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.

Fig. 1

Schematic representation of disease-causing HNRNPK mutations on the NM_002140.4 transcript. Introns (lines), coding exons (in black), and non-coding exons (in white) are represented. Published loss-of-function mutations (below) and missense mutation (above) and new mutations (above) are indicated. The scale bar represents 100 base pairs

Fig. 2

Photographs of AKS patients. a Patient 1 at 19 years of age. b Patient 1 demonstrates narrow palate and deeply grooved tongue. c Patient 2 at 9 years of age. Note metopic ridging. d Patient 3 at 11 years. e–g Patient 8 as a newborn, age 16 months and age 4 years 5 months. h Patient 6. Note “M” shaped upper lip and deep groove to tongue. i Patient 7 at age 7. j Patient 7 demonstrates deep groove to tongue and mildly bifid tip. k, l Patient 9 at 6 months. Note excess nuchal skin. m, n Patient 10 at 4 weeks. o Patient 10 at 1 year 9 months. p Patient 10 at 8 years