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 This section summarizes information from 20 individuals with Au-Kline syndrome (AKS), including published and unpublished reports [Au et al 2015; Lange et al 2016; Au et al 2018; Dentici et al 2018; Author, personal communication].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 ). 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.