A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus

Abstract

Introduction: Sandestig-Stefanova syndrome (MIM:618804) is characterized by pre- and postnatal microcephaly, trigonocephaly, bilateral congenital cataracts, microphthalmia, cleft lip and palate or high-arched palate, camptodactyly, rocker-bottom feet, heart anomalies, periventricular white matter loss, thin corpus callosum, and delayed myelination. Bi-allelic loss-of-function variants in the Nucleoporin 188 (NUP188) (MIM:615587) gene are implicated in the etiology.

Case presentation: Our patient, born to consanguineous parents, presented with tetralogy of Fallot, bilateral congenital cataracts, hydrocephalus, a bifid uvula, a right pelvic kidney, hepatomegaly, facial feature findings, and a history of a similarly affected ex-sibling. Whole exome sequence analysis in the index case revealed a novel homozygous variant NM_015354.2: c.124C>T/p.(Arg42Ter) in the NUP188 gene.

Conclusion: This study describes a new patient with Sandestig-Stefanova syndrome harboring a novel pathogenic variant in the NUP188 gene.

Keywords: Autosomal recessive; Hydrocephalus; NUP188; Novel mutation; Whole exome sequencing.

Fig. 1.

Pedigree of the family. I-1: affected by trisomy 21, II-1: mother, II-2: father, III-1: similar clinical affected ex-sibling, III-2: healthy brother, III-3: index case affected by Sandestig-Stefanova syndrome (MIM:618804).

Fig. 2.

Postmortem examination of the case. a Short neck, bilateral hypoplastic nipples, major edema of the female labium. b Increased hair growth on the forehead, scattered eyebrows on the medial side, flat nasal root, short nose, bulbous nasal tip, short columella, long philtrum, fish-mouth appearance. c Positional anomaly of the right foot (4th finger located below).

Fig. 3.

Electropherogram images of segregation analysis using Sanger sequencing. a Proband, homozygous. b Healthy brothers, heterozygous. c Mother, heterozygous. d Father, heterozygous.