Partial gonadal dysgenesis associated with a pathogenic variant ofPBX1transcription factor

Abstract

A term neonate was admitted to the Neonatal Intensive Care Unit for respiratory distress, hypotonia and atypical genitalia. Significant findings included a small phallic structure, labial folds, no palpable gonads and two perineal openings. Pelvic ultrasound showed uterine didelphys and a gonad in the right inguinal canal. The right gonad was removed during diagnostic laparoscopy with microscopic evaluation showing infantile testicular tissue and fluorescence in-situ hybridisation showed only XY signal suggesting that the removed gonad was a male-developed testis. Infant was 46,XY, SRY probe positive. The parents chose a female sex assignment prior to gonadectomy. The infant had respiratory insufficiency and central hypotonia that persisted on discharge. Whole exome sequencing showed a heterozygous pathogenic variant of the PBX1 gene. This variant encodes the pre-B-cell leukaemia homeobox PBX transcription factor and has been associated with malformations and severe hypoplasia or aplasia of multiple organs including lungs and gonads. Whole exome sequencing was crucial in providing a unifying diagnosis for this patient.

Paternal mosaicism for a novel PBX1 mutation associated with recurrent perinatal death: Phenotypic expansion of the PBX1‐related syndrome

“…Genital abnormalities are commonly reported in male patients with PBX1 mutations (10/14), with the phenotypic spectrum ranging from cryptorchidism to partial development of female internal and/or external genitalia (Alankarage et al, ; Eozenou et al, ; Kia et al, ; Riedhammer et al, ; Slavotinek et al, ; Le Tanno et al, ). Interestingly, the second affected sibling (II‐5; 46, XY) presented here showed complete sex reversal of both internal and external organs, without any signs of male gonad development (no streak gonad).…”

“…These include facial dysmorphism, and anatomic abnormalities of the ear, genitalia, heart, and lung. Developmental delay/intellectual disability is common, and growth restriction and hearing loss have also been reported (Table S1; Alankarage et al, ; Eozenou et al, ; Heidet et al, ; Kia, Sarafoglou, Mooganayakanakote Siddappa, & Roberts, ; Riedhammer et al, ; Slavotinek et al, ; Sun et al, ; Le Tanno et al, ). We present two cases of perinatal death, from independent pregnancies in one family, with a recurrent disease‐causing mutation in PBX1 due to paternal mosaicism for the mutation.…”

The TALE never ends: A comprehensive overview of the role of PBX1, a TALE transcription factor, in human developmental defects

“…Of these 13 patients, 9 had detailed clinical features (Arts et al, 2020; Eozenou et al, 2019; Kia et al, 2019; Slavotinek et al, 2017) (Figure 2B and Supporting Information: Table ). Renal or urinary anomalies were less prevalent in this group than in the PBX1 LOF group and were milder (hypoplastic or horseshoe kidneys, ureteral dilatation, or hyperechogenic kidneys).…”