported to date with AKS whose parents have undergone molecular genetic testing have the disorder as a result of a de novo HNRNPK pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the HNRNPK pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the pathogenic variant most likely occurred de novo in the proband. Another possible explanation is that the proband inherited a pathogenic variant from a parent with germline mosaicism. Although theoretically possible, no instances of germline mosaicism have been reported to date.
• Theoretically, if the parent is the individual in whom the HNRNPK pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents: if the HNRNPK pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].

Offspring of a proband. Individuals with AKS are not known to reproduce; however, many of the reported probands are not yet of reproductive age.

Other family members. Given that all probands with AKS reported to date have the disorder as a result of a de novo HNRNPK pathogenic variant, the risk to other family members is presumed to be low.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Risk to future pregnancies is presumed to be low as the proband most likely has a de novo HNRNPK pathogenic variant. There is, however, a recurrence risk (~1%) to sibs based on the theoretic possibility of parental germline mosaicism [Rahbari et al 2016]. Given this risk, prenatal testing and preimplantation genetic testing may be considered.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Gene structure. HNRNPK has 17 exons and four alternative splice isoforms [Kimura et al 2010]. The longest transcript spans 3,123 base pairs and encodes the longest isoform. See Table A, Gene for a detailed summary of gene and protein information.

Pathogenic variants. Pathogenic variants associated with Au-Kline syndrome (AKS) are typically loss-of-function variants, which include nonsense, frameshift, and splice variants. Pathogenic variants identified to date have all been de novo. The variant c.257G>A (p.Arg86His) has been identified in two affected individuals. Although predicted to result in a missense change, this variant has been confirmed to be a splice variant, and cell-based functional studies have demonstrated decreased protein production consistent with haploinsufficiency [Au et al 2015]. The variant c.998dupA (p.Tyr333Ter) has now also been identified in two individuals [Dentici et al 2018; Author, personal communication].

Normal gene product. HNRNPK encodes heterogeneous ribonucleoprotein type K (hnRNP K). There are four isoforms reported in the literature. The longest isoform (isoform a) is 464 amino acids. The alternative protein isoforms have an either basic or acidic C terminus consisting of either ⁴⁵⁹SGKFF⁴⁶³ or ⁴⁵⁹ADVEGF⁴⁶⁴, or they differ due to alternative splicing of exon 8, resulting in missing of residues p.Gly111-p.Asn134 [Kimura et al 2010].

HnRNP K is involved with binding single-stranded DNA or RNA, which is mediated through its three KH domains. There are two consecutive KH domains at the N terminus (encoded by exons 4-7 and 9-10) and a third located at the C terminus (encoded by exons 15-16). HnRNP K also acts as a docking platform for interaction of kinases and signal transduction factors that have roles in nucleic acid-related cellular activities, implicating hnRNP K in chromatin remodeling, transcriptional regulation, and translational regulation [Barboro et al 2014].

Abnormal gene product. Deletion of HNRNPK has been associated with the AKS disease phenotype, thus supporting haploinsufficiency as the underlying disease mechanism [Pua et al 2014, Hancarova et al 2015, Au et al 2018]. Most reported pathogenic single-nucleotide variants are expected to lead to nonsense-mediated decay and/or decreased or absent hnRNP K protein. Only one individual with an AKS phenotype with a de novo missense variant in HNRNPK, c.464T>C (p.Leu155Pro), has been reported in the literature [Miyake et al 2017]. It is not clear if this variant leads to reduction or loss of function.

Cancer and Benign Tumors

Somatic pathogenic variants in HNRNPK have been implicated in human myelodysplasia and leukemia, and mice that are haploinsufficient for HNRNPK are at higher risk for tumors [Barboro et al 2014, Gallardo et al 2015]. However, no hematologic abnormalities or malignancies have been identified in individuals with AKS. The oldest reported individual is age 19 years. Utility of screening for myelodysplasia is unknown and therefore no recommendations regarding cancer surveillance can be made.

Author Notes

There is an AKS Facebook group for affected individuals and families.

Acknowledgments

We would like to acknowledge the individuals with AKS and their families. We would also like to acknowledge the Rare Disease Foundation for providing support for phenotype studies.

Revision History

• 18 April 2019 (sw) Review posted live
• 15 October 2018 (pyba) Original submission

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