Extending the clinical spectrum of X-linked Tonne-Kalscheuer syndrome (TOKAS): new insights from the fetal perspective

Abstract

Introduction: Tonne-Kalscheuer syndrome (TOKAS) is a recessive X-linked multiple congenital anomaly disorder caused by RLIM variations. Of the 41 patients reported, only 7 antenatal cases were described.

Method: After the antenatal diagnosis of TOKAS by exome analysis in a family followed for over 35 years because of multiple congenital anomalies in five male fetuses, a call for collaboration was made, resulting in a cohort of 11 previously unpublished cases.

Results: We present a TOKAS antenatal cohort, describing 11 new cases in 6 French families. We report a high frequency of diaphragmatic hernia (9 of 11), differences in sex development (10 of 11) and various visceral malformations. We report some recurrent dysmorphic features, but also pontocerebellar hypoplasia, pre-auricular skin tags and olfactory bulb abnormalities previously unreported in the literature. Although no clear genotype-phenotype correlation has yet emerged, we show that a recurrent p.(Arg611Cys) variant accounts for 66% of fetal TOKAS cases. We also report two new likely pathogenic variants in RLIM, outside of the two previously known mutational hotspots.

Conclusion: Overall, we present the first fetal cohort of TOKAS, describe the clinical features that made it a recognisable syndrome at fetopathological examination, and extend the phenotypical spectrum and the known genotype of this rare disorder.

Keywords: Exome Sequencing; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Genetics; Genomics.

Figure 1

Family pedigree and corresponding variant of each antenatal Tonne-Kalscheuer syndrome case.

Figure 2

Prenatal imaging. Patient 5 (A) ultrasound at 24 GW then (B) MRI at 28 GW, both showing a short corpus callosum at the third percentile and the persistence of a nuchal thickening. Patient 6 (C) MRI at 29 GW, revealing a bilateral CDH, with intrathoracic right and left sides of the liver and an intrathoracic stomach. Patient 11 (D–I) showing at 27 GW ultrasound scans (D–G), a short corpus callosum at the third percentile (D), a cerebellar hypotrophy <1st percentile (E), a bilateral thoracic effusion (F) and a CDH with herniation of the right lobe of the liver (G). Fetal brain MRI at 30 GW (H,I) showing on coronal T2-weighted image a markedly enlarged subarachnoid space related to microcephaly (H), and on sagittal T2, biometries of the brainstem and cerebellum bellow the third percentile, supporting pontocerebellar hypoplasia (I). CDH, congenital diaphragmatic hernia; GW, gestational weeks.

Figure 3

Postmortem findings. Patient 1 (A.1–A.4) at 23+5 GW, showing pre-axial polydactyly of the right foot (A.1), overlapping toes of the left foot (A.2), large thumb (A.3) and DSD (A.4). Patient 2 (B.1–B.2) at 37 GW showing small low-set ears (B1) and DSD (B.2). Patient 6 (C.1–C.4) at 31 GW. Note the large bilateral pre-auricular skin tags (C.1, C.2), bilateral posterior CDH with intrathoracic left and right sides of the liver (C.3), DSD with hypospadias and empty scrotum (C.4). Patient 7 (D.1–D.5) at 20 GW. Note a small right ear (D.1), two left pre-auricular skin tags (D.2), broad thumbs, short distal phalanges of the second and third fingers (D.3, D.4), broad halluces and short distal phalanx of the third toes (D.5). Patient 8 (E.1–E.3) at 38 GW, showing single transverse palmar crease (E.1), DSD with hypospadias (E.2), left CDH with ipsilateral lung hypoplasia and intrathoracic digestive tract on X-rays (E.3). Patient 9 (F.1–F.6) at 25 GW. Note abnormal facial shape with hypertelorism, anteverted nares, low-set ears and retrognathism (F.1, F.3–F.5), CDH (F.2) and DSD (F.6). Patient 10 (G.1–G.7) at 21 GW, showing DSD (G.1), microretrognathism (G.5–G.6), broad hallux and two to three-toe syndactyly (G.2), duplicate right thumb (G.3, G.4) and left CDH with intrathoracic digestive loops (G.7).

Figure 4

Genetic findings of individuals with RLIM variants. A schematic view of RLIM exon sequence (NM_16120.3), its Metadome missense tolerance landscape (from Radboud University Medical Center) and the variants identified in the different studies: new cases from our cohort in red, antenatal cases from literature in orange and postnatal cases from literature in blue. The amino acid numbering is based on PeCan Data of Proteinpaint. The domain representation is based on previous work by Gontan et al : nuclear localisation sequence (NLS) in blue (amino acid 207–231), basic region in orange (amino acid 333–431), nuclear export sequence (NES) in green (amino acid 526–537) and RING ubiquitin ligase domain in red (amino acid 548–624).