PBX1 Gene Disorder in the United Kingdom: Case Report and Review of Available Literature

Case history

A 35-year-old lady, gravida 2 para 0 plus 1, booked for antenatal care with no medical or social problems. She and her partner had no known medical problems and did not smoke or drink alcohol. She had a medical termination of pregnancy at 8weeks of gestation without any complications. Family history in both partners revealed no significant information. Her pregnancy was classed as a low-risk pregnancy. She had a dating scan at 13weeks and no fetal or pregnancy-related problems were noted. Routine combined screening gave a low risk for trisomy 21, 18, and 13. She had an anomaly scan at 19 weeks of gestation, and the following were the findings:

Fetal growth and amniotic fluid were normal.

Flexed breech, fetal movements were visualised.

Placenta, anterior, high. 3 vessel cord. Hyperechoic bowel. Enlarged heart.

The significant findings were discussed with her, and she was told these findings could be normal, related to PV bleeding, fetal infection, cyst fibrosis, or a rare chromosomal and genetic anomaly. Amniocentesis was discussed, and the couple later accepted it. She was later tested for CMV, toxoplasmosis, and cystic fibrosis (CF), all of which returned negative findings.

She was booked for a fetal echo and a rescan in the Fetal Medicine Unit (FMU). The findings were: a ventricular septal defect (VSD), depressed sternum, and generalised skin oedema. There was a hypoplastic right lung, and an eventration of the diaphragm was suspected. The latter was further confirmed on subsequent fetal MRI. There was a small stomach and a low-lying and mal-rotated leftkidney. Amniocentesis revealed the following:

A normal QF-PCR analysis for chromosomes 21, 18, and 13 and X, and a normal arrayCGH.

In view of the abnormalities, exome sequencing was offered and accepted.

Exome sequencing was consistent with a molecular diagnosis of PBX1-related disorder:

The male fetus is heterozygous for the PBX1 c.863G>A p.(Arg288Gin) pathogenic variant.

Pathogenic variants in the PBX1 gene (MIM176310) are associated with congenital anomalies of the kidney and urinary tract with or without hearing loss, abnormal ears, or developmental delay (MIM617641).

After an MDT, it was decided that the PBX1 disorder contributed to the fetal presentation and that diaphragmatic eventration and respiratory issues after birth had been reported in neonates with this condition. However, the apparent absence of kidney/or urinary tract anomalies in the index fetus seemed to be unusual for the rate of PBX1-related disorder. Testing the couple showed no evidence of this variant in their lymphocyte DNA. These results were consistent with PBX1 c.863G>A p.(Arg288Gin), a pathogenic variant having arisen de novo in the index fetus, and supported the evidence that this is a pathogenic variant of this disorder.

Further testing:

Following MDT discussion, further imaging of the fetal kidney and urinary tract was recommended. Prenatal testing could be offered to the couple in any future pregnancy to rule out the low risk of recurrence due to germline mosaicism.

Since this pathogenic germline was detected, the remaining filtered variants were not fully analysed. If the variant is not sufficient to fully explain the clinical phenotype in the fetus, scientists advised staff to contact the laboratory to initiate the analysis of the remaining data.

The last growth scan was at 30 weeks and 6 days. The findings were as follows:

Amniotic fluid, mildly increased, largest pool 10.5 cm

Fetal growth and dopplers maintained with AC on the 2nd centile

Small chest but proportional to a small abdomen.

Indentation on the chest (sternum).

Collapsed stomach.

Increased amniotic fluid volume suggestive of upper gastrointestinal obstruction

Fetal echo indicated cardiomegaly and a small muscular apical VSD.

Fetal movements were seen on the scan.

The couple was attended to by the FMU Specialist and the Clinical and Paediatric Genetic Specialist. The latter counseled the couple, and the options for management were: continuation of the pregnancy or termination of the pregnancy. The couple opted for the termination of the pregnancy.

Three days later, the woman was given oral mifepristone and advised to attend the labour ward two days later or earlier if she had signs of labour. She attended the labour ward 2 days later, as advised, for the induction of labour. She was given a bereavement package and placed under the local bereavement protocol.

Following vaginal examination, her cervix was closed and she was given vaginal misoprostol 100 mcg and then 6 hours later commenced on oral misoprostol 100 mcg 6 hourly. She was placed on 4-hourly observation.

