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. Congenital heart disease, hydronephrosis, palate abnormalities, and oligodontia are reported in the majority of affected individuals. Variable autonomic dysfunction (gastrointestinal dysmotility, high pain threshold, heat intolerance, recurrent fevers, abnormal sweating) is found in more than one third of affected individuals. Additional complications can include craniosynostosis, feeding difficulty, vision issues, hearing loss, osteopenia, and other skeletal anomalies. Epilepsy and brain malformations are rare.

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: Physical therapy may be helpful for hypotonia. Feeding therapy for poor weight gain; gastrostomy tube placement may be required for persistent feeding issues. Referral to neurologist with experience in management of autonomic dysfunction. Bisphosphonate treatment could be considered for those with osteopenia who experience recurrent fractures. Standard treatment for developmental delay / intellectual disability, behavior concerns, epilepsy, craniosynostosis, palatal anomalies, congenital heart defects / aortic dilatation / cardiomyopathy, hydronephrosis, cryptorchidism, bowel dysfunction, skeletal anomalies, refractive errors, keratopathy, hearing loss, malocclusion / open bite, oligodontia, hypothyroidism, hypoventilation, and obstructive sleep apnea.

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.

Surveillance: At each visit, measure growth parameters and evaluate nutritional status; monitor developmental progress and educational needs; assess for neurobehavioral/psychiatric manifestations; monitor those with seizures; assess for signs and symptoms of sleep apnea. At all health visits in the first few months of life, screen for craniosynostosis. At all health visits and at least annually, assess for new manifestations, such as seizures or dysautonomia; clinical examination for scoliosis. At least every 6 months, dental and/or orthodontic evaluation. Annually, TSH and free T₄. Annually or as clinically indicated, audiology evaluation. The frequency of echocardiogram and assessment for cardiomyopathy should be determined by a cardiologist. The frequency of ophthalmology evaluations should be determined by an ophthalmologist. Consideration of bone densitometry is based on the severity of osteopenia and history of fractures.

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 at least four of the following six characteristic facial features (see Figure 1):

Figure 1.

Three individuals with Au-Kline syndrome A-C. Proband 1 at age 14 months, age eight 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.

• 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 [Au et al 2015, Au et al 2018, Choufani et al 2022]; however, molecular genetic testing (see Establishing the Diagnosis) is still recommended.

Further supportive features may include:

• 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)

Establishing the Diagnosis

The diagnosis of AKS is established in a proband by identification of a heterozygous pathogenic (or likely pathogenic) variant in HNRNPK on molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis, although a distinctive epigenetic signature of Au-Kline syndrome has been identified (see Epigenetic signature analysis / methylation array).

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

To date, at least 75 individuals have been identified with a pathogenic variant in HNRNPK [Au et al 2015, Lange et al 2016, Au et al 2018, Dentici et al 2018, Choufani et al 2022]. The following description of the phenotypic features associated with this condition is based on these reports.

Developmental delay (DD) and intellectual disability (ID). All affected individuals to date have been found to have developmental delay and/or intellectual disability. However, the degree of delay can be variable. Individuals with loss-of-function HNRNPK pathogenic variants typically have moderate-to-severe intellectual disability, whereas developmental outcome in those with missense pathogenic variants may be better [Au et al 2018; Choufani et al 2022; Authors, personal communication]. Autism spectrum disorder appears to be rare.

• In a group of older individuals with loss-of-function pathogenic variants (ranging in age from eight years to young adulthood), independent ambulation was achieved by 5/11 individuals, although some still required assistive devices for longer distances.
  Nine out of 12 individuals used verbal communication, with 6/12 using mostly single words and 3/12 using phrases to communicate.
  Eight out of 11 individuals were able to use sign language or communication devices to supplement their communication.
• In nine older individuals with missense pathogenic variants, 8/9 were able to walk independently, with 6/9 achieving this skill before age three years. Six out of eight individuals in this group were able to speak in phrases.
• Many older children and adults are also able to use signs (sometimes up to several hundred) and devices to supplement their communication.

Neurobehavioral/psychiatric manifestations. In individuals where information was available, autism spectrum disorder was reported in 2/13, attention-deficit/hyperactivity disorder in 2/14, anxiety in 2/14, obsessive-compulsive disorder in 1/14, and issues with impulse control in 1/14.

Other neurologic features

• Hypotonia has been reported in all known individuals with Au-Kline syndrome (AKS) and often persists into adulthood.

• Reflexes are typically reduced or absent.
• Some individuals have suspected neuropathy on exam, but formal nerve conduction studies / electromyography have not typically been pursued.
• Some individuals describe muscle weakness and/or easy fatigability.
  • Muscle biopsy may be abnormal but 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.
• Several individuals have been diagnosed with autonomic dysfunction, presenting with gastrointestinal dysmotility, high pain threshold (37%), heat intolerance, recurrent fevers, and abnormal sweating.

