Phenotypic spectrum of Au–Kline syndrome: a report of six new cases and review of the literature

Abstract

Au-Kline syndrome (AKS, OMIM 616580) is a multiple malformation syndrome, first reported in 2015, associated with intellectual disability. AKS has been associated with de novo loss-of-function variants in HNRNPK (heterogeneous ribonucleoprotein K), and to date, only four of these patients have been described in the literature. Recently, an additional patient with a missense variant in HNRNPK was also reported. These patients have striking facial dysmorphic features, including long palpebral fissures, ptosis, deeply grooved tongue, broad nose, and down-turned mouth. Patients frequently also have skeletal and connective tissue anomalies, craniosynostosis, congenital heart malformations, and renal anomalies. In this report, we describe six new patients and review the clinical information on all reported AKS patients, further delineating the phenotype of AKS. There are now a total of 9 patients with de novo loss-of-function variants in HNRNPK, one individual with a de novo missense variant in addition to 3 patients with de novo deletions of 9q21.32 that encompass HNRNPK. While there is considerable overlap between AKS and Kabuki syndrome (KS), these additional patients demonstrate that AKS does have a distinct facial gestalt and phenotype that can be differentiated from KS. This growing AKS patient cohort also informs an emerging approach to management and health surveillance for these patients.

Okamoto syndrome has features overlapping with Au–Kline syndrome and is caused by HNRNPK mutation

“…Patients with OS and AKS experience a variety of symptoms including neurological abnormalities and internal anomalies. As Au et al () reported that the genitourinary system associated with morbidity and mortality in patients with AKS, our two original patients with severe congenital hydronephrosis died at an early age.…”

“…Au et al () reported a new syndrome (AKS) due to loss‐of‐function variants in HNRNPK . They (Au et al, ) summarized 12 patients with AKS. The patients with AKS have dysmorphic features, including long palpebral fissures, ptosis, a deeply grooved tongue, broad nose, and down‐turned mouth.…”

“…Some patients with AKS show Kabuki‐like or Noonan‐like features, but they have more marked ID and atypical dysmorphic features. Au et al () suggested that AKS patients show a distinct facial gestalt and phenotype that can be differentiated from those of Kabuki syndrome patients.…”

“…Lange et al (), Dentici et al (), and Miyake et al (), respectively, reported AKS patients with Kabuki‐like features. Au et al () reported six new patients with AKS.…”

A second case of Okamoto syndrome caused by HNRNPK mutation

“…The phenotypic spectrum of individuals with HNRNPK mutations was further delineated over the next few years and these patients were subsequently called "AKS." AKS was defined by the association of hypotonia, developmental delay, moderate-to-severe intellectual disability, facial dysmorphic features, autonomic dysfunction, congenital heart disease, hydronephrosis, palate abnormalities, oligodontia, and inconstant craniosynostosis or other skeletal anomalies (Au et al, 2018). The close similarities between OS and AKS were then noted by Dr Okamato in his recent paper (Okamoto, 2019).…”