At 21:00 the following day, her temperature was 38.9 degrees centigrade. She was given antipyretics, had venous access and a sepsis screen, and commenced on intravenous broad-spectrum antibiotics. She was placed under close observation.

The next day at 10:00 hours, her cervix was 2-3 cm dilated and significantly effaced. And oral misoprostol was continued.

At 14:00 hours, her cervix was 4 cm dilated and then 8 cm dilated at 15.30, and she delivered at 15:41.

Findings at delivery were:

Slightly macerated male fetus, with no signs of life.

The head circumference of the baby was 31 cm.

The length of the baby was 40 cm. The weight of the baby was 1,870 g.

Estimated blood loss was 200 mls.

24 hours later, her temperature remained normal; the intravenous antibiotics were stopped, and she went back on 4-hourly observations. Her temperature remained normal following delivery, and sepsis screen results did not reveal any significant findings. The couple declined post-mortem examination and also declined contraception, three days post-delivery. Two weeks later, placental histology stated:

Macroscopic description

A singleton placenta measuring 227X182x21 mm with a trimmed weight of 299 g. The umbilical cord is inserted marginally and measures 249 mm in length and 11 mm in diameter. The cord is oedematous in appearance; on slicing, three vessels are identified. Foetal membranes are present and appear slightly fibrotic. The maternal surface appeared complete and is lobulated. On slicing of the placental disc, a beefy red cut surface is identified and is unremarkable.

Microscopic description

The membranes show no inflammation. There is no funisitis of chorionic vasculitis. The chorionic villi show normal maturation. There are no avascular villi or thrombosed foetal vessels. There is no villitis or intervillositis. There is no infarction or increased perivillous fibrin deposit. There is no decidual vasculopathy.

Final diagnosis: normal weight and histology of the placenta. The ratio of the baby’s weight at birth and the placental weight; that is, 1,870 g: 299 g, and the result was 6.25, which was normal.

Discussion

Pre-B-cell (PB) leukemia transcription factor 1 is a protein that in humans is encoded by the PBX1 gene. PBX1 is a member of the Three Amino Acid Loop Extension (TALE) class of homeodomain transcription factors, which are components of heteromeric protein complexes that regulate developmental gene expression and maintain differentiated cell states [5].

It made sense to open this discussion with Perry, et al. 2024 [6], which was one of the two citations of the Rare and Inherited Disease Genomic Laboratory. These authors stated that the Pre-B cell leukemia homeobox 1 (PBX1) gene on chromosome 1 encodes a transcription factor belonging to a family of proteins that interact with Hox proteins to regulate cellular proliferation and differentiation. The authors stated further that PBX1 was constitutively expressed in many tissues throughout the body, including the bladder, kidneys, heart, and brain. During embryonic development, it was crucial in various pathophysiological processes in osteogenesis, renal morphogenesis, and morphologic mapping, these authors concluded.

Also, Perry, et al. [6] went on to state that several PBX1 variants have been recently reported to be associated with congenital anomalies of the kidney and urinary tract (CAKUT) syndrome, characterized by kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay (CAKUTHED). Additional case reports demonstrated de novo missense PBX1 variants in patients with congenital cardiac defects, such as outflow tract anomalies, septal defects, and great arteries.

Chen H, et al. [7], in a similar way, stated that PBX1 enhanced the recruitment of homeobox genes and the expression of target genes that regulate cellular proliferation and differentiation, and was a key transcriptional regulator of the development of multiple tissues and organs. The authors stated that it's tight binding to homeobox genes facilitated their transcriptional regulation, and that in the nervous system, PBX1 and its family members were important transcriptional regulators of neurons.

Peltenburge and Murre [8] stated that the PBX1 is a three-amino acid loop extension (TALE)-class homeodomain transcription factor that forms heterodimeric complexes with a subset of Hox homeodomain proteins essential for regulating segmental identities during development. However, in 1997, Peltenburg and Murre [9] stated that two classes of homeodomain proteins, Hox and Engrailed, have been shown to act in concert with the atypical homeodomain proteins PBX and extradenticle. 

According to Arts P, et al. [10], autosomal dominant (de novo) mutations in PBX1 are known to cause congenital abnormalities of the kidney and urinary tract (CAKUT), with or without extra‐renal abnormalities. The authors stated that using trio exome sequencing, they were able to identify a PBX1 p.(Arg107Trp) mutation in a deceased one‐day‐old neonate presenting with CAKUT, asplenia, and severe bilateral diaphragmatic thinning and eventration.