Epilepsy. Seizures are rare, present in only 3% of affected individuals. For three individuals in which seizure information is available, absence seizures were reported in one and partial complex epilepsy in another. Seizures were controlled with anti-seizure medication in both individuals. The third individual had seizures that resolved.

Neuroimaging. Brain anomalies have been identified in several individuals. The most common abnormalities are gray matter heterotopia and thinning (hypoplasia) of the corpus callosum [Lange et al 2016, Au et al 2018]. Other findings can include spinal syrinx (particularly in those who also have scoliosis) and hypomyelination.

Craniofacial

• Craniosynostosis is present in approximately one quarter of individuals with AKS who have loss-of-function pathogenic variants but is rare in those who have pathogenic missense variants.
  Sagittal and metopic sutures are typically affected, and many individuals have metopic ridging without obvious or confirmed synostosis.
  Approximately half of the individuals with craniosynostosis have required surgical intervention. However, it is unclear if surgical intervention improves cognitive outcome in individuals with AKS.
• Palate abnormalities are common. Cleft palate has only been reported in individuals with loss-of-function pathogenic variants to date. Other palate anomalies, including bifid uvula and high-arched or narrow palate, have been observed in both genotypic groups (those with loss-of-function pathogenic variants and those with missense pathogenic variants; see Genotype-Phenotype Correlations).
• Typical facial features (see Figure 1). In the majority of individuals, the face is long, the orbits are shallow, and the palpebral fissures are long. There can be lateral lid eversion of the eyelids similar to Kabuki syndrome, but typically the lid eversion in AKS 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 thick alae nasi with notched nares. The mouth is frequently downturned and held in an 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/or a bifid tip to the tongue. Many individuals also have macroglossia. Facial features may appear coarse. The face may appear rounder in infancy and elongates with time. Some individuals may have subtle facial findings that are not easily recognizable.

Cardiovascular. Congenital heart disease is present in approximately 63% of individuals with AKS (see Genotype-Phenotype Correlations).

• 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.
• Two affected individuals have had left ventricular non-compaction cardiomyopathy.

Genitourinary

• Hydronephrosis is present in up to 52% of individuals with AKS (see Genotype-Phenotype Correlations). It is often identified prenatally and typically associated with vesicoureteral reflux or obstructive uropathy. It can sometimes be severe, as in one individual who was affected with prune-belly syndrome [Au et al 2018].
• Cryptorchidism is common in males.

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 (i.e., two individuals have needed long-term G-tube support). These issues may be associated with bowel dysmotility (e.g., delayed gastric emptying, recurrent vomiting, pseudo-obstruction). Constipation is common and can range from mild to severe.

Growth

• Most neonates with AKS have normal growth parameters.
• Approximately 30% of affected individuals demonstrate growth deficiency over time, affecting both height and weight.
• Age of onset of growth restriction has been variable, and the true incidence and degree of severity is unclear, as stature is also often affected by the presence of scoliosis.
• Occasionally, there may be mild microcephaly, which is usually noted by early childhood (see Genotype-Phenotype Correlations).
• Overgrowth consisting of increased length and weight at birth has been described in two individuals; two other individuals have been reported to have obesity with increased weight versus height [Au et al 2018].

Skeletal

• Thirty-nine percent of individuals with AKS have scoliosis, which can range from mild to severe and can require surgical intervention.
• Vertebral segmentation anomalies may be present and are more likely to be associated with severe scoliosis.
• Congenital hip dysplasia is observed in about one third of individuals with AKS.
• Talipes equinovarus and pes planus are also common.
• Some individuals have joint hypermobility, although joint dislocations have not been reported.
• Contractures are also occasionally reported, typically affecting large joints.
• Postaxial polydactyly has also been rarely reported.

Ears/hearing

• Hearing loss is present in approximately one quarter of affected individuals.
  Conductive hearing loss may be due to chronic middle ear effusion, but sensorineural hearing loss has been described in three individuals.
• Branchial defects have also been rarely reported.

Ophthalmologic

• Myopia and hyperopia have both been reported in individuals with AKS.
• Optic nerve anomalies, including hypoplasia of the optic nerve or the presence of a coloboma, have been identified in four affected individuals.
• There is theoretical risk for exposure keratopathy in individuals with particularly shallow orbits and long palpebral fissures, but this has not been observed in individuals with AKS.

Dental. The majority of affected individuals have malocclusion, and some have an open bite. Oligodontia is common. Bruxism is frequently observed.

Other associated features

• Endocrine. Osteopenia has been identified in several affected individuals; fractures have been seen in two individuals with AKS. Hypothyroidism is also present in several individuals.
• Respiratory. Most individuals with AKS who have been assessed have had normal sleep studies. One individual was reported to hypoventilate at night and required bilevel positive airway pressure. One individual was reported to have obstructive sleep apnea.
• Integument. Skin laxity has also been noted in several individuals. Inverted nipples and supernumerary nipples have also been identified in individuals with AKS.

Prognosis. It is unknown whether life span in individuals with AKS is abnormal. One reported individual is alive at age 40 years [Authors, person communication], and the oldest published individual was age 36 years at the time of publication [Choufani et al 2022], demonstrating that survival into adulthood is possible. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.

Genotype-Phenotype Correlations

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 [Choufani et al 2022]. 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.

General findings to date pertaining to specific features and genotype include the following:

• Microcephaly has only been observed so far in individuals with loss-of-function pathogenic variants.
• Cleft palate. All individuals with cleft palate have had loss-of-function or splice site pathogenic variants; cleft palate has not been reported in individuals with missense pathogenic variants.
• Craniosynostosis. The majority of individuals with craniosynostosis have loss-of-function pathogenic variants, whereas only one individual with a missense pathogenic variant has been reported to have craniosynostosis.
• Congenital heart defects are statistically significantly more common in individuals with loss-of-function pathogenic variants compared to those with missense pathogenic variants (86% vs 23%, respectively).
• High pain tolerance affects about two thirds of individuals with loss-of-function pathogenic variants and one fifth of individuals with missense pathogenic variants.
• Scoliosis is observed in more than two thirds of individuals with loss-of-function pathogenic variants and around 15% of individuals with missense pathogenic variants.
• Vertebral segmentation defects are present in about 10% of individuals with loss-of-function pathogenic variants; these have not been reported in individuals with missense pathogenic variants.
• Hyporeflexia or areflexia is observed in about half of individuals with loss-of-function pathogenic variants and in about 10%-15% of individuals with missense pathogenic variants.
• Developmental delay. The degree of developmental delay may be less severe in individuals with missense pathogenic variants, but evidence for correlating genotype with neurodevelopmental outcomes is still limited.

Nomenclature

The disorder name "HNRNPK-related neurodevelopmental disorder" is based on the dyadic naming approach proposed by Biesecker et al [2021], in which mendelian disorders are designated by combining the mutated gene and resulting phenotype.

Okamoto syndrome was initially described in 1997, although the underlying molecular genetic etiology was unknown [Okamoto et al 1997]. Since then, additional individuals resembling Okamoto syndrome have been identified who share clinical features with AKS and who also have de novo pathogenic variants in HNRNPK. Okamoto syndrome and AKS are therefore now recognized as the same condition [Okamoto 2019, Maystadt et al 2020].

Prevalence

Prevalence is currently unknown. AKS is a rare disorder first described in 2015. The authors are aware of more than 75 affected individuals worldwide, with more than 40 individuals formally reported in the literature [Pua et al 2014, Au et al 2015, Hancarova et al 2015, Lange et al 2016, Miyake et al 2017, Au et al 2018, Dentici et al 2018, Maystadt et al 2020, Choufani et al 2022].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with AKS, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

There is no cure for AKS.

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

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

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Evaluation of Relatives at Risk

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 an autosomal dominant disorder 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 the result of a de novo HNRNPK pathogenic variant.
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
    * Theoretically, a parent with somatic and germline mosaicism for an HNRNPK pathogenic variant 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 for future sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• Theoretically, if a parent of the proband is known to have the pathogenic variant identified in the proband, the risk to future sibs of inheriting the pathogenic variant is 50%.

Offspring of a proband. To date, 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 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

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 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].

Mechanism of disease causation. Loss of function

HNRNPK-specific laboratory technical considerations. There are five known cases of AKS with deep intronic pathogenic variants affecting splicing of the gene. Pathogenic variants like this may be missed on exome capture-based platforms.

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 Au-Kline syndrome. The oldest reported individual is age 40 years. Utility of screening for myelodysplasia is unknown, and therefore no recommendations regarding cancer surveillance can be made.

Author Notes

There is an Au-Kline syndrome (AKS) Facebook group for affected individuals and families. Additional support can also be found through the HNRNP Family Foundation.

Dr Ping-Yee Billie Au ([email protected]) is actively involved in clinical research regarding individuals with AKS. She would be happy to communicate with persons who have any questions regarding diagnosis of AKS or other considerations.

Acknowledgments

We would like to acknowledge the individuals with AKS and their families. We would also like to acknowledge our large group of international collaborators who have contributed to case findings. We would further like to acknowledge the Rare Disease Foundation for providing initial support for phenotype studies. We would like to acknowledge the HNRNP Family Foundation for providing support for patient meetings.

Revision History

• 1 February 2024 (ma) Comprehensive update posted live
• 18 April 2019 (sw) Review posted live
• 15 October 2018 (pyba) Original submission

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