Writing from China, Nie L, et al. [11] stated in relation to a Chinese patient that congenital anomalies of the kidney and urinary tract syndrome(CAKUT) with or without hearing loss, abnormal ears, or developmental delay(CAKUTHED) was a rare autosomal dominant disorder, and variants in PBX1 were involved in the etiology of this syndrome. Precise diagnosis was difficult without genetic tests, the authors concluded.

Other Chinese researchers, Lou M, et al. 2022 [12], stated the PBX1 gene was located on chromosome 1q23.3. And encoded a transcription factor that promoted protein interaction and played a crucial role in several developmental processes. These researchers went further to state that PBX1 haploinsufficiency had been reported to lead to syndromic congenital anomalies of the kidney and urinary tract, and that patients with deletions involving the long arm of chromosome 1 were rare.

Researchers from Australia [13] noted that translocation (t1:19) q23:p13) occurs in about 5% of children with acute lymphoblastic leukemia and is often identified in African children, but the exact incidence in caucasian children remained unknown.

The case history chronicled the evolving scene from 19 weeks of gestation when the hyperechoic bowel and enlarged heart were identified on a routine anomaly scan, and investigations were therefore escalated, to the final genetic confirmation.

According to further evidence for classification from the Rare & Inherited Disease Genomic Laboratory, this variant was absent from the genomAD population database (PM2_moderate), hence the author felt the need to report it. The apparent absence of kidney/or urinary tract anomalies in the index fetus seemed to be unusual to rare in PBX1-related disorder, which also made this case unique. This disorder had been reported to be de novo in individuals with PBX 1 1-related disorder [6], and our case also arose de novo with prenatal relationship as confirmed in this fetus (PS4_moderate, PS2_strong), by scientists at the Rare & Inherited Disease Genomic Laboratory.

From the USA, Fitzgerald KK, et al. [4] reported three individuals with inherited pathogenic intragenic PBX1 deletion with variable clinical features typical of this syndrome, and all have de novo variants, as in our case. The authors stated that heterozygous de novo pathogenic variants in PBX1 disorder resulting in haloinsufficiency were associated with congenital malformations of the kidney and urinary tract, most commonly renal hypoplasia, as well as malformations involving the external ear, branchial arch, heart, and genitalia. The authors noted that the deletion also caused intellectual disability and developmental delay.

Petzold F, et al. [14], from Germany, reported a case of novel somatic PBX1 mosaicism likely masking syndromic CAKUT in an adult with bilateral kidney hypoplasia, which was found on a University of Manchester Library search.

An extensive literature search with the search term “PBX1-related disorders in the UK” did not reveal significant local or national publications. However, AI Overview stated that in the UK, PBX1-related disorders, especially those affecting kidney and urinary tract development, were rare but could be associated with congenital anomalies, hearing loss, and other developmental issues, with some cases linked to B-lymphoblastic leukemia (AI Overview, 2024).

McNeill A (undated) [15] from the University of Sheffield, England, United Kingdom stated the following: “After the initial report in 2017 of a neurodevelopmental disorder associated with PBX1 single nucleotide variants, only single case reports have been published. We have collected 25 novel patients with PBX1 variants via DDD/100K/Genematcher. We wish to examine any genotype-phenotype correlation of missense and loss-of-function variants. We have pilot data of an episignature. We would like additional cases to help refine our genotype-phenotype correlation and episignature work”.

Also in Genomics England, there have been three inputs by Genomic England Curators; one had low evidence and was on the red list, two had some evidence and were on the amber list, unconfirmed by a curator, and seven were on the green list, confirmed by a curator [16]. We note there are indeed similarities between the presentation of this case and some of the other cases reported in Australia, Germany, China, and the US.

The author strongly believes an autopsy would have revealed more information about the various similar anatomical anomalies reported on serial ultrasound scans and MRI in this case, especially in relation to CAKUT and CAKUTHED syndromes. However, the author recognised the importance of respecting the wishes of a severely traumatised couple, who made an informed decision to decline an autopsy.

Conclusion

This case provided staff with new knowledge about the evolving and dynamic nature of advancing science. It emphasised the need for clinical vigilance, a high index of suspicion, and to look beyond what we already know, in relation to congenital and inherited anomalies, as new ones can present without warning. Our case was unique, as stated, and worthy of being reported and added to the medical literature.